A randomized, open-label, multicenter study of switching to brolucizumab with or without a loading dose for patients with suboptimal anatomically controlled neovascular age-related macular degeneration-the FALCON study.

BACKGROUND: Treatment initiation with brolucizumab, a new potent anti-vascular endothelial growth factor (VEGF) agent, is typically performed with three monthly injections (loading dose) and has been well studied in treatment-naïve patients. However, no clinical data are available yet on whether or not anti-VEGF pretreated patients also benefit from a loading dose. In the clinical setting, different heterogeneous treatment patterns are used as no clinical trial has addressed this so far in a head-to-head comparison. Therefore, the FALCON study is investigating whether patients with unsatisfactory response to previous anti-VEGF treatments benefit from a loading dose at the switch to brolucizumab treatment. METHODS: FALCON is a 52-week, two-arm, randomized, open-label, multicenter, multinational study in patients with residually active neovascular age-related macular degeneration (nAMD) who will be randomized 1:1 and started with brolucizumab 6 mg loading (three monthly loading doses) or brolucizumab 6 mg non-loading (one initial injection) and consecutive treatment every 12 weeks, respectively. The primary objective is to demonstrate non-inferiority of the non-loading vs. loading arm in mean change of best-corrected visual acuity (BCVA) from baseline to the mean value at week 40 to week 52. Secondary objectives include the assessment of anatomical outcomes, treatment intervals, safety and tolerability. RESULTS: FALCON will be the first study to assess treatment initiation with an anti-VEGF agent in a switch situation with or without loading dose in patients with nAMD. CONCLUSIONS: The results will support the optimization of treatment of patients with previous unsatisfactory anti-VEGF response. Therefore, we expect to see an impact on current clinical practice which has been established for more than a decade. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04679935, date of registration-22-Dec 2020; EUDRACT number: 2019-004763-53, date of registration-03 Dec 2019.

Inter-observer variation of hippocampus delineation in hippocampal avoidance prophylactic cranial irradiation.

BACKGROUND: Hippocampal avoidance prophylactic cranial irradiation (HA-PCI) techniques have been developed to reduce radiation damage to the hippocampus. An inter-observer hippocampus delineation analysis was performed and the influence of the delineation variability on dose to the hippocampus was studied. MATERIALS AND METHODS: For five patients, seven observers delineated both hippocampi on brain MRI. The intra-class correlation (ICC) with absolute agreement and the generalized conformity index (CIgen) were computed. Median surfaces over all observers' delineations were created for each patient and regional outlining differences were analysed. HA-PCI dose plans were made from the median surfaces and we investigated whether dose constraints in the hippocampus could be met for all delineations. RESULTS: The ICC for the left and right hippocampus was 0.56 and 0.69, respectively, while the CIgen ranged from 0.55 to 0.70. The posterior and anterior-medial hippocampal regions had most variation with SDs ranging from approximately 1 to 2.5 mm. The mean dose (Dmean) constraint was met for all delineations, but for the dose received by 1% of the hippocampal volume (D1%) violations were observed. CONCLUSION: The relatively low ICC and CIgen indicate that delineation variability among observers for both left and right hippocampus was large. The posterior and anterior-medial border have the largest delineation inaccuracy. The hippocampus Dmean constraint was not violated.

Inhibition of the bacterial lectins of Pseudomonas aeruginosa with monosaccharides and peptides.

Pseudomonas aeruginosa (PA) can cause infections in compromised hosts by interacting with the glycocalyx of host epithelial cells. It binds to glycostructures on mucosal surfaces via two lectins, which are carbohydrate-binding proteins, named PA-IL and PA-IIL, and blocking this interaction is, thus, an attractive anti-adhesive strategy. The aim of this study was to determine by ciliary beat frequency (CBF) analysis whether monosaccharides or peptides mimicking glycostructures represent blockers of PA lectin binding to human airway cilia. The treatment with monosaccharides and peptides alone did not change the CBF compared to controls and the tested compounds did not influence the cell morphology or survival, with the exception of peptide pOM3. PA-IL caused a decrease of the CBF within 24 h. D-galactose as well as the peptides mimicking HNK-1, polysialic acid and fucose compensated the CBF-modulating effect of PA-IL with different affinities. PA-IIL also bound to the human airway cilia in cell culture and resulted in a decrease of the CBF within 24 h. L(-)-fucose and pHNK-1 blocked the CBF-decreasing effect of PA-IIL. The HNK-1-specific glycomimetic peptide had a high affinity for binding to both PA-IL and PA-IIL, and inhibited the ciliotoxic effect of both lectins, thus, making it a strong candidate for a therapeutic anti-adhesive drug.

Cost-effective expression and purification of antimicrobial and host defense peptides in Escherichia coli.

Cationic antimicrobial host defense peptides (HDPs) combat infection by directly killing a wide variety of microbes, and/or modulating host immunity. HDPs have great therapeutic potential against antibiotic-resistant bacteria, viruses and even parasites, but there are substantial roadblocks to their therapeutic application. High manufacturing costs associated with amino acid precursors have limited the delivery of inexpensive therapeutics through industrial-scale chemical synthesis. Conversely, the production of peptides in bacteria by recombinant DNA technology has been impeded by the antimicrobial activity of these peptides and their susceptibility to proteolytic degradation, while subsequent purification of recombinant peptides often requires multiple steps and has not been cost-effective. Here we have developed methodologies appropriate for large-scale industrial production of HDPs; in particular, we describe (i) a method, using fusions to SUMO, for producing high yields of intact recombinant HDPs in bacteria without significant toxicity and (ii) a simplified 2-step purification method appropriate for industrial use. We have used this method to produce seven HDPs to date (IDR1, MX226, LL37, CRAMP, HHC-10, E5 and E6). Using this technology, pilot-scale fermentation (10L) was performed to produce large quantities of biologically active cationic peptides. Together, these data indicate that this new method represents a cost-effective means to enable commercial enterprises to produce HDPs in large-scale under Good Laboratory Manufacturing Practice (GMP) conditions for therapeutic application in humans.

Use of B-type natriuretic peptide to predict blood pressure improvement after percutaneous revascularisation for renal artery stenosis.

OBJECTIVES: The purpose of this study was to evaluate the utility of B-type natriuretic peptide (BNP) to predict blood pressure (BP) response in patients with renal artery stenosis (RAS) after renal angioplasty and stenting (PTRA). METHODS: In 120 patients with RAS and hypertension referred for PTRA, 24-h ambulatory BP recordings were obtained before and 6 months after intervention. BNP was measured before, 1 day and 6 months after PTRA. RESULTS: BP improved in 54% of patients. Median BNP levels pre-intervention were 97 pg ml(-1) (interquartile range (IQR) 35-250) and decreased significantly within 1 day of PTRA to 62 pg ml(-1) (IQR 24-182) (p < 0.001), remaining at 75 pg ml(-1) (IQR 31-190) at 6 months. The area under the receiver operating curve for pre-intervention BNP to predict BP improvement was 0.57 (95% confidence interval (CI) 0.46-0.67). Pre-intervention BNP >50 pg ml(-1) was seen in 79% of patients with BP improvement compared with 56% in patients without improvement (p = 0.01). In a multivariate logistic regression analysis, BNP >50 pg ml(-1) was significantly associated with BP improvement (odds ratio (OR) 4.0, 95% CI 1.2-13.2). CONCLUSIONS: BNP levels are elevated in patients with RAS and decrease after revascularisation. Although BNP does not seem useful as a continuous variable, pre-interventional BNP >50 pg ml(-1) may be helpful to identify patients in whom PTRA will improve BP.

Giant arteriovenous fistula after implantation of a percutaneous left ventricular assist device.

INTRODUCTION: Percutaneous left ventricular assist devices are an important tool in the management of patients with severe cardiogenic shock. Limited experiences concerning vascular complications after long term implantation of these devices exist. We report on a large arteriovenous fistula after placement of a left ventricular assist device, which has not been described in the literature. The arteriovenous fistula was of clinical relevance because it represented a supplementary cardiac burden in a patient with impaired left ventricular function after a severe myocardial infarction.

Memory priming during light anaesthesia with desflurane and remifentanil anaesthesia.

BACKGROUND: Previous studies of memory priming during anaesthesia with EEG monitoring have observed implicit memory effects for words presented during light and deep anaesthesia with and without surgical stimulation. We hypothesized that memory priming occurs under each of five different combinations of anaesthesia and surgery, and no significant differences occur in memory priming among the five conditions or between the two test points such as, 12 vs 24 h after surgery. METHODS: Forty gynaecological patients (aged between 28 and 66 yr, median 44.5 yr) were included in the study. They received propofol and remifentanil induction followed by desflurane and remifentanil anaesthesia in conjunction with neuromuscular blocking agents. Each patient was exposed to 60 of 120 nouns in a double-blind randomized design. These 60 nouns were divided into 5 groups of 12 words, presented under one of the five different conditions, namely, intubation, skin incision, deep anaesthesia and moderate anaesthesia (both during surgery), and light anaesthesia during the emergence phase. The depth of anaesthesia was measured using the EEG monitor, Narcotrend. RESULTS: No explicit memories were observed in a free recall or in a yes-no recognition test. A word-stem completion test revealed a significant implicit priming only for light anaesthesia (P < 0.01). No significant differences were detected among the five conditions. An overall implicit memory effect occurred for the second test point (P < 0.05). CONCLUSIONS: Our hypotheses could not be verified. Implicit memory priming occurred only under light anaesthesia, when the patients were most probably conscious. Priming effects may be enhanced after night's sleep.

Reduction mammaplasty for benign phyllodes tumour in an adolescent female--a 13-year follow up.

Phyllodes tumours are rare neoplasms of the female breast, especially among adolescent women. We present the case of a 17-year old female patient with a large benign phyllodes tumour. The patient was treated by one-stage excision with reduction mammaplasty. Symmetry of breast contour and nipple-areola complex position could be restored. At follow-up after 13 years good cosmetic result was maintained and there was no evidence of local recurrence. Standard plastic surgical techniques like reduction mammaplasty might be applied in treating large benign tumours compromising the aesthetic aspect of the breast.

Initial characterization of a blue-light sensing, phototropin-related protein from Pseudomonas putida: a paradigm for an extended LOV construct.

The open reading frame PP2739 from Pseudomonas putida KT2440 encodes a 151 amino acid protein with sequence similarity to the LOV domains of the blue-light sensitive protein YtvA from Bacillus subtilis and to the phototropins (phot) from plants. This sensory box LOV protein, PpSB2-LOV, comprises a LOV core, followed by a C-terminal segment predicted to form an alpha-helix, thus constituting a naturally occurring paradigm for an extended LOV construct. The recombinant PpSB2-LOV shows a photochemistry very similar to that of YtvA and phot-LOV domains, yet the lifetime for the recovery dark reaction, taurec=114 s at 20 degrees C, resembles that of phot-LOV domains (5-300 s) and is much faster than that of YtvA or YtvA-LOV (>3000 s). Time-resolved optoacoustics reveals phot-like, light-driven reactions on the ns-micros time window with the sub-nanosecond formation of a flavin triplet state (PhiT=0.46) that decays into the flavin-cysteine photoadduct with 2 micros lifetime (Phi390=0.42). The fluorescence spectrum and lifetime of the conserved W97 resembles the corresponding W103 in full-length YtvA, although the quantum yield, PhiF, is smaller (about 55% of YtvA) due to an enhanced static quenching efficiency. The anisotropy of W97 is the same as for W103 in YtvA (0.1), and considerably larger than the value of 0.06, found for W103 in YtvA-LOV. Different to YtvA and YtvA-LOV, the fluorescence for W97 becomes larger upon photoproduct formation. These data indicate that W97 is located in a similar environment as W103 in full-length YtvA, but undergoes larger light-driven changes. It is concluded that the protein segment located C-terminally to the LOV core (analogous to an interdomain linker) is enough to confer to the conserved tryptophan the fluorescence characteristics typical of full-length YtvA. The larger changes experienced by W97 upon light activation may reflect a larger conformational freedom of this protein segment in the absence of a second domain.

[Complications due to patient positioning: anaesthesiological considerations]. / Lagerungsschäden aus der Sicht des Anästhesisten.

Anaesthetist and surgeon cooperate in positioning the patient for surgery according to interdisciplinary agreements. The legal demands on documentation for standard positioning procedures are met with a symbol or short notice on the anaesthesia protocol. In the case of damage to the patient, however, the doctor has to furnish evidence that the patient has been positioned correctly. Complications associated with perioperative patient positioning are reported to be 1 to 1000. Peripheral nerves are at highest risk, but soft tissue, joint, vascular and ocular damages are also reported. The problems and adequate care of different positioning modes, such as recumbent, lateral, prone, seated and lithotomy position, are discussed in detail.

Reduction of catheter-related infections in neutropenic patients: a prospective controlled randomized trial using a chlorhexidine and silver sulfadiazine-impregnated central venous catheter.

Antiseptic coating of intravascular catheters may be an effective means of decreasing catheter-related colonization and subsequent infection. The purpose of this study was to assess the efficacy of chlorhexidine and silver sulfadiazine (CH-SS)-impregnated central venous catheters (CVCs) to prevent catheter-related colonization and infection in patients with hematological malignancies who were subjected to intensive chemotherapy and suffered from severe and sustained neutropenia. Proven CVC-related bloodstream infection (BSI) was defined as the isolation of the same species from peripheral blood culture and CVC tip (Maki technique). This randomized, prospective clinical trial was carried out in 106 patients and compared catheter-related colonization and BSI using a CH-SS-impregnated CVC (n=51) to a control arm using a standard uncoated triple-lumen CVC (n=55). Patients were treated for acute leukemia (n=89), non-Hodgkin's lymphoma (n=10), and multiple myeloma (n=7). Study groups were balanced regarding to age, sex, underlying diseases, insertion site, and duration of neutropenia. The CVCs were in situ a mean of 14.3+/-8.2 days (mean+/-SD) in the study group versus 16.6+/-9.7 days in the control arm. Catheter-related colonization was observed less frequently in the study group (five vs nine patients; p=0.035). CVC-related BSI were significantly less frequent in the study group (one vs eight patients; p=0.02). In summary, in patients with severe neutropenia, CH-SS-impregnated CVCs yield a significant antibacterial effect resulting in a significantly lower rate of catheter-related colonization as well as CVC-related BSI.

[Breast-reduction surgery--a long-term survey of indications and outcomes]. / Leichter--freier--unbeschwerter. Das neue Leben mit der kleineren Brust.

Between 1986 and 2003, breast-reduction surgery was performed in a total of 814 women. The indication was established on the basis of physical complaints, chronic back pain, stiff neck or recurrent intertrigo in the foldbeneath the breasts. A proportion of the patients were interviewed postoperatively using a questionnaire, to determine the impact of the operation on their quality of life. 91% of those surveyed reported a postoperative improvement in the perception of their own body, and 80% were satisfied with the reduced size of their breasts. In conclusion, in the hands of an experienced breast surgeon, breast-reduction surgery for the proper indication results in a reliable and safe diminishment in breast size and tightening of slack tissue, leading to a significant enhancement in the patient's quality of life.

[Anaesthesia in cataract surgery for elderly people]. / Narkoseverfahren in der Kataraktchirurgie bei geriatrischen Patienten - Patientensicherheit, Aufwachverhalten, Patientenzufriedenheit und Kosten im Vergleich der "Totalen Intravenösen Anästhesie" mit der "Balancierten Anästhesie" -

OBJECTIVE: In the cataract surgery the problems of anaesthesia in ophthalmo-surgery and anaesthesia in elderly people are combined. For this patients we compared intravenous anaesthesia with balanced anaesthesia in cardiac and circulatory side effects (security), patients satisfaction and costs. METHODS: In a prospective, randomised study we compared in 52 (26 vs. 26) elderly patients (ASA II and III, mean age 78.7 +/- 8.6 years) undergoing a cataract operation cardiac and circulatory side effects, recovery time and patients satisfaction with the either type of anaesthesia by a score from 1 = best to 6 = worse and the occurrence of nausea/vomiting (controlled 24 h). The difference in costs were measured by the hospital management. RESULTS: Cardiac and circulatory side effects with hypotonic reactions were similar in both groups (TIVA 18 = 69.2 %/BA 20 = 76.9 %). Hypertonic reactions were mainly seen in BA (Tiva 1.9 %, BA 69.2 %/p < 0,001). There was no problem in the treatment of these side-effects. The frequency of postoperative nausea and vomiting was lower (but not significantly) in the TIVA group (TIVA 8 %/ BA 27 %) than in the BA group (7 and 4). The recovery times were shorter (p < 0.001) in TIVA, those patients were staying 24 (+/- 6.70) minutes in the post operative unit vs. 59 (+/- 28.83) minutes in BA. Patients satisfaction was better in the TIVA-group (1.65) than in the patients treated with BA. In the calculation of costs there was a disadvantage in BA. CONCLUSIONS: This study showed, that in respect of cardiac and respiratory side effects TIVA and BA are safe methods in anaesthesia for elderly people in ophthalmic surgery. Nevertheless, because of shorter recovery-times, lower incidence of hypertonic reactiones, more patients satisfaction and lower costs TIVA had better results in this study. We have to ask for the evaluation of economy in anaesthesia that not only prices of medicaments but the complete costs of the cases have to be calculated.

Impact of tobacco smoking on platelet function in apheresis products in vitro.

BACKGROUND AND OBJECTIVES: The aim of this study was to analyse the platelet function, over a 5-day time-period, of apheresis-derived platelet concentrates obtained from smokers and non-smokers. MATERIALS AND METHODS: Smoker and non-smoker plateletpheresis products were investigated on days 1, 3 and 5 of storage. Receptor expression (as evaluated by flow cytometry) and the platelet aggregation response were measured. RESULTS: There was only a slight loss of platelet function in apheresis products from smokers compared to non-smokers. CONCLUSIONS: Smoking does not significantly change the quality of platelet preparations. The current practice, of not to exclude smokers from platelet donation, can be continued.

Lack of toxic side effects in neutrophils following hyperbaric oxygen.

Conflicting data have been reported about the impact of repeated HBO2 exposure on the production of superoxide radicals during the neutrophil respiratory burst (RB) and on phagocytosis. In this study we wanted to see if exposure to hyperoxia would affect human neutrophil RB and phagocytosis. Short- and long-term effects after single or repetitive HBO2 exposure of 2.5 atmospheres absolute over a period of 90 min were studied in 40 healthy volunteers. The RB was measured by the intracellular oxidation of dihydrorhodamine after induction by Escherichia coli (E. coli), or priming with recombinant tumour necrosis factor alpha (TNF-alpha), followed by N-formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation. The phagocytic activity was determined by the intake of FITC-labelled opsonized E. coli. No differences could be found between RB and phagocytic activity before and after HBO2 therapy, regardless of short- or long-term exposure. These findings indicate that exposure to hyperoxia does not impair these two important functions of the human innate host defense.

[Influence of a bolus injection of thiopental and propofol on the expression density of P-selectin and fibrinogen receptors on the surface of human platelets ex vivo]. / Einfluss einer Bolusgabe von Thiopental und Propofol auf die Expressionsdichte von P-Selektin und Fibrinogenrezeptoren auf der Oberfläche humaner Thrombozyten.

OBJECTIVE: Exposure of platelets to anaesthetic agents may alter their functional characteristics and in patients undergoing surgery or long-term sedation this may be clinically relevant. We investigated the influence of thiopentone and propofol on the expression of platelet membrane P-selectin, fibrinogen receptor, and leukocyte-platelet aggregates ex vivo. METHODS: In patients undergoing surgery blood samples were taken from a peripheral vein cannula before induction of anaesthesia with propofol (3.0 mg kg (-1) BW) or thiopentone (7.0 mg kg (-1) BW) and five minutes later (n = 11 in each group). Surface expression of the fibrinogen receptor complex (GP Ib/IIIa), P-selectin, and the percentage of leukocyte-platelet aggregates were measured by flow cytometry after stimulation via the ADP or thrombin receptor pathway. RESULTS: There was no significant difference in the expression of gpIIb/IIIa, P-selectin, and percentage of leukocyte-platelet aggregates in the thiopentone and propofol group after induction of anaesthesia. CONCLUSIONS: In clinically relevant concentrations thiopentone and propofol did not influence the surface expression density of fibrinogen receptors, P-selectin molecules, and the percentage of leukocyte-platelet aggregates ex vivo.

pH, hypoxia and metastasis.

The vascular supply to tumours is often poorly formed and irregular with the result that tumours may contain regions of poor nutritional supply with hypoxia and acidic pH. Clinical studies have demonstrated substantial heterogeneity in oxygenation in human tumours. In some studies tumours with poorer oxygenation were more likely to have metastasized. In our studies of carcinoma of the cervix, nodal metastases were 1.5 times more likely at diagnosis in patients with more hypoxic tumours relative to those with less hypoxic tumours. Transplanted rodent KHT fibrosarcomas and SCC-VII squamous cell tumours also have variability in levels of oxygenation; again, the more hypoxic tumours are found to be more metastatic. Furthermore, deliberate exposure of KHT tumours to cyclic hypoxia (12 cycles of 5% oxygen breathing for 10 min interspersed with 10 min air breathing) every day during their growth, doubled the level of micrometastases that were detected in the lungs of the mice. These findings are consistent with in vitro studies demonstrating that KHT and SCC-VII cells and B-16 melanoma cells exposed to hypoxia or low pH have increased propensity to form metastases following injection into-mice. This effect is transient and is lost within about 48 h of removal of exposure to hypoxia or low pH, suggesting that the effect may be due to changes in gene expression associated with that stress. Recent studies have implicated a number of genes, such as vascular endothelial growth factor and interleukin 8, in the effect of hypoxic and acid pH on metastasis.