Diorganotin (IV) amino acid complexes as potential anticancer agents. Synthesis, structural characterization, and in vitro assays.

Nine new organotin (IV) derivatives from L-amino acids (l-lysine, L-ornithine, L-glutamic acid, and L-aspartic acid) were synthesized by one-pot ultrasound-assisted methodology. All compounds were characterized by ATR-FTIR (Attenuated Total Reflectance-Fourier Transform Infrared), LRMS (Low-Resolution Mass Spectrometry), and solution NMR (1H, 13C, 119Sn Nuclear Magnetic Resonance) spectroscopies. Complexes Bu2Sn(Lys) (1), Ph2Sn(Lys) (2), Bu2Sn(Orn) (3), and Ph2Sn (Glu-OMe) (6a) were crystallized, and the structures were established by single-crystal X-ray diffraction analysis. Diffraction results evidenced that complexes 1 to 3 were five-coordinated mononuclear species while the phenyl substituted derivative Ph2Sn (Glu-OMe) (6a) forms a polymeric network via Sn-O-Sn bridging whereby the tin atom is six-coordinated. In turn, 119Sn NMR results revealed that all tin complexes exist as mononuclear penta-coordinated species in solution. The tin derivatives were screened for ADME (Adsorption, Distribution, Metabolism, and Excretion) properties via the freely available tools SWISS ADME, and the results were analyzed hereafter. The antiproliferative activity of the complexes was tested against three human cancer cell lines: colorectal adenocarcinoma HT-29, breast adenocarcinoma MDA-MB-231, and chondrosarcoma SW-1353 using a non-tumoral cell line of human osteoblast as control, demonstrating selective inhibitory activities against cancer cells. Hence, these compounds could be a promising alternative to classical chemotherapy agents.

Effect of nanoporous membranes thickness in electrochemical biosensing performance: application for the detection of a wound infection biomarker.

Introduction: Nanoporous alumina membranes present a honeycomb-like structure characterized by two main parameters involved in their performance in electrochemical immunosening: pore diameter and pore thickness. Although this first one has been deeply studied, the effect of pore thickness in electrochemical-based nanopore immunosensors has been less taken into consideration. Methods: In this work, the influence of the thickness of nanoporous membranes in the steric blockage is studied for the first time, through the formation of an immunocomplex in their inner walls. Finally, the optimal nanoporous membranes were applied to the detection of catalase, an enzyme related with chronic wound infection and healing. Results: Nanoporous alumina membranes with a fixed pore diameter (60 nm) and variable pore thicknesses (40, 60, 100 µm) have been constructed and evaluated as immunosensing platform for protein detection. Our results show that membranes with a thickness of 40 µm provide a higher sensitivity and lower limit-of-detection (LOD) compared to thicker membranes. This performance is even improved when compared to commercial membranes (with 20 nm pore diameter and 60 µm pore thickness), when applied for human IgG as model analyte. A label-free immunosensor using a monoclonal antibody against anti-catalase was also constructed, allowing the detection of catalase in the range of 50-500 ng/mL and with a LOD of 1.5 ng/mL. The viability of the constructed sensor in real samples was also tested by spiking artificial wound infection solutions, providing recovery values of 110% and 118%. Discussion: The results obtained in this work evidence the key relevance of the nanochannel thickness in the biosensing performance. Such findings will illuminate nanoporous membrane biosensing research, considering thickness as a relevant parameter in electrochemical-based nanoporous membrane sensors.

Principles for management of hip fracture for older adults taking direct oral anticoagulants: an international consensus statement.

Hip fracture is a common serious injury among older adults, yet the management of hip fractures for patients taking direct oral anticoagulants remains inconsistent worldwide. Drawing from a synthesis of available evidence and expert opinion, best practice approaches for managing patients with a hip fracture and who are taking direct oral anticoagulants pre-operatively were considered by a working group of the Fragility Fracture Network Hip Fracture Audit Special Interest Group. The literature and related clinical guidelines were reviewed and a two-round modified Delphi study was conducted with a panel of experts from 16 countries and involved seven clinical specialities. Four consensus statements were achieved: peripheral nerve blocks can reasonably be performed on presentation for patients with hip fracture who are receiving direct oral anticoagulants; hip fracture surgery can reasonably be performed for patients taking direct oral anticoagulants < 36 h from last dose; general anaesthesia could reasonably be administered for patients with hip fracture and who are taking direct oral anticoagulants < 36 h from last dose (assuming eGFR > 60 ml.min-1.1.73 m-2); and it is generally reasonable to consider recommencing direct oral anticoagulants (considering blood loss and haemoglobin) < 48 h after hip fracture surgery. No consensus was achieved regarding timing of spinal anaesthesia. The consensus statements were developed to aid clinicians in their decision-making and to reduce practice variations in the management of patients with hip fracture and who are taking direct oral anticoagulants. Each statement will need to be considered specific to each individual patient's treatment.

Host biomarkers for early identification of severe imported Plasmodium falciparum malaria.

BACKGROUND: Severe imported P. falciparum malaria is a source of morbi-mortality in non-endemic regions. WHO criteria don't accurately classify patients at risk of complications. There is a need to evaluate new tools such as biomarkers to better identify patients with severe imported malaria. METHODS: A case-control study was conducted in Barcelona, from January 2011-January 2021. Adult patients with microbiologically confirmed P. falciparum malaria were classified according to WHO criteria. Patients with imported non-malarial fevers were included as controls. In each group, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), soluble triggering receptor expressed on myeloid cells (sTREM-1), C-reactive protein (CRP) and platelets were measured and their concentrations were compared between groups. New groups were made with a modified WHO severity classification and biomarkers' performance was evaluated using multiple imputation models. RESULTS: 131 participants were included: 52 severe malaria, 30 uncomplicated malaria and 49 non-malarial fever cases. All biomarkers except sTREM-1 showed significant differences between groups. Using the modified WHO severity classification, Ang-2 and CRP presented the best AUROC; 0.79 (95%CI 0.64-0.94) and 0.80(95%CI 0.67-0.93). A model combining CRP and Ang-2 showed the best AUROC, of 0.84(95%CI 0.68-0.99), with the highest sensitivity and specificity: 84.6%(95%CI 58.9-98.1) and 77.4% (95%CI 65.9-87.7), respectively. CONCLUSIONS: The combination of Ang-2 and CRP may be a reliable tool for the early identification of severe imported malaria. The use of a rapid prognostic test including the mentioned biomarkers could optimize imported malaria management, with the potential to decrease the rate of complications and hospitalizations in patients with imported malaria.

An integral approach to sludge handling in a WWTP operated for EBPR aiming phosphorus recovery: Simulation of alternatives, LCA and LCC analyses.

As phosphorus is a non-renewable resource mainly used to produce fertilizers and helps to provide food all over the world, the proper management of its reserves is a global concern since it is expected to become scarcer in the near future. In this work we assessed two different sludge line configurations aiming for P extraction and recovery before anaerobic digestion and compared them with the classical configuration. This study has been performed by simulation with the model BNRM2 integrated in the software package DESASS 7.1. Configuration 1 was based on the production of a PO4-enriched stream from sludge via elutriation in the primary thickeners, while Configuration 2 was based on the WASSTRIP® process and its PO4-enriched stream was mechanically obtained with dynamic thickeners. In both alternatives recovery was enhanced by promoting poly-phosphate (poly-P) extraction under anaerobic conditions, for which both configurations were fully evaluated in a full-scale WWTP. Both were also optimized to maximize phosphorus extraction. Their costs and life cycles were also analysed. The novelty of this research lies in the lack of literature about the integral evaluation of pre-anaerobic digestion P recovery from wastewaters. This study included a holistic approach and an optimization study of both alternatives plus their economic and environmental aspects. In Configuration 1, the PO4-P load in the recovery stream reached 43.1% of the total influent P load and reduced uncontrolled P-precipitation in the sludge line up to 52.9%. In Configuration 2, extraction was 48.2% of the influent P load and it reduced precipitation by up to 60.0%. Despite Configuration 1's lower phosphorus recovery efficiency, it had a 23.0% lower life cycle cost and a 14.2% lower global warming impact per hm3 of treated influent than Configuration 2. Configuration 1 also reduced the TAEC by 17.6% and global warming impact by 2.0% less than Configuration 0.

Genetic history of the African Sahelian populations.

From a biogeographic perspective, Africa is subdivided into distinct horizontal belts. Human populations living along the Sahel/Savannah belt south of the Sahara desert have often been overshadowed by extensive studies focusing on other African populations such as hunter-gatherers or Bantu in particular. However, the Sahel together with the Savannah bordering it in the south is a challenging region where people had and still have to cope with harsh climatic conditions and show resilient behaviours. Besides exponentially growing urban populations, several local groups leading various lifestyles and speaking languages belonging to three main linguistic families still live in rural localities across that region today. Thanks to several years of consistent population sampling throughout this area, the genetic history of the African Sahelian populations has been largely reconstructed and a deeper knowledge has been acquired regarding their adaptation to peculiar environments and/or subsistence modes. Distinct exposures to pathogens-in particular, malaria-likely contributed to their genetic differentiation for HLA genes. In addition, although food-producing strategies spread within the Sahel/Savannah belt relatively recently, during the last five millennia according to recent archaeological and archaeobotanical studies, remarkable amounts of genetic differences are also observed between sedentary farmers and more mobile pastoralists at multiple neutral and selected loci, reflecting both demographic effects and genetic adaptations to distinct cultural traits, such as dietary habits.

Risk of End-Stage Renal Disease in HIV-Positive Potential Live Kidney Donors.

New federal regulations allow HIV-positive individuals to be live kidney donors; however, potential candidacy for donation is poorly understood given the increased risk of end-stage renal disease (ESRD) associated with HIV infection. To better understand this risk, we compared the incidence of ESRD among 41 968 HIV-positive participants of North America AIDS Cohort Collaboration on Research and Design followed for a median of 5 years with the incidence of ESRD among comparable HIV-negative participants of National Health and Nutrition Examination III followed for a median of 14 years. We used risk associations from multivariable Cox proportional hazards regression to derive cumulative incidence estimates for selected HIV-positive scenarios (no history of diabetes, hypertension, AIDS, or hepatitis C virus coinfection) and compared these estimates with those from similarly selected HIV-negative scenarios. For 40-year-old HIV-positive individuals with health characteristics that were similar to those of age-matched kidney donors, viral load <400 copies/mL, and CD4+ count ≥500 cells/µL, the 9-year cumulative incidence of ESRD was higher than that of their HIV-negative peers, yet still low: 2.5 versus 1.1 per 10 000 among white women, 3.0 versus 1.3 per 10 000 among white men, 13.2 versus 3.6 per 10 000 among black women, and 15.8 versus 4.4 per 10 000 among black men. HIV-positive individuals with no comorbidities and well-controlled disease may be considered low-risk kidney donor candidates.

A comprehensive and efficient daily quality assurance for PBS proton therapy.

There are several general recommendations for quality assurance (QA) measures, which have to be performed at proton therapy centres. However, almost each centre uses a different therapy system. In particular, there is no standard procedure for centres employing pencil beam scanning and each centre applies a specific QA program. Gantry 2 is an operating therapy system which was developed at PSI and relies on the most advanced technological innovations. We developed a comprehensive daily QA program in order to verify the main beam characteristics to assure the functionality of the therapy delivery system and the patient safety system. The daily QA program entails new hardware and software solutions for a highly efficient clinical operation. In this paper, we describe a dosimetric phantom used for verifying the most critical beam parameters and the software architecture developed for a fully automated QA procedure. The connection between our QA software and the database allows us to store the data collected on a daily basis and use it for trend analysis over longer periods of time. All the data presented here have been collected during a time span of over two years, since the beginning of the Gantry 2 clinical operation in 2013. Our procedure operates in a stable way and delivers the expected beam quality. The daily QA program takes only 20 min. At the same time, the comprehensive approach allows us to avoid most of the weekly and monthly QA checks and increases the clinical beam availability.

Contour scanning for penumbra improvement in pencil beam scanned proton therapy.

Proton therapy, especially in the form of pencil beam scanning (PBS), allows for the delivery of highly conformal dose distributions for complex tumor geometries. However, due to scattering of protons inside the patient, lateral dose gradients cannot be arbitrarily steep, which is of importance in cases with organs at risk (OARs) in close proximity to, or overlapping with, planning target volumes (PTVs). In the PBS approach, physical pencil beams are planned using a regular grid orthogonal to the beam direction. In this work, we propose an alternative to this commonly used approach where pencil beams are placed on an irregular grid along concentric paths based on the target contour. Contour driven pencil beam placement is expected to improve dose confirmation by allowing the optimizer to best enhance the penumbra of irregularly shaped targets using edge enhancement. Its effectiveness has been shown to improve dose confirmation to the target volume and reduce doses to OARs in head-and-neck planning studies. Furthermore, the deliverability of such plans, as well as the dosimetric improvements over conventional grid-based plans, have been confirmed in first phantom based verifications.

Laser printing of resonant plasmonic nanovoids.

Hollow reduced-symmetry resonant plasmonic nanostructures possess pronounced tunable optical resonances in the UV-vis-IR range, being a promising platform for advanced nanophotonic devices. However, the present fabrication approaches require several consecutive technological steps to produce such nanostructures, making their large-scale fabrication rather time-consuming and expensive. Here, we report on direct single-step fabrication of large-scale arrays of hollow parabolic- and cone-shaped nanovoids in silver and gold thin films, using single-pulse femtosecond nanoablation at high repetition rates. The lateral and vertical size of such nanovoids was found to be laser energy-tunable. Resonant light scattering from individual nanovoids was observed in the visible spectral range, using dark-field confocal microspectroscopy, with the size-dependent resonant peak positions. These colored geometric resonances in far-field scattering were related to excitation and interference of transverse surface plasmon modes in nanovoid shells. Plasmon-mediated electromagnetic field enhancement near the nanovoids was evaluated via finite-difference time-domain calculations for their model shapes simulated by three-dimensional molecular dynamics, and experimentally verified by means of photoluminescence microscopy and Raman spectroscopy.

Fire-induced pine woodland to shrubland transitions in Southern Europe may promote shifts in soil fertility.

Since the mid of the last century, fire recurrence has increased in the Iberian Peninsula and in the overall Mediterranean basin due to changes in land use and climate. The warmer and drier climate projected for this region will further increase the risk of wildfire occurrence and recurrence. Although the impact of wildfires on soil nutrient content in this region has been extensively studied, still few works have assessed this impact on the basis of fire recurrence. This study assesses the changes in soil organic C and nutrient status of mineral soils in two Southern European areas, Várzea (Northern Portugal) and Valencia (Eastern Spain), affected by different levels of fire recurrence and where short fire intervals have promoted a transition from pine woodlands to shrublands. At the short-term (<1year), the amount of soil organic matter was higher in burned than in unburned soils while its quality (represented as labile to total organic matter) was actually lower. In any case, total and labile soil organic matter showed decreasing trends with increasing fire recurrence (one to four fires). At the long-term (>5years), a decline in overall soil fertility with fire recurrence was also observed, with a drop between pine woodlands (one fire) and shrublands (two and three fires), particularly in the soil microsites between shrubs. Our results suggest that the current trend of increasing fire recurrence in Southern Europe may result in losses or alterations of soil organic matter, particularly when fire promotes a transition from pine woodland to shrubland. The results also point to labile organic matter fractions in the intershrub spaces as potential early warning indicators for shifts in soil fertility in response to fire recurrence.

Improving Radiation Awareness and Feeling of Personal Security of Non-Radiological Medical Staff by Implementing a Traffic Light System in Computed Tomography.

PURPOSE: Non-radiological medical professionals often need to remain in the scanning room during computed tomography (CT) examinations to supervise patients in critical condition. Independent of protective devices, their position significantly influences the radiation dose they receive. The purpose of this study was to assess if a traffic light system indicating areas of different radiation exposure improves non-radiological medical staff's radiation awareness and feeling of personal security. MATERIAL AND METHODS: Phantom measurements were performed to define areas of different dose rates and colored stickers were applied on the floor according to a traffic light system: green = lowest, orange = intermediate, and red = highest possible radiation exposure. Non-radiological medical professionals with different years of working experience evaluated the system using a structured questionnaire. Kruskal-Wallis and Spearman's correlation test were applied for statistical analysis. RESULTS: Fifty-six subjects (30 physicians, 26 nursing staff) took part in this prospective study. Overall rating of the system was very good, and almost all professionals tried to stand in the green stickers during the scan. The system significantly increased radiation awareness and feeling of personal protection particularly in staff with ≤ 5 years of working experience (p < 0.05). The majority of non-radiological medical professionals stated that staying in the green stickers and patient care would be compatible. Knowledge of radiation protection was poor in all groups, especially among entry-level employees (p < 0.05). CONCLUSION: A traffic light system in the CT scanning room indicating areas with lowest, intermediate, and highest possible radiation exposure is much appreciated. It increases radiation awareness, improves the sense of personal radiation protection, and may support endeavors to lower occupational radiation exposure, although the best radiation protection always is to re-main outside the CT room during the scan. KEY POINTS: • A traffic light system indicating areas with different radiation exposure within the computed tomography scanner room is much appreciated by non-radiological medical staff. • The traffic light system increases non-radiological medical staff's radiation awareness and feeling of personal protection. • Knowledge on radiation protection was poor in non-radiological medical staff, especially in those with few working experience.

Massive Plasmodium falciparum visceral sequestration: a cause of maternal death in Africa.

Sequestration of Plasmodium falciparum-infected erythrocytes (PfIE) in the capillaries of the central nervous system (CNS) is the pathognomonic feature of cerebral malaria, a condition frequently leading to death. Sequestration of PfIE in the placental intervillous spaces is the characteristic feature of malaria in pregnancy and is associated with low birthweight and prematurity. Although both patterns of sequestration are thought to result from the expression of different parasite proteins involved in cytoadhesion to human receptors, scant information exists on whether both conditions can coexist and whether this can lead to death. We conducted a prospective autopsy study including all consecutive pregnancy-related deaths in a tertiary-level referral hospital in Maputo, Mozambique, between October 2002 and December 2006. Extensive sampling of all major viscera was performed. All cases showing parasites in any of the viscera were included in the analysis. From 317 complete autopsies PfIEs were identified in ten women (3.2%). All cases showed massive accumulation of PfIE in small capillaries of the CNS but also in most visceral capillaries (heart, lung, kidney, uterus). Placental tissue, available in four cases, showed a massive accumulation of maternal PfIE in the intervillous space. Coma (six women) and dyspnoea (five women) were the most frequent presenting clinical symptoms. In conclusion, massive visceral sequestration of PfIE with significant involvement of the CNS is an infrequent but definite direct cause of maternal death in endemic areas of Africa. The PfIE sequestered in cerebral capillaries and the placenta coexist in these fatal cases.

ER stress activates the NLRP3 inflammasome via an UPR-independent pathway.

Uncontrolled endoplasmic reticulum (ER) stress responses are proposed to contribute to the pathology of chronic inflammatory diseases such as type 2 diabetes or atherosclerosis. However, the connection between ER stress and inflammation remains largely unexplored. Here, we show that ER stress causes activation of the NLRP3 inflammasome, with subsequent release of the pro-inflammatory cytokine interleukin-1ß. This ER-triggered proinflammatory signal shares the same requirement for reactive oxygen species production and potassium efflux compared with other known NLRP3 inflammasome activators, but is independent of the classical unfolded protein response (UPR). We thus propose that the NLRP3 inflammasome senses and responds to ER stress downstream of a previously uncharacterized ER stress response signaling pathway distinct from the UPR, thus providing mechanistic insight to the link between ER stress and chronic inflammatory diseases.

Factors associated with metabolic syndrome in patients with systemic lupus erythematosus from Puerto Rico.

The aim of this study was to determine the factors associated with metabolic syndrome in patients with systemic lupus erythematosus from Puerto Rico. A total of 204 patients with systemic lupus erythematosus (per the American College of Rheumatology classification criteria) were evaluated. Metabolic syndrome was assessed using the American Heart Association and the National Heart, Lung, and Blood Institute classification. Socioeconomic-demographic parameters, health-related behaviours, clinical manifestations, autoantibodies, pharmacological treatments, disease activity (per the Systemic Lupus Activity Measure--Revised), and damage accrual (per the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) were determined at study visit. Factors associated with metabolic syndrome were examined by univariable analyses and multivariable logistic regression models. A total of 196 (96.2%) were women. The mean age at study visit was 43.6 +/- 13.0 years, and the mean disease duration was 8.7 +/- 7.7 years. Seventy-eight patients (38.2%) had metabolic syndrome. In the multivariable analysis, age (odds ratio [OR] = 1.05; 95% confidence interval [CI] 1.02-1.09), government health insurance (OR = 2.06; 95% CI 1.07-4.22), exercise (OR = 0.33; 95% CI 0.14-0.92), thrombocytopenia (OR = 4.19; 95% CI 1.54-11.37), erythrocyte sedimentation rate (OR = 1.64; 95% CI 1.03-2.63), disease activity (OR = 1.14; 95% CI 1.00-1.30), and prednisone >10 mg/day (OR = 3.69; 95% CI 1.22-11.11) were associated with metabolic syndrome. In conclusion, older age, low socioeconomic status, lack of exercise, thrombocytopenia, increased erythrocyte sedimentation rate , higher disease activity, and prednisone >10 mg/day were independently associated with metabolic syndrome in patients with systemic lupus erythematosus from Puerto Rico.

Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration.

Inflammasomes are Nod-like receptor(NLR)- and caspase-1-containing cytoplasmic multiprotein complexes, which upon their assembly, process and activate the proinflammatory cytokines interleukin (IL)-1beta and IL-18. The inflammasomes harboring the NLR members NALP1, NALP3 and IPAF have been best characterized. While the IPAF inflammasome is activated by bacterial flagellin, activation of the NALP3 inflammasome is triggered not only by several microbial components, but also by a plethora of danger-associated host molecules such as uric acid. How NALP3 senses these chemically unrelated activators is not known. Here, we provide evidence that activation of NALP3, but not of the IPAF inflammasome, is blocked by inhibiting K(+) efflux from cells. Low intracellular K(+) is also a requirement for NALP1 inflammasome activation by lethal toxin of Bacillus anthracis. In vitro, NALP inflammasome assembly and caspase-1 recruitment occurs spontaneously at K(+) concentrations below 90 mM, but is prevented at higher concentrations. Thus, low intracellular K(+) may be the least common trigger of NALP-inflammasome activation.