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Background and Purpose: Decompressive surgery is a potentially life-saving treatment in patients with malignant space-occupying cerebellar infarction. However, there is only limited literature on functional outcomes and complications after surgery. Our aim was to establish markers which predict poor outcome. Methods: We retrospectively analyzed data of all patients who underwent surgery due to malignant swelling of a space-occupying cerebellar infarction in our hospital between 2005 and 2023. Statistical analyses were conducted on multiple parameters to identify predictors of poor functional outcome (mRS 4–6) 90 days after surgery. Complications during hospitalization were reviewed for each patient. Results: In total, 58 patients received decompressive surgery. The 90-day mortality rate was 27.6% (n = 16). A good functional outcome (mRS 0–3) 90 days after surgery was achieved in 24 patients (41.4%). Multivariable analysis revealed multiple factors associated with a poor outcome on day 90 (mRS 4–6): a higher premorbid mRS score (OR 2.715 [95% CI, 1.166–6.323]; p = 0.021), higher NIHSS score on admission (OR 1.088 [95% CI, 1.014, 1.168]; p = 0.019) and the presence of an additional brainstem infarction (OR 7.035, [95% CI, 1.255, 39.424], p = 0.027). Hyperactive delirium was associated with good clinical outcome (OR 0.020 [95%CI, 0.001–0.623]; p = 0.026). Aspiration pneumonia (n = 22, 37.9%), urinary tract infection (n = 15, 25.9%), and hyperactive delirium (n = 8, 13.8%) were the most common complications during hospitalization. Conclusions: Decompressive surgery is a safe, life-saving treatment for malignant space-occupying cerebellar infarction. Higher premorbid mRS, higher NIHSS score on admission and the presence of brainstem infarction are associated with a poor functional outcome.

Abstract Low back pain (LBP) is a global issue involving biological, psychological, and social factors. Pain-related fear has been shown to influence movement behavior, however, its association with some measures of movement behavior, such as spinal movement variability, remains inconclusive. To further investigate this, spinal kinematics during various activities of daily living (i.e., walking, running, lifting, and stair climbing) of 49 patients with chronic LBP and a group of 51 sex-, age-, and BMI-matched healthy controls were used to calculate lumbar spine movement variability which was quantified using different indices (i.e., coefficient of variation, coupling angle variability in vector coding, deviation phase of the continuous relative phase and an angle-angular velocity variability). General and task-specific pain-related fear was assessed using the Tampa Scale of Kinesiophobia and the Photograph Series of Daily Activities—Short Electronic Version, respectively. Linear regression analyses showed no significant association between movement variability and pain-related fear, however, the sample consisted of younger individuals with moderate disability and with low levels of pain and pain-related fear. In addition, the different variability indices were weakly correlated and varied greatly depending on the method used and the task performed. Therefore, comparisons between studies with different movement variability calculation methods or different activities should be treated with caution.

Abstract The extended period of coexistence between Neanderthals and Homo sapiens in Europe coincided with the emergence of regionally distinctive lithic industries, signalling the onset of the Upper Palaeolithic. The Iberian Peninsula was on the periphery of pioneering Upper Palaeolithic developments, with archaeological remains primarily found in northern territories. We report the discovery of an initial Upper Palaeolithic lithic industry at Cueva Millán in the hinterlands of Iberia. This industry, termed here Arlanzian, not only represents the earliest and southernmost evidence of such industries in Iberia but also lacks a direct counterpart. However, it exhibits chronological and technological parallels with the lithic industries associated with the earliest expansion of Homo sapiens throughout Eurasia. We interpret this as potential evidence of its intrusive nature, but not necessarily associated with a migration event, as more complex scenarios derived from inter-population connectivity must be also considered. The biological identity of the Arlanzian makers remains unknown, but they coexisted with declining Neanderthal groups from neighbouring territories.

Abstract BackgroundThe universal availability of smartphones has created new opportunities for innovative telemedicine applications in health care. The COVID-19 pandemic has heightened the demand for contactless health care services, making SARS-CoV-2 polymerase chain reaction (PCR) testing a crucial component of pandemic containment. ObjectiveThis feasibility study aimed to examine a comprehensive telemedicine approach for SARS-CoV-2 testing, focusing on the practicality, user satisfaction, and economic implications of self-sampling guided by a telemedicine platform. MethodsThe study process involved shipping self-sampling kits, providing instructions for at-home sample collection, processing biomaterials (swabs and capillary blood), communicating test results, and providing interoperable data for clinical routine and research through a medical mobile app. A total of 100 individuals were randomly assigned to either the conventional health care professional (HCP)–performed SARS-CoV-2 testing group (conventional testing group, CG) or the telemedicine-guided SARS-CoV-2 self-sampling approach (telemedicine group, TG). Feasibility of the TG approach, user satisfaction, user-centered outcomes, and economic aspects were assessed and compared between the groups. ResultsIn the TG group, 47 out of 49 (95%) individuals received a self-sampling kit via mail (76%) individuals successfully returned at least one sample for diagnostics. SARS-CoV-2 PCR tests were conducted in 95% () of TG cases compared with 88% () in the CG. Users in the TG reported high satisfaction levels with ease of use (5.2/7), interface satisfaction (5.2/7), and usefulness (4.3/7). A microcosting model indicated a slightly higher cost for the TG approach than the CG approach. The TG demonstrated the potential to facilitate interoperable data transmission by providing anonymized, standardized datasets for extraction using Health Level 7-Fast Healthcare Interoperability Resources. This supports the national COVID-19 Data Exchange Platform and facilitates epidemiological evaluation based on the German COVID Consensus dataset. ConclusionThese preliminary findings suggest that a telemedicine-based approach to SARS-CoV-2 testing is feasible and could be integrated into existing hospital data infrastructures. This model has the potential for broader application in medical care, offering a scalable solution that could improve user satisfaction and treatment quality in the future.

Abstract Mammals are generally resistant to Mycobacterium avium complex (MAC) infections. We report here on a primary immunodeficiency disorder causing increased susceptibility to MAC infections in a canine breed. Adult Miniature Schnauzers developing progressive systemic MAC infections were related to a common founder, and pedigree analysis was consistent with an autosomal recessive trait. A genome-wide association study and homozygosity mapping using 8 infected, 9 non-infected relatives, and 160 control Miniature Schnauzers detected an associated region on chromosome 9. Whole genome sequencing of 2 MAC-infected dogs identified a codon deletion in the CARD9 gene (c.493_495del; p.Lys165del). Genotyping of Miniature Schnauzers revealed the presence of this mutant CARD9 allele worldwide, and all tested MAC-infected dogs were homozygous mutants. Peripheral blood mononuclear cells from a dog homozygous for the CARD9 variant exhibited a dysfunctional CARD9 protein with impaired TNF-α production upon stimulation with the fungal polysaccharide β-glucan that activates the CARD9-coupled C-type lectin receptor, Dectin-1. While CARD9-deficient knockout mice are susceptible to experimental challenges by fungi and mycobacteria, Miniature Schnauzer dogs with systemic MAC susceptibility represent the first spontaneous animal model of CARD9 deficiency, which will help to further elucidate host defense mechanisms against mycobacteria and fungi and assess potential therapies for animals and humans.

Abstract Background Teaching professionalism in medical schools is central to medical education and society. We evaluated how medical students view the values of the medical profession on their first day of medical school and the influence of a conference about the competences of this profession on these students’ levels of reflection. Methods We studied two groups of medical students who wrote narratives about the values of the medical profession and the influence of the COVID-19 pandemic on these values. The first group wrote the narratives after a conference about the competences of the medical profession (intervention group), and the second group wrote the same narratives after a biochemistry conference (control group). We also compared the levels of reflection of these two groups of students. Results Among the 175 medical students entering in the 2022 academic year, 159 agreed to participate in the study (response rate = 90.8%). There were more references to positive than negative models of doctor‒patient relationships experienced by the students (58.5% and 41.5% of responses, respectively). The intervention group referred to a more significant number of values than the control group did. The most cited values were empathy, humility, and ethics; the main competences were technical competence, communication/active listening, and resilience. The students’ perspectives of the values of their future profession were strongly and positively influenced by the pandemic experience. The students realized the need for constant updating, basing medical practice on scientific evidence, and employing skills/attitudes such as resilience, flexibility, and collaboration for teamwork. Analysis of the levels of reflection in the narratives showed a predominance of reflections with a higher level in the intervention group and of those with a lower level in the control group. Conclusions Our study showed that medical students, upon entering medical school, already have a view of medical professionalism, although they still need to present a deeper level of self-reflection. A single, planned intervention in medical professionalism can promote self-reflection. The vision of medical professional identity was strongly influenced by the COVID-19 pandemic, positively impacting the formation of a professional identity among the students who decided to enter medical school.

Hantavirus pulmonary syndrome (HPS) is an American emerging disease caused by the rodent-borne virus genus Orthohantavirus (Family: Hantaviridae: Order: Elliovirales Class: Bunyaviricetes). In Argentina, almost half of the HPS infections occur in the northwestern endemic region. In this study, we monitored rodent abundance during 2022 and 2023 in three sites with different sampling methods (removal trapping, live trapping and hunted rodents by domestic cats) to evaluate their relationship with human infections. We found a similar pattern of variation in rodent abundance across time, and particularly a synchronous rise of rodent abundance that anticipated an HPS outbreak in 2023. Our dynamic regression models revealed a positive relationship between HPS cases and rodent abundance with a three-month lag, as well as rainfall with an eight-month lag. Our results provide a framework for the planning and implementation of public health prevention campaigns based on climatology and rodent monitoring. Domestic cats bringing rodents into houses can be an overlooked risk factor, particularly if viral shedding of infected rodents is magnified by stress. HPS is a disease of public health concern due to its high mortality rate, the lack of a specific therapeutic treatment and no vaccine. Thus, prevention of infections is of the utmost importance.

[This corrects the article DOI: 10.1371/journal.pone.0281978.].

Carbapenem-resistant Enterobacterales (CRE) are a subject of global concern as limited therapeutic options are available. New combinations of β-lactams and β-lactamase inhibitors, such as ceftazidime-avibactam (CAZ-AVI), have recently been approved in Brazil for the treatment of CRE infections. Cases of resistance during treatment or even without previous CAZ-AVI use have been published and it is worrisome in scenarios where KPC-producing Gram-negative bacilli are endemic, as in Brazil. We aimed to assess CAZ-AVI susceptibility among a CRE population recovered from hospitalized patients in Southern Brazil from 2015 to 2021. CAZ-AVI minimal inhibitory concentration (MIC) was determined by antibiotic gradient strips. All the 238 evaluated KPC-producing Enterobacterales were susceptible to CAZ-AVI (MIC = 0.25 to 8 µg/mL), with seven isolates presenting borderline MICs (8 µg/mL). Considering the clinical importance of this new antibiotic in Brazil, we emphasize the importance of surveillance studies to eventually detect resistance phenotypes or even increasing CAZ-AVI MICs.

Abstract Patients with non-small cell lung cancer (NSCLC) who have distant metastases have a poor prognosis. To determine which genomic factors of the primary tumor are associated with metastasis, we analyzed data from 759 patients originally diagnosed with stage I–III NSCLC as part of the AACR Project GENIE Biopharma Collaborative consortium. We found that TP53 mutations were significantly associated with the development of new distant metastases. TP53 mutations were also more prevalent in patients with a history of smoking, suggesting that these patients may be at increased risk for distant metastasis. Our results suggest that additional investigation of the optimal management of patients with early-stage NSCLC harboring TP53 mutations at diagnosis is warranted in light of their higher likelihood of developing new distant metastases.

Abstract Background Currently, there is no regenerative therapy for patients with neurological and neurodegenerative disorders. Cell-therapies have emerged as a potential treatment for numerous brain diseases. Despite recent advances in stem cell technology, major concerns have been raised regarding the feasibility and safety of cell therapies for clinical applications. Methods We generated good manufacturing practice (GMP)-compatible neural progenitor cells (NPCs) from transgene- and xeno-free induced pluripotent stem cells (iPSCs) that can be smoothly adapted for clinical applications. NPCs were characterized in vitro for their differentiation potential and in vivo after transplantation into wild type as well as genetically immunosuppressed mice. Results Generated NPCs had a stable gene-expression over at least 15 passages and could be scaled for up to 1018 cells per initially seeded 106 cells. After withdrawal of growth factors in vitro, cells adapted a neural fate and mainly differentiated into active neurons. To ensure a pure NPC population for in vivo applications, we reduced the risk of iPSC contamination by applying micro RNA-switch technology as a safety checkpoint. Using lentiviral transduction with a fluorescent and bioluminescent dual-reporter construct, combined with non-invasive in vivo bioluminescent imaging, we longitudinally tracked the grafted cells in healthy wild-type and genetically immunosuppressed mice as well as in a mouse model of ischemic stroke. Long term in-depth characterization revealed that transplanted NPCs have the capability to survive and spontaneously differentiate into functional and mature neurons throughout a time course of a month, while no residual pluripotent cells were detectable. Conclusion We describe the generation of transgene- and xeno-free NPCs. This simple differentiation protocol combined with the ability of in vivo cell tracking presents a valuable tool to develop safe and effective cell therapies for various brain injuries.

Abstract Machine learning methods trained on cancer cell line panels are intensively studied for the prediction of optimal anti-cancer therapies. While classification approaches distinguish effective from ineffective drugs, regression approaches aim to quantify the degree of drug effectiveness. However, the high specificity of most anti-cancer drugs induces a skewed distribution of drug response values in favor of the more drug-resistant cell lines, negatively affecting the classification performance (class imbalance) and regression performance (regression imbalance) for the sensitive cell lines. Here, we present a novel approach called SimultAneoUs Regression and classificatiON Random Forests (SAURON-RF) based on the idea of performing a joint regression and classification analysis. We demonstrate that SAURON-RF improves the classification and regression performance for the sensitive cell lines at the expense of a moderate loss for the resistant ones. Furthermore, our results show that simultaneous classification and regression can be superior to regression or classification alone.

Introduction Surgical site infection (SSI) after laparotomy still represents the most frequent postoperative complicationin abdominal surgery. The effectiveness of reducing SSI rates by intra-operative irrigation of the incisional wound with antiseptic solutions or saline has been much debated, and recommendations on its use are divergent. Therefore, we aim to conduct a systematic review and meta-analysis, focusing specifically on procedures by laparotomy and considering recent evidence only.Methods and analysis The systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement. On 1 July 2022, PubMed/MEDLINE, Cochrane, Central Register of Controlled Trials and EMBASE were searched for the following predefined terms: (Surgical site infection) AND ((irrigation) OR (wound irrigation) OR (lavage)) AND ((abdominal surgery) OR (laparotomy). The search was limited to peer-revied publications, dating after 1 January 2000 in English or German language. Systematic reviews and meta-analyses were included for reference screening. Case reports, case series, non-systematic reviews and studies without follow-up information were excluded. The primary outcome is the rate of postoperative SSI after abdominal surgery by laparotomy. Meta-analysis is pooled using the Mantel-Haenszel method for random effects. The risk of bias in randomised studies will be assessed using the Cochrane developed RoB 2-tool, and the ROBINS-I tool for non-randomised studies. Completion of the analysis and publication is planned in March 2023.Ethics and dissemination Ethical approval is not necessary for this study, as no new data will be collected. The results of the final study will be published in a peer-reviewed open-access journal.PROSPERO registration number CRD42022321458.

The study of the cultural materials associated with the Neanderthal physical remains from the sites in the Caucasus, Central Asia and Siberian Altai and adjacent areas documents two distinct techno-complexes of Micoquian and Mousterian. These findings potentially outline two dispersal routes for the Neanderthals out of Europe. Using data on topography and Palaeoclimate, we generated computer-based least-cost-path modelling for the Neanderthal dispersal routes from Caucasus towards the east. In this regard, two dispersal routes have been identified: A northern route from Greater Caucasus associated with Micoquian techno-complex towards Siberian Altai and a southern route from Lesser Caucasus associated with Mousterian towards Siberian Altai via the Southern Caspian Corridor. Based on archaeological, bio- and physio-geographical data, our model hypothesises that during climatic deterioration phases (e.g. MIS 4) the connection between Greater and Lesser Caucasus was limited. This issue perhaps resulted in the separate development and spread of two cultural groups of Micoquian and Mousterian with an input from two different population sources of Neanderthal influxes: eastern and southern Europe refugia for these two northern and southern dispersal routes respectively. Of these two, we focus on the southern dispersal route, for it comprises a ‘rapid dispersal route’ towards east. The significant location of the Southern Caspian corridor between high mountains of Alborz and the Caspian Sea, provided a special biogeographical zone and a refugium. This exceptional physio-geographic condition brings forward the Southern Caspian corridor as a potential place of admixture of different hominin species including Neanderthals and homo sapiens.

Until now, it was considered certain that the last reindeer hunters of the Ahrensburgian (tanged point groups) existed exclusively in northwestern Central Europe during the Younger Dryas Cold Period (~ Greenland Stadial 1). The excavations carried out since 2006 on the forecourt (Vorplatz) of the small Blätterhöhle in Hagen on the northern edge of the Sauerland uplands of southern Westphalia (North Rhine-Westphalia, western Germany) have now changed this view. Beneath a surprisingly extensive sequence of Mesolithic find horizons, Pleistocene sediments could be reached whose excavations yielded a Final Palaeolithic lithic ensemble of the Younger Dryas, unusual for the region and beyond. It is characterised by numerous backed lithic projectile points of high variability. Comparisons suggest a typological-technological connection with the Western European Laborian / Late Laborian. Neither in the nearer nor in the wider surroundings has a comparable lithic find ensemble been found so far. In addition, there is a lack of clear evidence for the reindeer in the fauna. Surprisingly, the vast majority of radiocarbon dates of bones and charcoals from the investigated archaeological horizon of the Final Pleistocene proved to be significantly older than expected from their stratigraphic position. This phenomenon has not yet been clarified.

Abstract As the south-westernmost region of Europe, the Iberian Peninsula stands as a key area for understanding the process of modern human dispersal into Eurasia. However, the precise timing, ecological setting and cultural context of this process remains controversial concerning its spatiotemporal distribution within the different regions of the peninsula. While traditional models assumed that the whole Iberian hinterland was avoided by modern humans due to ecological factors until the retreat of the Last Glacial Maximum, recent research has demonstrated that hunter-gatherers entered the Iberian interior at least during Solutrean times. We provide a multi-proxy geoarchaeological, chronometric and paleoecological study on human–environment interactions based on the key site of Peña Capón (Guadalajara, Spain). Results show (1) that this site hosts the oldest modern human presence recorded to date in central Iberia, associated to pre-Solutrean cultural traditions around 26,000 years ago, and (2) that this presence occurred during Heinrich Stadial 2 within harsh environmental conditions. These findings demonstrate that this area of the Iberian hinterland was recurrently occupied regardless of climate and environmental variability, thus challenging the widely accepted hypothesis that ecological risk hampered the human settlement of the Iberian interior highlands since the first arrival of modern humans to Southwest Europe.

The Cueva de Ardales is a hugely important Palaeolithic site in the south of the Iberian Peninsula owing to its rich inventory of rock art. From 2011–2018, excavations were carried out in the cave for the first time ever by a Spanish-German research team. The excavation focused on the entrance area of the cave, where the largest assemblage of non-figurative red paintings in the cave is found. A series of 50 AMS dates from the excavations prove a long, albeit discontinuous, occupation history spanning from the Middle Palaeolithic to the Neolithic. The dating of the Middle Palaeolithic layers agrees with the U/Th dating of some red non-figurative paintings in the entrance area. In addition, a large assemblage of ochre lumps was discovered in the Middle Palaeolithic layers. Human visits of the cave in the Gravettian and Solutrean can be recognized, but evidence from the Aurignacian and Magdalenian cannot be confirmed with certainty. The quantity and nature of materials found during the excavations indicate that Cueva de Ardales was not a campsite, but was mainly visited to carry out non-domestic tasks, such as the production of rock art or the burial of the dead.

BackgroundCOVID-19 has so far affected more than 250 million individuals worldwide, causing more than 5 million deaths. Several risk factors for severe disease have been identified, most of which coincide with advanced age. In younger individuals, severe COVID-19 often occurs in the absence of obvious comorbidities. Guided by the finding of cytomegalovirus (CMV)-specific T cells with some cross-reactivity to SARS-CoV-2 in a COVID-19 intensive care unit (ICU) patient, we decided to investigate whether CMV seropositivity is associated with severe or critical COVID-19. Herpes simplex virus (HSV) serostatus was investigated as control.MethodsNational German COVID-19 bio-sample and data banks were used to retrospectively analyze the CMV and HSV serostatus of patients who experienced mild (n = 101), moderate (n = 130) or severe to critical (n = 80) disease by IgG serology. We then investigated the relationship between disease severity and herpesvirus serostatus via statistical models.ResultsNon-geriatric patients (< 60 years) with severe COVID-19 were found to have a very high prevalence of CMV-seropositivity, while CMV status distribution in individuals with mild disease was similar to the prevalence in the German population; interestingly, this was not detectable in older patients. Prediction models support the hypothesis that the CMV serostatus, unlike HSV, might be a strong biomarker in identifying younger individuals with a higher risk of developing severe COVID-19, in particular in absence of other co-morbidities.ConclusionsWe identified 'CMV-seropositivity' as a potential novel risk factor for severe COVID-19 in non-geriatric individuals in the studied cohorts. More mechanistic analyses as well as confirmation of similar findings in cohorts representing the currently most relevant SARS-CoV-2 variants should be performed shortly.

Background: Pain due to pancreatic cancer/PCa or chronic pancreatitis/CP, is notoriously resistant to the strongest pain medications. Here, we aimed at deciphering the specific molecular mediators of pain at surgical-stage pancreatic disease and to discover novel translational targets. Methods: We performed a systematic, quantitative analysis of the neurotransmitter/neuroenzmye profile within intrapancreatic nerves of CP and PCa patients. Ex vivo neuronal cultures treated with human pancreatic extracts, conditional genetically engineered knockout mouse models of PCa and CP, and the cerulein-induced CP model were employed to explore the therapeutic potential of the identified targets. Findings: We identified a unique enrichment of neuronal nitric-oxide-synthase (nNOS) in the pancreatic nerves of CP patients with increasing pain severity. Employment of ex vivo neuronal cultures treated with pancreatic tissue extracts of CP patients, and brain-derived-neurotrophic-factor-deficient (BDNF+/−) mice revealed neuronal enrichment of nNOS to be a consequence of BDNF loss in the progressively destroyed pancreatic tissue. Mechanistically, nNOS upregulation in sensory neurons was induced by tryptase secreted from perineural mast cells. In a head-to-head comparison of several genetically induced, painless mouse models of PCa (KPC, KC mice) or CP (Ptf1a-Cre;Atg5fl/fl) against the hypersecretion/cerulein-induced, painful CP mouse model, we show that a similar nNOS enrichment is present in the painful cerulein-CP model, but absent in painless genetic models. Consequently, mice afflicted with painful cerulein-induced CP could be significantly relieved upon treatment with the specific nNOS inhibitor NPLA. Interpretation: We propose nNOS inhibition as a novel strategy to treat the unbearable pain in CP. Fund: Deutsche Forschungsgemeinschaft/DFG (DE2428/3-1 and 3-2). Keywords: Pain, Neurology of the digestive tract, nNOS, Nitrergic, Chronic pancreatitis, Pancreatic cancer, Genetically engineered mice, Atg5

Background: Low back pain (LBP) is the leading global cause of disability and is associated with intervertebral disc degeneration (DD) in some individuals. However, many adults have DD without LBP. Understanding why DD is painful in some and not others may unmask novel therapies for chronic LBP. The objectives of this study were to a) identify factors in human cerebrospinal fluid (CSF) associated with chronic LBP and b) examine their therapeutic utility in a proof-of-concept pre-clinical study. Methods: Pain-free human subjects without DD, pain-free human subjects with DD, and patients with chronic LBP linked to DD were recruited and lumbar MRIs, pain and disability levels were obtained. CSF was collected and analyzed by multiplex cytokine assay. Interleukin-8 (IL-8) expression was confirmed by ELISA in CSF and in intervertebral discs.The SPARC-null mouse model of progressive, age-dependent DD and chronic LBP was used for pre-clinical validation. Male SPARC-null and control mice received systemic Reparixin, a CXCR1/2 (receptors for IL-8 and murine analogues) inhibitor, for 8 weeks. Behavioral signs of axial discomfort and radiating pain were assessed. Following completion of the study, discs were excised and cultured, and conditioned media was evaluated with a protein array. Findings: IL-8 was elevated in CSF of chronic LBP patients with DD compared to pain-free subjects with or without DD. Chronic inhibition with reparixin alleviated low back pain behaviors and attenuated disc inflammation in SPARC-null mice. Interpretation: These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. Fund: Supported by NIH, MMF, CIHR and FRQS. Keywords: Intervertebral disc degeneration, CXCL1, CXCL5, Cerebrospinal fluid, CXCR1/2, Reparixin

Patients undergoing complex pediatric cardiac surgery in early infancy are at risk of postoperative secondary end-organ dysfunction. The aim of this study was to determine specific risk factors promoting the development of peri- and postoperative hepatopathy after surgery for congenital heart disease. In this retrospective study, we identified 20 consecutive patients operated between 2011 and 2019 from our institutional cohort who developed significant postsurgical hepatic dysfunction. These patients were compared to a control group of 30 patients with comparable initial cardiac conditions and STS-EACTS risk score. Patients who developed hepatopathy in the intensive care unit have chronic cholestasis and decreased liver synthesis. The impact of postoperative hepatopathy on morbidity was marked. In six patients (30%), liver transplantation was executed as ultima ratio, and two (10%) were listed for liver transplantation. The overall mortality related to postoperative hepatopathy is high: We found nine patients (45%) having severe hepatopathy and mostly multiple organ dysfunction who died in the postoperative course. According to risk analysis, postoperative right and left heart dysfunction in combination with a postoperative anatomical residuum needing a re-operation or re-intervention in the postoperative period is associated with a high risk for the development of cardiac hepatopathy. Furthermore, postoperative complications (pleural effusion, heart rhythm disorders, etc.), postoperative infections, and the need for parenteral nutrition also raise the risk for cardiac hepatopathy. Further investigations are needed to reduce hepatic complications and improve the general prognosis of such complex patients.

Powassan virus (POWV) lineage II is an emerging tickborne flavivirus with an unknown seroprevalence in humans. In a Lyme disease–endemic area, we examined the seroreactivity to POWV in 2 patient cohorts and described the clinical features of the POWV-seroreactive patients. POWV disease might be less neuroinvasive than previously thought.

This paper investigates the correlation between climate, environment and human land use in the Westernmost Mediterranean on both sides of the Strait of Gibraltar during the Late Glacial. Using a multi-proxy approach on a sample of 300 sites from the Solutrean and Magdalenian of the Iberian Peninsula and from the Iberomaurusian in Morocco, we find evidence for significant changes in settlement patterns and site density after the Last Glacial Maximum. In Southern Iberia, during Heinrich Stadial 1, hyperarid zones expanded drastically from the south-eastern coast to the West through the Interior. This aridification process heavily affected Magdalenian settlement in the South and caused a strong decline of hunter-gatherer population. Southern Iberia during Heinrich Stadial 1 turned out to be a high-risk environment when compared to Northern Iberia. At the same time, the Late Iberomaurusian of Morocco, although considered to be situated in a high-risk environment as well, experiences an increase of sites and expansion of settlement area.

INTRODUCTION:In southern European countries, multicentric lymphoma and leishmaniosis are the main differential diagnoses in dogs presented with generalized lymphadenomegaly. The cytological examination is in some cases inconclusive and polymerase chain reaction (PCR) for antigen receptor rearrangement (PARR) has become a common method to confirm or rule out a lymphoproliferative neoplasia. According to the literature, leishmaniosis may lead to clonal arrangements and therefore to a false diagnosis of lymphoma, but this assumption is made from a single leishmania infected dog. Therefore, the objective of this study was to prospectively evaluate results from PARR in dogs with lymphadenomegaly due to clinical leishmaniosis at the moment of diagnosis. MATERIALS AND METHODS:31 dogs with a diagnosis of leishmaniosis based on the LeishVet guidelines were included in the study. Samples from enlarged lymph nodes were taken for cytological examination, clonality testing and Leishmania infantum PCR. RESULTS:All 31 dogs had medium to high positive antibody titers against Leishmania spp. and 30/31 had a positive Leishmania PCR from the lymph node. A polyclonal arrangement for B cells (immunoglobulin heavy chain gene) and T cells (T-cell receptor gamma chain gene) antigen receptors was found in 28/31 dogs. Two out of 31 dogs showed a monoclonal arrangement for Ig with high (1:2) and low (1:7) polyclonal background respectively; and one of the 31 dogs showed a monoclonal arrangement for T cell receptor with low (1:3) polyclonal background. CONCLUSION:Infections with Leishmania infantum resulted in clonal rearrangement, and therefore in a possible false diagnosis of lymphoma, in 3 out of 31 dogs (9.7%). Although, PARR is a useful method to differentiate lymphoma from reactive lymphoid hyperplasia in dogs with leishmaniosis, mono-/biclonal results should be interpreted carefully, especially in the presence of any degree of polyclonal background, and together with other clinicopathological findings.

BACKGROUND The majority of germ cell tumour (GCT) patients can be cured by orchiectomy followed by active surveillance or subsequent systemic and/or local treatments. There are various guidelines for a structured follow-up including radiographic and clinical examinations. OBJECTIVE The Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS) prospectively evaluates follow-up, indicator of relapse and late toxicities. This is a descriptive analysis; we present baseline characteristics and treatment strategies for the first 299 patients with primary GCT or relapsed GCT after completion of treatment. RESULTS Of the patients included in this study, 192 (64.2%) had seminoma and 107 (35.8%) non-seminoma. Mean age was 41 years (standard deviation [SD] 11.7) for seminoma and 31 (SD 9.3) years for non-seminoma patients. Median tumour size was 3.5 cm (interquartile range 2.5­‒5.0 and 2.3‒4.5 in seminoma and non-seminoma, respectively) in both histological groups. Among seminoma patients, 81 (42.2%) had primary tumours >4cm; 154 (80.2%) seminoma patients had stage I, 26 (13.5%) stage II and 12 (6.3%) stage III disease. Fifty-seven (53.3%) non-seminoma tumours were stage I, 29 (27.1%) stage II and 21 (19.6%) stage III. Marker-positive disease was present in 58 (30.2%) seminoma patients and 78 (72.9%) non-seminoma patients. Of 154 stage I seminoma patients, 89 (57.8%) chose active surveillance and 65 (42.2%) adjuvant chemotherapy. Twenty-six (45.6%) stage I non-seminoma patients had high-risk disease; 23 of these were treated with adjuvant chemotherapy and 3 chose active surveillance. Among the 30 (52.6%) low risk stage I patients, all opted for active surveillance. Twelve (46.2%) stage II seminoma patients had radiotherapy, 14 (53.8%) were treated with three to four cycles of chemotherapy. All stage III seminoma patients, and all stage II and III non-seminoma patients were treated with three to four cycles of chemotherapy. Treatment decisions were made at the respective centre. Eleven patients did not receive therapy that conformed with guidelines. CONCLUSION It is important to enrol GCT patients in prospective studies in general, but also in follow-up studies to assess baseline characteristics, oncological outcome, and long-term toxicity and to validate the performance of follow-up schedules. This is the first time that the distribution of disease, detailed baseline characteristics and the respective treatment of men with GCT is collected in a prospective manner in German speaking countries (Switzerland, Austria and Germany) and therefore patterns of care have been evaluated. SAG TCCS results will inform on future modifications of surveillance schedules and follow-up procedures. ​ Trial registration number: NCT02229916 (Clinicaltrials.gov)

The Clarkia lagerstätte (Latah Formation) of Idaho is well known for its beautifully preserved plant fossils as well as a fauna of insects and fish. Here we present the first known tetrapod fossil from these deposits. This specimen, recovered from the lower anoxic zone of the beds, is preserved as a carbonaceous film of a partial skeleton associated with a partial lower incisor and some tooth fragments. The morphology of the teeth indicates that the first tetrapod reported from Clarkia is a rodent. Its skeletal morphology as well as its bunodont and brachydont dentition suggests that it is a member of the squirrel family (Sciuridae). It is a large specimen that cannot be assigned to a known genus. Instead, it appears to represent the first occurrence of a new taxon with particularly gracile postcranial morphology likely indicative of an arboreal ecology. This new specimen is a rare glimpse into the poorly known arboreal mammal fossil record of the Neogene. It supports a greater taxonomic and ecological diversity of Miocene Sciuridae than previously recognized and offers new lines of inquiry in the paleoecological research enabled by the unique preservation conditions of the Clarkia biota.

In domestic cats, the AB blood group system consists of the three types A, B, and C (usually called AB), which vary in frequency among breeds and geographic regions. Mismatches cause acute hemolytic transfusion reactions and hemolysis of the newborn due to the presence of naturally occurring anti-A alloantibodies. Cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) converts N-acetylneuraminic acid (type B) to N-glycolylneuraminic acid (type A), and type C erythrocytes express both antigens. We examined the feline CMAH coding regions and genotyped cats to characterize type A, B, and C animals. Of 421 phenotypically typed cats, 60% were A, 35% B and 5% C. Among the 70 cats for which the CMAH coding region was sequenced, 13 new variants were identified in addition to 16 of the previously reported 18 variants. The CMAH variant c.268T>A is seen in type B cats of most breeds, and the variant c.179G>T results in type B in Turkish breeds. The variants c.1322delT and c.933delA cause frameshifts with early stop codons and thereby type B in some Ragdolls and domestic shorthair cats, respectively. Protein modeling with PROVEAN affirmed their deleterious effects. No type A and C cats had more than one allele with one of the above variants. Variant analysis of three SNVs (c.142G>A, c.268T>A and Δ-53) and blood typing of an additional 351 typed cats showed complete phenotype-genotype concordance. In conclusion, the three CMAH variants c.179G>T, c.268T>A and c.1322delT are the main reasons for the defective NeuGc synthesis causing blood type B in domestic purebred and non-pedigreed cats. Together with the variant c.364C>T for type C in Ragdolls they offer a molecular screening scheme for clinical diagnostics to assure blood type compatibility.

Although the Iberian Peninsula is a key area for understanding the Middle to Upper Paleolithic transition and the demise of the Neandertals, valuable evidence for these debates remains scarce and problematic in its interior regions. Sparse data supporting a late Neandertal persistence in the Iberian interior have been recently refuted and hence new evidence is needed to build new models on the timing and causes of Neandertal disappearance in inland Iberia and the whole peninsula. In this study we provide new evidence from Los Casares, a cave located in the highlands of the Spanish Meseta, where a Neandertal-associated Middle Paleolithic site was discovered and first excavated in the 1960's. Our main objective is twofold: (1) provide an updated geoarcheological, paleoenvironmental and chronological framework for this site, and (2) discuss obtained results in the context of the time and nature of the last Neandertal presence in Iberia.We conducted new fieldwork in an interior chamber of Los Casares cave named 'Seno A'. Our methods included micromorphology, sedimentology, radiocarbon dating, Uranium/Thorium dating, palinology, microfaunal analysis, anthracology, phytolith analysis, archeozoology and lithic technology. Here we present results on site formation processes, paleoenvironment and the chronological setting of the Neandertal occupation at Los Casares cave-Seno A.The sediment sequence reveals a mostly in situ archeological deposit containing evidence of both Neandertal activity and carnivore action in level c, dated to 44,899-42,175 calendar years ago. This occupation occurred during a warm and humid interval of Marine Isotopic Stage 3, probably correlating with Greenland Interstadial 11, representing one of the latest occurrences of Neandertals in the Iberian interior. However, overlying layer b records a deterioration of local environments, thus providing a plausible explanation for the abandonment of the site, and perhaps for the total disappearance of Neandertals of the highlands of inland Iberia during subsequent Greenland Stadials 11 or 10, or even Heinrich Stadial 4. Since layer b provided very few signs of human activity and no reliable chronometric results, and given the scarce chronostratigrapic evidence recorded so far for this period in interior Iberia, this can only be taken as a working hypothesis to be tested with future research. Meanwhile, 42,000 calendar years ago remains the most plausible date for the abandonment of interior Iberia by Neandertals, possibly due to climate deterioration. Currently, a later survival of this human species in Iberia is limited to the southern coasts.