Autologous matrix-induced chondrogenesis provides better outcomes in comparison to autologous minced cartilage implantation in the repair of knee chondral defects.

PURPOSE: In symptomatic mid-sized focal chondral defects, autologous matrix-induced chondrogenesis (AMIC) and minced cartilage implantation (MCI) offer two versatile treatment options. This study aimed to conduct a matched-patient analysis of patient-reported outcome measures to compare these two surgical treatment methods for focal chondral defects. METHODS: At the first centre, patients underwent a single-stage procedure in which autologous cartilage was hand-minced, implanted into the defect and fixed with fibrin glue. At the second centre, patients underwent AMIC, which was fixed in place with fibrin glue. All patients were seen 2-4 years postoperatively. Postoperative outcomes were assessed using the visual analogue scale for pain (VAS), the Lysholm score and the five domains of the knee osteoarthritis outcome score (KOOS). Patients from each surgical centre were matched by age, sex, defect size and defect localisation. RESULTS: In total, 48 patients from two surgical centres (24 from each site) were matched for sex, age (MCI 30.3 ± 14.9 years vs. AMIC 30.8 ± 13.7 years) and defect size (MCI 2.49 ± 1.5 cm2 vs. AMIC 2.65 ± 1.1 cm2). Significantly better scores in the AMIC cohort were noted for VAS (p = 0.004), Lysholm (p = 0.043) and the KOOS subscales for pain (p = 0.016) and quality of life (p = 0.036). There was a significantly greater proportion of positive responders for Lysholm in the AMIC group (92%) compared with the MCI group (64%). CONCLUSIONS: The AMIC procedure delivers superior patient outcomes compared with hand-minced autologous cartilage implantation. These are mid-term outcomes, with follow-up between 2 and 4 years. LEVEL OF EVIDENCE: Level III.

Influence of perioperative step volume on complication rate and length of hospital stay after colorectal cancer surgery (IPOS trial): study protocol for a randomised controlled single-centre trial at a German university hospital.

BACKGROUND: Perioperative mobilisation and physical activity are critical components of postoperative rehabilitation. Physical inactivity is a significant risk factor for complications and prolonged hospitalisation. However, specific recommendations for preoperative and postoperative physical activity levels are currently lacking. Evidence suggests that daily step count before and after surgery may impact the length of hospital stay and complication rate.The goal of this study is to determine the effectiveness of perioperative step volume recommendations, measured by pedometers, in reducing the length of hospital stay and complication rate for patients undergoing colorectal cancer surgery. METHODS: This study is a single-centre randomised controlled trial with two arms, allocated at a 1:1 ratio. The trial includes individuals undergoing colorectal surgery for either suspected or confirmed colorectal malignancy. A total of 222 patients will be randomly assigned to either an intervention or a control group. Step counts will be measured using a pedometer. Patients assigned to the intervention group will be given a predetermined preoperative and postoperative step count goal. The analysis will be conducted on preoperative and postoperative physical activity, quality of life, health, duration of hospitalisation, complication rate and bowel function, among other factors. ETHICS AND DISSEMINATION: The trial was approved by the ethics committee of the Ludwig-Maximilians-University of Munich, Germany (reference number: 22-0758, protocol version 2022.02). Results will be published in peer-reviewed journals and shared at academic conferences. After the publication of the results, a fully anonymised data set and the statistical code can be made available on justified scientific request and after ethical approval has been granted. TRIAL REGISTRATION NUMBER: DRKS00030017.

Prevalence and Therapeutic Implications of Clonal Hematopoiesis of Indeterminate Potential in Young Patients With Stroke.

BACKGROUND: Undetermined stroke etiology hampers optimal secondary prevention in a large proportion of young patients. We explored whether genetic screening for clonal hematopoiesis of indetermined potential (CHIP), a novel risk factor for stroke, could identify patients with myeloid precursor lesions or covert myeloid neoplasm requiring specific treatment. METHODS: We performed targeted sequencing on 56 genes recurrently mutated in hematologic neoplasms in a prospective cohort of patients with acute brain ischemia between 18 and 60 years. CHIP prevalence was compared with age-matched healthy controls from the Nijmegen Biomedical Study (n=1604) and the UK Biobank (n=101 678). Patients with suspicion of high-risk CHIP or myeloid neoplasm were invited for further hematologic evaluation. RESULTS: We included 248 consecutive patients (39% women) of whom 176 (71%) had cryptogenic stroke etiology. Fifty-one (21%) patients had CHIP, 3-fold more than in the general population (7.7% versus 2.6% for the Nijmegen Biomedical Study and 11.9% versus 4.1% for UK Biobank; P<0.001 for both). Patients with CHIP were older (median [interquartile range], 53 [50-59] versus 51 [41-56] years; P<0.001), had higher carotid intima-media thickness (0.68 [0.58-0.80] versus 0.59 [0.51-0.73] mm; P=0.009), and had higher burden of atherosclerosis (29.4% versus 16.7%; P=0.04). We invited 11 patients (4.4%) for further hematologic assessment, which in 7 led to the diagnosis of high-risk CHIP and in 2 to the new diagnosis of a myeloproliferative neoplasm with indication for cytoreductive therapy. CONCLUSIONS: Using genetic screening for myeloid disorders in patients with stroke of predominantly undetermined etiology, we found a 3-fold higher CHIP prevalence than in the general population. We identified high-risk CHIP and previously covert myeloproliferative neoplasms as potential stroke etiologies in 4.4% and 1% of patients, respectively. Our findings demonstrate the diagnostic and therapeutic yield of genetic screening in young patients with stroke. Future studies should investigate the role of CHIP for stroke recurrence and optimal secondary prevention.

Novel Synthesis Pathways for Highly Oxidative Iron Species: Generation, Stability, and Treatment Applications of Ferrate(IV/V/VI).

Difficulties arise related to the economy-of-scale and practicability in applying conventional water treatment technologies to small and remote systems. A promising oxidation technology better suited for these applications is that of electro-oxidation (EO), whereby contaminants are degraded via direct, advanced, and/or electrosynthesized oxidant-mediated reactions. One species of oxidants of particular interest includes ferrates (Fe(VI)/(V)/(IV)), where only recently has their circumneutral synthesis been demonstrated, using high oxygen overpotential (HOP) electrodes, namely boron-doped diamond (BDD). In this study, the generation of ferrates using various HOP electrodes (BDD, NAT/Ni-Sb-SnO2, and AT/Sb-SnO2) was investigated. Ferrate synthesis was pursued in a current density range of 5-15 mA cm-2 and initial Fe3+ concentrations of 10-15 mM. Faradaic efficiencies ranged from 11-23%, depending on operating conditions, with BDD and NAT significantly outperforming AT electrodes. Speciation tests revealed that NAT synthesizes both ferrate(IV/V) and ferrate(VI), while the BDD and AT electrodes synthesized only ferrate(IV/V) species. A number of organic scavenger probes were used to test the relative reactivity, including nitrobenzene, carbamazepine, and fluconazole, whereby ferrate(IV/V) was significantly more oxidative than ferrate(VI). Finally, the ferrate(VI) synthesis mechanism by NAT electrolysis was elucidated, where coproduction of ozone was found to be a key phenomenon for Fe3+ oxidation to ferrate(VI).

Inline Quality Monitoring of Reverse Extruded Aluminum Parts with Cathodic Dip-Paint Coating (KTL).

Perfectly coated surfaces are an essential quality feature in the automotive and consumer goods industries. They are the result of an optimized, controlled coating process. Because entire assemblies could be rejected if Out-of-Specification (OOS) parts are installed, this has a severe economic impact. This paper presents a novel, line-integrated multi-camera system with intelligent algorithms for anomaly detection on small KTL-coated aluminum parts. The system also aims to automatize the previously used human inspection to a sophisticated and automated vision system that efficiently detects defects and anomalies on coated parts.

Immersive virtual reality fitness games for enhancement of recovery after colorectal surgery: study protocol for a randomised pilot trial.

BACKGROUND: Physical inactivity after surgery is an important risk factor for postoperative complications. Compared to conventional physiotherapy, activity-promoting video games are often more motivating and engaging for patients with physical impairments. This effect could be enhanced by immersive virtual reality (VR) applications that visually, aurally and haptically simulate a virtual environment and provide a more interactive experience. The use of VR-based fitness games in the early postoperative phase could contribute to improved mobilisation and have beneficial psychological effects. Currently, there is no data on the use of VR-based fitness games in the early postoperative period after colorectal surgery. METHODS: This pilot trial features a single-centre, randomised, two-arm study design with a 1:1 allocation. Patients undergoing elective abdominal surgery for colorectal cancer or liver metastases of colorectal cancer will be recruited. Participants will be randomly assigned to an intervention group or a control group. Patients randomised to the intervention group will perform immersive virtual reality-based fitness exercises during their postoperative hospital stay. Feasibility and clinical outcomes will be assessed. DISCUSSION: Early mobilisation after surgery is crucial for reducing many postoperative complications. VR-based interventions are easy to use and often inexpensive, especially compared to interventions that require more medical staff and equipment. VR-based interventions could serve as an alternative or complement to regular physiotherapy and enhance mobilisation after surgery. The proposed pilot study will be the first step to evaluate the feasibility of VR-based interventions in the perioperative period, with the aim of improving the postoperative rehabilitation of cancer patients. TRIAL REGISTRATION: The trial has been registered in the German Clinical Trials Register (DRKS) Nr. DRKS00024888 , on April 13, 2021, WHO Universal Trial Number (UTN) U1111-1261-5968.

Stereotactic body radiotherapy of adrenal metastases-A dose-finding study.

Optimal doses for the treatment of adrenal metastases with stereotactic radiotherapy (SBRT) are unknown. We aimed to identify dose-volume cut-points associated with decreased local recurrence rates (LRR). A multicenter database of patients with adrenal metastases of any histology treated with SBRT (biologically effective dose, BED10 ≥50 Gy, ≤12 fractions) was analyzed. Details on dose-volume parameters were required (planning target volume: PTV-D98%, PTV-D50%, PTV-D2%; gross tumor volume: GTV-D50%, GTV-mean). Cut-points for LRR were optimized using the R maxstat package. One hundred and ninety-six patients with 218 lesions were included, the largest histopathological subgroup was adenocarcinoma (n = 101). Cut-point optimization resulted in significant cut-points for PTV-D50% (BED10: 73.2 Gy; P = .003), GTV-D50% (BED10: 74.2 Gy; P = .006), GTV-mean (BED10: 73.0 Gy; P = .007), and PTV-D2% (BED10: 78.0 Gy; P = .02) but not for the PTV-D98% (P = .06). Differences in LRR were clinically relevant (LRR ≥ doubled for cut-points that were not achieved). Further dose-escalation was not associated with further improved LRR. PTV-D50%, GTV-D50%, and GTV-mean cut-points were also associated with significantly improved LRR in the adenocarcinoma subgroup. Separate dose optimizations indicated a lower cut-point for the PTV-D50% (BED10: 69.1 Gy) in adenocarcinoma lesions, other values were similar (<2% difference). Associations of cut-points with overall survival (OS) and progression-free survival were not significant but durable freedom from local recurrence was associated with OS in a landmark model (P < .001). To achieve a significant improvement of LRR for adrenal SBRT, a moderate escalation of PTV-D50% BED10 >73.2 Gy (adenocarcinoma: 69.1 Gy) should be considered.

Intraoperative endoluminal pyloromyotomy for reduction of delayed gastric emptying after pylorus preserving partial pancreaticoduodenectomy (PORRIDGE trial): study protocol for a randomised controlled trial.

BACKGROUND: Pylorus-preserving pancreaticoduodenectomy (ppPD) is a standard surgical procedure for the treatment of resectable neoplasms of the periampullary region. One of the most common postoperative complications after ppPD is delayed gastric emptying (DGE) which reduces quality of life, prevents a timely return to a solid oral diet and prolongs the length of hospital stay. In a retrospective analysis, intraoperative endoluminal pyloromyotomy was associated with a reduced rate of DGE. The aim of this study is to investigate the effect of intraoperative endoluminal pyloromyotomy on postoperative DGE after ppPD in a randomised and controlled setting. METHODS: This randomised trial features parallel group design with a 1:1 allocation ratio and a superiority hypothesis. Patients with a minimum age of 18 years and an indication for ppPD are eligible to participate in this study and will be randomised intraoperatively to receive either endoluminal pyloromyotomy or atraumatic stretching of the pylorus. The sample size calculation (n=64 per study arm) is based on retrospective data. The primary endpoint is the rate of DGE within 30 days. Secondary endpoints are quality of life, operation time, estimated blood loss, length of hospital stay, morbidity and mortality. DISCUSSION: DGE after ppPD is a common complication with an incomplete understood aetiology. Prevention of DGE could improve outcomes and enhance quality of life after one of the most common procedures in pancreatic surgery. This trial will expand the existing evidence on intraoperative pyloromyotomy, and the results will provide additional data on a simple surgical technique that could reduce the incidence of postoperative DGE. TRIAL REGISTRATION: German Clinical Trials Register DRKS00013503 . Registered on 27 December 2017.

[Telemedical applications in ophthalmology in times of COVID-19]. / Telemedizinische Ansätze in der Augenheilkunde in Zeiten von COVID-19.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic access to and utilization of ophthalmologic healthcare providers was partially restricted. OBJECTIVE: This article provides an overview of already available tele-ophthalmologic applications for better care during the pandemic as well as those still under development. MATERIAL AND METHODS: The study included an analysis of current scientific publications, analysis of unrestricted screening applications in smart device app stores as well as telemetric medical products specifically designed for home monitoring and discussion of the requirements of an integrated ophthalmologic video consultation. RESULTS: There is significant interest in tele-ophthalmologic applications and devices as evidenced by a rise in the number of relevant publications. Freely available screening tests for smart phones and tablets are as a rule currently not validated and show significant discrepancies from established standard tests. Telemetric medical devices show great potential for home monitoring in chronic ophthalmologic diseases but must first become established in the clinical routine. CONCLUSION: There is an unmet need for systematic analysis, development and validation of telemedical applications and medical products for ophthalmology in order to advantageously utilize the potential of telemedicine and to incorporate this into an ophthalmologic video consultation.

Single-Cell Phenotypic Analysis and Digital Molecular Detection Linkable by a Hydrogel Bead-Based Platform.

Cell heterogeneity, such as antibiotic heteroresistance and cancer cell heterogeneity, has been increasingly observed. To probe the underlying molecular mechanisms in the dynamically changing heterogeneous cells, a high throughput platform is urgently needed to establish single cell genotype-phenotype correlations. Herein, we report a platform combining single-cell viability phenotypic analysis with digital molecular detection for bacterial cells. The platform utilizes polyethylene glycol hydrogel that cross-links through a thiol-Michael addition, which is biocompatible, fast, and spontaneous. To generate uniform nanoliter-sized hydrogel beads (Gelbeads), we developed a convenient and disposable device made of needles and microcentrifuge tubes. Gelbead-based single cell viability and molecular detection assays were established. Enhanced thermal stability and uncompromised efficiency were achieved for digital polymerase chain reaction (PCR) and digital loop-mediated isothermal amplification (LAMP) within the Gelbeads. Reagent exchange for in situ PCR following viability phenotypic analyses was demonstrated. The combined analyses may address the genotypic differences between cellular subpopulations exhibiting distinct phenotypes. The platform promises unique perspectives in mechanism elucidation of environment-evolution interaction that may be extended to other cell types for medical research.

Stereotactic or conformal radiotherapy for adrenal metastases: Patient characteristics and outcomes in a multicenter analysis.

To report outcome (freedom from local progression [FFLP], overall survival [OS] and toxicity) after stereotactic, palliative or highly conformal fractionated (>12) radiotherapy (SBRT, Pall-RT, 3DCRT/IMRT) for adrenal metastases in a retrospective multicenter cohort within the framework of the German Society for Radiation Oncology (DEGRO). Adrenal metastases treated with SBRT (≤12 fractions, biologically effective dose [BED10] ≥ 50 Gy), 3DCRT/IMRT (>12 fractions, BED10 ≥ 50 Gy) or Pall-RT (BED10 < 50 Gy) were eligible for this analysis. In addition to unadjusted FFLP (Kaplan-Meier/log-rank), we calculated the competing-risk-adjusted local recurrence rate (CRA-LRR). Three hundred twenty-six patients with 366 metastases were included by 21 centers (median follow-up: 11.7 months). Treatment was SBRT, 3DCRT/IMRT and Pall-RT in 260, 27 and 79 cases, respectively. Most frequent primary tumors were non-small-cell lung cancer (NSCLC; 52.5%), SCLC (16.3%) and melanoma (6.7%). Unadjusted FFLP was higher after SBRT vs Pall-RT (P = .026) while numerical differences in CRA-LRR between groups did not reach statistical significance (1-year CRA-LRR: 13.8%, 17.4% and 27.7%). OS was longer after SBRT vs other groups (P < .05) and increased in patients with locally controlled metastases in a landmark analysis (P < .0001). Toxicity was mostly mild; notably, four cases of adrenal insufficiency occurred, two of which were likely caused by immunotherapy or tumor progression. Radiotherapy for adrenal metastases was associated with a mild toxicity profile in all groups and a favorable 1-year CRA-LRR after SBRT or 3DCRT/IMRT. One-year FFLP was associated with longer OS. Dose-response analyses for the dataset are underway.

Electromagnetic navigation reduces radiation exposure for retrograde drilling in osteochondrosis dissecans of the talus.

BACKGROUND: Retrograde drilling in osteochondrosis dissecans (OCD) is a widely used surgical intervention. A radiation-free electromagnetic navigation system (ENS)-based method was compared with the standard freehand fluoroscopic (SFF) method regarding clinical applicability. METHODS: We performed a clinical cohort study at a department of Orthopaedics in a Level 1 children's hospital with 40 patients (20 SFF and 20 ENS). Retrograde drilling of the talar dome was used in patients with unstable medial OCD (MRI stage 2 according to Hepple's revised classification; stage 2 according to the International Cartilage Repair Society). The outcome measurements were: (a) Intraoperative fluoroscopy exposure and length of surgery and (b) Postoperative serial follow-up MRIs every 6 months. RESULTS: 22 female and 18 male patients aged 13.8 ± 1.6 years (range: 11-17 years) were included. Using the ENS technique, length of surgery was significantly reduced to 20.2 ± 6.4 min compared to 36.1 ± 11.8 min (p < 0.01) for the SFF technique. The average x-ray radiation time for the SFF technique was 23.5 ± 13.5 sec and 1.9 ± 1.7 sec for the ENS technique (p < 0.01). Radiation exposure was significantly reduced from 44.6 ± 19.7 mSv (SFF technique) to 5.6 ± 2.8 mSv (ENS technique) (p < 0.01). Intraoperative perforation of cartilage occurred once in the SFF group. Correct placement of the drilling channel was verified in all patients on follow-up MRI after six months and a timely healing was seen after two years. CONCLUSIONS: The ENS method provides for a significant reduction in length of surgery and radiation exposure. ENS was without intraoperative cartilage perforation. The clinical and radiological follow-up parameters are comparable for SFF- and ENS-guided retrograde drilling. TRIAL REGISTRATION: WF - 085/20, 05/2020 "retrospectively registered" https://www.aerztekammer-hamburg.org/ethik_kommission.html .

Intraoperative endoluminal pyloromyotomy as a novel approach to reduce delayed gastric emptying after pylorus-preserving pancreaticoduodenectomy-a retrospective study.

BACKGROUND: Delayed gastric emptying (DGE) is one of the most common complications after pylorus-preserving partial pancreaticoduodenectomy (ppPD). The aim of this retrospective study was to assess whether an intraoperative pyloromyotomy during ppPD prior to the creation of duodenojejunostomy reduces DGE. METHODS: Patients who underwent pylorus-preserving pancreaticoduodenectomy between January 2015 and December 2017 were divided into two groups on the basis of whether an intraoperative pyloromyotomy was performed (pyloromyotomy (PM) group) or not (no pyloromyotomy (NP) group). The primary endpoint was DGE according to the ISGPS definition. The confirmatory analysis of the primary endpoint was performed with multivariate analysis. RESULTS: One hundred and ten patients were included in the statistical analysis. Pyloromyotomy was performed in 44 of 110 (40%) cases. DGE of any grade was present in 62 patients (56.4%). The DGE rate was lower in the PM group (40.9%) compared with the NP group (66.7%), and pyloromyotomy was associated with a reduced risk for DGE in univariate (OR 0.35, 95% CI 0.16-0.76; P = 0.008) and multivariate analyses (OR 0.32, 95% CI 0.13-0.77; P = 0.011). The presence of an intra-abdominal complication was an independent risk factor for DGE in the multivariate analysis (OR 5.54, 95% CI 2.00-15.36; P = 0.001). CONCLUSION: Intraoperative endoluminal pyloromyotomy during ppPD was associated with a reduced risk for DGE in this retrospective study. Pyloromyotomy should be considered a simple technique that can potentially reduce DGE rates after ppPD.

Blood Parameters Demonstrating a Significant Survival Impact in Patients With Locally Advanced NSCLC Undergoing Definitive Chemoradiotherapy.

AIM: We investigated blood parameters in patients with inoperable stage III non-small cell lung cancer (NSCLC) to predict individual outcomes after definitive chemoradiotherapy (CRT). PATIENTS AND METHODS: Blood parameters of consecutive patients undergoing definitive CRT between 2010 and 2016 for inoperable stage III NSCLC before multimodal treatment and at first follow-up were measured and analyzed. RESULTS: Blood parameters from 99 patients were evaluated. Histologically, about 50% of patients had an adenocarcinoma. All patients received platinum-based sequential or concurrent CRT. The median total dose to the primary tumor was 60 (range=48-70) Gy. On multivariate analysis after adjustment for all co-founders, median overall survival for pre-treatment cutoffs were: lactate dehydrogenase (LDH) >250 U/l was 17 vs. 27 months [hazard ratio (HR)=2.05, 95% confidence intervaI (CI)=1.15-3.66; p=0.015], thrombocytosis >400×106/l: 11 vs. 23 months (HR=2.75, 95% CI=1.1-6.88; p=0.03), hypoalbuminemia <3.5 g/dl: 12 vs. 24 months (HR=2.42, 95% CI=1.21-4.84; p=0.013) and post-treatment neutrophilia >7×106/l: 12 vs. 27 months (HR=2.5, 95% CI=1.21-5.17; p=0.013). CONCLUSION: Pre-treatment elevated LDH, thrombocytosis, hypoalbuminemia and post-treatment neutrophilia were associated with significantly worse overall survival in patients with inoperable stage III NSCLC treated with CRT. Patients with both pre-therapeutic elevated LDH and hypoalbuminemia demonstrated a dismal prognosis despite completion of multimodal treatment.

[Central venous occlusion in Wyburn-Mason syndrome]. / Zentralvenenverschluss bei Wyburn-Mason-Syndrom.

The diagnostic findings, therapy and course of disease are described for a case of central venous occlusion in Wyburn-Mason-Syndrome. The diagnosis was based on OCT, fluorescein angiography and cMRI. In addition, due to the macular edema an intravitreal injection with Ranibizumab was applied. The macular edema regressed and further Ranibizumab-injections as well as a panretinal laser-coagulation and possibly a cryocoagulation were planned. For a central venous occlusion with macular edema also in Wyburn-Mason-Syndrome an intravitreal anti-VEGF-inhibition leads to an improvement.

Operative versus non-operative treatment of traumatic brain injuries in patients 80 years of age or older.

Traumatic brain injury (TBI) in older adults is an increasing issue in modern medicine. Nevertheless, it remains unclear which patients presenting with TBI and 80 years of age or older benefit from an operative treatment. The aim of this study was to explore the effect of an operative treatment in isolated TBI patients ≥ 80 years of age. Data were derived from the TraumaRegister DGU® from 2002 to 2016. Inclusion criteria were ≥ 80 years of age, an Abbreviated Injury ScaleHead (AIS) ≥ 3, and an AISNon-Head ≤ 1. The cohort was split in operatively and non-operatively treated patients, and outcome was assessed at discharge using the Glasgow Outcome Scale (GOS). A favorable outcome was defined as a GOS of 4 or 5. A total of 1.693 patients (431 operatively and 1.262 non-operatively treated patients) were analyzed. Mortality rate was 54.4% (687 patients) in the non-operative group and 49.4% in the operative group. Simultaneously, there were more patients discharged with a GOS 2 (persistent vegetative state) in the operative group (7.9%, 34 patients) than in the non-operative group (1.0%, 13 patients). An analysis of the operatively treated patients showed an association between a higher mortality risk and brainstem hemorrhage (p = 0.04), fixed pupils (p = 0.001), initial intubation (p = 0.03), and an AISHead of 5/6 (p = 0.03). Patients 80 years of age or older seem to benefit from an operative treatment regarding mortality rate. However, there has been a higher rate of a poor neurological outcome particularly with regard to persistent vegetative state in the operative treatment group at discharge.

Impaired SIRT3 activity mediates cardiac dysfunction in endotoxemia by calpain-dependent disruption of ATP synthesis.

BACKGROUND: Sepsis-induced cardiomyopathy contributes to the high mortality of septic shock in critically ill patients. Since the underlying mechanisms are incompletely understood, we hypothesized that sepsis-induced impairment of sirtuin 3 (SIRT3) activity contributes to the development of septic cardiomyopathy. METHODS AND RESULTS: Treatment of mice with lipopolysaccharide (LPS) for 6 h resulted in myocardial NAD+ depletion and increased mitochondrial protein acetylation, indicating impaired myocardial SIRT3 activity due to NAD+ depletion. LPS treatment also resulted in impaired cardiac output in isolated working hearts, indicating endotoxemia-induced cardiomyopathy. Maintaining normal myocardial NAD+ levels in LPS-treated mice by Poly(ADP-ribose)polymerase 1 (PARP1) deletion prevented cardiac dysfunction, whereas additional SIRT3 deficiency blunted this beneficial effect, indicating that impaired SIRT3 activity contributes to cardiac dysfunction in endotoxemia. Measurements of mitochondrial ATP synthesis suggest that LPS-induced contractile dysfunction may result from cardiac energy depletion due to impaired SIRT3 activity. Pharmacological inhibition of mitochondrial calpains using MDL28170 normalized LPS-induced cleavage of the ATP5A1 subunit of ATP synthase and normalized contractile dysfunction, suggesting that cardiac energy depletion may result from calpain-mediated cleavage of ATP5A1. These beneficial effects were completely blunted by SIRT3 deficiency. Finally, a gene set enrichment analysis of hearts of patients with septic, ischemic or dilated cardiomyopathy revealed a sepsis-specific suppression of SIRT3 deacetylation targets, including ATP5A1, indicating a functional relevance of SIRT3-dependent pathways in human sepsis. CONCLUSIONS: Impaired SIRT3 activity may mediate cardiac dysfunction in endotoxemia by facilitating calpain-mediated disruption of ATP synthesis, suggesting SIRT3 activation as a potential therapeutic strategy to treat septic cardiomyopathy.

Multiphase Porous Electrochemical Catalysts Derived from Iron-Based Metal-Organic Framework Compounds.

Herbicide use has attracted attention recently due to potential damage to human health and lethality to the honey bees and other pollinators. Fenton reagent treatment processes can be applied for the degradation of herbicidal contaminants from water. However, the need to carry out the normal Fenton reactions under acidic conditions often hinders their practical application for pollution control. Herein, we report on the synthesis and application of multiphasic porous electro-Fenton catalysts prepared from calcinated metal-organic framework compounds, CMOF@PCM, and their application for the mineralization of herbicides in aqueous solution at circum-neutral pH. CMOF nanoparticles (NPs) are anchored on porous carbon monolithic (PCM) substrates, which allow for binder-free application. H2O2 is electrochemically generated on the PCM substrate which serves as a cathode, while ·OH is generated by the CMOF NPs at low applied potentials (-0.14 V). Results show that the structure and reactivity of the CMOF@PCM electro-Fenton catalysts are dependent on the specific MOF precursor used during synthesis. For example, CMIL-88-NH2, which is prepared from MIL-88(Fe)-NH2, is a porous core-shell structured NP comprised of a cementite (Fe3C) intermediate layer that is sandwiched between a graphitic shell and a magnetite (Fe3O4) core. The electro-Fenton production of hydroxyl radical on the CMOF@PCM composite material is shown to effectively degrade an array of herbicides.

Biosynthesis and Heterologous Production of Argyrins.

Argyrins represent a family of cyclic octapeptides exhibiting promising antimicrobial, antitumorigenic and immunosuppressant activities. They derive from a nonribosomal peptide synthetase pathway, which was identified and characterized in this study from the myxobacterial producer strain Cystobacter sp. SBCb004. Using the native biosynthetic gene cluster (BGC) sequence as template synthetic BGC versions were designed and assembled from gene synthesis fragments. A heterologous expression system was established after chromosomal deletion of a well-expressed lipopeptide pathway from the host strain Myxococcus xanthus DK1622. Different approaches were applied to engineer and improve heterologous argyrin production, which was finally increased to 160 mg/L, around 20-fold higher yields compared to the native producer. Heterologous production platform also led to identification of several novel argyrin derivatives (A2, F3, G3, I, J, K, and L). The optimized production system provides a versatile platform for future supply of argyrins and novel derivatives thereof.