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Data substantiating the optimal patient body temperature during cooling procedures in cardiac operations are currently unavailable. To explore the optimal temperature strategy, we examined the association between temperature management and survival among patients during cardiopulmonary bypass assisted coronary artery bypass grafting (CABG) procedures on 30-days and 5-year postoperative survival. Adult patients (n = 5,672, 23.6% female and mean (SD) age of 66 (10) years) operated between 1997 and 2015 were included, with continuous measured intraoperative nasopharyngeal temperatures. The association between mortality and patient characteristics, laboratory parameters, the lowest intraoperative plateau temperature and intraoperative cooling/rewarming rates were examined by multivariate Cox regression analysis. Machine learning-based cluster analysis was used to identify patient subgroups based on pre-cooling parameters and explore whether specific subgroups benefitted from a particular temperature management. Mild hypothermia (32–35°C) was independently associated with improved 30-days and 5-year survival compared to patients in other temperature categories regardless of operation year. 30 days and 5-year survival were 98% and 88% in the mild hypothermia group, whereas it amounted 93% and 80% in the severe hypothermia (<30°C). Normothermia (35–37°C) showed the lowest survival after 30 days and 5 years amounting 93% and 72%, respectively. Cluster analysis identified 8 distinct patient subgroups principally defined by gender, age, kidney function and weight. The full cohort and all patient subgroups displayed the highest survival at a temperature of 32°C. Given these associations, further prospective randomized controlled trials are needed to ascertain optimal patient temperatures during CPB.

Serial x-ray crystallography can uncover binding events, and subsequent chemical conversions occurring during enzymatic reaction. Here, we reveal the structure, binding and cleavage of moxalactam antibiotic bound to L1 metallo-β-lactamase (MBL) from Stenotrophomonas maltophilia . Using time-resolved serial synchrotron crystallography, we show the time course of β-lactam hydrolysis and determine ten snapshots (20, 40, 60, 80, 100, 150, 300, 500, 2000 and 4000 ms) at 2.20 Å resolution. The reaction is initiated by laser pulse releasing Zn 2+ ions from a UV-labile photocage. Two metal ions bind to the active site, followed by binding of moxalactam and the intact β-lactam ring is observed for 100 ms after photolysis. Cleavage of β-lactam is detected at 150 ms and the ligand is significantly displaced. The reaction product adjusts its conformation reaching steady state at 2000 ms corresponding to the relaxed state of the enzyme. Only small changes are observed in the positions of Zn 2+ ions and the active site residues. Mechanistic details captured here can be generalized to other MBLs. Metallo-β-lactamases cleave β-lactam moiety of many broadly used antibiotics. Here the authors captured mechanistic details of the enzyme catalyzed reaction using time-resolved xray synchrotron serial crystallography.

Serial X-ray crystallography allows macromolecular structure determination at both X-ray free electron lasers (XFELs) and, more recently, synchrotron sources. The time resolution for serial synchrotron crystallography experiments has been limited to millisecond timescales with monochromatic beams. The polychromatic, “pink”, beam provides a more than two orders of magnitude increased photon flux and hence allows accessing much shorter timescales in diffraction experiments at synchrotron sources. Here we report the structure determination of two different protein samples by merging pink-beam diffraction patterns from many crystals, each collected with a single 100 ps X-ray pulse exposure per crystal using a setup optimized for very low scattering background. In contrast to experiments with monochromatic radiation, data from only 50 crystals were required to obtain complete datasets. The high quality of the diffraction data highlights the potential of this method for studying irreversible reactions at sub-microsecond timescales using high-brightness X-ray facilities. Serial X-ray crystallography (SX) is used for data collection at X-ray Free Electron Lasers. Here the authors show that a polychromatic “pink” synchrotron X-ray beam can be used for SX, which is useful when crystal supply is limited and will allow time-resolved measurements at synchrotron sources in the future.

Acute kidney injury (AKI) develops frequently in the course of patients with sepsis and strongly associates with in-hospital mortality. However, diagnosing AKI involves a considerable lag-time because it depends on assessing an increase in serum creatinine, and offers no insight in the underlying pathophysiology. Consequently, identifying a set of proteins reflecting the development of AKI may improve earlier recognition of AKI and the understanding of its pathophysiology. A targeted plasma proteomic approach was performed in early sepsis patients with and without subsequent AKI development in a matched pair design ( n  = 19 each). Principal component analysis identified 53 proteins associated with development of AKI, which were further analysed using Enrichr gene ontology and pathway analysis. Nine differentially expressed proteins from the targeted proteomics were increased among patients who subsequently developed AKI and correlated with principal components, namely CALCA, CALR, CA12, CLEC1A, PTK7, KIM-1, NPPC, NUCB2 and PGF. We demonstrated the biological insight in the development of AKI in early sepsis compared to non-AKI sepsis.

Tau protein hyperphosphorylation and aggregation are key pathological events in neurodegenerative tauopathies such as Alzheimer’s disease. Interestingly, seasonal hibernators show extensive tau hyperphosphorylation during torpor, i.e., the hypothermic and hypometabolic state of hibernation, which is completely reversed during arousal. Torpor-associated mechanisms that reverse tau hyperphosphorylation may be of therapeutic relevance, however, it is currently not known to what extent they apply to human tau. Here we addressed this issue using daily torpor in wildtype mice that express mouse tau (mtau) and in mice that lack mtau expression and instead express human tau (htau). AT8, AT100 and Ser396 immunoblotting and immunohistochemistry were used to assess tau (hyper)phosphorylation at clinically relevant phosphorylation sites. We found that torpor robustly and reversibly increases the levels of phosphorylated tau in both mtau and htau mice. Immunohistochemistry revealed four brain areas that show prominent tau phosphorylation: the hippocampus, posterior parietal cortex, piriform cortex and cortical amygdala. Whereas wildtype mice primarily showed increased levels of diffusely organized hyperphosphorylated tau during torpor, htau mice contained clear somato-dendritic accumulations of AT8 reactivity resembling tau pre-tangles as observed in the Alzheimer brain. Interestingly, AT8-positive accumulations disappeared upon arousal, and tau phosphorylation levels at 24 h after arousal were lower than observed at baseline, suggesting a beneficial effect of torpor-arousal cycles on preexisting hyperphosphorylated tau. In conclusion, daily torpor in mice offers a quick and standardized method to study tau phosphorylation, accumulation and clearance in mouse models relevant for neurodegeneration, as well as opportunities to discover new targets for the treatment of human tauopathies.

Pancreatic ductal adenocarcinoma is an aggressive cancer that interacts with stromal cells to produce a highly inflammatory tumor microenvironment that promotes tumor growth and invasiveness. The precise interplay between tumor and stroma remains poorly understood. TLRs mediate interactions between environmental stimuli and innate immunity and trigger proinflammatory signaling cascades. Our finding that TLR7 expression is upregulated in both epithelial and stromal compartments in human and murine pancreatic cancer led us to postulate that carcinogenesis is dependent on TLR7 signaling. In a mouse model of pancreatic cancer, TLR7 ligation vigorously accelerated tumor progression and induced loss of expression of PTEN, p16, and cyclin D1 and upregulation of p21, p27, p53, c-Myc, SHPTP1, TGF-β, PPARγ, and cyclin B1. Furthermore, TLR7 ligation induced STAT3 activation and interfaced with Notch as well as canonical NF-κB and MAP kinase pathways, but downregulated expression of Notch target genes. Moreover, blockade of TLR7 protected against carcinogenesis. Since pancreatic tumorigenesis requires stromal expansion, we proposed that TLR7 ligation modulates pancreatic cancer by driving stromal inflammation. Accordingly, we found that mice lacking TLR7 exclusively within their inflammatory cells were protected from neoplasia. These data suggest that targeting TLR7 holds promise for treatment of human pancreatic cancer.

Myasthenic crisis (MC) requiring mechanical ventilation is a serious complication of myasthenia gravis (MG). Here we analyze the frequency and risk factors of weaning- and extubation failure as well as its impact on the clinical course in a large cohort. We performed a retrospective chart review on patients treated for MC in 12 German neurological departments between 2006 and 2015. Weaning failure (WF) was defined as negative spontaneous breathing trial, primary tracheostomy, or extubation failure (EF) (reintubation or death). WF occurred in 138 episodes (64.2%). Older Age (p = 0.039), multiple comorbidities (≥ 3) (p = 0.007, OR = 4.04), late-onset MG (p = 0.004, OR = 2.84), complications like atelectasis (p = 0.008, OR = 3.40), pneumonia (p < 0.0001, OR = 3.45), cardio-pulmonary resuscitation (p = 0.005, OR = 5.00) and sepsis (p = 0.02, OR = 2.57) were associated with WF. WF occurred often in patients treated with intravenous immungloblins (IVIG) (p = 0.002, OR = 2.53), whereas WF was less often under first-line therapy with plasma exchange or immunoadsorption (p = 0.07, OR = 0.57). EF was observed in 58 of 135 episodes (43.0%) after first extubation attempt and was related with prolonged mechanical ventilation, intensive care unit stay and hospital stay (p ≤ 0.0001 for all). Extubation success was most likely in a time window for extubation between day 7 and 12 after intubation (p = 0.06, OR = 2.12). We conclude that WF and EF occur very often in MC and are associated with poor outcome. Older age, multiple comorbidities and development of cardiac and pulmonary complications are associated with a higher risk of WF and EF. Our data suggest that WF occurs less frequently under first-line plasma exchange/immunoadsorption compared with first-line use of IVIG.

Purpose Management of scrotal hernias presents as a common challenge, with operative interventions to address these hernias associated with higher rates of morbidity compared to those of less-complex pathology. Surgeons have advocated for the use of techniques such as primary abandonment of the distal sac as a potential means to reduce complications for operative intervention, with preliminary findings demonstrating feasibility. We sought to assess outcomes related to primary sac abandonment among patients undergoing minimally invasive (MIS) repair of scrotal hernias. Methods A review of prospectively maintained databases among two academic hernia centers was conducted to identify patients who underwent MIS inguinal hernia repairs with primary sac abandonment. Patient demographics, hernia risk factors, intraoperative factors, and postoperative outcomes were evaluated. Short-term outcomes related to patient-reported experiences and surgical-site occurrences requiring procedural intervention were queried. Results Sixty-seven male patients [median age: 51.6 years; interquartile range (IQR): 45–65 years] underwent inguinal hernia repair with primary sac abandonment. Anatomic polypropylene mesh was used in 98.5% cases. Rates of postoperative complications were low and included postoperative urinary retention (6%), clinically identified or patient-reported seromas/hematomas within a 30-day follow-up period (23.9%), deep venous thrombosis (1.5%), and pelvic hematoma (1.5%). No seromas or hematomas necessitated procedural interventions, with resolution of symptoms within three months of their operation date. Conclusion We report a multi-center experience of patients managed with primary abandonment of the sac technique during repair of inguinoscrotal hernias. Utilization of this technique appears to be safe and reproducible with a low burden of short-term complications.

CALIOPE, or CP(T) Aberrant Leptons in ortho-Positronium Experiment, is a tabletop search for fundamental symmetry violations, including CP- and CPT-violation, in ortho-positronium (o-Ps). We use a tagged 22Na source adjacent to a cylinder of aerogel to generate o-Ps at the center of a cylindrical array of 24 NaI(Tl) bars. We search for CPT - violating angular correlations in the gamma rays emitted in the decay of o-Ps. With an angular acceptance of 75% of 4π, and the ability to acquire statistics over a longer period of time, CALIOPE will improve upon the limit set by previous experiments. The experimental setup can also be used in a search for CP-violation in o-Ps with the addition of an electromagnet. We describe the design of the experiment, results from a characterization of the systematics for the CPT- and CP-violating measurements, and a demonstration of the DAQ.

Myasthenic crisis (MC) is a life-threatening condition for patients with myasthenia gravis (MG). Seronegative patients represent around 10–15% of MG, but data on outcome of seronegative MCs are lacking. We performed a subgroup analysis of patients who presented with MC with either acetylcholine-receptor-antibody-positive MG (AChR-MG) or seronegative MG between 2006 and 2015 in a retrospective German multicenter study. We identified 15 seronegative MG patients with 17 MCs and 142 AChR-MG with 159 MCs. Seronegative MCs were younger (54.3 ± 14.5 vs 66.5 ± 16.3 years; p = 0.0037), had a higher rate of thymus hyperplasia (29.4% vs 3.1%; p = 0.0009), and were more likely to be female (58.8% vs 37.7%; p = 0.12) compared to AChR-MCs. Time between diagnosis of MG and MC was significantly longer in seronegative patients (8.2 ± 7.6 vs 3.1 ± 4.4 years; p < 0.0001). We found no differences in duration of mechanical ventilation (16.2 ± 15.8 vs 16.5 ± 15.9 days; p = 0.94) and length of stay at intensive care unit (17.6 ± 15.2 vs 17.8 ± 15.4 days; p = 0.96), or in-hospital mortality (11.8% vs. 10.1%; p = 0.69). We conclude that MC in seronegative MG affects younger patients after a longer period of disease, but that crisis treatment efficacy and outcome do not differ compared to AChR-MCs.