Solar photocatalysts: non-metal (C, N, and S)-doped ZnO synthesized through an industrially sustainable in situ approach for environmental remediation applications.

One of the biggest issues the world is currently experiencing is the scarcity of pure water due to the contamination of pure water by human activities. Highly efficient, semiconducting photocatalytic materials have great potential as future catalytic materials for facilitating the clean-up process of contaminated water. Among the many semiconductor photocatalysts, non-metal-doped zinc oxide (ZnO) nanoparticles have attracted special attention in the scientific field for environmental remediation applications. The present paper reports an easy and viable synthesis of C-, N-, and S-based ZnO semiconductor photocatalysts through a simple heating method. The structural changes in the obtained samples were studied using XRD, TG/DTA, and FT-IR analyses, and morphological examinations were performed using TEM and SEM. The quantification of non-metal dopants was carried out using CNS and XPS analyses. The surface areas of the samples were analyzed using the BET method and the band energies of the samples were measured using UV-vis-diffuse reflectance Kubelka-Munk plots. Photoactivity studies were performed and revealed that the utilized in situ method resulted in the development of high-performance sulphur - (81.4%, k = 1.951 × 10-2 min-1), nitrogen - (78.5%, k = 2.271 × 10-2 min-1), and carbon - (67.2%, k = 1.392 × 10-2 min-1) doped ZnO photocatalysts. As revealed through XPS and UV analyses, a possible electron-transfer mechanism is suggested, wherein electronic transition occurred from different sub-bands when non-metal elements were introduced into the ZnO lattice. The study paves the way for the bulk-scale fabrication of doped nanoparticles through a simple heating method, whereby the unique combination of the present method with bandgap engineering will ultimately produce advanced non-metal-based ZnO photocatalysts that could find useful applications in sustainable industrial sectors.

Telomere-to-telomere assembled and centromere annotated genomes of the two main subspecies of the button mushroom Agaricus bisporus reveal especially polymorphic chromosome ends.

Agaricus bisporus, the most cultivated edible mushroom worldwide, is represented mainly by the subspecies var. bisporus and var. burnettii. var. bisporus has a secondarily homothallic life cycle with recombination restricted to chromosome ends, while var. burnettii is heterothallic with recombination seemingly equally distributed over the chromosomes. To better understand the relationship between genomic make-up and different lifestyles, we have de novo sequenced a burnettii homokaryon and synchronised gene annotations with updated versions of the published genomes of var. bisporus. The genomes were assembled into telomere-to-telomere chromosomes and a consistent set of gene predictions was generated. The genomes of both subspecies were largely co-linear, and especially the chromosome ends differed in gene model content between the two subspecies. A single large cluster of repeats was found on each chromosome at the same respective position in all strains, harbouring nearly 50% of all repeats and likely representing centromeres. Repeats were all heavily methylated. Finally, a mapping population of var. burnettii confirmed an even distribution of crossovers in meiosis, contrasting the recombination landscape of var. bisporus. The new findings using the exceptionally complete and well annotated genomes of this basidiomycete demonstrate the importance for unravelling genetic components underlying the different life cycles.

A randomised phase II trial of three dosing regimens of radium-223 in patients with bone metastatic castration-resistant prostate cancer.

BACKGROUND: Radium-223 prolongs overall survival and delays symptomatic skeletal events (SSEs) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. The approved radium-223 regimen is 55 kBq/kg every 4 weeks (q4w) for six cycles (standard dose). We investigated different radium-223 regimens in patients with mCRPC. PATIENTS AND METHODS: Patients were randomised 1 : 1 : 1 to radium-223 standard-dose, high-dose (88 kBq/kg q4w for six cycles) or extended-schedule arms (55 kBq/kg q4w for 12 cycles). The primary end point, SSE-free survival (SSE-FS), was compared in patients treated with a high- versus standard-dose regimen, or with a standard dose in an extended (>6 to 12 cycles) versus standard schedule (six cycles). RESULTS: A total of 391 patients were randomised; baseline characteristics were balanced between arms. On-treatment SSEs developed in 37/130 (28%), 42/130 (32%) and 48/131 (37%) patients in the standard-dose, high-dose and extended-schedule arms, respectively. There was no statistically significant difference in SSE-FS in the high- versus standard-dose arms [median 12.9 months versus 12.3 months; hazard ratio (HR) 1.06, 80% confidence interval (CI) 0.88-1.27, P = 0.70], and in the extended- versus standard-schedule arms (median 10.8 months versus 13.2 months; HR 1.26, 80% CI 0.94-1.69, P = 0.31). Overall survival in the three treatment arms was similar. As many as 370 (95%) patients received treatment (median of six cycles) in each arm. Grade ≥3 treatment-emergent adverse events (TEAEs) affected 34% of patients in the standard-dose, 48% in the high-dose and 53% in the extended-schedule arm, causing permanent discontinuation in 9%, 16% and 17% of patients, respectively. CONCLUSION: Radium-223 high-dose or extended-schedule regimens resulted in no change in SSE-FS or other efficacy end points and were associated with more grade ≥3 TEAEs. The extended-schedule regimen (beyond six doses) could not be implemented in a large proportion of patients due to disease progression. Therefore, the standard-dose schedule remains one of the standard therapies for patients with symptomatic mCRPC. TRIAL REGISTRATION: ClinicalTrials.govNCT02023697.

Risk of potential drug-drug interactions in the cardiac intensive care units. A comparative analysis between 2 tertiary care hospitals.

OBJECTIVES: To identify and compare the prevalence of drug-drug interactions (DDIs) in the intensive cardiac care units (CCUs) of 2 tertiary care hospitals and analyze their association with various predictors. Methods: This one-year prospective cross-sectional study was conducted in 2 tertiary care hospitals of Peshawar, Khyber Teaching Hospital (KTH) and Hayatabad Medical Complex (HMC), Peshawar, Pakistan, between January 2014 to Janury 2015. The patient medication profiles from the respective CCUs were evaluated for potential DDIs (PDDIs) using Micromedex DrugReax and Drug interaction facts. Results: The prevalence of PDDIs was 96.5% and  95.7% in the 2 hospitals, with over 1200 PDDIs in total. A significant association was found between the number of prescribed drugs and PDDIs in both  hospitals.  Conclusion: The knowledge of PDDIs is either lacking among the clinicians or is not taken into consideration. Monitoring PDDIs and timely interventions are required to minimize the adverse outcomes.

Re-treatment with radium-223: first experience from an international, open-label, phase I/II study in patients with castration-resistant prostate cancer and bone metastases.

BACKGROUND: Six radium-223 injections at 4-week intervals is indicated for patients with castration-resistant prostate cancer and symptomatic bone metastases. However, patients usually develop disease progression after initial treatment. This prospective phase I/II study assessed re-treatment safety and efficacy of up to six additional radium-223 injections. PATIENTS AND METHODS: Patients had castration-resistant prostate cancer and bone metastases and six initial radium-223 injections with no on-treatment bone progression; all had subsequent radiologic or clinical progression. Concomitant agents were allowed at investigator discretion, excluding chemotherapy and initiation of new abiraterone or enzalutamide. The primary endpoint was safety; additional exploratory endpoints included time to radiographic bone progression, time to total alkaline phosphatase and prostate-specific antigen progression, radiographic progression-free survival, overall survival, time to first symptomatic skeletal event (SSE), SSE-free survival, and time to pain progression. RESULTS: Among 44 patients, 29 (66%) received all six re-treatment injections. Median time from end of initial radium-223 treatment was 6 months. Forty-one (93%) reported ≥1 treatment-emergent adverse event. No grade 4-5 hematologic treatment-emergent adverse events occurred. Only one (2%) patient had radiographic bone progression; eight (18%) had radiographic soft tissue tumor progression (three lymph node and five visceral metastases). Median times to total alkaline phosphatase and prostate-specific antigen progression were not reached and 2.2 months, respectively. Median radiographic progression-free survival was 9.9 months (12.8-month maximum follow-up). Five (11%) patients died and eight (18%) experienced first SSEs. Median overall survival, time to first SSE, and SSE-free survival were not reached. Five (14%) of 36 evaluable patients (baseline worst pain score ≤7) had pain progression. After 2 years of follow-up, 28 (64%) patients died, and the median overall survival was 24.4 months. CONCLUSIONS: Re-treatment with a second course of six radium-223 injections after disease progression is well tolerated, with minimal hematologic toxicity and low radiographic bone progression rates in this small study with limited follow-up. Favorable safety and early effects on disease progression indicate that radium-223 re-treatment is feasible and warrants further evaluation in larger prospective trials.

Imaging response during therapy with radium-223 for castration-resistant prostate cancer with bone metastases-analysis of an international multicenter database.

BACKGROUND: The imaging response to radium-223 therapy is at present poorly described. We aimed to describe the imaging response to radium-223 treatment. METHODS: We retrospectively evaluated the computed tomography (CT) and bone scintigraphy response of metastatic castration-resistant prostate cancer (CRPC) patients treated with radium-223, in eight centers in three countries. RESULTS: A total of 130 patients were included, the majority (n=84, 65%) received radium-223 post docetaxel. Thirty-four of 99 patients with available data (34%) received concomitant abiraterone or enzalutamide. A total of 54% (n=70) patients completed the planned six injections of radium-223. In patients with available data, a transient increase in bone metastases-related pain was observed in 27% (n=33/124) and an improvement of bone metastases-related pain on treatment with radium-223 was noted in 49% of patients (n=61/124). At 3 and 6 months of treatment with radium-223, bone imaging showed stable disease in 74% (n=84/113) and 94% of patients (n=93/99) with available data, respectively. An increase in the number of bone lesions was documented at 3 months compared with baseline in 26% (n=29/113) and at 6 months compared with 3 months in 6% of patients (n=6/99), respectively. Radiological extraskeletal disease progression occurred in 46% of patients (n=57/124) with available CT data at 3 and/or 6 months. CONCLUSIONS: Progression of bone metastases during radium-223 therapy is uncommon. A bone flare (pain and/or radiological) may be noted during the first 3 months, and should not be confused with progression. Imaging by CT scan should be considered after three and six doses of radium-223 to rule out extraskeletal disease progression.

In Vivo Predictive Dissolution (IPD) and Biopharmaceutical Modeling and Simulation: Future Use of Modern Approaches and Methodologies in a Regulatory Context.

The overall objective of OrBiTo, a project within Innovative Medicines Initiative (IMI), is to streamline and optimize the development of orally administered drug products through the creation and efficient application of biopharmaceutics tools. This toolkit will include both experimental and computational models developed on improved understanding of the highly dynamic gastrointestinal (GI) physiology relevant to the GI absorption of drug products in both fasted and fed states. A part of the annual OrBiTo meeting in 2015 was dedicated to the presentation of the most recent progress in the development of the regulatory use of PBPK in silico modeling, in vivo predictive dissolution (IPD) tests, and their application to biowaivers. There are still several areas for improvement of in vitro dissolution testing by means of generating results relevant for the intraluminal conditions in the GI tract. The major opportunity is probably in combining IPD testing and physiologically based in silico models where the in vitro data provide input to the absorption predictions. The OrBiTo project and other current research projects include definition of test media representative for the more distal parts of the GI tract, models capturing supersaturation and precipitation phenomena, and influence of motility waves on shear and other forces of hydrodynamic origin, addressing the interindividual variability in composition and characteristics of GI fluids, food effects, definition of biorelevant buffer systems, and intestinal water volumes. In conclusion, there is currently a mismatch between the extensive industrial usage of modern in vivo predictive tools and very limited inclusion of such data in regulatory files. However, there is a great interest among all stakeholders to introduce recent progresses in prediction of in vivo GI drug absorption into regulatory context.

A survey on IVIVC/IVIVR development in the pharmaceutical industry - Past experience and current perspectives.

The present work aimed to describe the current status of IVIVC/IVIVR development in the pharmaceutical industry, focusing on the use and perception of specific approaches as well as successful and failed case studies. Two questionnaires have been distributed to 13 EFPIA partners of the Oral Biopharmaceutics Tools Initiative and to the Pharmacokinetics Working Party of the European Medicines Agency in order to capture the perspectives and experiences of industry scientists and agency members, respectively. Responses from ten companies and three European Agencies were received between May 21st 2014 and January 19th 2016. The majority of the companies acknowledged the importance of IVIVC/IVIVR throughout the drug development stages and a well-balanced rate of return on investment. However, the IVIVC/IVIVR approach seemed to be underutilized in regulatory submissions. Four of the ten companies stated to have an internal guidance related to IVIVC/IVIVR modelling, whereas three felt that an overall strategy is not necessary. Successful models mainly served to support formulation development and to provide a better mechanistic understanding. There was not yet much experience with safe-space IVIVRs as well as the use of physiologically based modelling in the field of IVIVC. At the same time, the responses from both industry and agencies indicated that there might be a need for a regulatory framework to guide the application of these novel approaches. The relevance of IVIVC/IVIVR for oral IR drug products was recognized by most of the companies. For IR formulations, relationships other than Level A correlation were more common outcomes among the provided case studies, such as multiple Level C correlation or safe-space IVIVR, which could be successfully used for requesting regulatory flexibility. Compared to the responses from industry scientists, there was a trend towards a higher appreciation of the BCS among the regulators, but a less positive attitude towards the utility of non-compendial dissolution methods for establishing a successful IVIVC/IVIVR. The lack of appropriate in vivo data and regulatory uncertainty were considered the major difficulties in IVIVC/IVIVR development. The results of this survey provide unique insights into current IVIVC/IVIVR practices in the pharmaceutical industry. Pursuing an IVIVC/IVIVR should be generally encouraged, considering its high value from both industry and regulators' perspective.

Single- and multiple-dose pharmacokinetic studies of tramadol immediate-release tablets in children and adolescents.

In these combined analyzes from 3 open-label, phase-1 studies, the pharmacokinetic profile of tramadol and its metabolite (M1) following administration of tramadol immediate-release (IR) tablets in children and adolescents, 7-16 years old (studies 1 and 2: n = 38; study 3: n = 21) with painful conditions following single oral dose of tramadol IR (25-100 mg) (studies 1 and 2) or multiple oral doses of tramadol IR tablets every 6 hours for 3 days (study 3) were compared with that of healthy adults following similar treatment. Area under the curve of tramadol and its metabolite M1 in children and adolescents was lower compared with adults (Dose-normalized [DN] AUC, h ng/mL: tramadol: 1316.87 [children]; 1418.02 [adolescents];1838.29 [adults]; M1: 342.56 [children]; 475.4 [adolescents]; 636.13 [adults]) while the Cmax remained similar (DN Cmax , ng/mL: tramadol: 203.75 [children]; 165.35 [adolescents]; 226.92 [adults]; M1: 34.93 [children]; 38.42 [adolescents]; 52.14 [adults]). The DN AUC was further lower in children and adolescents with a lower body weight (<50 kg). The weight normalized oral clearance of tramadol was higher in children and adolescents compared with adults (CL/F, mL/min/kg: 12.66 [children]; 11.75 [adolescents]; 9.06 [adults]). No new safety findings emerged. Tramadol was generally safe and well-tolerated by children and adolescents with painful conditions.

Indeterminate pulmonary nodules in colorectal-cancer: do radiologists agree?

BACKGROUND: The clinical significance of indeterminate pulmonary nodules (IPN) at staging computed tomography (CT) for colorectal cancer (CRC), and the optimal diagnostic approach, are debated. This study aimed to analyse variability in radiologists' detection of IPN at staging CT for CRC. METHODS: All patients with CRC referred to our center between 2006 and 2011 were included. Primary staging CT scans were re-evaluated by an experienced thoracic radiologist whose findings were entered into a dedicated database and merged with data from the Danish Colorectal Cancer Group database, the National Patient Registry, the Danish Pathology Registry, and the primary CT evaluation. Inter-reader agreement was calculated by Kappa statistics, and associations between variables and malignancy of pulmonary nodules were analyzed with χ (2) and Mann-Whitney-Wilcoxon tests. Multivariable logistic regression analyses were used to adjust for potential confounding variables. RESULTS: In total, 841 patients were included. The primary CT assessment reported IPN in 9.8 % of patients and pulmonary metastases in 5.1 % of patients compared with 5.6 and 7.0 %, respectively, reported by the experienced thoracic radiologist. Kappa for agreement between the primary assessor and the thoracic radiologist on IPN was 0.31 and 0.65 for pulmonary metastases. Synchronous liver metastases were predictive of malignancy of IPN (adjusted odds ratio 20.1; 95 % confidence interval 2.64-437.66; p = 0.012), whereas no other investigated radiological characteristics or clinicopathological factors were significantly associated with malignancy of IPN. CONCLUSION: The characterization of pulmonary findings on staging CT for CRC varied greatly between the radiologists, and double-reading of scans with IPN is recommended prior to further diagnostic work-up.

Diabetes as a risk factor for medication-related osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe devastating complication for which the exact pathogenesis is not completely understood. Multiple systemic and local factors may contribute to the development of MRONJ. A growing body of evidence supports diabetes mellitus (DM) as an important risk factor for this complication; however, the exact mechanism by which DM may promote MRONJ has yet to be determined. The current review elucidates the role of DM in the pathogenesis of MRONJ and the mechanisms by which DM may increase the risk for MRONJ. Factors related to DM pathogenesis and treatment may contribute to poor bone quality through multiple damaged pathways, including microvascular ischemia, endothelial cell dysfunction, reduced remodeling of bone, and increased apoptosis of osteoblasts and osteocytes. In addition, DM induces changes in immune cell function and promotes inflammation. This increases the risk for chronic infection in the settings of cancer and its treatment, as well as antiresorptive medication exposure, thus raising the risk of developing MRONJ. A genetic predisposition for MRONJ, coupled with CYP 450 gene alterations, has been suggested to affect the degradation of medications for DM such as thiazolidinediones and may further increase the risk for MRONJ.

Occurrence and survival of synchronous pulmonary metastases in colorectal cancer: a nationwide cohort study.

OBJECTIVE: To investigate the occurrence of synchronous colorectal cancer metastases (SCCM) confined to the lungs, risk factors for these metastases and their impact on survival. METHODS: In a nationwide cohort study of 26,200 patients data were prospectively entered into the Danish Colorectal Cancer Group's (DCCG's) database between May 2001 and December 2011. The recorded data were merged with data from the Danish Pathology Registry and the National Patient Registry. Multivariable logistic- and extended Cox regression analyses were used to adjust for confounding variables. RESULTS: In total, 1970 patients (7.5%) had pulmonary SCCM of whom 736 (37%) had metastases exclusively in the lungs. Advanced age, recent years of diagnosis and a rectal index cancer were significantly associated with pulmonary SCCM. Adjustment for excess use of thoracic CT scans in rectal cancer patients did not alter this association (adjusted OR=1.81 (95% CI: 1.46-2.25, P<0.001)). Patients subjected to pulmonary metastasectomy, resection of primary tumour and chemotherapy had a superior overall survival compared with non-treated patients, especially when these therapeutic modalities were combined. CONCLUSIONS: The occurrence of pulmonary SCCM was higher than previously reported and had a severe impact on survival. Our analyses suggest that pulmonary metastasectomy, resection of the primary tumour and chemotherapy may be a sound strategy in patients with confined pulmonary SCCM, but the risk of selection bias and consequent exaggeration of the treatment effect should be kept in mind. This study may serve as a reliable un-biased reference for future evaluation on detection strategies and potential therapeutic interventions.

A BCI using VEP for continuous control of a mobile robot.

A brain-computer interface (BCI) translates brain activity into commands to control devices or software. Common approaches are based on visual evoked potentials (VEP), extracted from the electroencephalogram (EEG) during visual stimulation. High information transfer rates (ITR) can be achieved using (i) steady-state VEP (SSVEP) or (ii) code-modulated VEP (c-VEP). This study investigates how applicable such systems are for continuous control of robotic devices and which method performs best. Eleven healthy subjects steered a robot along a track using four BCI controls on a computer screen in combination with feedback video of the movement. The average time to complete the tasks was (i) 573.43 s and (ii) 222.57 s. In a second non-continuous trial-based validation run the maximum achievable online classification accuracy over all subjects was (i) 91.36 % and (ii) 98.18 %. This results show that the c-VEP fits the needs of a continuous system better than the SSVEP implementation.

Indeterminate pulmonary nodules at colorectal cancer staging: a systematic review of predictive parameters for malignancy.

BACKGROUND: This study aimed to estimate the prevalence of indeterminate pulmonary nodules and specific radiological and clinical characteristics that predict malignancy of these at initial staging chest computed tomography (CT) in patients with colorectal cancer. A considerable number of indeterminate pulmonary nodules, which cannot readily be classified as either benign or malignant, are detected at initial staging chest CT in colorectal cancer patients. METHODS: A systematic review based on a search in EMBASE, Medline, the Cochrane library and science citation index, PubMed databases, Google scholar, and relevant conference proceedings was performed in cooperation with the Cochrane Colorectal Cancer Group. RESULTS: A total of 2,799 studies were identified, of which 12 studies met the inclusion criteria. The studies primarily consisted of case series and included a total of 5,873 patients. Of these patients, 9% (95% confidence interval [95% CI] 8.9-9.2%) had indeterminate pulmonary nodules at chest CT, of which 10.8% (95% CI 10.3-11.2%) turned out to be colorectal cancer metastases at follow-up. Generally, regional lymph node metastasis, and multiple numbers of indeterminate pulmonary nodules were reported to predict malignancy, whereas calcification of the nodules indicated benign lesions. CONCLUSION: It was found that 1 in 100 colorectal cancer patients subjected to preoperative staging chest CT will have an indeterminate pulmonary nodule that proves to be metastatic disease. Such a low risk suggests that indeterminate pulmonary nodules should not cause further preoperative diagnostic workup or follow-up besides routine regimens.

NDM-1 imported from India--first reported case in South Africa.

Carbapenem-resistant Enterobacteriaceae have been increasingly reported throughout the world. The first South African report of a New Delhi metallo-beta-lactamase was from Gauteng in August 2011. Despite maintaining a high degree of vigilance, the first such case was seen in KwaZulu-Natal almost a year later. Other cases have been unable to confirm a definite link to any other affected areas; this is the first case in South Africa showing this direct epidemiological link.