The Abeer Children Dental Anxiety Scale (ACDAS) cross-cultural adaptation and validity of self-report measures in the Malaysian Children Context (MY-ACDAS).

BACKGROUND: The Abeer Children Dental Anxiety Scale (ACDAS) source language was developed and validated in an English-speaking country in the UK to measure dental anxiety among children. The ACDAS also included the child's cognitive assessment, as well as feedback from the parent or the legal guardian and a dental health professional (DHP). This is the first study to validate the application of the ACDAS in Malay or Bahasa Melayu for children aged 6-16 years. AIM: To assess the Malay-translated version of the ACDAS, postadaptation into the local context and validation by the content and construct experts. DESIGN: The English ACDAS was translated into Malay first through forward translation and then through backward translation. The prefinal translated version of the instrument was designed, with the participation of 61 children and 61 parents or legal guardians. Subsequently, a final cross-cultural adaptation of the instrument was then made for another group of participants and evaluated for validity and test-retest reliability among 144 children and 144 parents or legal guardians participating in the self-report feedback process at the Paediatric Dental Clinic, Faculty of Dentistry, Universiti Malaya, Kuala Lumpur, Malaysia. The cross-cultural adaptation of the instrument considered translating to Malaysian national language and adapting to its culture. RESULTS: The Malay-translated ACDAS consisted of 19 items. The translated version of Malaysian-ACDAS (MY-ACDAS) achieved an acceptable agreement between six expert committee members with an internal consistency (Cronbach's alpha value, αconsistency) of 0.839. The test-retest reliability results of all participants support semantic and conceptual equivalence as an accepted construct validity between the children, parents and DHPs across the multicultural Malaysian population. CONCLUSION: The MY-ACDAS is a valid and reliable scale for measuring dental anxiety among Malaysian children.

Pilot scale validation campaign of gel dosimetry for pre-treatment quality assurance in stereotactic radiotherapy.

PURPOSE: Complex stereotactic radiotherapy treatment plans require prior verification. A gel dosimetry system was developed and tested to serve as a high-resolution 3D dosimeter for Quality Assurance (QA) purposes. MATERIALS AND METHODS: A modified version of a polyacrylamide polymer gel dosimeter based on chemical response inhibition was employed. Different sample geometries (cuvettes and phantoms) were manufactured for calibration and QA acquisitions. Irradiations were performed with a Varian Trilogy linac, and analyses of irradiated gel dosimeters were performed via MRI with a 1.5 T Philips Achieva at 1 mm3 or 2 mm3 isotropic spatial resolution. To assess reliability of polymer gel data, 54 stereotactic clinical treatment plans were delivered both on dosimetric gel phantoms and on the Delta4 dosimeter. Results from the two devices were evaluated through a global gamma index over a range of acceptance criteria and compared with each other. RESULTS: A quantitative and tunable control of dosimetric gel response sensitivity was achieved through chemical inhibition. An optimized MRI analysis protocol allowed to acquire high resolution phantom dose data in timeframes of ≈ 1 h. Conversion of gel dosimeter data into absorbed dose was achieved through internal calibration. Polymer gel dosimeters (2 mm3 resolution) and Delta4 presented an agreement within 4.8 % and 2.7 % at the 3 %/1 mm and 2 %/2 mm gamma criteria, respectively. CONCLUSIONS: Gel dosimeters appear as promising tools for high resolution 3D QA. Added complexity of the gel dosimetry protocol may be justifiable in case of small target volumes and steep dose gradients.

High 1-h glucose in youths with obesity as marker of prediabetes and cardiovascular risk.

PURPOSE: Testing 1-h glucose (1HG) concentration during oral glucose tolerance test is cost-effective to identify individuals at risk of incident type 2 diabetes. Aim of the study was to define 1HG cutoffs diagnostic of incident impaired glucose tolerance (IGT) in youths with obesity, and to evaluate prevalence and association of cutoffs identified in the cohort and from the literature (133 and 155 mg/dl) to cardiovascular disease (CVD) in a population of youths with obesity. METHODS: This is a longitudinal study of 154 youths to identify 1HG cutoffs, and cross-sectional study of 2295 youths to estimate prevalence of high 1HG and association to CVD. Receiver-operating characteristic curves (ROC) were used to establish 1HG cutoffs, and univariate regression analyses to test association of 1HG to blood pressure, lipids and aminotransferases. RESULTS: ROC analysis identified the 1HG cutoff of 159 mg/dl as having diagnostic accuracy of IGT with area under the ROC 0.82 (95% CI 0.66-0.98), sensitivity 0.86% and specificity 0.79%. In the cross-sectional population, prevalence of high 1HG was 36% and 15% for 133 and 155 mg/dl cutoffs, respectively, and 17% for the 159 mg/dl value. All the examined cutoffs were significantly associated with worse lipid profile, liver function test, reduced insulin sensitivity, secretion and disposition index. CONCLUSION: High 1HG is marker of persistent IGT and increased risk of metabolic abnormalities in youths. The 155 mg/dl cutoff is a convenient estimate in young people but longitudinal studies with retinopathy and overt diabetes as end points are advised to verify the 1HG cutoff with the best diagnostic accuracy.

Extended follow-up from JAVELIN Renal 101: subgroup analysis of avelumab plus axitinib versus sunitinib by the International Metastatic Renal Cell Carcinoma Database Consortium risk group in patients with advanced renal cell carcinoma.

BACKGROUND: We report updated data for avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma from the third interim analysis of the phase III JAVELIN Renal 101 trial. PATIENTS AND METHODS: Progression-free survival (PFS), objective response rate (ORR), and duration of response per investigator assessment (RECIST version 1.1) and overall survival (OS) were evaluated in the overall population and in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups; safety was also assessed. RESULTS: Overall, median OS [95% confidence interval (CI)] was not reached [42.2 months-not estimable (NE)] with avelumab plus axitinib versus 37.8 months (31.4-NE) with sunitinib [hazard ratio (HR) 0.79, 95% CI 0.643-0.969; one-sided P = 0.0116], and median PFS (95% CI) was 13.9 months (11.1-16.6 months) versus 8.5 months (8.2-9.7 months), respectively (HR 0.67, 95% CI 0.568-0.785; one-sided P < 0.0001). In patients with IMDC favorable-, intermediate-, poor-, or intermediate plus poor-risk disease, respectively, HRs (95% CI) for OS with avelumab plus axitinib versus sunitinib were 0.66 (0.356-1.223), 0.84 (0.649-1.084), 0.60 (0.399-0.912), and 0.79 (0.636-0.983), and HRs (95% CIs) for PFS were 0.71 (0.490-1.016), 0.71 (0.578-0.866), 0.45 (0.304-0.678), and 0.66 (0.550-0.787), respectively. ORRs, complete response rates, and durations of response favored avelumab plus axitinib overall and across all risk groups. In the avelumab plus axitinib arm, 81.1% had a grade ≥3 treatment-emergent adverse event (TEAE), and incidences of TEAEs and immune-related AEs were highest <6 months after randomization. CONCLUSIONS: Avelumab plus axitinib continues to show improved efficacy versus sunitinib and a tolerable safety profile overall and across IMDC risk groups. The OS trend favors avelumab plus axitinib versus sunitinib, but data remain immature; follow-up is ongoing. TRIAL REGISTRATION: ClinicalTrials.govNCT02684006; https://clinicaltrials.gov/ct2/show/NCT02684006.

Real-life experience with ixekizumab in plaque psoriasis: a multi-center, retrospective, 3-year study.

BACKGROUND: Confirmatory data on the long-term effectiveness and safety of ixekizumab in psoriatic patients from real-world studies are needed. OBJECTIVES: The primary aim was to evaluate the 3-year drug survival of ixekizumab in the treatment of patients with moderate-to-severe plaque psoriasis, in a multicenter real-world setting. The secondary aim was to assess the influence of predictive factors on the drug survival of ixekizumab. METHODS: A retrospective analysis was performed on a cohort of patients with chronic plaque psoriasis, who received at least one dose of ixekizumab before December 2018. The drug survival analysis was performed and descriptively analyzed using Kaplan-Meier survival curves. Multivariable Cox regression analyses were carried out including variables considered to be of clinical importance. RESULTS: A total of 306 patients were enrolled. The overall drug survival at 12, 24, and 36 months of treatment with ixekizumab was 92.11%, 83.85%, and 80.19%, respectively. A higher probability (HR 2.34) of drug withdrawal was found among patients who had already received an anti-IL-17 agent compared with bio-naive patients (p 0.017). CONCLUSIONS: We found that ixekizumab is a biological agent characterized by long-term effectiveness, not influenced by several clinical factors and associated with a good safety profile.

Multicentric Italian case-control study on 25OH vitamin D levels in children and adolescents with Prader-Willi syndrome.

PURPOSE: 25OHD levels in patients with Prader-Willi Syndrome (PWS), the most frequent cause of genetic obesity with a peculiar fat mass distribution, are still debated. Insulin resistance (IR), Body Mass Index-SDS (BMI-SDS), Growth Hormone Therapy (GHT), and puberty onset seem to interact with 25OHD levels. The objectives of the study are: (1) To analyze 25OHD levels in pediatric PWS patients in comparison with a control group (CNT) (2) To evaluate a possible correlation between BMI-SDS, HOMA-IR, puberty, GHT, and 25OHD levels. METHODS: This is a retrospective case-control, multicenter study. Data were collected among 8 different Italian Hospitals (outpatient clinics), over a period of four years (2016-2020). We included 192 genetically confirmed PWS and 192 CNT patients, aged 3-18 years, matched 1:1 for age, gender, BMI-SDS, Tanner stage, sun exposure, and month of recruitment. RESULTS: No statistically significant differences in 25OHD levels were observed between the PWS population and the CNT (PWS 24.0 ng/mL vs CNT 22.5 ng/mL, p > 0.05), OR = 0.89 (95% CI 0.58-1.35). We observed a slight, although non-significant, reduction in 25OHD levels comparing NW and OB populations. HOMA-IR, puberty onset, genotype and GHT (previous or ongoing) did not show statistically significant correlation with 25OHD levels. CONCLUSIONS: Our findings could be useful for clinicians to optimize the therapeutic management as well as to increase awareness of PWS.

Association of C-reactive protein with efficacy of avelumab plus axitinib in advanced renal cell carcinoma: long-term follow-up results from JAVELIN Renal 101.

BACKGROUND: C-reactive protein (CRP) is an important prognostic and predictive factor in advanced renal cell carcinoma (aRCC). We report the association of CRP levels at baseline and early after treatment with efficacy of avelumab plus axitinib or sunitinib from the phase III JAVELIN Renal 101 trial. PATIENTS AND METHODS: Patients were categorized into normal (baseline CRP <10 mg/l), normalized (baseline CRP ≥10 mg/l and ≥1 CRP value decreased to <10 mg/l during 6-week treatment), and non-normalized (CRP ≥10 mg/l at baseline and during 6-week treatment) CRP groups. Progression-free survival and best overall response from the second interim analysis and overall survival (OS) from the third interim analysis were assessed. RESULTS: In the avelumab plus axitinib and sunitinib arms, respectively, 234, 51, and 108 patients and 232, 36, and 128 patients were categorized into normal, normalized, and non-normalized CRP groups. In respective CRP groups, objective response rates [95% confidence interval (CI)] were 56.0% (49.4% to 62.4%), 66.7% (52.1% to 79.2%), and 45.4% (35.8% to 55.2%) with avelumab plus axitinib and 30.6% (24.7% to 37.0%), 41.7% (25.5% to 59.2%), and 19.5% (13.1% to 27.5%) with sunitinib; complete response rates were 3.8%, 11.8%, and 0.9% and 3.0%, 0%, and 1.6%, respectively. Median progression-free survival (95% CI) was 15.2 months (12.5-21.0 months), not reached (NR) [11.1 months-not estimable (NE)], and 7.0 months (5.6-9.9 months) with avelumab plus axitinib and 11.2 months (8.4-13.9 months), 11.2 months (6.7-13.8 months), and 4.2 months (2.8-5.6 months) with sunitinib; median OS (95% CI) was NR (42.2 months-NE), NR (30.4 months-NE), and 23.0 months (18.4-33.1 months) and NR (39.0 months-NE), 39.8 months (21.7-NE), and 19.1 months (16.3-25.3 months), respectively. Multivariate analyses demonstrated that normalized or non-normalized CRP levels were independent factors for the prediction of objective response rate or OS, respectively, with avelumab plus axitinib. CONCLUSIONS: In patients with aRCC, CRP levels at baseline and early after treatment may predict efficacy with avelumab plus axitinib.

Mild hypothermia during cardiopulmonary bypass assisted CABG is associated with improved short- and long-term survival, a 18-year cohort study.

Data substantiating the optimal patient body temperature during cooling procedures in cardiac operations are currently unavailable. To explore the optimal temperature strategy, we examined the association between temperature management and survival among patients during cardiopulmonary bypass assisted coronary artery bypass grafting (CABG) procedures on 30-days and 5-year postoperative survival. Adult patients (n = 5,672, 23.6% female and mean (SD) age of 66 (10) years) operated between 1997 and 2015 were included, with continuous measured intraoperative nasopharyngeal temperatures. The association between mortality and patient characteristics, laboratory parameters, the lowest intraoperative plateau temperature and intraoperative cooling/rewarming rates were examined by multivariate Cox regression analysis. Machine learning-based cluster analysis was used to identify patient subgroups based on pre-cooling parameters and explore whether specific subgroups benefitted from a particular temperature management. Mild hypothermia (32-35°C) was independently associated with improved 30-days and 5-year survival compared to patients in other temperature categories regardless of operation year. 30 days and 5-year survival were 98% and 88% in the mild hypothermia group, whereas it amounted 93% and 80% in the severe hypothermia (<30°C). Normothermia (35-37°C) showed the lowest survival after 30 days and 5 years amounting 93% and 72%, respectively. Cluster analysis identified 8 distinct patient subgroups principally defined by gender, age, kidney function and weight. The full cohort and all patient subgroups displayed the highest survival at a temperature of 32°C. Given these associations, further prospective randomized controlled trials are needed to ascertain optimal patient temperatures during CPB.

MKRN3 circulating levels in Prader-Willi syndrome: a pilot study.

CONTEXT: Hypogonadism in Prader-Willi syndrome (PWS) is generally attributed to hypothalamic dysfunction or to primary gonadal defect. MKRN3, a maternal imprinted gene located on 15q11.2-q13 region, encodes makorin ring finger protein 3, whose deficiency causes precocious puberty, an extremely rare symptom in PWS. OBJECTIVE: This study aimed to evaluate MKRN3 levels in patients with PWS and to analyze its correlation with sexual hormone levels, insulin resistance and Body Mass Index (BMI). METHODS: We performed an observational cross-sectional study and enrolled 80 patients with genetically confirmed diagnosis of PWS with median age of 9.6 years. RESULTS: MKRN3 levels were measurable in 49 PWS patients with a geometric mean of 34.9 ± 22 pg/ml (median: 28.4). Unmeasurable levels of MKRN3 were found in 31 patients. No statistically significant differences were found between patients with and without measurable MKRN3 levels for any clinical, biochemical, or genetic characteristics. However, MKRN3 levels were inversely correlated with HOMA-IR index (p: 0.005) and HbA1c (p: 0.046) values. No statistically significant correlations were found between MKRN3 and LH, estradiol and testosterone concentrations, pubertal development and genetic defect, whereas a direct correlation with FSH was found (p: 0.007). CONCLUSIONS: The typical genetic defect of PWS should lead to unmeasurable levels of the MKRN3 protein due to the inactivation of the paternal allele. Measurable circulating MKRN3 could suggest the possible involvement of tissue-specific imprinting mechanisms and other regulatory factors in gene expression. Correlations with HOMA-IR index, HbA1c, and FSH suggest peripheral actions of MKRN3, but future studies are warranted to investigate this topic.

Efficacy and safety of avelumab plus axitinib in elderly patients with advanced renal cell carcinoma: extended follow-up results from JAVELIN Renal 101.

BACKGROUND: In the phase III JAVELIN Renal 101 trial, first-line avelumab plus axitinib demonstrated a progression-free survival (PFS) and objective response rate (ORR) benefit versus sunitinib in patients with advanced renal cell carcinoma (aRCC). However, efficacy in elderly patients remains unclear. We report efficacy and safety by age group from the second interim analysis of overall survival (OS). PATIENTS AND METHODS: PFS and ORR as per blinded independent central review (RECIST 1.1), OS, and safety were assessed in patient groups aged <65, ≥65 to <75, and ≥75 years. RESULTS: In the avelumab plus axitinib and sunitinib arms, 271/138/33 and 275/128/41 patients aged <65, ≥65 to <75, and ≥75 years, respectively, were randomized. At data cut-off (January 2019), median PFS [95% confidence interval (CI)] with avelumab plus axitinib versus sunitinib in these respective age groups was 11.6 (8.4-19.4) versus 6.9 (5.6-8.4) months [hazard ratio (HR), 0.63; 95% CI 0.501-0.786], 13.8 (11.1-18.0) versus 11.0 (7.8-16.6) months (HR, 0.88; 95% CI 0.627-1.231), and 13.8 [7.0-not estimable (NE)] versus 9.8 (4.3-NE) months (HR, 0.76; 95% CI 0.378-1.511). Median OS (95% CI) in the respective age groups was not reached (NR) (NE-NE) versus 28.6 (25.5-NE) months (HR, 0.74; 95% CI 0.541-1.022), 30.0 (30.0-NE) versus NR (NE-NE) months (HR, 0.89; 95% CI 0.546-1.467), and 25.3 (19.9-NE) versus NR (19.4-NE) months (HR, 0.87; 95% CI 0.359-2.106). ORR (95% CI) in the respective age groups was 49.4% (43.3% to 55.6%) versus 27.3% (22.1% to 32.9%), 60.9% (52.2% to 69.1%) versus 28.9% (21.2% to 37.6%), and 42.4% (25.5% to 60.8%) versus 22.0% (10.6% to 37.6%). In the avelumab plus axitinib arm, grade ≥3 adverse events (AEs) and immune-related AEs occurred in 76.9%/81.2%/72.7% and 45.5%/48.1%/36.4% in the respective age groups. CONCLUSIONS: First-line avelumab plus axitinib demonstrated favorable efficacy across age groups, including patients aged ≥75 years. OS data were still immature; follow-up is ongoing. The safety profile was generally consistent across age groups.

Left Atrial Appendage Exclusion in Atrial Fibrillation Radiofrequency Ablation during Mitral Valve Surgery: A Single-Center Experience.

BACKGROUND: Atrial fibrillation surgical radiofrequency ablation (AFSA) during mitral valve surgery (MVS) has almost completely superseded the Cox-Maze procedure for the treatment of atrial fibrillation. METHODS: We retrospectively analyzed 100 patients who underwent MVS + AFSA in our institution from January 2008 to June 2017. We compared the effectiveness of AFSA in patients who underwent LAA exclusion to those who did not. Moreover, we analyzed the role of preoperative AF duration (≤ or >1 year) and medial-lateral left atrial dimensions (ML-LAD) (≤ or >6 cm). The efficacy endpoint was freedom from AF at discharge and at 2-year follow-up. The safety endpoints were need of a permanent pacemaker (PMK), surgical re-exploration, occurrence of stroke, and left circumflex artery or esophageal lesions. RESULTS: Overall, the rate of AF freedom was 69% at discharge and 80% at 2-year follow-up. LAA exclusion did not influence AF freedom at 2-year follow-up, and 84.6% of patients who underwent LAA exclusion were in the sinus rythm (SR) at 2 year compared to 75% of those who did not receive LAA exclusion free from AF as well (p=0.230). AF duration ≤1 or >1 year did not influence sinus rhythm (SR) maintenance (85.7% vs. 75.8%; p=0.224), and in these two groups, LAA exclusion did not change the efficacy of AFSA. ML-LAD ≤ 6 cm was associated with better results in terms of SR maintenance. A statistically significant association between LAA exclusion and SR maintenance at 2-year follow-up (p=0.017) was found among patients with ML-LAD ≤ 6 cm. Complications included 7 cases of PMK implantation, 2 cases of surgical re-exploration, and 1 case of stroke. No circumflex artery or esophageal lesions occurred after surgical procedures. CONCLUSIONS: In our experience, AFSA during isolated MVS resulted in good outcomes in terms of SR maintenance and incidence of complications. AF duration ≤ 1 year did not influence results, while patients with ML-LAD ≤ 6 cm had significantly better results regarding SR at follow-up. In patients with ML-LAD ≤ 6 cm, LAA exclusion significantly increased the success rate of SR maintenance at 2-year follow-up.

Efficacy and correlative analyses of avelumab plus axitinib versus sunitinib in sarcomatoid renal cell carcinoma: post hoc analysis of a randomized clinical trial.

BACKGROUND: Among patients with advanced renal cell carcinoma (RCC), those with sarcomatoid histology (sRCC) have the poorest prognosis. This analysis assessed the efficacy of avelumab plus axitinib versus sunitinib in patients with treatment-naive advanced sRCC. METHODS: The randomized, open-label, multicenter, phase III JAVELIN Renal 101 trial (NCT02684006) enrolled patients with treatment-naive advanced RCC. Patients were randomized 1 : 1 to receive either avelumab plus axitinib or sunitinib following standard doses and schedules. Assessments in this post hoc analysis of patients with sRCC included efficacy (including progression-free survival) and biomarker analyses. RESULTS: A total of 108 patients had sarcomatoid histology and were included in this post hoc analysis; 47 patients in the avelumab plus axitinib arm and 61 in the sunitinib arm. Patients in the avelumab plus axitinib arm had improved progression-free survival [stratified hazard ratio, 0.57 (95% confidence interval, 0.325-1.003)] and a higher objective response rate (46.8% versus 21.3%; complete response in 4.3% versus 0%) versus those in the sunitinib arm. Correlative gene expression analyses of patients with sRCC showed enrichment of gene pathway scores for cancer-associated fibroblasts and regulatory T cells, CD274 and CD8A expression, and tumors with The Cancer Genome Atlas m3 classification. CONCLUSIONS: In this subgroup analysis of JAVELIN Renal 101, patients with sRCC in the avelumab plus axitinib arm had improved efficacy outcomes versus those in the sunitinib arm. Correlative analyses provide insight into this subtype of RCC and suggest that avelumab plus axitinib may increase the chance of overcoming the aggressive features of sRCC.

Modulation of membrane physical properties by natural insecticidal ketones.

The insecticidal activity of Mentha oil and its main components has been tested and established for various insects/pests. Several mint ketones have demonstrated to act on GABAA receptors (GABAA-R), a transmembrane channel target of several important insecticides whose activity can be modulated by surface-active compounds and by changes in the physical properties of the lipid membrane. In the present work, we analyze the capacity of monoterpenic ketones most commonly found in Mentha species, pulegone and menthone, to interact with DPPC membranes by molecular dynamics (MD) simulations and Langmuir monolayers. The experimental results indicate that the presence of menthone and pulegone in the subphase modify the interfacial characteristics of DPPC isotherms. The changes were reflected as expansion of the isotherms and disappearance or bringing forward of DPPC phase transition. MD simulation corroborate these results and indicate that both ketones are located at the region of the carbonyl group, at the interface with the acyl chains. Ketone intercalation between lipid molecules would induce an increasing intermolecular interaction, diminishing the film elasticity and causing an ordering effect. Our results suggest that the insecticidal activity of both ketones could involve their interaction with lipid molecules causing disturbance of the cell membrane as postulated for several larvicide compounds, or at least modulating the receptor surrounding.

Alkaline phosphatase (alp) levels in multiple myeloma and solid cancers with bone lesions: Is there any difference?

INTRODUCTION: Bone involvement in Multiple Myeloma results from increased osteoclast formation and activity that occurs in proximity to myeloma cells. The role of Alkaline Phosphatse (ALP) in this process and the diagnostic significance of plasma levels in patients with MM are unclear. AIM: To compare plasma ALP levels in patients with MM and solid cancers and metastatic lesions to the bone. RESULTS: In this observational retrospective study we enrolled 901 patients were enrolled: 440 patients (49%) with Multiple Myeloma, 461 (51%) with solid cancers. All 901 patients had bone lesions. Among patients with Multiple Myeloma, ALP values were mainly in the range of normality than those observed in patients with solid cancers and bone lesions. This difference is independent of stage, number and type of bone lesions. CONCLUSION: This study suggests that plasma ALP has a different clinical significance in MM than in other neoplasms and could be used as a discriminating marker in presence of bone lesions. In particular, lower or normal values, should suggest further investigations such as urinary and serum electrophoresis, associated with bone marrow aspirate in case of the presence of a monoclonal component, in order to confirm or exclude a MM diagnosis.

The impacts of intensive mining on terrestrial and aquatic ecosystems: A case of sediment pollution and calcium decline in cool temperate Tasmania, Australia.

Mining causes extensive damage to aquatic ecosystems via acidification, heavy metal pollution, sediment loading, and Ca decline. Yet little is known about the effects of mining on freshwater systems in the Southern Hemisphere. A case in point is the region of western Tasmania, Australia, an area extensively mined in the 19th century, resulting in severe environmental contamination. In order to assess the impacts of mining on aquatic ecosystems in this region, we present a multiproxy investigation of the lacustrine sediments from Owen Tarn, Tasmania. This study includes a combination of radiometric dating (14C and 210Pb), sediment geochemistry (XRF and ICP-MS), pollen, charcoal and diatoms. Generalised additive mixed models were used to test if changes in the aquatic ecosystem can be explained by other covariates. Results from this record found four key impact phases: (1) Pre-mining, (2) Early mining, (3) Intense mining, and (4) Post-mining. Before mining, low heavy metal concentrations, slow sedimentation, low fire activity, and high biomass indicate pre-impact conditions. The aquatic environment at this time was oligotrophic and dystrophic with sufficient light availability, typical of western Tasmanian lakes during the Holocene. Prosperous mining resulted in increased burning, a decrease in landscape biomass and an increase in sedimentation resulting in decreased light availability of the aquatic environment. Extensive mining at Mount Lyell in the 1930s resulted in peak heavy metal pollutants (Pb, Cu and Co) and a further increase in inorganic inputs resulted in a disturbed low light lake environment (dominated by Hantzschia amphioxys and Pinnularia divergentissima). Following the closure of the Mount Lyell Co. in 1994 CE, Ca declined to below pre-mining levels resulting in a new diatom assemblage and deformed diatom valves. Therefore, the Owen Tarn record demonstrates severe sediment pollution and continued impacts of mining long after mining has stopped at Mt. Lyell Mining Co.

Bacterial invasive infections in a neonatal intensive care unit: a 13 years microbiological report from an Italian tertiary care centre.

INTRODUCTION: To evaluate the aetiology of neonatal invasive diseases (positive cultures from blood or cerebrospinal fluid, CSF) due to bacteria other than coagulase-negative staphylococci in a large tertiary care centre and compare with results of surveillance cultures. METHODS: Retrospective analysis of microbiological data of children admitted in neonatal intensive care unit (NICU) of a large tertiary care centre from 2005 to 2018. RESULTS: 230 bacterial strains, 223 from blood and 7 from CSF, respectively, were detected as cause of invasive infections, while 152 were detected in surveillance cultures. Methicillin-susceptible Staphylococcus aureus (MSSA) was the most frequently isolated pathogen both in invasive infections (18%) and colonizations (23%) followed by Escherichia coli (16% on invasive disease and 20% of colonizations). Other common bacteria include Enterococcus faecalis and Streptococcus agalactiae for invasive disease and methicillin-resistant Staphylococcus aureus in colonizations. Invasive infection was due to a pathogen detected in surveillance cultures in 33% of cases. In more than 50% of invasive diseases the identified pathogen was not present in surveillance cultures. CONCLUSIONS: The high percentage of invasive infections due to bacteria not previously identified in surveillance cultures raises doubts about the efficiency of this procedure and highlights the need to search for alternative infection sources. This finding and the high prevalence of invasive infections due to nosocomial pathogens such as Staphylococcus aureus could be the result of horizontal transmission between patients through the hands of health care professionals, emphasizing once again the importance of applying stringent hand hygiene procedures and isolation standards.

Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma.

BACKGROUND: The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis. PATIENTS AND METHODS: Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population. RESULTS: Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392]. CONCLUSION: Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature. CLINICAL TRIAL NUMBER: NCT02684006.