A novel ground-potential monochromator design.

An electron monochromator design is presented as an instrumental development for electron energy loss spectroscopy (EELS) and imaging in (scanning) transmission electron microscopy ((S)TEM). The main purpose of this development is enhancing the energy resolving power in spectroscopy and filtering. In addition, it helps reducing the effect of the objective lens' chromatic aberration Cc in imaging and therefore, enhancing the spatial resolving power of electron microscopes. General estimates for the performance of a monochromator in energy distribution and the resulting usable beam currents are given. The special monochromator design presented is a ground-potential monochromator based on magnetic sector fields. The monochromator generates a spatially and angular un-dispersed spot and has no mechanically actuated parts in the filter sections. The optics can be operated at electron acceleration voltages from 30kV to 300kV and shows an energy resolving power of better than 2⋅10-7 relative to the primary electron energy. The actual device is designed to be retro-fittable to microscopes from various manufacturers.

Unified Total Syntheses of Benzenoid Cephalotane-Type Norditerpenoids: Cephanolides and Ceforalides.

Detailed herein are our synthetic studies toward the preparation of the C18- and C19-benzenoid cephalotane-type norditerpenoids. Guided by chemical network analysis, the core structure of this natural product family was constructed in a concise manner using an iterative cross-coupling, followed by a formal inverse-electron-demand [4 + 2] cycloaddition. Initial efforts to functionalize an alkene group in the [4 + 2] cycloadduct using a Mukaiyama hydration and a subsequent olefination led to the complete C18-carbon framework. While effective, this approach proved lengthy and prompted the development of a direct alkene difunctionalization that relies on borocupration to advance the cycloadduct to the natural products. Late-stage peripheral C-H functionalization facilitated access to all of the known cephanolides in 6-10 steps as well as five recently isolated ceforalides in 8-13 steps.

Is Vesicostomy Still a Contemporary Method of Managing Posterior Urethral Valves?

In boys with posterior urethral valves (PUVs) the main treatment aim is to preserve long-term bladder and renal function. To determine the effectiveness of secondary vesicostomy in boys with PUVs, the medical records of 21 patients with PUV (2010-2019), divided into two groups (group I: valve ablation; group II: secondary vesicostomy), were reviewed regarding the course of serum creatinine, renal ultrasound, voiding cystourethrogram, urodynamics, postoperative complications, need of further surgery, and long-term solution. The median age of all patients at first follow-up was 11 (9-13) months and at last follow-up 64.5 (39.5-102.5) months. Despite a significant difference of the SWDR score (shape, wall, reflux, and diverticula) (p = 0.014), both groups showed no significant differences preoperatively. Postoperatively, serum creatinine (p = 0.024), grade of vesicoureteral reflux (p = 0.003), side of upper tract dilatation (p = 0.006), side of megaureter (p = 0.004), and SWDR score (p = 0.002) were significantly decreased in group II. Postoperative urodynamic measurements showed comparable results in both groups. Stoma complications were found in three (20%) patients (group II). Eight (53.3%) patients already received a closure of the vesicostomy. Seven out of eight (87.5%) patients were able to micturate spontaneously. Vesicostomy remains a reliable treatment option for boys with PUV to improve bladder function and avoid further damage to the urinary tract.

Delayed primary closure of bladder exstrophy without osteotomy: 12 year experience in a safe and gentle alternative to neonatal surgery.

BACKGROUND: Successful primary closure of bladder exstrophy is of utmost importance for bladder capacity and urinary continence. We evaluated our concept of delayed primary closure that challenges the role of neonatal surgery, pelvic osteotomy, and perioperative pain management. MATERIAL AND METHODS: We reviewed the medical records of patients with classic bladder exstrophy (CBE) who had undergone delayed primary closure without osteotomy at our institution between January 2008 and May 2020. Data to be analyzed included patient demographics, intraoperative pelvic laxity, blood transfusion, postoperative ventilation time, requirement of pain medication, time to full feeds, length of ICU stay, postoperative complications, and total hospital stay. RESULTS: 66 patients (44 boys) met the inclusion criteria. Mean age at surgery was 64.8 days (SD±24.7). Pelvic approximation < 5 mm was possible in 66 (100%) patients. Blood transfusion was required by 31 (47%) patients. 14 (21.2%) patients needed postoperative ventilation for a mean time of 2.7 h. 45 (68.2%) children required intravenous opioids in addition to an epidural catheter. Oral feeding started on average 17.6 h after surgery. Mean ICU stay was 1.3 day. The initial success rate of delayed closure was 93.9%. None of the patients had bladder dehiscence. Girls developed more often minor postoperative complications than boys (m/f: 12 [27.3%] vs. 8 [36.4%]. Mean overall time of hospitalization was 19 days (13-34 d). CONCLUSION: Delayed primary closure of CBE without osteotomy but with continuous epidural blockage is a safe and promising procedure that has crucial advantages in the pre- and postoperative management of CBE. LEVEL OF EVIDENCE: Level III.

Total Synthesis of the Cephalotaxus Norditerpenoids (±)-Cephanolides A-D.

Concise syntheses of the Cephalotaxus norditerpenoids cephanolides A-D (8-14 steps from commercial material) using a common late-stage synthetic intermediate are described. The success of our approach rested on an early decision to apply chemical network analysis to identify the strategic bonds that needed to be forged, as well as the efficient construction of the carbon framework through iterative Csp2-Csp3 cross-coupling, followed by an intramolecular inverse-demand Diels-Alder cycloaddition. Strategic late-stage oxidations facilitated access to all congeners of the benzenoid cephanolides isolated to date.

Randomized Crossover-Controlled Evaluation of Simultaneous Bilateral Transcutaneous Electrostimulation of the Posterior Tibial Nerve During Urodynamic Studies in Patients With Lower Urinary Tract Symptoms.

PURPOSE: Transcutaneous tibial nerve stimulation (TTNS) has proven to be a valuable treatment option for various lower urinary tract conditions, such as overactive bladder syndrome and neurogenic detrusor overactivity. The aim of this study was to investigate acute changes in urodynamic parameters due to bilateral TTNS. METHODS: Fifty-one patients (18-87 years; 61% female) with various lower urinary tract symptoms were enrolled in this study. They were single-blinded and randomly assigned to receive simultaneous bilateral TTNS either during their first urodynamic examination, followed by a second round using a placebo stimulation technique, or vice versa. RESULTS: For subjects without signs of anatomical pathologies, the filling volume at the first desire to void (FDV) increased significantly by 54 mL (interquartile range [IQR], 26-81 mL; P<0.01) under the influence of TTNS compared to placebo. The maximum cystometric capacity increased by 41 mL (IQR, 10-65 mL; P=0.02). The median micturition volume of patients with pathological postvoid residual volumes (>100 mL) increased by 76 mL compared to patients without urinary retention (IQR, 6-166 mL; P=0.03). CONCLUSION: Compared to placebo, simultaneous bilateral TTNS showed significant improvements in bladder functioning, such as delayed FDV, increased maximum cystometric capacity, and reduced urinary retention. Patients with signs of anatomical pathologies did not seem to benefit from TTNS. Further studies need to be conducted to compare the effectiveness of bilateral versus unilateral TTNS.

[Juvenile granulosa cell tumor-Testicular tumor of the very young : Report of three cases and contemporary recommendations]. / Der juvenile Granulosazelltumor ­ der Hodentumor der Kleinsten : Aktuelle Handlungsempfehlungen anhand von drei Kasuistiken.

Juvenile granulosa cell tumor of the testis is a relevant differential diagnosis regarding testicular neoplasia of the very young. This benign lesion requires surgical treatment. Metastases or recurrences have not been described in literature. We present three different cases and give recommendations for diagnosis and treatment.

A Cleavable C2-Symmetric trans-Cyclooctene Enables Fast and Complete Bioorthogonal Disassembly of Molecular Probes.

Bioorthogonal chemistry is bridging the divide between static chemical connectivity and the dynamic physiologic regulation of molecular state, enabling in situ transformations that drive multiple technologies. In spite of maturing mechanistic understanding and new bioorthogonal bond-cleavage reactions, the broader goal of molecular ON/OFF control has been limited by the inability of existing systems to achieve both fast (i.e., seconds to minutes, not hours) and complete (i.e., >99%) cleavage. To attain the stringent performance characteristics needed for high fidelity molecular inactivation, we have designed and synthesized a new C2-symmetric trans-cyclooctene linker (C2TCO) that exhibits excellent biological stability and can be rapidly and completely cleaved with functionalized alkyl-, aryl-, and H-tetrazines, irrespective of click orientation. By incorporation of C2TCO into fluorescent molecular probes, we demonstrate highly efficient extracellular and intracellular bioorthogonal disassembly via omnidirectional tetrazine-triggered cleavage.

Mrs Movers & Shakers.

Y. Shirley Meng, University of California, San Diego, has earned the 2020 Faraday Medal from the Royal Society of Chemistry. The Faraday Medal is awarded annually by the Electrochemistry Group of the Royal Society of Chemistry to an electrochemist working outside of the UK and Ireland in recognition of their outstanding original contributions and innovation as a mid-career researcher in any field of electrochemistry.

Use and duration of antibiotic prophylaxis and the rate of urinary tract infection after radical cystectomy for bladder cancer: Results of a multicentric series.

OBJECTIVES: To assess the rate of urinary tract infection (UTI), the characteristics of the bacterial aetiological agents involved, the type and duration of antibiotics used, and the clinical risk factors of UTI in a multi-institutional cohort of patients who had undergone radical cystectomy (RC). PATIENTS AND METHODS: The pre- and postoperative characteristics of patients who had undergone open RC at 1 of 3 institutions between 2009 and 2015 were analyzed by means of the patient charts. Patients were classified according to the presence or absence of UTI. Analysis of the severity of UTI was based on the EAU/EAU Section of Infections in Urology (ESIU) classification system. The bacterial aetiological agents and their antibiotic susceptibility were also assessed. Factors predicting postoperative UTI were identified using univariable and multivariable logistic regression analysis. RESULTS: Of 217 patients, 42 (19.4%) had developed postoperative UTI, of whom 50% had urosepsis or uroseptic shock. Multivariable analysis showed continent urinary derivation as the only significant predictor of UTI with an odds ratio of 5.03 (95% confidence interval 2.12-11.9, P < 0.001). The duration of perioperative antibiotic prophylaxis was not associated with an increased risk of UTI. Enterococcus was the most commonly isolated bacteria (25.7%), but this species is not covered by the recommended antibiotic prophylaxis. CONCLUSION: Patients with continent urinary diversion after RC have a significantly higher risk of developing UTI. Prolonged perioperative administration of antibiotics does not seem to reduce the risk of UTI. Enterococcus as the most commonly isolated bacteria is not covered by most recommended antibiotic prophylaxis regimens. Therefore different antibiotic regimens should be considered for high-risk patients.

Impact of glutathione modulation on the toxicity of the Fusarium mycotoxins deoxynivalenol (DON), NX-3 and butenolide in human liver cells.

DON, NX-3 and butenolide (BUT) are secondary metabolites formed by Fusarium graminearum. Evidence for formation of DON-glutathione adducts exists in plants, and also in human liver (HepG2) cells mass spectrometric evidence for GSH-adduct formation was reported. NX-3 is a DON derivative lacking structural features for Thiol-Michael addition, while BUT has the structural requirements (conjugated double bond and keto group). In the present study, we addressed whether these structural differences affect levels of intracellular reactive oxygen species in HepG2 cells, and if intracellular GSH levels influence toxic effects induced by DON, NX-3 and BUT. Pre-treatment with an inhibitor of GSH bio-synthesis, L-buthionine-[S,R]-sulfoximine, aggravated substantially BUT-induced cytotoxicity (≥50 µM, 24 h), but only marginally affected the cytotoxicity of DON and NX-3 indicating that GSH-mediated detoxification is of minor importance in HepG2 cells. We further investigated whether BUT, a compound inducing alone low oral toxicity, might affect the toxicity of DON. Under different experimental designs with respect to pre- and/or co-incubations, BUT was found to contribute to the combinatorial cytotoxicity, exceeding the toxic effect of DON alone. The observed combinatorial effects underline the potential contribution of secondary metabolites like BUT, considered to be alone of low toxicological relevance, to the toxicity of DON or structurally related trichothecenes, arguing for further studies on the toxicological relevance of naturally occurring mixtures.

Chemical synthesis of culmorin metabolites and their biologic role in culmorin and acetyl-culmorin treated wheat cells.

The Fusarium metabolite culmorin (1) is receiving increased attention as an "emerging mycotoxin". It co-occurs with trichothecene mycotoxins and potentially influences their toxicity. Its ecological role and fate in plants is unknown. We synthesized sulfated and glucosylated culmorin conjugates as potential metabolites, which are expected to be formed in planta, and used them as reference compounds. An efficient procedure for the synthesis of culmorin sulfates was developed. Diastereo- and regioselective glucosylation of culmorin (1) was achieved by exploiting or preventing unexpected acyl transfer when using different glucosyl donors. The treatment of a wheat suspension culture with culmorin (1) revealed an in planta conversion of culmorin into culmorin-8-glucoside (6) and culmorin acetate, but no sulfates or culmorin-11-glucoside (7) was found. The treatment of wheat cells with the fungal metabolite 11-acetylculmorin (2) revealed its rapid deacetylation, but also showed the formation of 11-acetylculmorin-8-glucoside (8). These results show that plants are capable of extensively metabolizing culmorin.

Esters of valerenic acid as potential prodrugs.

Valerenic acid (VA) is a ß2/3 subunit-specific modulator of γ-aminobutyric acid (GABA) type A (GABAA) receptors inducing anxiolysis. Here we analyze if VA-esters can serve as prodrugs and if different ester structures have different in vitro/in vivo effects. Modulation of GABAA receptors expressed in Xenopus oocytes was studied with 2-microelectrode-voltage-clamp. Anxiolytic effects of the VA-esters were studied on male C57BL/6N mice by means of the elevated plus maze-test; anticonvulsant properties were deduced from changes in seizure threshold upon pentylenetetrazole infusion. VA was detected in plasma confirming hydrolysis of the esters and release of VA in vivo. Esterification significantly reduced the positive allosteric modulation of GABAA (α1ß3γ2S) receptors in vitro. in vivo, the studied VA-ester derivatives induced similar or even stronger anxiolytic and anticonvulsant action than VA. While methylation and propylation of VA resulted in faster onset of anxiolysis, the action of VA-ethylester was longer lasting, but occurred with a significant delay. The later finding is in line with the longer lasting anticonvulsant effects of this compound. The estimated VA plasma concentrations provided first insight into the release kinetics from different VA-esters. This might be an important step for its future clinical application as a potential non-sedative anxiolytic and anticonvulsant.

Direct Arylation of Benzo[b]furan and Other Benzo-Fused Heterocycles.

The direct arylation of benzo[b]furan, benzo[b]thiophene, and indole has been studied by using aromatic bromides as the aryl source. The protocol employing common reagents and a Pd catalyst has led to the regioselective arylation of these heterocycles at the 2-position. A range of functional groups were tolerated, providing quick access to a variety of arylated benzo-fused heterocycles that would be accessible more elaborately using classical synthetic strategies. This is the first systematic study of the direct arylation of benzo[b]furan.

Probing the out-of-plane distortion of single point defects in atomically thin hexagonal boron nitride at the picometer scale.

Crystalline systems often lower their energy by atom displacements from regular high-symmetry lattice sites. We demonstrate that such symmetry lowering distortions can be visualized by ultrahigh resolution transmission electron microscopy even at single point defects. Experimental investigation of structural distortions at the monovacancy defects in suspended bilayers of hexagonal boron nitride (h-BN) accompanied by first-principles calculations reveals a characteristic charge-induced pm symmetry configuration of boron vacancies. This symmetry breaking is caused by interlayer bond reconstruction across the bilayer h-BN at the negatively charged boron vacancy defects and results in local membrane bending at the defect site. This study confirms that boron vacancies are dominantly present in the h-BN membrane.

First application of Cc-corrected imaging for high-resolution and energy-filtered TEM.

Contrast-transfer calculations indicate that C(c) correction should be highly beneficial for high-resolution and energy-filtered transmission electron microscopy. A prototype of an electron optical system capable of correcting spherical and chromatic aberration has been used to verify these calculations. A strong improvement in resolution at an acceleration voltage of 80 kV has been measured. Our first C(c)-corrected energy-filtered experiments examining a (LaAlO(3))(0.3)(Sr(2)AlTaO(6))(0.7)/LaCoO(3) interface demonstrated a significant gain for the spatial resolution in elemental maps of La.

Advancing the hexapole Cs-corrector for the scanning transmission electron microscope.

Aberration correctors using hexapole fields have proven useful to correct for the spherical aberration in electron microscopy. We investigate the limits of the present design for the hexapole corrector with respect to minimum probe size for the scanning transmission electron microscope and discuss several ways in which the design could be improved by rather small and incremental design changes for the next generation of advanced probe-forming systems equipped with a gun monochromator.

Experimental evaluation of a spherical aberration-corrected TEM and STEM.

We have successfully developed a spherical aberration (Cs)-corrected electron microscope for probe- and image-forming systems using hexapole correctors. The performance of the microscope has been evaluated experimentally. The point resolution attained using the image-forming Cs-corrector is better than 0.12 nm. For scanning transmission electron microscopy, the Ronchigram flat area was >40 mrad in half-angle using the probe-forming Cs-corrector.