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1.
Sci Rep ; 14(1): 3270, 2024 Feb 08.
Article in English | MEDLINE | ID: mdl-38332222

ABSTRACT

Dissolved organic matter (DOM) and its composition in aquatic ecosystems is a key indicator of ecosystem function and an important component of the global carbon cycle. Tropical rainforest headwaters play an important role in global carbon cycling. However, there is a large uncertainty on how DOM sources interact during mobilisation and the potential fate of associated carbon and nutrients. Using field techniques to measure dissolved organic carbon (DOC) concentration and composition, changes in DOM source from headwaters to larger downstream rivers were observed. This study shows that the hydrological connectivity, developed during the transition from dry to wet seasons, changes the DOM supply and transport across a tropical river catchment. The observed variability in the DOC-river discharge relationship provides further evidence of the changes in the DOM supply in a small headwater. This novel insight into the seasonal changes of the dynamics of DOM supply to the river helps understanding the mobilization of terrestrial DOM to tropical headwaters and its export from smaller to larger rivers. It also highlights the data gap in the study of smaller headwaters which may account for uncertainty in estimating the terrestrial carbon transported by inland waters.

2.
Clin Radiol ; 78(9): 666-670, 2023 09.
Article in English | MEDLINE | ID: mdl-37349201

ABSTRACT

AIM: To investigate the opinions of clinician referrers on the presence and type of management advice in reports of positron-emission tomography (PET)-computed tomography (CT) examinations. MATERIALS AND METHODS: Eighteen clinicians were interviewed using a structured questionnaire about their opinions on further management advice in PET-CT reports. RESULTS: Opinions varied amongst clinicians, but some themes predominated: (1) advice on further imaging tests and areas outside the referrer's area of expertise are more welcome than other types of advice; (2) a differential diagnosis or clinical significance is of greater value than specific management advice; (3) some referrers do not want any further advice. CONCLUSION: Before advising on further management, reporters should consider clinicians' opinions regarding this. Seeking the opinion of clinicians in other hospitals may be necessary. A review of the Royal College of Radiologists Actionable Reports standard to ensure it is more in line with the opinions of clinicians may be useful.


Subject(s)
Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , Humans , Surveys and Questionnaires
3.
Acta Oncol ; 62(7): 689-695, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37151105

ABSTRACT

BACKGROUND: Testicular cancer survivors (TCS) are at risk of Leydig cell insufficiency, which is a condition characterized by elevated luteinising hormone (LH) in combination with low levels of testosterone. It has been suggested that this condition is associated with impaired metabolic profile and low bone mineral density (BMD). The primary aim of the randomized double-blind trial NCT02991209 was to evaluate metabolic profile after 12-months testosterone replacement therapy (TRT) in TCS with mild Leydig cell insufficiency. Here we present the secondary outcomes of changes in BMD and markers of bone turnover. METHODOLOGY: In total, 69 TCS with mild Leydig cell insufficiency were randomized 1:1 to 12 months TRT (n = 35) (Tostran, gel, 2%, applied transdermally, with a maximum daily dose of 40 mg) or placebo (n = 34). BMD and markers of bone turnover were evaluated at baseline, after 6- and 12-months TRT, and 3-months post-treatment. Linear mixed effects models were used to analyse changes in BMD, N-terminal propeptide of type 1 procollagen (P1NP) and C-terminal telopeptide of type I collagen (CTX). RESULTS: After 12 months treatment, TRT was not associated with a statistically significant difference in BMD compared to placebo; total body BMD: 0.01 g/cm2 (95% confidence interval (CI): -0.01 - 0.02), BMD of the lumbar spine: 0.01 g/cm2, (95% CI: -0.01-0.03), BMD of the left femoral neck: 0.00, (95% CI: -0.01-0.02). TRT was associated with a small but statistically significant increase in P1NP: 11.65 µg/L (95% CI: 3.96, 19.35), while there was no difference in CTX. CONCLUSION: 12 months of TRT did not change BMD, while there was as small and clinically irrelevant increase in P1NP compared to placebo in TCS with mild Leydig cell insufficiency. The findings need validation in a larger cohort.


Subject(s)
Bone Density , Testicular Neoplasms , Male , Humans , Testicular Neoplasms/drug therapy , Testosterone/pharmacology , Testosterone/therapeutic use , Bone Remodeling , Survivors , Double-Blind Method , Biomarkers
4.
J Am Vet Med Assoc ; 261(2): 217-222, 2022 12 01.
Article in English | MEDLINE | ID: mdl-36459451

ABSTRACT

OBJECTIVE: To evaluate the anesthetic and cardiopulmonary effects of ketamine-dexmedetomidine combined with local anesthesia, associated or not in the postoperative period with different doses of atipamezole, for orchiectomy in cats. ANIMALS: 24 healthy cats. PROCEDURES: Cats received ketamine (7 mg/kg) combined with dexmedetomidine (10 µg/kg) IM, and 1 mL of saline (group KDSAL), 25 µg/kg (group KDAT25), or 50 µg/kg (group KDAT50) of atipamezole IV, postoperatively. All cats received local anesthesia (2 mg/kg of lidocaine) intratesticular and SC. Physiologic variables were recorded at baseline and at time points during anesthesia. Ketamine rescue dose (1 mg/kg) was recorded. The quality of recovery, the degree of sedation, and side effects were evaluated postoperatively. RESULTS: 2 cats received a single additional bolus of ketamine to perform local anesthesia. Heart rate was lower in KDSAL, KDAT25, and KDAT50 during anesthesia, compared with baseline. Hypertension was observed intraoperatively in all groups. The time to head up, pedal reflex regained time, time to sternal recumbency, and time to standing were shorter in KDAT25 and KDAT50 compared to KDSAL. Lower sedation scores were assigned sooner to KDAT25 and KDAT50 than KDSAL. All groups resulted in low recovery quality scores and no side effects. CLINICAL RELEVANCE: At the doses used, ketamine-dexmedetomidine combined with local anesthesia allowed the performance of orchiectomy. Rescue dose of ketamine for performing local anesthesia may be required. This combination can result in hypertension. Both atipamezole doses shortened the anesthetic recovery, without differences among them, and side effects.


Subject(s)
Anesthetics , Cat Diseases , Dexmedetomidine , Hypertension , Ketamine , Male , Cats , Animals , Orchiectomy/veterinary , Anesthesia, Local/veterinary , Postoperative Period , Hypertension/veterinary
5.
J Vet Cardiol ; 41: 88-98, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35287008

ABSTRACT

OBJECTIVES: To describe the use of the Amplatzer vascular plug II (AVPII) for transvenous occlusion of patent ductus arteriosus in a non-selective population of dogs, with a focus on the surgical technique, short term outcome and associated complications. ANIMALS, MATERIALS AND METHODS: Retrospective study. Records of thirty-two consecutive dogs treated for a left-to-right shunting patent ductus arteriosus with the AVPII were reviewed. RESULTS: Ductal occlusion with an AVPII occlusion device was attempted in 32 dogs weighing 1.1-53.8 kg. Transvenous occlusion was successful in 30 dogs. One dog required a transarterial approach for occlusion. One dog died during catheterisation of the right heart but prior to transductal catheterisation. Mean ductal ampulla diameter was 7.9 mm (range, 4.1-15.4 mm) and median size of deployed devices was 10 mm (range 4-20 mm). Mean device to ampulla ratio was 1.34 ± 0.15. Device was positioned in situ with no residual flow on follow-up echocardiographic assessment (> one month) in all dogs where deployment was attempted. Occlusion success rate was 96.9% and mortality rate was 3.1%. Four dogs (13.3%) demonstrated minor complications, with none having long-term significance. CONCLUSIONS: The use of AVPII device via a transvenous approach is a feasible and effective method for occlusion of a left-to-right shunting patent ductus arteriosus in dogs of a wide range of weight. The method described may complement existing catheter-based occlusion methods.


Subject(s)
Dog Diseases , Ductus Arteriosus, Patent , Animals , Cardiac Catheterization/veterinary , Dog Diseases/diagnostic imaging , Dog Diseases/surgery , Dogs , Ductus Arteriosus, Patent/surgery , Ductus Arteriosus, Patent/veterinary , Echocardiography , Heart , Retrospective Studies , Treatment Outcome
6.
Appl Opt ; 61(5): B156-B163, 2022 Feb 10.
Article in English | MEDLINE | ID: mdl-35201136

ABSTRACT

Today's state-of-the-art automotive head-up displays (HUD) possess single- or double layer focal planes that limit the observers' eye focus to these planes when crucial information is shown. Other visual 3D cues such as motion parallax also suffer from this limitation. The resulting viewing experience contradicts the natural way of viewing during driving or interaction, when alerts and hints should appear at the correct projection depth where real objects of interest are located. Here we present a real-time holographic HUD with continuous depth that supports the intuitive and natural way of viewing and interacting with virtual environments outside and inside the car. We demonstrate full-color, 3D real-time encoding within a field-of-view of 5∘×3∘.


Subject(s)
Depth Perception , Holography , Cues , Motion
7.
Clin Radiol ; 77(3): 195-202, 2022 03.
Article in English | MEDLINE | ID: mdl-34953570

ABSTRACT

AIM: To assess the rates of nodal and metastatic disease and change in management when staging part-solid T1 lung adenocarcinomas using integrated 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)-computed tomography (CT) in a UK population. MATERIALS AND METHODS: This was a retrospective review of PET-CT examinations performed to stage radiologically suspected T1 part-solid lung adenocarcinoma (n=58) from two different centres. Rates of detection of nodal and metastatic disease, change in management, and final patient outcome were recorded. RESULTS: PET-CT changed the stage in one patient from N0 to N1. It did not change final management in any patient. CONCLUSIONS: In this UK population, PET-CT had minimal additional diagnostic benefit in staging patients with T1 part-solid lung adenocarcinoma. Especially given its cost, the inclusion of PET-CT for this indication in guidelines should be reviewed.


Subject(s)
Adenocarcinoma of Lung/diagnostic imaging , Fluorodeoxyglucose F18 , Lung Neoplasms/diagnostic imaging , Positron Emission Tomography Computed Tomography/methods , Radiopharmaceuticals , Adenocarcinoma of Lung/pathology , Aged , Aged, 80 and over , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Positron Emission Tomography Computed Tomography/economics , Retrospective Studies , United Kingdom
8.
Clin Radiol ; 76(8): 553-558, 2021 08.
Article in English | MEDLINE | ID: mdl-34053731

ABSTRACT

We present a multimodality pictorial review of axillary lymphadenopathy in patients recently vaccinated against COVID-19. As the mass vaccination programme continues to be rolled out worldwide in an effort to combat the pandemic, it is important that radiologists consider recent COVID-19 vaccination in the differential diagnosis of unilateral axillary lymphadenopathy and are aware of typical appearances across all imaging methods. We review current guidelines on the management of unilateral axillary lymphadenopathy in the context of recent COVID-19 vaccination.


Subject(s)
Axilla/diagnostic imaging , COVID-19 Vaccines , COVID-19/prevention & control , Lymphadenopathy/chemically induced , Lymphadenopathy/diagnostic imaging , Practice Guidelines as Topic , Humans , Mass Vaccination , Pandemics , SARS-CoV-2
9.
Monatsschr Kinderheilkd ; 169(4): 317-321, 2021.
Article in German | MEDLINE | ID: mdl-33686311

ABSTRACT

The boy of Egyptian origin was previously healthy. After a history of fever for 7 days, abdominal pain, vomiting and dry cough resistant to treatment with oral antibiotics, he was admitted to hospital. The clinical examination showed a slightly red throat, a tense abdomen and erythema. The blood tests revealed leukocytosis and significantly increased inflammatory parameters. The abdominal ultrasound showed thickened intestinal loops in the left lower abdomen and the echocardiography showed minimal mitral regurgitation, a narrow pericardial effusion lamella over both ventricles and normal coronary arteries. Accordingly, cardiac enzymes were elevated. The day after admission, the boy developed an increasing rash and was transferred to the PICU because of septic shock refractory to high volume resuscitation, requiring hemodynamic support with noradrenaline and noninvasive respiratory assistance. The initial testing for SARS-CoV­2 on nasopharyngeal aspirates was negative twice; however, serum IgG antibodies were positive. Other viral and bacterial infections were excluded as the cause of the symptoms.The patient received IVIG, ASS, furosemide and methylprednisolone and the antibiotic treatment was continued. The dosage of the catecholamine could be reduced according to the patient's condition and the serially performed echocardiographic findings. The patient recovered in his general condition and was discharged from the PICU after 8 days. With the help of a detailed family history, we were able to figure out that the whole family, including the patient himself, had symptoms of a cold about 1 month earlier. Hence, SARS-CoV­2 antibody tests carried out showed a positive result for all of them.Pediatric inflammatory multisystem syndrome (PIMS) can quickly lead to manifest shock symptoms, necessitating close monitoring. A PICU background is crucial to treat possibly occurring symptoms and complications. High-dose steroids are used therapeutically alongside supportive therapies.

10.
Clin Radiol ; 76(2): 84-87, 2021 Feb.
Article in English | MEDLINE | ID: mdl-32883516

ABSTRACT

The imaging report is a summary document of findings and the primary form of communication of such to referring clinicians. Expressing uncertainty in the summary report is clearly difficult and the literature is unanimous that there is no agreement between imaging consultants and clinicians, and even between imaging consultants themselves, as to the meaning of uncertainty phrases. It is important for the imaging consultants to express uncertainty in the imaging report, but it is equally important that the referring clinician understands the degree of that uncertainty. Individual terminology does not bridge that gap. The present study reviews the literature in order to differentiate between uncertainty phrasing and hedging, and to find best practice examples to inform practice. We suggest three approaches that may be applied.


Subject(s)
Diagnostic Imaging/methods , Research Report , Uncertainty , Humans
11.
J Dairy Sci ; 104(1): 928-936, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33162088

ABSTRACT

The introduction of heifers into the automatic milking system (AMS) can be associated with considerable stress for both animals and farm employees, as completely inexperienced heifers initially do not independently enter the unknown milking robot. This study investigated whether training heifers on an AMS phantom provides the possibility of preparing heifers for the following lactation at the AMS. For this purpose, 77 Holstein-Friesian heifers were randomly assigned to one of 2 experimental groups: control (CON) or phantom (PHAN). Four weeks before calving, the PHAN group was given free access to the phantom, which was similar to the actual milking robot, so that they could explore it and be positively conditioned by feeding concentrate in the phantom. The heifers of the CON group had no contact with the phantom or the AMS before the first milking at the AMS. The milking frequency per animal per day was recorded, and the proportion of animals that had to be fetched for milking was determined, to evaluate how the animals accepted the AMS after calving. To assess the stress level of the animals before and after introduction into the AMS, fecal cortisol concentrations and rumination times of the animals were measured. Additionally, lactation performance characteristics (milk yield, milk flow, electrical conductivity of milk, and milk composition) were recorded for 77 animals. The animals trained on the phantom showed a higher milking frequency (DIM 7: 2.70 ± 0.14 visits/d) than the control animals (DIM 7: 2.41 ± 0.14 visits/d) between the 4th and 10th day of lactation. In addition, between d 1 and d 5, the proportion of animals that had to be fetched for milking was lower in PHAN (DIM 1: 35.18 ± 4.16%) than in CON (DIM 1: 48.03 ± 4.46%). The PHAN heifers had unexpectedly high fecal cortisol levels (1 wk prepartum: 43.50 ± 0.93 ng/g of feces), although not considerably elevated compared with CON (1 wk prepartum: 40.76 ± 1.05 ng/g of feces). Training on the phantom had no appreciable influence on rumination time and lactation performance parameters. The increased number of milking visits and the reduced proportion of animals that had to be fetched into the AMS for milking indicate that training on the phantom prepares the animals well for being milked in the AMS. Therefore, training heifers on the phantom offers the possibility to facilitate the start into early lactation for the animals, providing a valuable contribution to improvement of animal welfare.


Subject(s)
Cattle , Dairying/methods , Milk , Animal Welfare , Animals , Automation , Farms , Female , Lactation , Learning
13.
Rev Sci Instrum ; 91(10): 103102, 2020 Oct 01.
Article in English | MEDLINE | ID: mdl-33138582

ABSTRACT

We present a novel locking scheme for active length-stabilization and frequency detuning of a cavity optomechanical device based on the optical spring effect. The error signal is generated by utilizing the position measurement of a thermally driven intra-cavity nanomechanical device and employing its detuning-dependent frequency shift caused by the dispersive coupling to the cavity field. The scheme neither requires external modulation of the laser or the cavity nor does it demand for additional error signal readout, rendering its technical implementation rather simple for a large variety of existing optomechanical devices. Specifically, for large-linewidth microcavities or in situations where other locking schemes appear unfavorable conceptually or are hard to realize technically, the optical spring lock represents a potential alternative for stabilizing the cavity length. We explain the functional principle of the lock and characterize its performance in terms of bandwidth and gain profile.

14.
Ecol Appl ; 30(8): e02187, 2020 12.
Article in English | MEDLINE | ID: mdl-32485044

ABSTRACT

Agricultural land use is typically associated with high stream nutrient concentrations and increased nutrient loading to lakes. For lakes, evidence for these associations mostly comes from studies on individual lakes or watersheds that relate concentrations of nitrogen (N) or phosphorus (P) to aggregate measures of agricultural land use, such as the proportion of land used for agriculture in a lake's watershed. However, at macroscales (i.e., in hundreds to thousands of lakes across large spatial extents), there is high variability around such relationships and it is unclear whether considering more granular (or detailed) agricultural data, such as fertilizer application, planting of specific crops, or the extent of near-stream cropping, would improve prediction and inform understanding of lake nutrient drivers. Furthermore, it is unclear whether lake N and P would have different relationships to such measures and whether these relationships would vary by region, since regional variation has been observed in prior studies using aggregate measures of agriculture. To address these knowledge gaps, we examined relationships between granular measures of agricultural activity and lake total phosphorus (TP) and total nitrogen (TN) concentrations in 928 lakes and their watersheds in the Northeastern and Midwest U.S. using a Bayesian hierarchical modeling approach. We found that both lake TN and TP concentrations were related to these measures of agriculture, especially near-stream agriculture. The relationships between measures of agriculture and lake TN concentrations were more regionally variable than those for TP. Conversely, TP concentrations were more strongly related to lake-specific measures like depth and watershed hydrology relative to TN. Our finding that lake TN and TP concentrations have different relationships with granular measures of agricultural activity has implications for the design of effective and efficient policy approaches to maintain and improve water quality.


Subject(s)
Lakes , Phosphorus , Agriculture , Bayes Theorem , China , Environmental Monitoring , Nitrogen/analysis , Phosphorus/analysis
15.
Appl Opt ; 59(13): D179-D188, 2020 May 01.
Article in English | MEDLINE | ID: mdl-32400641

ABSTRACT

Differential optical absorption spectroscopy (DOAS) is notably well suited for the retrieval of UV-absorbing trace gases present in the atmosphere. We combine multi-axis DOAS observations to perform a tomographic reconstruction of the distribution of gases emitted from different sources. We use a new algorithm based on a regularized minimization approach embedding key physical aspects of the solution to constrain the inversion. In this work, we take into account that the spatial sampling of the plume being scanned by the instruments is not homogeneous. Therefore, we introduce an adaptive approach with a locally tuned regularization weight according to the uncertainty levels introduced by the sampling scheme. We tested our approach on reconstructions of simulated gas distributions and different configurations applicable to multi-axis DOAS. Finally, our approach is applied to experimental data for the retrieval of the distribution of ${\rm NO}_2$NO2 within a plume cross section emitted from a group of stacks.

16.
Colorectal Dis ; 22(7): 818-823, 2020 07.
Article in English | MEDLINE | ID: mdl-31961476

ABSTRACT

AIM: Currently, there is no clear consensus on the role of extended pelvic resections for locally advanced or recurrent disease involving major vascular structures. The aims of this study were to report the outcomes of consecutive patients undergoing extended resections for pelvic malignancy involving the aortoiliac axis. METHODS: Prospective data were collected on patients having extended radical resections for locally advanced or recurrent pelvic malignancies, with aortoiliac axis involvement, requiring en bloc vascular resection and reconstruction, at a single institution between 2014 and 2018. RESULTS: Eleven patients were included (median age 60 years; range 31-69 years; seven women). The majority required resection of both arterial and venous systems (n = 8), and the technique for vascular reconstruction was either interposition grafts or femoral-femoral crossover grafts. The median operative time was 510 min (range 330-960 min). Clear resection margins (R0) were achieved in nine patients. The median length of stay was 25 days (range 7-83 days). Seven patients did not suffer an early complication. There was one serious complication (Clavien-Dindo ≥ 3), an arterial graft occlusion secondary to thrombus in the immediate postoperative period, requiring a return to theatre and thrombectomy. The median length of follow-up in this study was 22 months (range 4-58 months). CONCLUSION: This series demonstrates that en bloc major vascular resection and reconstruction can be performed safely and can achieve clear resection margins in selected patients with locally advanced or recurrent pelvic malignancy at specialist surgery centres.


Subject(s)
Pelvic Exenteration , Pelvic Neoplasms , Adult , Aged , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/surgery , Pelvic Exenteration/adverse effects , Pelvic Neoplasms/surgery , Prospective Studies , Retrospective Studies , Treatment Outcome
17.
Clin Radiol ; 74(10): 818.e17-818.e23, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31420186

ABSTRACT

AIM: To assess the diagnostic performance of combined 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography (PET)/computed tomography (CT) mediastinal blood pool (MBP) activity cut-off for staging nodal involvement, and to examine other variables that may improve the diagnostic performance of PET/CT in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: All patients diagnosed with NSCLC who underwent endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and 18F-FDG-PET/CT between June 2016 and August 2018 were included. Nodal station and nodal staging-based analyses were performed, comparing the MBP cut-off and five other PET/CT parameters (node maximum standardised uptake value [SUVmax], node/MBP SUVmax ratio, node/tumour SUVmax ratio, node short axis diameter, and node SUVmax/node short axis diameter ratio) with histopathology results. The optimal cut-off value for each PET/CT parameter was determined using receiver operating characteristic curve analysis. RESULTS: One hundred and thirteen patients with a total of 321 nodes with pathological sampling were included. Nodal activity above MBP on PET/CT demonstrated 97.4% sensitivity, 35.8% specificity, 32.8% positive predictive value, and 97.8% negative predictive value. Of the five other PET/CT parameters examined, the two most promising were node SUVmax and node/MBP SUVmax. The node SUVmax cut-off of 3.9 demonstrated 90.9% sensitivity and 61.9% specificity, and the node/MBP SUVmax cut-off of 1.7 demonstrated 90.9% sensitivity and 60.7% specificity. CONCLUSION: Compared to the MBP cut-off, use of a higher node/MBP SUVmax ratio cut-off and use of other PET/CT variables can improve the diagnostic performance of PET/CT for NSCLC nodal staging. In particular, specificity for detecting malignant nodal involvement is improved while maintaining high sensitivity.


Subject(s)
Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Lung Neoplasms/diagnostic imaging , Lymph Nodes/diagnostic imaging , Lymphatic Metastasis/diagnostic imaging , Positron Emission Tomography Computed Tomography , Adult , Aged , Aged, 80 and over , Biopsy, Fine-Needle , Carcinoma, Non-Small-Cell Lung/pathology , Female , Fluorodeoxyglucose F18 , Humans , Lung Neoplasms/pathology , Lymph Nodes/pathology , Male , Middle Aged , Radiopharmaceuticals , Sensitivity and Specificity
18.
Br J Dermatol ; 180(6): 1352-1360, 2019 06.
Article in English | MEDLINE | ID: mdl-30207587

ABSTRACT

BACKGROUND: The relevance of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the management of psoriasis has not been studied previously. GM-CSF is important in the initiation and maintenance of chronic inflammatory processes. OBJECTIVES: To investigate the clinical use of GM-CSF neutralization by evaluating the efficacy and safety of namilumab (AMG203), a monoclonal antibody GM-CSF inhibitor, in patients with moderate-to-severe plaque psoriasis. METHODS: A phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group, dose-finding, proof-of-concept study (NEPTUNE) was conducted. Four doses of namilumab (20, 50, 80 and 150 mg, via subcutaneous injection) were compared with placebo. Assessment of the primary end point - the proportion of patients achieving ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75 treatment response) - was performed at week 12. Exploratory investigation at the tissue level was conducted in a subset of the overall study population. The trial was registered with the number NCT02129777. RESULTS: In total, 122 patients were enrolled and 106 (86·9%) completed the double-blind treatment; 16 (13·1%) prematurely discontinued study medication. Serum concentration-time profiles were as expected for subcutaneous delivery of an IgG1 monoclonal antibody, and exposure increased proportionally with dose elevation. The number of patients showing PASI 75 treatment response at week 12 was low in all groups; no significant difference was recorded in this end point between placebo and any namilumab group. Similar outcomes were recorded for other clinical study end points. Moreover, no significant treatment-related changes from baseline were observed in laboratory investigations of cell types or subpopulations, or cytokines relevant to inflammatory pathways in psoriasis. CONCLUSIONS: GM-CSF blockade is not critical for suppression of key inflammatory pathways underlying psoriasis.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Dermatologic Agents/administration & dosage , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Psoriasis/drug therapy , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Dermatologic Agents/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Female , Humans , Male , Treatment Outcome
19.
mSphere ; 3(6)2018 11 07.
Article in English | MEDLINE | ID: mdl-30404935

ABSTRACT

Enterococcus faecium has a highly variable genome prone to recombination and horizontal gene transfer. Here, we have identified a novel genetic island with an insertion locus and mobilization genes similar to those of staphylococcus cassette chromosome elements SCCmec This novel element termed the enterococcus cassette chromosome (ECC) element was located in the 3' region of rlmH and encoded large serine recombinases ccrAB similar to SCCmec Horizontal transfer of an ECC element termed ECC::cat containing a knock-in cat chloramphenicol resistance determinant occurred in the presence of a conjugative reppLG1 plasmid. We determined the ECC::cat insertion site in the 3' region of rlmH in the E. faecium recipient by long-read sequencing. ECC::cat also mobilized by homologous recombination through sequence identity between flanking insertion sequence (IS) elements in ECC::cat and the conjugative plasmid. The ccrABEnt genes were found in 69 of 516 E. faecium genomes in GenBank. Full-length ECC elements were retrieved from 32 of these genomes. ECCs were flanked by attR and attL sites of approximately 50 bp. The attECC sequences were found by PCR and sequencing of circularized ECCs in three strains. The genes in ECCs contained an amalgam of common and rare E. faecium genes. Taken together, our data imply that ECC elements act as hot spots for genetic exchange and contribute to the large variation of accessory genes found in E. faeciumIMPORTANCEEnterococcus faecium is a bacterium found in a great variety of environments, ranging from the clinic as a nosocomial pathogen to natural habitats such as mammalian intestines, water, and soil. They are known to exchange genetic material through horizontal gene transfer and recombination, leading to great variability of accessory genes and aiding environmental adaptation. Identifying mobile genetic elements causing sequence variation is important to understand how genetic content variation occurs. Here, a novel genetic island, the enterococcus cassette chromosome, is shown to contain a wealth of genes, which may aid E. faecium in adapting to new environments. The transmission mechanism involves the only two conserved genes within ECC, ccrABEnt, large serine recombinases that insert ECC into the host genome similarly to SCC elements found in staphylococci.


Subject(s)
Chromosomes, Bacterial , Enterococcus faecium/genetics , Gene Transfer, Horizontal , Genomic Islands , Recombination, Genetic , Conjugation, Genetic , DNA Transposable Elements , Plasmids , Sequence Analysis, DNA
20.
J Proteomics ; 187: 28-38, 2018 09 15.
Article in English | MEDLINE | ID: mdl-29857065

ABSTRACT

Enterococcus faecium is a commensal but also a bacteremia causing pathogen, which is inherently resistant to several antimicrobials and has a great ability to acquire new traits. Bacterial membrane vesicles (MVs) are increasingly recognized as a mode of cell-free communication and a way to deliver virulence factors and/or antimicrobial resistance determinants. These features make MVs interesting research targets in research on critical hospital pathogens. This study describes for the first time that E. faecium strains produce MVs. It presents a morphological as well as a proteomic analysis of MVs isolated from four different, clinically relevant E. faecium strains grown under two different conditions and identifies MV-associated proteins in all of them. Interestingly, 11 virulence factors are found among the MV-associated proteins, including biofilm-promoting proteins and extracellular matrix-binding proteins, which may aid in enterococcal colonization. Additionally, 11 antimicrobial resistance-related proteins were MV-associated. Among those, all proteins encoded by the vanA-cluster of a vancomycin resistant strain were found to be MV-associated. This implies that E. faecium MVs may be utilized by the bacterium to release proteins promoting virulence, pathogenicity and antimicrobial resistance. SIGNIFICANCE: Enterococcal infections, especially bacteremia and endocarditis, are challenging to treat because E. faecium have acquired resistance to multiple classes of antimicrobials, including ampicillin, aminoglycosides, and glycopeptides. Thus, research on different modes of enterococcal pathogenicity is warranted. This study utilized a proteomic approach to identify MV-associated proteins of different nosocomial E. faecium strains representing four clinically relevant sequence types (STs), namely ST17, ST18, ST78, and ST192. The presented data suggest that E. faecium MVs are involved in virulence and antimicrobial resistance.


Subject(s)
Cytoplasmic Vesicles/metabolism , Drug Resistance, Bacterial , Enterococcus faecium/physiology , Gram-Positive Bacterial Infections/metabolism , Virulence Factors/metabolism , Anti-Bacterial Agents/pharmacology , Cell Membrane/metabolism , Cell Membrane/microbiology , Cytoplasmic Vesicles/microbiology , Gram-Positive Bacterial Infections/pathology , Proteomics/methods
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