The acute inflammatory response to copper(II)-doped biphasic calcium phosphates.

Infection and inflammation are two key features to consider to avoid septic or aseptic loosening of bone-implanted biomaterials. In this context, various approaches to fine-tune the biomaterial's properties have been studied in order to modulate the crosstalk between immune and skeletal cells. Cation-doping strategies for tuning of calcium phosphates properties has been evidenced as a promising way to control the biomaterial-induced inflammatory process, and thus improving their osteoimmunomodulatory properties. Copper(II) ions are recognized for their antibacterial potential, but the literature on their impact on particulate material-induced acute inflammation is scarce. We synthesized copper(II) ions-doped biphasic calcium phosphate (BCP), intended to exhibit osteoimmunomodulatory properties. We addressed in vitro, for the first time, the inflammatory response of human primary polymorphonuclear neutrophils (PMNs) to copper(II) ions-doped or undoped (BCP) powders, synthesized by an original and robust wet method, in the presence or absence of LPS as a costimulant to mimic an infectious environment. ELISA and zymography allowed us to evidence, in vitro, a specific increase in IL-8 and GRO-α secretion but not MIP-1ß, TNF-α, or MMP-9, by PMNs. To assess in vivo relevance of these findings, we used a mouse air pouch model. Thanks to flow cytometry analysis, we highlighted an increased PMN recruitment with the copper(II) ions-doped samples compared to undoped samples. The immunomodulatory effect of copper(II) ions-doped BCP powders and the consequent induced moderate level of inflammation may promote bacterial clearance by PMNs in addition to the antimicrobial potential of the material. Copper(II) doping provides new insights into calcium phosphate (CaP)-based biomaterials for prosthesis coating or bone reconstruction by effectively modulating the inflammatory environment.

Cardiovascular risk and kidney function profiling using conventional and novel biomarkers in young adults: the African-PREDICT study.

BACKGROUND: Low- and middle-income countries experience an increasing burden of chronic kidney disease. Cardiovascular risk factors, including advancing age, may contribute to this phenomenon. We (i) profiled cardiovascular risk factors and different biomarkers of subclinical kidney function and (ii) investigated the relationship between these variables. METHODS: We cross-sectionally analysed 956 apparently healthy adults between 20 and 30 years of age. Cardiovascular risk factors such as high adiposity, blood pressure, glucose levels, adverse lipid profiles and lifestyle factors were measured. Various biomarkers were used to assess subclinical kidney function, including estimated glomerular filtration rate (eGFR), urinary albumin, uromodulin and the CKD273 urinary proteomics classifier. These biomarkers were used to divide the total population into quartiles to compare extremes (25th percentiles) on the normal kidney function continuum. The lower 25th percentiles of eGFR and uromodulin and the upper 25th percentiles of urinary albumin and the CKD273 classifier represented the more unfavourable kidney function groups. RESULTS: In the lower 25th percentiles of eGFR and uromodulin and the upper 25th percentile of the CKD273 classifier, more adverse cardiovascular profiles were observed. In multi-variable adjusted regression analyses performed in the total group, eGFR associated negatively with HDL-C (ß= -0.44; p < 0.001) and GGT (ß= -0.24; p < 0.001), while the CKD273 classifier associated positively with age and these same risk factors (age: ß = 0.10; p = 0.021, HDL-C: ß = 0.23; p < 0.001, GGT: ß = 0.14; p = 0.002). CONCLUSION: Age, lifestyle and health measures impact kidney health even in the third decade.

Telemonitoring-guided ambulatory fixed CPAP titration versus ambulatory APAP titration in moderate obstructive sleep apnea: A non-inferiority randomized controlled trial.

The present study aimed to evaluate whether titration of fixed continuous positive airway pressure at home using telemonitoring produces patient outcomes equal to auto-adjusting positive airway pressure titration at home for patients with moderate obstructive sleep apnea. Patients were randomized with a 1:1 allocation ratio to receive either auto-adjusting positive airway pressure titration based on the median of the 95th percentile pressure across seven nights or fixed continuous positive airway pressure titration based on a fixed calculated pressure and specific adaptations after telemonitoring of device data after 3 and 7 nights. The results of the ambulatory titration were evaluated with in-laboratory polysomnography after 2 weeks. We hypothesized that fixed continuous positive airway pressure titration would be non-inferior to auto-adjusting positive airway pressure titration in respect to continuous positive airway pressure adherence at a 3-month follow-up. A non-inferiority margin of -0.75 hr was prespecified. One-hundred and four patients were randomly allocated to fixed continuous positive airway pressure (n = 52) and auto-adjusting positive airway pressure (n = 52) titration. The mean difference and the 95% confidence intervals in continuous positive airway pressure adherence after 3 months between the two arms were 0.80 (-0.08, 1.69) hr. The non-inferiority hypothesis was confirmed as the lower one-sided 97.5% confidence interval for the mean difference was above the prespecified margin. Patients in the fixed continuous positive airway pressure titration arm were titrated at significantly lower pressure level and had a significantly lower amount of average leaks compared with auto-adjusting positive airway pressure-titrated patients, while there was no difference in residual obstructive apnea-hypopnea index on polysomnography. Telemonitoring enables ambulatory continuous positive airway pressure titration with fixed pressure that is non-inferior to ambulatory titration with auto-adjusting pressure in patients with moderate obstructive sleep apnea.

Maintenance therapy of patients with recurrent epithelial ovarian carcinoma with the anti-tumor-associated-mucin-1 antibody gatipotuzumab: results from a double-blind, placebo-controlled, randomized, phase II study.

BACKGROUND: Gatipotuzumab is a humanized monoclonal antibody recognizing the carbohydrate-induced epitope of the tumor-associated mucin-1 (TA-MUC1). This study aimed to evaluate the efficacy and safety of switch maintenance therapy with gatipotuzumab in patients with TA-MUC1-positive recurrent ovarian, fallopian tube, or primary high-grade serous peritoneal cancer. PATIENTS AND METHODS: In this double-blind, randomized, placebo-controlled, phase II trial, patients with at least stable disease (SD) following chemotherapy were randomized 2:1 to receive intravenous gatipotuzumab (500 mg followed by 1700 mg 1 week later) or placebo every 3 weeks until tumor progression or unacceptable toxicity occurred. Stratification factors were the number of prior chemotherapy lines (2 versus 3-5), response versus SD after the most recent chemotherapy, and progression-free survival (PFS) <6 versus 6-12 months following the prior therapy. Primary endpoint was PFS according to modified immune-related RECIST 1.1 response criteria. Secondary endpoints were PFS at 6 months, safety, overall response rate, CA-125 progression, overall survival, quality of life, and pharmacokinetics. RESULTS: Overall, 216 patients were randomized to gatipotuzumab (n  = 151) or placebo (n  = 65). Median PFS with gatipotuzumab was 3.5 months as compared with 3.5 months with placebo (hazard ratio 0.96, 95% confidence interval 0.69-1.33, P  = 0.80). No advantage for gatipotuzumab over placebo was seen in the secondary efficacy endpoints or in any stratified subgroups. Gatipotuzumab was well tolerated, with mild to moderate infusion-related reactions being the most common adverse events. CONCLUSIONS: Gatipotuzumab switch maintenance therapy does not improve outcome in TA-MUC1-positive ovarian cancer patients. TRIAL REGISTRATION: ClinicalTrials.govNCT01899599; https://clinicaltrials.gov/ct2/show/NCT01899599.

Advancement of Photospheric Radius Expansion and Clocked Type-I X-Ray Burst Models with the New

We report the first (in)elastic scattering measurement of ^{25}Al+p with the capability to select and measure in a broad energy range the proton resonances in ^{26}Si contributing to the ^{22}Mg(α,p) reaction at type I x-ray burst energies. We measured spin-parities of four resonances above the α threshold of ^{26}Si that are found to strongly impact the ^{22}Mg(α,p) rate. The new rate advances a state-of-the-art model to remarkably reproduce light curves of the GS 1826-24 clocked burster with mean deviation <9% and permits us to discover a strong correlation between the He abundance in the accreting envelope of the photospheric radius expansion burster and the dominance of ^{22}Mg(α,p) branch.

A randomized phase II study comparing the efficacy and safety of the glyco-optimized anti-EGFR antibody tomuzotuximab against cetuximab in patients with recurrent and/or metastatic squamous cell cancer of the head and neck - the RESGEX study.

BACKGROUND: The aim of the RESGEX study was to compare the efficacy and safety of the anti-epidermal growth factor receptor (anti-EGFR) antibody tomuzotuximab against cetuximab both in combination with chemotherapy in patients with recurrent and/or metastatic squamous cell cancer of the head and neck in the first-line treatment. PATIENTS AND METHODS: In this phase II trial 240 patients were equally randomized for six cycles to receive either tomuzotuximab (initial dose 990 mg then 720 mg) weekly and cisplatin 100 mg/m2 and fluorouracil (5-FU; 1000 mg/m2/day, days 1-4) every 3 weeks or cetuximab (400 mg/m2 subsequent 250 mg/m2) weekly with the same chemotherapeutic backbone followed by antibody maintenance treatment. The primary endpoint was progression-free survival. RESULTS: Median progression-free survival was 6.5 months [95% confidence interval (CI) 5.9-7.9 months] in the tomuzotuximab group and 6.2 months (95% CI 5.8-7.3 months) in the cetuximab group (P = 0.86). The median overall survival (OS) estimate was 11.6 months (95% CI 9.5-17.2 months) in the tomuzotuximab group and 13.8 months (95% CI 12.3-16.4 months) in the cetuximab group (P = 0.96). In an exploratory analysis a small subgroup of p16-positive patients had a significantly longer OS compared with p16-negative patients (hazard ratio 1.860, 95% CI 1.09-3.16, P = 0.02). CONCLUSIONS: The glyco-engineered antibody tomuzotuximab failed to demonstrate improved efficacy with a chemotherapeutic backbone in the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma. It remains a so far unanswered question whether such antibody would partner better with different drugs such as checkpoint inhibitors.

[COVID-19 in old age-The geriatric perspective]. / COVID-19 im Alter ­ Die geriatrische Perspektive.

Predominantly the older population is affected by a severe course of COVID-19. The mortality of hospitalized patients with COVID-19 above the age of 80 years is up to 54% in international studies. These observations indicate the necessity to highlight the geriatric perspective on this disease. The diagnostics and treatment of COVID-19 do not differ between younger and older patients but atypical symptoms should be expected more frequently in old age. Older subjects show an increased need for rehabilitation after COVID-19. Paradoxically, increasing rehabilitation demands go along with a reduced availability of geriatric rehabilitation options, the latter being a consequence of closure or downsizing of rehabilitation departments during the pandemic. In general, measures of isolation and quarantine should be diligently balanced as the health and emotional consequences of such measures may be severe in older persons. In light of the poor prognosis of older COVID-19 patients, advanced care planning becomes even more relevant. Caregivers and physicians should be encouraged to compose advanced care directives that also reflect the specific circumstances of COVID-19. Fortunately, current data suggest that the effectiveness of the vaccination with the mRNA-vaccines approved in Germany may be equally high in older compared to younger persons.

Precision Mass Measurements of Neutron-Rich Scandium Isotopes Refine the Evolution of N=32 and N=34 Shell Closures.

We report high-precision mass measurements of ^{50-55}Sc isotopes performed at the LEBIT facility at NSCL and at the TITAN facility at TRIUMF. Our results provide a substantial reduction of their uncertainties and indicate significant deviations, up to 0.7 MeV, from the previously recommended mass values for ^{53-55}Sc. The results of this work provide an important update to the description of emerging closed-shell phenomena at neutron numbers N=32 and N=34 above proton-magic Z=20. In particular, they finally enable a complete and precise characterization of the trends in ground state binding energies along the N=32 isotone, confirming that the empirical neutron shell gap energies peak at the doubly magic ^{52}Ca. Moreover, our data, combined with other recent measurements, do not support the existence of a closed neutron shell in ^{55}Sc at N=34. The results were compared to predictions from both ab initio and phenomenological nuclear theories, which all had success describing N=32 neutron shell gap energies but were highly disparate in the description of the N=34 isotone.

Efficacy of a novel intradermal Lawsonia intracellularis vaccine in pigs against experimental infection and under field conditions.

BACKGROUND: The efficacy of a novel inactivated intradermal Lawsonia intracellularis vaccine, Porcilis® Lawsonia ID, was evaluated in two experimental vaccination-challenge studies and under field conditions on a farm with a history of recurrent acute ileitis. In addition, the efficacy of the vaccine was compared to that of a commercially available live attenuated vaccine. The novel inactivated vaccine consists of a freeze-dried antigen fraction that is dissolved just prior to use in either the adjuvant or in Porcilis® PCV ID; an existing intradermal vaccine against porcine Circovirus type 2. In the two experimental vaccination-challenge studies, groups of 25 piglets were vaccinated once at 3 weeks of age or left unvaccinated as challenge control. Vaccines tested were Porcilis® Lawsonia ID as standalone (study 1) or in associated mixed use with Porcilis® PCV ID (study 2) and an orally administered commercially available live vaccine (study 1). The pigs were challenged with virulent L. intracellularis at 4 weeks (study 1) or 21 weeks (study 2) after vaccination. Post-challenge, the pigs were evaluated for clinical signs, average daily weight gain, shedding and macroscopic as well as microscopic immuno-histological ileum lesion scores. In the field study, the mortality and key performance parameters were evaluated over a period of 8 months. RESULTS: The results of the two experimental vaccination-challenge studies showed that Porcilis® Lawsonia ID as single vaccine or in associated mixed use with Porcilis® PCV ID, induced statistically significant protection against experimental L. intracellularis infection, 4 weeks or 21 weeks after vaccination. This was demonstrated by lower clinical scores, improved weight gain, reduction of L. intracellularis shedding and reduction of macroscopic as well as microscopic ileum lesion scores when compared to the controls. The protection induced was superior to that of the commercially available live vaccine. In the field study Porcilis® Lawsonia ID was highly efficacious in reducing L. intracellularis associated mortality and improving key production parameters. CONCLUSION: The results support that this new intradermal vaccine is efficacious against L. intracellularis and may be used in associated mixed use with Porcilis® PCV ID.

PROSPECT guideline for oncological breast surgery: a systematic review and procedure-specific postoperative pain management recommendations.

Analgesic protocols used to treat pain after breast surgery vary significantly. The aim of this systematic review was to evaluate the available literature on this topic and develop recommendations for optimal pain management after oncological breast surgery. A systematic review using preferred reporting items for systematic reviews and meta-analysis guidance with procedure-specific postoperative pain management (PROSPECT) methodology was undertaken. Randomised controlled trials assessing postoperative pain using analgesic, anaesthetic or surgical interventions were identified. Seven hundred and forty-nine studies were found, of which 53 randomised controlled trials and nine meta-analyses met the inclusion criteria and were included in this review. Quantitative analysis suggests that dexamethasone and gabapentin reduced postoperative pain. The use of paravertebral blocks also reduced postoperative pain scores, analgesia consumption and the incidence of postoperative nausea and vomiting. Intra-operative opioid requirements were documented to be lower when a pectoral nerves block was performed, which also reduced postoperative pain scores and opioid consumption. We recommend basic analgesics (i.e. paracetamol and non-steroidal anti-inflammatory drugs) administered pre-operatively or intra-operatively and continued postoperatively. In addition, pre-operative gabapentin and dexamethasone are also recommended. In major breast surgery, a regional anaesthetic technique such as paravertebral block or pectoral nerves block and/or local anaesthetic wound infiltration may be considered for additional pain relief. Paravertebral block may be continued postoperatively using catheter techniques. Opioids should be reserved as rescue analgesics in the postoperative period. Research is needed to evaluate the role of novel regional analgesic techniques such as erector spinae plane or retrolaminar plane blocks combined with basic analgesics in an enhanced recovery setting.

[Paraneoplastic subacute degeneration of the cerebellum in non-small cell lung cancer and positive anti-Tr3 antibodies]. / Paraneoplastische subakute Degeneration des Kleinhirns bei nichtkleinzelligem Bronchialkarzinom und positiven Anti-Tr3-Antikörpern.

Neurological disorders can occur before the diagnosis of a malignoma is set. These disorders are induced by a misguided immune response with antibodies against intracellular or cell surface antigens. One of the most common paraneoplastic diseases is the subacute degeneration of the cerebellum. In most of the cases antibodies against Anti Hu, CRMP5/CV2, Amphiphysin and Ma/Ta are found and small cell bronchial carcinoma, breast cancer and lymphoma are diagnosed. We report about a 67 years old man with cerebellar symptoms and a weight loss of 10 kg who was treated in our clinic. After our diagnostic work up we found a non small cell cancer and diagnosed a subacute degeneration of the cerebellum as a paraneoplastic disorder. We found a high positive titer for Anti-Tr3 antibodies while the rest of the paraneoplastic antibodies described as typically associated with the subacute degeneration of the cerebellum were negative. The Anti-Tr3 antibodies are usually found in patients with Hodgkin and less often Non-Hodgkin disease. After initiation of a tumor specific therapy and intravenous immunoglobulin therapy the cerebellar symptoms decreased. In future follow up examinations we will see if the anti-Tr3 antibodies were associated with the non small cell bronchial carcinoma or if a lymphoma will occur in our patient.

Following in Jakobson and Lévi-Strauss' footsteps: A neurocognitive poetics investigation of eye movements during the reading of Baudelaire's 'Les Chats'.

Following Jakobson and Levi-Strauss [1] famous analysis of Baudelaire's poem 'Les Chats' ('The Cats'), in the present study we investigated the reading of French poetry from a Neurocognitive Poetics perspective. Our study is exploratory and a first attempt in French, most previous work having been done in either German or English (e.g. [2] [3] [4] [5] [6]). We varied the presentation mode of the poem Les Chats (verse vs. prose form) and measured the eye movements of our readers to test the hypothesis of an interaction between presentation mode and reading behavior. We specifically focussed on rhyme scheme effects on standard eye movement parameters. Our results replicate those from previous English poetry studies in that there is a specific pattern in poetry reading with longer gaze durations and more rereading in the verse than in the prose format. Moreover, presentation mode also matters for making salient the rhyme scheme. This first study generates interesting hypotheses for further research applying quantitative narrative analysis to French poetry and developing the Neurocognitive Poetics Model of literary reading [NCPM; 2] into a cross-linguistic model of poetry reading.

The benefits of experiential learning during a service-learning engagement in child psychiatric nursing education

Background. Children, families and communities are affected by mental health challenges caused by high levels of violence and domestic upheaval in South African (SA) communities. There are too few specialised healthcare professionals, e.g. nurses, psychologists, occupational therapists and social workers, to meet the enormous mental healthcare needs of children and adolescents in the country. Because of the unique challenges people face in this context, professionals need to be trained in all aspects of child psychiatric nursing. One important way to provide this training could be a service-learning strategy. In this approach, nursing students are taught how to engage and educate communities by means of community-outreach programmes that form part of the curriculum. The purpose of this article is to report on nursing students' experiences during their community-engagement outreach programmes in the challenging SA healthcare context.Objectives. To explore and describe students' community-based learning experiences during outreach programmes.Method. A qualitative methodological approach used structured reflection reports of 47 students over 3 years as data. Participants' responses were thematically analysed by content.Results. Nursing students experienced community-learning engagement as thought provoking. They were able to practise their professional development within a collaborative environment, which built self-confidence and stimulated critical thinking. They indicated that the experience made them aware of the needs of the community and enabled them to share reciprocal knowledge. It helped them to integrate theory with practice, develop responsible citizenship and enhance professional development.Conclusion. Evidence from a challenging context supports the use of service learning as an ideal approach to develop students' professionalism, ethical responsibility and personal growth to become responsible citizens who can engage with mental health users in the community

Efficacy of a novel inactivated Lawsonia intracellularis vaccine in pigs against experimental infection and under field conditions.

The efficacy of a novel inactivated Lawsonia intracellularis vaccine, Porcilis® Lawsonia, was compared to that of a commercially available live attenuated vaccine in three experimental vaccination-challenge studies in pigs. The efficacy of the new vaccine was further tested under field conditions on a farm with a history of acute ileitis. The novel inactivated vaccine consists of a freeze-dried antigen fraction that is dissolved just prior to use in either the adjuvant or in Porcilis® PCV M Hyo; an existing combination vaccine against porcine circovirus type 2 and Mycoplasma hyopneumoniae. The three experimental vaccination-challenge trials had a similar design and for each trial 75 piglets were used, randomly allotted to three groups of 25 piglets. The pigs were vaccinated at 4 or 5 weeks of age with either Porcilis® Lawsonia in adjuvant or in associated mixed use with Porcilis® PCV M Hyo (group 1), with the live vaccine (group 2), or left as unvaccinated controls (group 3). The pigs were challenged with virulent Lawsonia intracellularis 3, 4 or 17 weeks after vaccination. Post-challenge the pigs were evaluated for clinical signs, average daily weight gain, shedding and macroscopic as well as microscopic immuno-histological ileum lesion scores. In the field study, the mortality and key performance parameters were evaluated over a period of 8 months. The results of all three experimental vaccination-challenge trials showed that Porcilis® Lawsonia induced statistically significant protection against experimental Lawsonia intracellularis infection. This was demonstrated by lower clinical scores, improved weight gain, reduction of Lawsonia intracellularis shedding and reduction of macroscopic as well as microscopic ileum lesion scores when compared to the controls. The protection induced was superior to that of the commercially available live vaccine. In the field study, Porcilis® Lawsonia proved to be highly efficacious; reducing Lawsonia associated mortality to zero and improving key production parameters.

Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis.

Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for treatment of relapsing multiple sclerosis (MS). In the Phase II/III trials, patients received 12 or 24 mg/day of alemtuzumab in two treatment courses (5 days for course 1 and 3 days for course 2), 12 months apart. Serum concentrations of alemtuzumab peaked on the last day of dosing in each course and mostly fell below the limit of quantitation by day 30. Alemtuzumab rapidly depleted circulating T and B lymphocytes, with the lowest observed values occurring within days. Lymphocytes repopulated over time, with B cell recovery usually complete within 6 months. T lymphocytes recovered more slowly and generally did not return to baseline by 12 months post-treatment. Approximately 40 and 80% of patients had total lymphocyte counts, reaching the lower limit of normal by 6 and 12 months after each course, respectively. The clearance of alemtuzumab is dependent on circulating lymphocyte count. A majority of treated patients tested positive for anti-alemtuzumab antibodies, including inhibitory antibodies, during the 2-year studies, and a higher proportion of patients tested positive in course 2 than in course 1. The presence of anti-alemtuzumab antibody appeared to be associated with slower clearance of alemtuzumab from the circulation but had no impact on the pharmacodynamics. No effects of age, race or gender on the pharmacokinetics or pharmacodynamics were observed. Together, the pharmacokinetics, pharmacodynamics and immunogenicity results support the continued development and use of alemtuzumab for the treatment of MS, and probably explain its sustained effects beyond the dosing interval.