Clinical and immunological outcomes of SARS-CoV-2-infected vaccine responders, vaccine non-responders, and unvaccinated patients evaluated for neutralizing monoclonal antibody treatment at a single German tertiary care center: a retrospective cohort study with prospective follow-up.

PURPOSE: This study assessed the clinical and immunological outcomes of SARS-CoV-2-infected patients with risk factors for severe disease depending on their immunological status. METHODS: In this retrospective study with single follow-up visit, clinical outcome and humoral immunity was monitored in SARS-CoV-2 infected patients at risk. The results were compared based on the patients' initial immunological status: unvaccinated (UV), patients who did not develop neutralizing antibodies after vaccination (vaccine non-responders, VNR), and patients who expressed neutralizing antibodies after vaccination (vaccine responders, VR). Patients who lacked neutralizing antibodies (VNR and UV) were treated with nMABs. RESULTS: In total, 113 patients at risk of severe COVID-19 consented to participate in the study. VR and UV were not admitted to the hospital. During the observation period, UVs had the highest rate of SARS-CoV-2 re-infections. Three of 41 VNRs (7.3%) were hospitalized due to severe COVID-19, with two of them having undergone iatrogenic B-cell depletion. The humoral immune response after infection was significantly lower in the VNR group than in the VR group in terms of anti-N, anti-receptor-binding domain (RBD), anti-S antibody titers, and anti-S antibody avidity. In a sub-analysis of VNR, B cell-deficient non-responders had significantly lower levels of anti-N antibodies and anti-S avidity after infection than other VNRs. CONCLUSION: VNR, particularly B-cell-depleted VNR, remained at risk of hospitalization due to COVID-19. In the VR group, however, no clinical complications or severe disease were observed, despite not receiving nMAbs. Tailoring the administration of nMABs according to patient vaccination and immunological status may be advisable.

Advantage of ostarine over raloxifene and their combined treatments for muscle of estrogen-deficient rats.

PURPOSE: Selective androgen (ostarine, OST) and estrogen (raloxifene, RAL) receptor modulators with improved tissue selectivity have been developed as alternatives to hormone replacement therapy. We investigated the combined effects of OST and RAL on muscle tissue in an estrogen-deficient rat model of postmenopausal conditions. METHODS: Three-month-old Sprague Dawley rats were divided into groups: (1) untreated non-ovariectomized rats (Non-OVX), (2) untreated ovariectomized rats (OVX), (3) OVX rats treated with OST, (4) OVX rats treated with RAL, (5) OVX rats treated with OST and RAL. Both compounds were administered in the diet. The average dose received was 0.6 ± 0.1 mg for OST and 11.1 ± 1.2 mg for RAL per kg body weight/day. After thirteen weeks, rat activity, muscle weight, structure, gene expression, and serum markers were analyzed. RESULTS: OST increased muscle weight, capillary ratio, insulin-like growth factor 1 (Igf-1) expression, serum phosphorus, uterine weight. RAL decreased muscle weight, capillary ratio, food intake, serum calcium and increased Igf-1 and Myostatin expression, serum follicle stimulating hormone (FSH). OST + RAL increased muscle nucleus ratio, uterine weight, serum phosphorus, FSH and luteinizing hormone and decreased body and muscle weight, serum calcium. Neither treatment changed muscle fiber size. OVX increased body and muscle weight, decreased uterine weight, serum calcium and magnesium. CONCLUSION: OST had beneficial effects on muscle in OVX rats. Side effects of OST on the uterus and serum electrolytes should be considered before using it for therapeutic purposes. RAL and RAL + OST had less effect on muscle and showed endocrinological side effects on pituitary-gonadal axis.

Measurement of Lepton-Jet Correlation in Deep-Inelastic Scattering with the H1 Detector Using Machine Learning for Unfolding.

The first measurement of lepton-jet momentum imbalance and azimuthal correlation in lepton-proton scattering at high momentum transfer is presented. These data, taken with the H1 detector at HERA, are corrected for detector effects using an unbinned machine learning algorithm (multifold), which considers eight observables simultaneously in this first application. The unfolded cross sections are compared with calculations performed within the context of collinear or transverse-momentum-dependent factorization in quantum chromodynamics as well as Monte Carlo event generators.

A combined treatment with selective androgen and estrogen receptor modulators prevents bone loss in orchiectomized rats.

PURPOSE: Enobosarm (EN), a selective androgen receptor modulator and raloxifene (RAL), a selective estrogen receptor modulator, have been shown to improve bone tissue in osteoporotic males. The present study evaluated the effects of a combination therapy of EN and RAL on bone properties in orchiectomized rats compared to the respective single treatments. METHODS: Eight-month-old male Sprague-Dawley rats were either left intact (Non-Orx) or orchiectomized (Orx). The Orx rats were divided into four groups (n = 15 each): 1) Orx, 2) EN treatment (Orx + EN), 3) RAL treatment (Orx + RAL), 4) combined treatment (Orx + EN + RAL). EN and RAL (0.4 mg and 7 mg/kg body weight/day) were applied immediately after Orx with a soy-free pelleted diet for up to 18 weeks. The lumbar spine and femora were examined by micro-CT, biomechanical, histomorphological, ashing, and gene expression analyses. RESULTS: EN exhibited an anabolic effect on bone, improving some of its parameters in Orx rats, but did not affect biomechanical properties. RAL exhibited antiresorptive activity, maintaining the biomechanical and trabecular parameters of Orx rats at the levels of Non-Orx rats. EN + RAL exerted a stronger effect than the single treatments, improving most of the bone parameters. Liver weight increased after all treatments; the kidney, prostate, and levator ani muscle weights increased after EN and EN + RAL treatments. BW was reduced due to a decreased food intake in the Orx + RAL group and due a reduced visceral fat weight in the Orx + EN + RAL group. CONCLUSION: The EN + RAL treatment appeared to be promising in preventing male osteoporosis, but given the observed side effects on liver, kidney, and prostate weights, it requires further investigation.

Combination of selective androgen and estrogen receptor modulators in orchiectomized rats.

PURPOSE: Selective androgen and estrogen receptor modulators, ostarine (OST) and raloxifen (RAL), reportedly improve muscle tissue and offer therapeutic approaches to muscle maintenance in the elderly. The present study evaluated the effects of OST and RAL and their combination on musculoskeletal tissue in orchiectomized rats. METHODS: Eight-month-old Sprague Dawley rats were analyzed. Experiment I: (1) Untreated non-orchiectomized rats (Non-ORX), (2) untreated orchiectomized rats (ORX), (3) ORX rats treated with OST during weeks 0-18 (OST-P), (4) ORX rats treated with OST during weeks 12-18 (OST-T). Experiment II: 1) Non-ORX, (2) ORX, 3) OST-P, (4) ORX rats treated with RAL, during weeks 0-18 (RAL-P), 5) ORX rats treated with OST + RAL, weeks 0-18 (OST + RAL-P). The average daily doses of OST and RAL were 0.4 and 7 mg/kg body weight (BW). Weight, fiber size, and capillarization of muscles, gene expression, serum markers and the lumbar vertebral body were analyzed. RESULTS: OST-P exerted favorable effects on muscle weight, expression of myostatin and insulin growth factor-1, but increased prostate weight. OST-T partially improved muscle parameters, showing less effect on the prostate. RAL-P did not show anabolic effects on muscles but improved body constitution by reducing abdominal area, food intake, and BW. OST + RAL-P had an anabolic impact on muscle, reduced androgenic effect on the prostate, and normalized food intake. OST and RAL improved osteoporotic bone. CONCLUSIONS: The OST + RAL treatment appeared to be a promising option in the treatment of androgen-deficient conditions and showed fewer side effects than the respective single treatments.

Benchmark Experiment to Prove the Role of Projectile Excited States Upon the Ion Stopping in Plasmas.

We report on a precision energy loss measurement and theoretical investigation of 100 keV/u helium ions in a hydrogen-discharge plasma. Collision processes of helium ions with protons, free electrons, and hydrogen atoms are ideally suited for benchmarking plasma stopping-power models. Energy loss results of our experiments are significantly higher than the predictions of traditional effective charge models. We obtained good agreement with our data by solving rate equations, where in addition to the ground state, also excited electronic configurations were considered for the projectile ions. Hence, we demonstrate that excited projectile states, resulting from collisions, leading to capture-, ionization-, and radiative-decay processes, play an important role in the stopping process in plasma.

An altered heparan sulfate structure in the articular cartilage protects against osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is a progressive degenerative disease of the articular cartilage caused by an unbalanced activity of proteases, cytokines and other secreted proteins. Since heparan sulfate (HS) determines the activity of many extracellular factors, we investigated its role in OA progression. METHODS: To analyze the role of the HS level, OA was induced by anterior cruciate ligament transection (ACLT) in transgenic mice carrying a loss-of-function allele of Ext1 in clones of chondrocytes (Col2-rtTA-Cre;Ext1e2fl/e2fl). To study the impact of the HS sulfation pattern, OA was surgically induced in mice with a heterozygous (Ndst1+/-) or chondrocyte-specific (Col2-Cre;Ndst1fl/fl) loss-of-function allele of the sulfotransferase Ndst1. OA progression was evaluated using the OARSI scoring system. To investigate expression and activity of cartilage degrading proteases, femoral head explants of Ndst1+/- mutants were analyzed by qRT-PCR, Western Blot and gelatin zymography. RESULTS: All investigated mouse strains showed reduced OA scores (Col2-rtTA-Cre;Ext1e2fl/e2fl: 0.83; 95% HDI 0.72-0.96; Ndst1+/-: 0.83, 95% HDI 0.74-0.9; Col2-Cre;Ndst1fl/fl: 0.87, 95% HDI 0.76-1). Using cartilage explant cultures of Ndst1 animals, we detected higher amounts of aggrecan degradation products in wildtype samples (NITEGE 4.24-fold, 95% HDI 1.05-18.55; VDIPEN 1.54-fold, 95% HDI 1.54-2.34). Accordingly, gelatin zymography revealed lower Mmp2 activity in mutant samples upon RA-treatment (0.77-fold, 95% HDI: 0.60-0.96). As expression of major proteases and their inhibitors was not altered, HS seems to regulate cartilage degeneration by affecting protease activity. CONCLUSION: A decreased HS content or a reduced sulfation level protect against OA progression by regulating protease activity rather than expression.

[Refixation of osteochondral fragments with resorbable polylactid implants : Long-term clincal and MRI results]. / Refixation von osteochondralen Fragmenten mit resorbierbaren Polylactid-Implantaten : Klinische und MR-morphologische Langzeitergebnisse.

BACKGROUND: Refixation with resorbable implants is a common surgical treatment in patients who suffer an injury with shearing of an osteochondral flake due to trauma of the knee or the upper ankle joint. To date there are no studies which outline long-term outcomes for this procedure. The aim of this study was to evaluate long-term clinical and magnetic resonance imaging (MRI) results after refixation with resorbable polylactide (PLLA) implants. MATERIAL AND METHODS: In this retrospective study 12 patients with 13 injuries were examined 13.9 years (±1.2 years) after refixation of an osteochondral fragment of the knee (10 patients) and the upper ankle joint (2 patients) with a mean size of 3.33 cm2 (±2.33) by resorbable polylactide (PLLA) implants (nails, pins, screws, Bionx, Tampere, Finland). To objectify the clinical results eight established clinical scores (VASS, Tegner, Lysholm, McDermott, KSS, WOMAC, AOFAS, FADI+Sports) were used. Furthermore, the morphological integration of bone and cartilage was assessed by MRI (3 T) using proton-weighted and cartilage-sensitive 3D double-echo steady-state (DESS) sequences. The morphological results were objectified with a modified MRI score according to Henderson et al. RESULTS: After 13.9 years (±1.2) the patients with an injury of the knee as well as of the upper ankle joint showed good to excellent results (knee: VASS 1.2 (±1.7), Tegner 4.4 (±1.3), Lysholm 85.7 (±12.2), McDermott 90.7 (±8.6), KSS 189 (±14.2), WOMAC (6.16% (±8.45)) (upper ankle joint: VASS 2.5 (±2.5), Tegner 5.5 (±1.5), Lysholm 87 (±13), McDermott 88 (±12); WOMAC (8.54% (±8.54), AOFAS 75.5 (±24.5), FADI+Sports 118 (±18)). In all cases there was evidence of good integration of the osteochondral fragment in MRI. In five patients there was moderate subchondral cyst formation (∅ ≤1 mm); however, mild changes of the cartilage contour were found in all patients. The mean modified Henderson score achieved was 14.4 (±2.0, best 8, worst 32), which corresponds to a good morphological result. CONCLUSION: Because of good clinical and morphological results shown by MRI, refixation through resorbable implants (PLLA) can be recommended for treatment of traumatic osteochondral flakes.

Evaluation of ostarine as a selective androgen receptor modulator in a rat model of postmenopausal osteoporosis.

Selective androgen receptor modulators (SARMs) have shown beneficial effects on muscle wasting, general physical function and bone properties in male mammals. However, data on the effects of SARMs in postmenopausal osteoporotic bone are scarce. We evaluated the effects of the SARM drug ostarine on postmenopausal osteoporotic bone in a rat osteoporosis model. Ovariectomy was performed on 46 of 56 3-month-old female Sprague-Dawley rats. Eight weeks after ovariectomy, ostarine was orally administered daily for 5 weeks in dosages of 0.04 (low, OVX + Ost. 0.04), 0.4 (intermediate, OVX + Ost. 0.4), and 4 mg/kg (high, OVX + Ost. 4) body weight. Another ovariectomized group received no ostarine. Lumbar vertebrae and femora were removed for biomechanical, gene expression, ashing, and computer tomography analyses. Low dose showed no effects. The effects of intermediate and high doses were comparable overall. Improvements were mainly seen in structural properties such as bone mineral density and bone volume density. However, the effects in femora were superior to effects in vertebrae. Ostarine treatment for 5 weeks did not improve significantly biomechanical properties. mRNA expression of the receptor activator of NF-κB ligand decreased after treatment, and uterine weight increased. Serum levels of phosphorus increased following ostarine treatment in intermediate and high-dose groups. Short-term treatment of osteoporotic bone with ostarine leads to improvement of several microstructural bone indices. While we did not observe changes in biomechanics, it is conceivable that longer treatment may also improve biomechanical properties. Further studies are needed to characterize longer time effects and side effects of ostarine in osteoporosis.

[Patellar dislocation in children and adolescents : Current developments in diagnostics and treatment]. / Patellaluxation im Kindes- und Jugendalter : Aktuelle Entwicklung bei Diagnostik und Therapie.

BACKGROUND: The latest results concerning patellar instability in children and adolescents lead to a better understanding of the underlying pathology. OBJECTIVES: Determination of necessary diagnostic procedures and treatment of patellar instability in children and adolescents. MATERIAL AND METHODS: Analysis of available literature based on a systematic MEDLINE analysis. RESULTS: Diagnostics, risk factors und treatment of adult patellar instability are applicable in the treatment of children. A trend towards early surgical stabilization after primary dislocation was identified. Growth plate-preserving methods for autologous MPFL reconstruction can safely be used in children. CONCLUSIONS: For children with a high risk of redislocation, primary surgical intervention should be performed. The necessary method must be determined by individual risk factor analysis.

The Advantages of Bilateral Osteotomy Over Unilateral Osteotomy for Osteoporotic Bone Healing.

Most models of osteoporotic bone fractures are performed unilaterally (UL). We investigated healing of tibia osteotomy performed either UL or bilaterally (BL) in ovariectomized rats. Behavior of animals and muscle structure were assessed. Three-month-old female Sprague-Dawley rats were ovariectomized (n = 32). After 10 weeks, half the rats underwent UL osteotomy of tibia metaphysis (right limb) with plate osteosynthesis. The other rats were osteotomized BL. Half of the rats in each group received either standard pain treatment with carprofen (5 mg/kg body weight (BW), 1x/day for 2 days) or carprofen and buprenorphine (5 mg/kg BW, 1x/day and 0.03 mg/kg BW, 2x/day for 5 days) after osteotomy. The UL rats started to load the injured limb from day 27 ± 9; BL rats did this from day 4 ± 4 onward. The UL rats more frequently loaded only one hind limb; BL rats more often loaded both hind limbs. Osteotomy was not bridged in 20% of UL rats and in 4% of BL rats. Callus volume and bone volume fraction were lower in UL group. Weight and fiber size of UL-intact limb muscles were enhanced, compared to the osteotomized limb and those in BL group. Most of the other parameters which assess physiology, activity, body posture, head, or coat were not different. The effect of two pain therapies was not significant on any variable studied. Welfare of the animals was acceptable in all rats. In UL rats, bone healing was delayed. The more advanced healing in BL rats suggested a positive effect of earlier loading. In studies on bone healing, it is advisable to perform BL osteotomy.

Effect of Strontium Ranelate on the Muscle and Vertebrae of Ovariectomized Rats.

Osteoporosis is often accompanied by sarcopenia. The effect of strontium ranelate (SR) on muscle tissue has not been investigated sufficiently. In this study, the effect of different SR treatments on muscle was studied. Additionally, the lumbar vertebrae were analyzed. Three-month-old female rats were divided into five groups (n = 12): Group 1: untreated (NON-OVX); Group 2: ovariectomized and left untreated (OVX); Group 3: SR after OVX until the study ended (13 weeks, SR prophylaxis and therapy = pr+th); Group 4: OVX and SR for 8 weeks (SR prophylaxis = pr); Group 5: SR for 5 weeks from the 8 week after OVX (SR therapy = SR th). SR was applied in food (630 mg/kg body weight). The size of muscle fibers, capillary density, metabolic enzymes, and mRNA expression were assessed in soleus, gastrocnemius, and longissimus muscles. The vertebral bodies underwent micro-CT, biomechanical, and ashing analyses. In general, SR did not alter the muscle histological parameters. The changes in fiber size and capillary ratio were related to the body weight. Myostatin mRNA was decreased in Sr pr+th; protein expression was not changed. SR th led to increase in mRNA expression of vascular endothelial growth factor (Vegf-B). In lumbar spine, SR pr+th enhanced biomechanical properties, bone mineral density, trabecular area, density, and thickness and cortical density. The reduced calcium/phosphate ratio in the SR pr+th group indicates the replacement of calcium by strontium ions. SR has no adverse effects on muscle tissue and it shows a favorable time-dependent effect on vertebrae. A functional analysis of muscles could verify these findings.

A cluster of two human cases of tick-borne encephalitis (TBE) transmitted by unpasteurised goat milk and cheese in Germany, May 2016.

In May 2016, two cases of tick-borne encephalitis (TBE) were confirmed by serology (positive IgM and IgG antibodies against TBE virus (TBEV) in serum), with a possible link to raw milk and cheese from a goat farm in a region in Baden-Württemberg, Germany not previously known as TBE-endemic. The outbreak investigation identified 32 consumers of goat dairy products (29 consumers, one farm employee, two owners) of whom none had IgM antibodies against TBEV 3-8 weeks after consumption. Of the 27 notified TBE cases in the State, none reported consumption of raw goat milk or cheese from the suspected farm. Five of 22 cheese samples from 18 different batches were RT-qPCR-positive for TBEV -genome, and two of the five samples were confirmed by virus isolation, indicating viability of TBEV in the cheese. Nine of the 45 goats had neutralising TBEV antibodies, two of them with a high titre indicating recent infection. One of 412 Ixodes ricinus was RT-qPCR-positive, and sequencing of the E gene from nucleic acid extracted from the tick confirmed TBEV. Phylogenetic analyses of tick and cheese isolates showed 100% amino acid homology in the E gene and a close relation to TBEV strains from Switzerland and Austria.

Detailed comparison of retroviral vectors and promoter configurations for stable and high transgene expression in human induced pluripotent stem cells.

Correction of patient-specific induced pluripotent stem cells (iPSC) upon gene delivery through retroviral vectors offers new treatment perspectives for monogenetic diseases. Gene-modified iPSC clones can be screened for safe integration sites and differentiated into transplantable cells of interest. However, the current bottleneck is epigenetic vector silencing. In order to identify the most suitable retroviral expression system in iPSC, we systematically compared vectors from different retroviral genera, different promoters and their combination with ubiquitous chromatin opening elements (UCOE), and several envelope pseudotypes. Lentiviral vectors (LV) pseudotyped with vesicular stomatitis virus glycoprotein were superior to gammaretroviral and alpharetroviral vectors and other envelopes tested. The elongation factor 1α short (EFS) promoter mediated the most robust expression, whereas expression levels were lower from the potent but more silencing-prone spleen focus forming virus (SFFV) promoter. Both full-length (A2UCOE) and minimal (CBX3) UCOE juxtaposed to two physiological and one viral promoter reduced transgene silencing with equal efficiency. However, a promoter-specific decline in expression levels was not entirely prevented. Upon differentiation of transgene-positive iPSC into endothelial cells, A2UCOE.EFS and CBX3.EFS vectors maintained highest transgene expression in a larger fraction of cells as compared with all other constructs tested here. The function of UCOE diminished, but did not fully counteract, vector silencing and possibilities for improvements remain. Nevertheless, the CBX3.EFS in a LV background exhibited the most promising promoter and vector configuration for both high titer production and long-term genetic modification of human iPSC and their progeny.

Role of Gag mutations in PI resistance in the Swiss HIV cohort study: bystanders or contributors?

Background: HIV Gag mutations have been reported to confer PI drug resistance. However, clinical implications are still controversial and most current genotyping algorithms consider solely the protease gene for assessing PI resistance. Objectives: Our goal was to describe for HIV infections in Switzerland the potential role of the C-terminus of Gag (NC-p6) in PI resistance. We aimed to characterize resistance-relevant mutational patterns in Gag and protease and their possible interactions. Methods: Resistance information on plasma samples from 2004-12 was collected for patients treated by two diagnostic centres of the Swiss HIV Cohort Study. Sequence information on protease and the C-terminal Gag region was paired with the corresponding patient treatment history. The prevalence of Gag and protease mutations was analysed for PI treatment-experienced patients versus PI treatment-naive patients. In addition, we modelled multiple paths of an assumed ordered accumulation of genetic changes using random tree mixture models. Results: More than half of all PI treatment-experienced patients in our sample set carried HIV variants with at least one of the known Gag mutations, and 17.9% (66/369) carried at least one Gag mutation for which a phenotypic proof of PI resistance by in vitro mutagenesis has been reported. We were able to identify several novel Gag mutations that are associated with PI exposure and therapy failure. Conclusions: Our analysis confirmed the association of Gag mutations, well known and new, with PI exposure. This could have clinical implications, since the level of potential PI drug resistance might be underestimated.

The spectrum of aseptic central nervous system infections in southern Germany - demographic, clinical and laboratory findings.

BACKGROUND AND PURPOSE: Aseptic infections of the central nervous system (CNS) are frequently observed in Germany. However, no study has systematically addressed the spectrum of aseptic CNS infections in Germany. METHODS: Data on 191 adult patients diagnosed from January 2007 to December 2014 with aseptic meningitis or encephalitis/meningoencephalitis at our hospital were collected by chart review and analyzed for demographic, clinical and laboratory findings. Patients were stratified according to the causative virus and findings were compared between groups. RESULTS: In our cohort, meningitis was caused in 36% by enterovirus (EV), 15% by herpes simplex virus (HSV), 12% by varicella zoster virus (VZV) and 5% by tick borne encephalitis (TBE). Encephalitis/meningoencephalitis was caused in 13% by HSV, 13% by VZV, and three out of 11 tested patients were positive for TBE. The highest incidence of EV infections was between 25 and 35 years and of HSV infections between 30 and 60 years. VZV infections had a bimodal distribution peaking below 30 and above 70 years. VZV and EV infections were more frequently observed during summer, whereas HSV infections showed no seasonal preference. Inflammatory changes in cerebrospinal fluid (CSF) were highest in HSV and lowest in EV infections. CONCLUSIONS: Polymerase chain reaction tests for HSV, VZV and EV in CSF and TBE serology determined the causative virus in over 60% of tested patients. The age of affected patients, seasonal distribution, disease course and inflammatory changes in CSF differ between groups of patients affected by the most common viral infections.

Comparison of parathyroid hormone and strontium ranelate in combination with whole-body vibration in a rat model of osteoporosis.

We investigated the combinatorial effects of whole-body vertical vibration (WBVV) with the primarily osteoanabolic parathyroid hormone (PTH) and the mainly antiresorptive strontium ranelate (SR) in a rat model of osteoporosis. Ovariectomies were performed on 76 three-month-old Sprague-Dawley rats (OVX, n = 76; NON-OVX, n = 12). After 8 weeks, the ovariectomized rats were divided into 6 groups. One group (OVX + PTH) received daily injections of PTH (40 µg/kg body weight/day) for 6 weeks. Another group (OVX + SR) was fed SR-supplemented chow (600 mg/kg body weight/day). Three groups (OVX + VIB, OVX + PTH + VIB, and OVX + SR + VIB) were treated with WBVV twice a day at 70 Hz for 15 min. Two groups (OVX + PTH + VIB, OVX + SR + VIB) were treated additionally with PTH and SR, respectively. The rats were killed at 14 weeks post-ovariectomy. The lumbar vertebrae and femora were removed for biomechanical and morphological assessment. PTH produced statistically significant improvements in biomechanical and structural properties, including bone mineral density (BMD) and trabecular bone quality. In contrast, SR treatment exerted mild effects, with significant effects in cortical thickness only. SR produced no significant improvement in biomechanical properties. WBVV as a single or an adjunctive therapy produced no significant improvements. In conclusion, vibration therapy administered as a single or dual treatment had no significant impact on bones affected by osteoporosis. PTH considerably improved bone quality in osteoporosis cases and is superior to treatment with SR.

Two stage Innoslab amplifier for energy scaling from 100 to >500 mJ for future lidar applications.

An Nd:YAG-MOPA system consisting of a stable oscillator and two subsequent Innoslab-based amplifier stages has been designed and built as a technology demonstrator for future lidar applications. Overall, the authors demonstrate that it generates more than 500 mJ of pulse energy at a 1064 nm wavelength and 100 Hz pulse repetition frequency at about 30 ns pulse duration in the single longitudinal mode. Seeded with 75 mJ pulses, the second amplifier stage achieved an optical efficiency (extracted energy to pump energy) of more than 23% while preserving excellent beam quality. To address the 500 mJ regime while retaining the basic system properties, an established Innoslab design was scaled geometrically.

Successful retreatment with combined BRAF/MEK inhibition in metastatic BRAFV600-mutated melanoma.

BACKGROUND: The combination treatment with BRAF and MEK inhibitors is amongst the current standard of care for stage IIIC/IV BRAF-mutated melanoma. However, therapeutic options are limited once patients have progressed upon both targeted and immunotherapy. OBJECTIVE: To investigate whether retreatment with BRAF and MEK inhibitor combination is an option for patients with metastatic BRAF-mutated melanoma upon previous progression on kinase inhibitors. METHODS: Two patients with metastatic BRAF-mutated melanoma were rechallenged with BRAF and MEK inhibitor combination after progression on targeted therapy and subsequent immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies. RESULTS: Both patients responded to retreatment. Responses were limited to a few months and associated with a considerable increase in quality of life. CONCLUSION: Retreatment with BRAF and MEK inhibitors may present a feasible treatment option upon progression on both kinase inhibitors and immunotherapy, and should be considered when all other treatment options have been exhausted.

1,3-ß-D-Glucan contamination of common antimicrobials.

BACKGROUND: 1,3-ß-D-Glucan (BDG) is a fungal cell wall constituent used in the diagnosis of invasive fungal infections. BDG testing, although endorsed by the European Organization for Research and Treatment of Cancer, suffers from limited specificity. False-positive results have been linked to haemodialysis membranes, blood products, antineoplastic agents and antimicrobial use. OBJECTIVES: The aim of this study was to determine whether false-positive BDG results in the context of antimicrobial use are caused by BDG present in infusion solutions. METHODS: We obtained 35 antimicrobial drugs (30 antibiotics and 5 antifungals) and analysed their BDG content using two different assays. RESULTS: Twenty-five antimicrobials (20 antibiotics and all the tested antifungals) contained enough BDG to trigger a positive test. Depending on the substance, BDG varied between 9 and 2818 pg/mL. CONCLUSIONS: A majority of the available antimicrobial substances contained BDG, potentially limiting the utility of BDG testing in the context of prior exposure to these drugs. As the cumulative effects of repeated BDG exposure are unknown, efforts to reduce contamination should be considered.