Homo sapiens reached the higher latitudes of Europe by 45,000 years ago.

The Middle to Upper Palaeolithic transition in Europe is associated with the regional disappearance of Neanderthals and the spread of Homo sapiens. Late Neanderthals persisted in western Europe several millennia after the occurrence of H. sapiens in eastern Europe1. Local hybridization between the two groups occurred2, but not on all occasions3. Archaeological evidence also indicates the presence of several technocomplexes during this transition, complicating our understanding and the association of behavioural adaptations with specific hominin groups4. One such technocomplex for which the makers are unknown is the Lincombian-Ranisian-Jerzmanowician (LRJ), which has been described in northwestern and central Europe5-8. Here we present the morphological and proteomic taxonomic identification, mitochondrial DNA analysis and direct radiocarbon dating of human remains directly associated with an LRJ assemblage at the site Ilsenhöhle in Ranis (Germany). These human remains are among the earliest directly dated Upper Palaeolithic H. sapiens remains in Eurasia. We show that early H. sapiens associated with the LRJ were present in central and northwestern Europe long before the extinction of late Neanderthals in southwestern Europe. Our results strengthen the notion of a patchwork of distinct human populations and technocomplexes present in Europe during this transitional period.

Portable polygraphic device (Somnocheck micro CARDIO®) provides accurate diagnostic information in psychiatric patients at risk for obstructive sleep apnoea: an observational cohort study.

BACKGROUND: Symptoms of obstructive sleep apnoea (OSA) overlap significantly with those of psychiatric disorders, making accurate diagnosis of OSA challenging within psychiatric settings. Diagnosing OSA in psychiatric patients is crucial because untreated OSA can exacerbate psychiatric symptoms, reduce treatment efficacy, and impair overall quality of life. This study aimed to determine the diagnostic accuracy of a readily accessible procedure for psychiatric patients in a real-world clinical setting by comparing the Somnocheck micro CARDIO® (SCm) portable cardiorespiratory polygraphy device with the gold standard polysomnography (PSG). METHODS: This observational cohort study included consecutive psychiatric patients at intermediate to high risk for OSA based on screening with the STOP-Bang questionnaire, admitted to a single tertiary care centre between June 1, 2016 and December 31, 2022. The Apnoea-Hypopnoea-Index (AHI), Apnoea-Index (AI), Oxygen-Desaturation-Index (ODI), and minimum oxygen saturation were measured sequentially by SCm and PSG. RESULTS: A total of 57 patients were analysed (median age 62.0 [Interquartile Range (IQR), 51.5-72.5] years; 34 [59.6%] men). Regarding AHI, no significant differences (AHI measured by PSG, median, 16.6 [IQR, 6.2-26.7] vs. AHI measured by SCm, median, 14.9 [IQR, 10.0-22.8]; p = 0.812; r = 0.71) were found between SCm and PSG. AI, ODI and minimum oxygen saturation differed significantly between SCm and PSG. Using optimised cut-off values (any OSA: AHISCm ≥ 9.25), SCm showed high sensitivity (0.894) and high specificity (0.800) for the diagnosis of OSA, with an area under the receiver operating characteristic curve of 0.877. CONCLUSIONS: This study found that the SCm portable device was accurate in identifying psychiatric patients with OSA. AHI measurement by SCm provided reliable diagnostic performance in comparison with the gold standard polysomnography. These findings support the integration of polygraphic measurements into the routine sleep assessment of psychiatric patients. Early and accurate diagnosis of OSA in this population can significantly improve the management of both sleep disorders and psychiatric conditions, potentially enhancing overall treatment outcomes and quality of life for these patients.

Icenticaftor, a CFTR Potentiator, in COPD: A Multicenter, Parallel-Group, Double-Blind Clinical Trial.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction is associated with mucus accumulation and worsening chronic obstructive pulmonary disease (COPD) symptoms. Objectives: The aim of this phase IIb dose-finding study was to compare a CFTR potentiator, icenticaftor (QBW251), with placebo in patients with COPD and chronic bronchitis. Methods: Patients with COPD on triple therapy for at least three months were randomized to six treatment arms (icenticaftor 450, 300, 150, 75, or 25 mg or placebo twice daily [b.i.d.]) in a 24-week, multicenter, parallel-group, double-blind study. The primary endpoint was change from baseline in trough FEV1 after 12 weeks. Secondary endpoints included change from baseline in trough FEV1 and Evaluating Respiratory Symptoms in COPD (E-RS) total and cough and sputum scores after 24 weeks. Multiple comparison procedure-modeling was conducted to characterize dose-response relationship. Rescue medication use, exacerbations, and change in serum fibrinogen concentration after 24 weeks were assessed in exploratory and post hoc analyses, respectively. Measurements and Main Results: Nine hundred seventy-four patients were randomized. After 12 weeks of icenticaftor treatment, no dose-response relationship for change from baseline in trough FEV1 was observed; however, it was observed for E-RS cough and sputum score. A dose-response relationship was observed after 24 weeks for trough FEV1, E-RS cough and sputum and total scores, rescue medication use, and fibrinogen. A dose of 300 mg b.i.d. was consistently the most effective. Improvements for 300 mg b.i.d. versus placebo were also seen in pairwise comparisons of these endpoints. All treatments were well tolerated. Conclusions: The primary endpoint was negative, as icenticaftor did not improve trough FEV1 over 12 weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV1; reduced cough, sputum, and rescue medication use; and lowered fibrinogen concentrations at 24 weeks. Clinical trial registered with www.clinicaltrials.gov (NCT04072887).

Development of a disease-specific health utility score for chronic obstructive pulmonary disease from a discrete choice experiment patient preference study.

OBJECTIVES: While patient input to health technology assessment (HTA) has traditionally been of a qualitative nature, there is increasing interest to integrate quantitative evidence from patient preference studies into HTA decision making. Preference data can be used to generate disease-specific health utility data. We generated a health utility score for patients with chronic obstructive pulmonary disease (COPD) and consider its use within HTAs. METHODS: Based on qualitative research, six symptoms were identified as important to COPD patients: shortness of breath, exacerbations, chronic cough, mucus secretion, sleep disturbance, and urinary incontinence. We employed a discrete choice experiment (DCE) and the random parameter logistic regression technique to estimate utility scores for all COPD health states. The relationship between patients' COPD health utility scores, self-perceived COPD severity, and EQ-5D-3L utility scores was analyzed, with data stratified according to disease severity and comorbidity subgroups. RESULTS: The COPD health utility score had face validity, with utility scores negatively correlated with patients' self-perceived COPD severity. The correlation between the COPD health utility scores and EQ-5D-3L values was only moderate. While patient EQ-5D-3L scores were impacted by comorbidities, the COPD health utility score was less impacted by comorbid conditions. CONCLUSIONS: Our COPD utility measure, derived from a DCE, provides a patient-centered health utility score and is more sensitive to the COPD health of the individual and less sensitive to other comorbidities. This disease-specific instrument should be considered alongside generic health-related quality of life instruments when valuing new COPD therapies in submissions to licensing and reimbursement agencies.

Perioperative continuation or ultra-early resumption of antithrombotics in elective neurosurgical cranial procedures.

OBJECTIVE: Discontinuation of antithrombotics (AT) prior to elective cranial procedures is common practice, despite the higher risk of thromboembolic complications in these patients. The aim of this study was to investigate the risks and benefits of a new perioperative management protocol of continuation or ultra-early AT resumption in elective cranial procedures. METHODS: This study was an analysis of a prospectively collected cohort of patients undergoing elective cranial surgery with (AT group) and without (control group) AT. For extraaxial or shunt surgeries, acetylsalicylic acid (ASA) was continued perioperatively. For intraaxial pathologies, ASA was discontinued 2 days before surgery and resumed on postoperative day 3. All other AT were discontinued according to their pharmacokinetics, and resumed on postoperative day 3 after unremarkable postoperative imaging. Additionally, the authors performed a retrospective analysis of patients with AT who underwent surgery before implementation of this new AT management protocol (historical AT group). Primary and secondary outcomes were the incidence of hemorrhagic and thromboembolic complications within 3 months after surgery. RESULTS: Outcomes of 312 patients were analyzed (83 [27%] in the AT group, 106 [34%] in the control group, and 123 [39%] in the historical AT group). For all 3 patient groups, the most common type of surgery was craniotomy for intraaxial tumors (14 [17%] in the AT group, 28 [26%] in the control group, and 60 [49%] in the historical AT group). The most commonly used AT were ASA (38 [46%] in the AT group and 78 [63%] in the historical AT group), followed by non-vitamin K oral anticoagulants (32 [39%] in the AT group and 18 [15%] in the historical AT group). The total perioperative discontinuation time in the AT group was significantly shorter than in the historical AT group (median of 4 vs 16 days; p < 0.001). The rate of hemorrhagic complications was 4% (95% CI 1-10) (n = 3/83) in the AT group, 6% (95% CI 2-12) (n = 6/106) in the control group, and 7% (95% CI 3-13) (n = 9/123) in the historical AT group (p = 0.5). The rate of thromboembolic complications was 5% (95% CI 1-12) (n = 4/82) in the AT group, 8% (95% CI 3-15) (n = 8/104) in the control group, and 7% (95% CI 3-13) (n = 8/120) in the historical AT group (p = 0.7). CONCLUSIONS: The presented perioperative management protocol of continuation or ultra-early resumption of AT in elective cranial procedures does not seem to increase the hemorrhagic risk. Moreover, it appears to potentially protect patients from thromboembolic complications.

Lung function from school age to adulthood in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) presents with symptoms early in life and the disease course may be progressive, but longitudinal data on lung function are scarce. This multinational cohort study describes lung function trajectories in children, adolescents and young adults with PCD. We analysed data from 486 patients with repeated lung function measurements obtained between the age of 6 and 24 years from the International PCD Cohort and calculated z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio using the Global Lung Function Initiative 2012 references. We described baseline lung function and change of lung function over time and described their associations with possible determinants in mixed-effects linear regression models. Overall, FEV1, FVC and FEV1/FVC z-scores declined over time (average crude annual FEV1 decline was -0.07 z-scores), but not at the same rate for all patients. FEV1 z-scores improved over time in 21% of patients, remained stable in 40% and declined in 39%. Low body mass index was associated with poor baseline lung function and with further decline. Results differed by country and ultrastructural defect, but we found no evidence of differences by sex, calendar year of diagnosis, age at diagnosis, diagnostic certainty or laterality defect. Our study shows that on average lung function in PCD declines throughout the entire period of lung growth, from childhood to young adult age, even among patients treated in specialised centres. It is essential to develop strategies to reverse this tendency and improve prognosis.

One-Year Outcome of Postoperative Stroke and Nerve Injury After Supraclavicular Revascularization of The Left Subclavian Artery for Proximal Landing Zone Extension in Thoracic Endovascular Aortic Repair.

OBJECTIVE: To assess the outcome of stroke and nerve injury after supraclavicular revascularization of the left subclavian artery for proximal landing zone extension in thoracic endovascular aortic repair (TEVAR). METHODS: Retrospective analysis of all patients undergoing left-sided carotid-subclavian bypass (CSB) and subclavian-carotid transposition (SCT) with simultaneous or staged TEVAR between January 2010 and June 2019. Endpoints were perioperative cerebrovascular events and nerve injuries, patency and re-intervention due to the debranching, and mortality at 30 days and during follow-up. RESULTS: Forty-eight patients (median age 66 years, 81 % male) had 25 (52%) CSB and 23 (48%) SCT. TEVAR was performed simultaneously in 39 (81%) patients, 11 (23%) of them in an emergent setting. There were 7 (15%) re-interventions within 30 days: 3 due to local hematoma, one for bypass occlusion, 2 for stenosis (of which one was not confirmed intraoperatively), and one after initially abandoned SCT with subsequent CSB on the next day. 30-day mortality was 2%; 1 patient died on the first postoperative day after emergency coronary artery bypass surgery and multiorgan failure. 4 (8%) patients suffered postoperative strokes; 3 occurred after simultaneous emergency procedures and none was fatal. There were 9 (19%) left neck nerve injuries in 8 patients, 5 patients had SCT and 3 CSB. During a median follow-up of 37.5 months (IQR 23-83) with a Follow-up Index of 0.77, there were no reinterventions or occlusions, and no graft infections. Primary patency was 90% and primary assisted patency 98% during follow-up. 8 patients died during follow-up, all of them with patent cervical debranching. CONCLUSION: Supraclavicular LSA revascularization for proximal landing zone extension in TEVAR is safe with an acceptable rate of early re-interventions. There is higher risk for perioperative stroke during concomitant emergency LSA revascularization and TEVAR. Left neck nerve injuries are common complications but resolve completely in vast majority of the cases during first postoperative year. During follow-up, excellent patency could be expected.

Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial.

BACKGROUND: Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT). PATIENTS AND METHODS: This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). RESULTS: Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups. CONCLUSIONS: The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.

Osteoporosis and fracture risk associated with inhaled corticosteroid use among Swedish COPD patients: the ARCTIC study.

The effect of inhaled corticosteroids (ICS) on the risk of osteoporosis and fracture in patients with chronic obstructive pulmonary disease (COPD) remains uncertain. The aim of this study was to assess this risk in patients with COPD.Electronic medical record data linked to National Health Registries were collected from COPD patients and matched reference controls at 52 Swedish primary care centres from 2000 to 2014. The outcomes analysed were the effect of ICS on all fractures, fractures typically related to osteoporosis, recorded osteoporosis diagnosis, prescriptions of drugs for osteoporosis and a combined measure of any osteoporosis-related event. The COPD patients were stratified by the level of ICS exposure.A total of 9651 patients with COPD and 59 454 matched reference controls were analysed. During the follow-up, 19.9% of COPD patients had at least one osteoporosis-related event compared with 12.9% of reference controls (p<0.0001). Multivariate analysis in the COPD population demonstrated a dose-effect relationship, with high-dose ICS being significantly associated with any osteoporosis-related event (risk ratio 1.52 (95% CI 1.24-1.62)), while the corresponding estimate for low-dose ICS was 1.27 (95% CI 1.13-1.56) compared with COPD patients not using ICS. A similar dose-related adverse effect was found for all four of the specific osteoporosis-related events: all fractures, fractures typically related to osteoporosis, prescriptions of drugs for osteoporosis and diagnosis of osteoporosis.We conclude that patients with COPD have a greater risk of bone fractures and osteoporosis, and high-dose ICS use increased this risk further.

tailfindr: alignment-free poly(A) length measurement for Oxford Nanopore RNA and DNA sequencing.

Polyadenylation at the 3'-end is a major regulator of messenger RNA and its length is known to affect nuclear export, stability, and translation, among others. Only recently have strategies emerged that allow for genome-wide poly(A) length assessment. These methods identify genes connected to poly(A) tail measurements indirectly by short-read alignment to genetic 3'-ends. Concurrently, Oxford Nanopore Technologies (ONT) established full-length isoform-specific RNA sequencing containing the entire poly(A) tail. However, assessing poly(A) length through base-calling has so far not been possible due to the inability to resolve long homopolymeric stretches in ONT sequencing. Here we present tailfindr, an R package to estimate poly(A) tail length on ONT long-read sequencing data. tailfindr operates on unaligned, base-called data. It measures poly(A) tail length from both native RNA and DNA sequencing, which makes poly(A) tail studies by full-length cDNA approaches possible for the first time. We assess tailfindr's performance across different poly(A) lengths, demonstrating that tailfindr is a versatile tool providing poly(A) tail estimates across a wide range of sequencing conditions.

Magnetic resonance imaging and spectroscopy in late-onset GM2-gangliosidosis.

OBJECTIVE: Our study aimed to quantify structural changes in relation to metabolic abnormalities in the cerebellum, thalamus, and parietal cortex of patients with late-onset GM2-gangliosidosis (LOGG), which encompasses late-onset Tay-Sachs disease (LOTS) and Sandhoff disease (LOSD). METHODS: We enrolled 10 patients with LOGG (7 LOTS, 3 LOSD) who underwent a neurological assessment battery and 7 age-matched controls. Structural MRI and MRS were performed on a 3 T scanner. Structural volumes were obtained from FreeSurfer and normalized by total intracranial volume. Quantified metabolites included N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cr), and combined glutamate-glutamine (Glx). Metabolic concentrations were corrected for partial volume effects. RESULTS: Structural analyses revealed significant cerebellar atrophy in the LOGG cohort, which was primarily driven by LOTS patients. NAA was lower and mI higher in LOGG, but this was also significantly driven by the LOTS patients. Clinical ataxia deficits (via the Scale for the Assessment and Rating of Ataxia) were associated with neuronal injury (via NAA), neuroinflammation (via mI), and volumetric atrophy in the cerebellum. INTERPRETATION: The decrease of NAA in the cerebellum suggests that, in addition to cerebellar atrophy, there is ongoing impaired neuronal function and/or loss, while an increase in mI indicates possible neuroinflammation in LOGG (more so within the LOTS subvariant). Quantifying cerebellar atrophy in relation to neurometabolic differences in LOGG may lead to improvements in assessing disease severity, progression, and pharmacological efficacy. Lastly, additional neuroimaging studies in LOGG are required to contrast LOTS and LOSD more accurately.

Antimicrobial Prophylaxis for Postoperative Urinary Tract Infections in Transurethral Resection of Bladder Tumors: A Systematic Review and Meta-Analysis.

PURPOSE: The administration of antimicrobial prophylaxis for postoperative urinary tract infections following transurethral resection of bladder tumors is controversial. We aimed to systematically review evidence on the potential effect of antimicrobial prophylaxis on postoperative urinary tract infections and asymptomatic bacteriuria. MATERIALS AND METHODS: We conducted a systematic search in Embase®, Medline® and the Cochrane Central Register of Controlled Trials. Randomized controlled trials and nonrandomized controlled trials assessing the effect of any form of antimicrobial prophylaxis in patients with transurethral resection of bladder tumors on postoperative urinary tract infections or asymptomatic bacteriuria were included. Risk of bias was assessed using RoB 2.0 or the Newcastle-Ottawa Scale. Fixed and random effects meta-analyses were conducted. As a potential basis for a scoping review, we exploratorily searched Medline for risk factors for urinary tract infections after transurethral resection of bladder tumors. The protocol was registered on PROSPERO (CRD42019131733). RESULTS: Of 986 screened publications, 7 studies with 1,725 participants were included; the reported effect sizes varied considerably. We found no significant effect of antimicrobial prophylaxis on urinary tract infections: the pooled odds ratio of the random effects model was 1.55 (95% CI 0.73-3.31). The random effects meta-analysis examining the effect of antimicrobial prophylaxis on asymptomatic bacteriuria showed an OR of 0.43 (0.18-1.04). Risk of bias was moderate. Our exploratory search identified 3 studies reporting age, preoperative pelvic radiation, preoperative hospital stay, duration of operation, tumor size, preoperative asymptomatic bacteriuria and pyuria as risk factors for urinary tract infections following transurethral resection of bladder tumors. CONCLUSIONS: We observed insufficient evidence supporting routine antimicrobial prophylaxis in patients undergoing transurethral resection of bladder tumors for the prevention of postoperative urinary tract infections; our findings may inform harmonization of international guidelines.

Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF-2 in adipose tissue during endotoxemia.

Sepsis is a leading cause of death worldwide and recent studies have shown white adipose tissue (WAT) to be an important regulator in septic conditions. In the present study, the role of the inflammatory cytokine macrophage migration inhibitory factor (MIF) and its structural homolog D-dopachrome tautomerase (D-DT/MIF-2) were investigated in WAT in a murine endotoxemia model. Both MIF and MIF-2 levels were increased in the peritoneal fluid of LPS-challenged wild-type mice, yet, in visceral WAT, the proteins were differentially regulated, with elevated MIF but downregulated MIF-2 expression in adipocytes. Mif gene deletion polarized adipose tissue macrophages (ATM) toward an anti-inflammatory phenotype while Mif-2 gene knockout drove ATMs toward a pro-inflammatory phenotype and Mif-deficiency was found to increase fibroblast viability. Additionally, we observed the same differential regulation of these two MIF family proteins in human adipose tissue in septic vs healthy patients. Taken together, these data suggest an inverse relationship between adipocyte MIF and MIF-2 expression during systemic inflammation, with the downregulation of MIF-2 in fat tissue potentially increasing pro-inflammatory macrophage polarization to further drive adipose inflammation.

A multistakeholder Delphi consensus core outcome set for clinical trials in moderate-to-severe asthma (coreASTHMA).

BACKGROUND: Treatments for long-term control of asthma have improved and include a promising but expensive class of biologic therapies. However, the clinical trials evaluating these and other novel treatments have used a variety of different outcomes to evaluate efficacy. The evolution of asthma care calls for a re-examination of outcomes that are most important to patients and other stakeholders. OBJECTIVE: To develop a core set of outcomes to be measured in phase 3 and phase 4 clinical drug trials in patients with moderate-to-severe asthma. METHODS: We used a robust and in-depth multistakeholder consensus process bringing together patients, clinicians, regulators, payers, health technology assessors, researchers, and product developers to reach consensus on outcomes. We used a modified Delphi method to reach consensus, an approach adapted from the Core Outcome Measures in Effectiveness Trials Initiative aligned with contemporary methodological standards for core outcome set development. RESULTS: The following outcomes were included in the final core set: severe asthma exacerbation, change in asthma control, asthma-specific or severe asthma-specific quality of life, asthma-specific hospital stay (ie, >24-hour stays at any level of care) or admission, and asthma-specific emergency department visit. CONCLUSION: These 5 outcomes represent a minimum set of core outcomes for use in phase 3 and phase 4 clinical drug trials in moderate-to-severe asthma. Consistent collection of these outcomes as minimum, independent of whether additional heterogeneous primary or secondary outcomes are included, will allow for meaningful comparisons of the effect of asthma therapies across clinical trials.

HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases.

The HIV Nef protein recruits the polycomb protein Eed and mimics an integrin receptor signal for reasons that are not entirely clear. Here we demonstrate that Nef and Eed complex with the integrin effector paxillin to recruit and activate TNFα converting enzyme (TACE alias ADAM 17) and its close relative ADAM10. The activated proteases cleaved proTNFα and were shuttled into extracellular vesicles (EVs). Peripheral blood mononuclear cells that ingested these EVs released TNFα. Analyzing the mechanism, we found that Pak2, an established host cell effector of Nef, phosphorylated paxillin on Ser272/274 to induce TACE-paxillin association and shuttling into EVs via lipid rafts. Conversely, Pak1 phosphorylated paxillin on Ser258, which inhibited TACE association and lipid raft transfer. Interestingly, melanoma cells used an identical mechanism to shuttle predominantly ADAM10 into EVs. We conclude that HIV-1 and cancer cells exploit a paxillin/integrin-controlled mechanism to release TACE/ADAM10-containing vesicles, ensuring better proliferation/growth conditions in their microenvironment.

Consensus statement from the international consensus meeting on post-traumatic cranioplasty.

BACKGROUND: Due to the lack of high-quality evidence which has hindered the development of evidence-based guidelines, there is a need to provide general guidance on cranioplasty (CP) following traumatic brain injury (TBI), as well as identify areas of ongoing uncertainty via a consensus-based approach. METHODS: The international consensus meeting on post-traumatic CP was held during the International Conference on Recent Advances in Neurotraumatology (ICRAN), in Naples, Italy, in June 2018. This meeting was endorsed by the Neurotrauma Committee of the World Federation of Neurosurgical Societies (WFNS), the NIHR Global Health Research Group on Neurotrauma, and several other neurotrauma organizations. Discussions and voting were organized around 5 pre-specified themes: (1) indications and technique, (2) materials, (3) timing, (4) hydrocephalus, and (5) paediatric CP. RESULTS: The participants discussed published evidence on each topic and proposed consensus statements, which were subject to ratification using anonymous real-time voting. Statements required an agreement threshold of more than 70% for inclusion in the final recommendations. CONCLUSIONS: This document is the first set of practical consensus-based clinical recommendations on post-traumatic CP, focusing on timing, materials, complications, and surgical procedures. Future research directions are also presented.

Social Media Use in COPD Patients in Germany and Switzerland.

Use of social media and the Internet has changed the information-seeking behaviour and exchange of experience and information by patients. Passive observation of such online interaction between patients (social media listening) is conducted in order to understand the burden of the disease, symptom perception, and expectations from a patient perspective. For most conditions, it remains to be established how representative the social media user community is for the overall patient population. In this study, we describe internet and social media use in a population of 570 COPD patients from Germany and Switzerland. This study population is a good representation of the overall patient population in Germany and Switzerland with regards to socioeconomic data. Patients were analyzed in an exploratory fashion whether usage of the Internet to obtain disease-specific information and exchanging on COPD via social media is associated with or is independent from certain socioeconomic criteria. About three-fourths of patients indicated using the Internet to search information about COPD and about a third of patients indicated using social media to exchange with others about their disease. Results indicated that among the patients using the Internet to seek information and among those sharing information via social media, patients with very severe COPD (GOLD stage 4) were overrepresented versus milder forms of the disease. Similarly, patients with more advanced educational background were also overrepresented in the groups using social media and Internet in relation to COPD. Differences in mean age were statistically significant, but surprisingly small between social media users and non-users. No relationship with regards to social media and Internet use for COPD were observed for domiciling situation and sex.

Bis(perfluoropinacolato)silane: A Neutral Silane Lewis Superacid Activates Si-F Bonds.

Despite the earth abundance and easy availability of silicon, only few examples of isolable neutral silicon centered Lewis superacids are precedent in the literature. To approach the general drawbacks of limited solubility and unselective deactivation pathways, we introduce a Lewis superacid, based on perfluorinated pinacol substituents. The compound is easily synthesized on a gram-scale as the corresponding acetonitrile mono-adduct 1⋅(MeCN) and was fully characterized, including single crystal X-ray diffraction analysis (SC-XRD) and state-of-the-art computations. Lewis acidity investigations by the Gutmann-Beckett method and fluoride abstraction experiments indicate a Lewis superacidic nature. The challenging Si-F bond activation of Et3 SiF is realized and promising catalytic properties are demonstrated, consolidating the potential applicability of silicon centered Lewis acids in synthetic catalysis.

Adipose tissue and the vascularization of biomaterials: Stem cells, microvascular fragments and nanofat-a review.

Tissue defects in the human body after trauma and injury require precise reconstruction to regain function. Hence, there is a great demand for clinically translatable approaches with materials that are both biocompatible and biodegradable. They should also be able to adequately integrate within the tissue through sufficient vascularization. Adipose tissue is abundant and easily accessible. It is a valuable tissue source in regenerative medicine and tissue engineering, especially with regard to its angiogenic potential. Derivatives of adipose tissue, such as microfat, nanofat, microvascular fragments, stromal vascular fraction and stem cells, are commonly used in research, but also clinically to enhance the vascularization of implants and grafts at defect sites. In plastic surgery, adipose tissue is harvested via liposuction and can be manipulated in three ways (macro-, micro- and nanofat) in the operating room, depending on its ultimate use. Whereas macro- and microfat are used as a filling material for soft tissue injuries, nanofat is an injectable viscous extract that primarily induces tissue remodeling because it is rich in growth factors and stem cells. In contrast to microfat that adds volume to a defect site, nanofat has the potential to be easily combined with scaffold materials due to its liquid and homogenous consistency and is particularly attractive for blood vessel formation. The same is true for microvascular fragments that are easily isolated from adipose tissue through collagenase digestion. In preclinical animal models, it has been convincingly shown that these vascular fragments inosculate with host vessels and subsequently accelerate scaffold perfusion and host tissue integration. Adipose tissue is also an ideal source of stem cells. It yields larger quantities of cells than any other source and is easier to access for both the patient and doctor compared with other sources such as bone marrow. They are often used for tissue regeneration in combination with biomaterials. Adipose-derived stem cells can be applied unmodified or as single cell suspensions. However, certain pretreatments, such as cultivation under hypoxic conditions or three-dimensional spheroids production, may provide substantial benefit with regard to subsequent vascularization in vivo due to induced growth factor production. In this narrative review, derivatives of adipose tissue and the vascularization of biomaterials are addressed in a comprehensive approach, including several sizes of derivatives, such as whole fat flaps for soft tissue engineering, nanofat or stem cells, their secretome and exosomes. Taken together, it can be concluded that adipose tissue and its fractions down to the molecular level promote, enhance and support vascularization of biomaterials. Therefore, there is a high potential of the individual fat component to be used in regenerative medicine.