Phenoxy Group-Containing Asymmetric Non-Fullerene Acceptors Achieved Higher VOC over 1.0 V through Alkoxy Side-Chain Engineering for Organic Solar Cells.
Alkoxy side chain engineering on the β-position of the thienothiophene units of Y6 derivatives plays a vital role in improving photovoltaic performances with simultaneously increasing open-circuit voltage (Voc) and fill factor (FF). In this work, we prepared a series of asymmetric non-fullerene acceptors (NFAs) by introducing alkoxy side chains and phenoxy groups on the state-of-the-art Y6-derivative BTP-BO-4F. For the comparison, 2O-BO-4F with a symmetric alkoxy side chain on the outer thiophene units and BTP-PBO-4F with an asymmetric N-attached phenoxy alkyl chain on the pyrrole ring are synthesized from BTP-BO-4F. Thereafter, we construct four asymmetric NFAs by introducing different lengths of linear/branched alkoxy chains on the β-position of the thienothiophene units of BTP-PBO-4F. The resulting NFAs, named L10-PBO, L12-PBO, B12-PBO, and B16-PBO (L = linear and B = branched alkoxy side chains), are collectively called OR-PBO-series. Unexpectedly, all OR-PBO NFAs exhibit strong edge-on molecular packing and weaker π-π interactions in the film state, which diminish the charge transfer in organic solar cell (OSC) devices. As a consequence, the optimal devices of OR-PBO-based binary blends show poor photovoltaic performances [power conversion efficiency (PCE) = 6.52-9.62%] in comparison with 2O-BO-4F (PCE = 12.42%) and BTP-PBO-4F (PCE = 15.30%) reference blends. Nevertheless, the OR-PBO-based binary devices show a higher Voc and smaller Vloss. Especially, B12-PBO- and B16-PBO-based devices achieve Voc over 1.00 V, which is the highest value of Y-series OSC devices to the best of our knowledge. Therefore, by utilizing higher Voc of OR-PBO binary blends, B12-PBO and B16-PBO are incorporated into the PM6:BTP-PBO-4F-based binary blend and fabricated ternary devices. As a result, the PM6:BTP-PBO-4F:B12-PBO ternary device delivers the best PCE of 15.60% with an increasing Voc and FF concurrently.


Predicting algal blooms: Are we overlooking groundwater?
Significant advances in understanding and predicting freshwater algal bloom dynamics have emerged in response to both increased occurrence and financial burden of nuisance and harmful blooms. Several factors have been highlighted as key controls of bloom occurrence, including nutrient dynamics, local hydrology, climatic perturbations, watershed geomorphology, biogeochemistry, food-web control, and algal competition. However, a major research gap continues to be the degree to which groundwater inputs modulate microbial biomass production and food-web dynamics at the terrestrial-aquatic interface. We present a synthesis of groundwater related algal bloom literature, upon which we derive a foundational hypothesis: long residence times cause groundwater to be geochemically and biologically distinct from surface water, allowing groundwater inputs to modulate algal bloom dynamics (growth, decline, toxicity) through its control over in-stream water chemistry. Distinct groundwater chemistry can support or prevent algal blooms, depending on specific local conditions. We highlight three mechanisms that influence the impact of groundwater discharge on algal growth: 1) redox state of the subsurface, 2) extent of water-rock interactions, and 3) stability of groundwater discharge. We underscore that in testing hypotheses related to groundwater control over algal blooms, it is critical to understand how changes in land use, water management, and climate will influence groundwater dynamics and, thus, algal bloom probabilities. Given this challenge, we argue that advances in both modeling and data integration, including genomics data and integrated process-based models that capture groundwater dynamics, are needed to illuminate mechanistic controls and improve predictions of algal blooms.


Multicenter feasibility study of combination therapy with fluorouracil, leucovorin and paclitaxel (FLTAX) for peritoneal disseminated gastric cancer with massive ascites or inadequate oral intake.
Oral fluoropyrimidine plus cisplatin is a standard treatment for advanced gastric cancer, but patients with severe peritoneal metastasis often cannot tolerate this regimen. The aim of this study was to assess the feasibility of fluorouracil, l-leucovorin and paclitaxel therapy in such patients. In the first phase of the study, we investigated the maximum tolerated dose and recommended dose in Cycle 1 of fluorouracil, l-leucovorin and paclitaxel, at two dose levels [Level 1 (n = 6): 5-fluorouracil/l-leucovorin/paclitaxel = 500/250/60 mg/m(2); Level 2 (n = 6): 600/250/80 mg/m(2) on Days 1, 8 and 15, every 28 days]. Nineteen additional patients at the recommended dose level were enrolled in the second phase to investigate the feasibility of fluorouracil, l-leucovorin and paclitaxel therapy. The primary endpoint in the second phase was the completion rate of two cycles. Dose-limiting toxicities were observed in a patient at Level 1 with Grade 4 gastrointestinal perforation (the site of primary tumor), and in two patients at Level 2 with Grade 3 febrile neutropenia and Grade 3 infection, respectively. In Cycle 2, treatment-related death occurred at Level 2 in one patient who had Grade 4 febrile neutropenia with pneumonia. The maximum tolerated dose was set at Level 2, and the recommended dose was determined as Level 1. In the second phase, the completion rate of two cycles was 92% and the ascites response was 44%. Median progression-free survival was 4.2 months and overall survival was 8.0 months. Grade 3/4 neutropenia was observed in 12% of patients. Fluorouracil, l-leucovorin and paclitaxel at Level 1 is feasible as first-line treatment for peritoneal disseminated gastric cancer patients with massive ascites or inadequate oral intake.


MicroRNA‑378b regulates α‑1‑type 1 collagen expression via sirtuin 6 interference.
Ultraviolet (UV) light mediates skin aging and induces destruction of the dermis by modulating the expression levels of extracellular matrix‑associated genes, including collagen and matrix metalloproteinases. Sirtuin 6 (SIRT6), a member of the sirtuin family of proteins, regulates collagen metabolism and is an established anti‑aging protein. However, the exact underlying mechanism by which SIRT6 expression is regulated in dermal fibroblasts during the aging process is unclear. The present study demonstrated that expression of microRNA‑378b (miR‑378b) is induced in UVB‑exposed human dermal fibroblasts (HDFs), and this was inversely associated with the mRNA expression levels of α‑1‑type 1 collagen (COL1A1). In addition, knockdown of miR‑378b enhanced the mRNA expression levels of COL1A1 in HDFs. A target analysis for miR‑378b was performed, and the results revealed that SIRT6, a regulator of COL1A1, contains a target sequence for miR‑378b in its 3'untranslated region. Notably, the present study demonstrated that an miR‑378b mimic and inhibitor may directly regulate SIRT6 expression in HDFs. In conclusion, the present study suggested that miR‑378b represses the mRNA expression levels of COL1A1 via interference with SIRT6 in HDFs, and may contribute to the underlying molecular mechanism by which UVB inhibits collagen I in dermal fibroblasts.


Reducing the risks of proximal and distal shunt failure in adult hydrocephalus: a shunt outcomes quality improvement study.
Patient outcomes of ventriculoperitoneal (VP) shunt surgery, the mainstay treatment for hydrocephalus in adults, are poor because of high shunt failure rates. The use of neuronavigation or laparoscopy can reduce the risks of proximal or distal shunt catheter failure, respectively, but has less independent effect on overall shunt failures. No adult studies to date have combined both approaches in the setting of a shunt infection prevention protocol to reduce shunt failure. The goal of this study was to determine whether combining neuronavigation and laparoscopy with a shunt infection prevention strategy would reduce the incidence of shunt failures in adult hydrocephalic patients. Adult patients (age ≥ 18 years) undergoing VP shunt surgery at a tertiary care institution prior to (pre-Shunt Outcomes [ShOut]) and after (post-ShOut) the start of a prospective continuous quality improvement (QI) study were compared. Pre-ShOut patients had their proximal and distal catheters placed under conventional freehand approaches. Post-ShOut patients had their shunts inserted with neuronavigational and laparoscopy assistance in placing the distal catheter in the perihepatic space (falciform technique). A shunt infection reduction protocol had been instituted 1.5 years prior to the start of the QI initiative. The primary outcome of interest was the incidence of shunt failure (including infection) confirmed by standardized criteria indicating shunt revision surgery. There were 244 (115 pre-ShOut and 129 post-ShOut) patients observed over 7 years. With a background of shunt infection prophylaxis, combined neuronavigation and laparoscopy was associated with a reduction in overall shunt failure rates from 37% to 14%, 45% to 22%, and 51% to 29% at 1, 2, and 3 years, respectively (HR 0.44, p < 0.001). Shunt infection rates decreased from 8% in the pre-ShOut group to 0% in the post-ShOut group. There were no proximal catheter failures in the post-ShOut group. The 2-year rates of distal catheter failure were 42% versus 20% in the pre- and post-ShOut groups, respectively (p < 0.001). Introducing a shunt infection prevention protocol, placing the proximal catheter under neuronavigation, and placing the peritoneal catheter in the perihepatic space by using the falciform technique led to decreased rates of infection, distal shunt failure, and overall shunt failure.


Low-field and variable-field NMR relaxation studies of H2O and D2O molecular dynamics in articular cartilage.
Osteoarthritis (OA) as the main degenerative disease of articular cartilage in joints is accompanied by structural and compositional changes in the tissue. Degeneration is a consequence of a reduction of the amount of macromolecules, the so-called proteoglycans, and of a corresponding increase in water content, both leading to structural weakening of cartilage. NMR investigations of cartilage generally address only the relaxation properties of water. In this study, two-dimensional (T1-T2) measurements of bovine articular cartilage samples were carried out for different stages of hydration, complemented by molecular exchange with D2O and treatment by trypsin which simulates degeneration by OA. Two signal components were identified in all measurements, characterized by very different T2 which suggests liquid-like and solid-like dynamics. These measurements allow the quantification of separate hydrogen components and their assignment to defined physical pools which had been discussed repeatedly in the literature, i.e. bulk-like water and a combination of protein hydrogens and strongly bound water. The first determination of 2H relaxation dispersion in comparison to 1H dispersion suggests intramolecular interactions as the dominating source for the pronounced magnetic field dependence of the longitudinal relaxation time T1.


Prognosis-a wearable health-monitoring system for people at risk: methodology and modeling.
Wearable health-monitoring systems (WHMSs) represent the new generation of healthcare by providing real-time unobtrusive monitoring of patients' physiological parameters through the deployment of several on-body and even intrabody biosensors. Although several technological issues regarding WHMS still need to be resolved in order to become more applicable in real-life scenarios, it is expected that continuous ambulatory monitoring of vital signs will enable proactive personal health management and better treatment of patients suffering from chronic diseases, of the elderly population, and of emergency situations. In this paper, we present a physiological data fusion model for multisensor WHMS called Prognosis. The proposed methodology is based on a fuzzy regular language for the generation of the prognoses of the health conditions of the patient, whereby the current state of the corresponding fuzzy finite-state machine signifies the current estimated health state and context of the patient. The operation of the proposed scheme is explained via detailed examples in hypothetical scenarios. Finally, a stochastic Petri net model of the human-device interaction is presented, which illustrates how additional health status feedback can be obtained from the WHMS' user.


Biomarkers of fibroproliferative healing in fibrosing idiopathic interstitial pneumonias.
The main feature of fibrosing idiopathic interstitial pneumonias (fIIPs) is the fibroproliferative potential of underlying pathogenetic process. We hypothesize that the concentration of potential markers of fibroproliferative healing, PAR-2, TGF-β1, TNF-α and IL-4Rα in bronchoalveolar lavage fluid (BALF) differ in patients with fIIPs compared to controls (C). 10 patients with fIIPs and 9 controls (C) were included to the study. Concentrations of CD124 (IL4Rα), PAR-2, TGF-β1 and TNF-α in BALF were determined using the ELISA method. We observed higher concentrations of IL4Rα (fIIPS 1499.4 pg/ml vs C 255.5 pg/ml; p < 0.05), PAR-2 (fIIPS 1807.9 pg/ml vs C 421.0 pg/ml; p < 0.05) and TGF-β1(fIIPS 283.0 pg/ml vs C 197.1 pg/ml; p < 0.01) in BALF in fIIPs versus C. The values of TNF-a in BALF did not differ significantly in fIIPs compared to controls. The ratios also showed differences in fIIPS and C: IL4Rα/TGF-β1 (fIIPS 6.19 vs C 0.68; p = 0.0143); TNF-α/IL4Rα (fIIPS 0.84 vs C 7.93; p = 0.043); TGF-β1/TNF-α (fIIPS 0.21 vs C 0.16; p = 0.0179) and protein/PAR-2 (fIIPS 0.06 vs C 0.28; p = 0.0033). We found that PAR-2, TGF-β1 and IL-4Rα are significantly up-regulated in the BALF of fIIPs compared to controls, therefore we suppose they could become biomarkers of fibroproliferative healing.


Endotoxin in vivo impairs endothelium-dependent relaxation of canine arteries in vitro.
We studied the effect of endotoxin administration in vivo on arterial smooth muscle responses in vitro, testing the hypotheses that endotoxin augments adrenergic vasoconstriction and impairs endothelium-dependent vascular relaxation. Ten mongrel dogs were anesthetized and mechanically ventilated. Five received a bolus infusion of Escherichia coli endotoxin (5 mg/kg), and the remainder received a sham infusion. After 4 to 5 h, the anesthetized dogs were rapidly exsanguinated, and femoral, renal, and superior mesenteric arteries were removed. Arterial rings were mounted on force transducers in organ baths; contraction to phenylephrine or potassium-substituted Krebs-Henseleit solution (KCl), and relaxation to nitroprusside or acetylcholine were studied. Smooth muscle contractions to phenylephrine or KCl were similar between sham and endotoxin for each agonist. Also, nitroprusside-elicited relaxation from half-maximal phenylephrine-elicited contraction was similar. However, relaxation elicited by acetylcholine was markedly impaired in vessels from endotoxin-treated dogs. The negative log molar concentration of acetylcholine producing 50% relaxation for femoral arteries was 7.38 +/- 0.11 (endotoxin) versus 8.09 +/- 0.12 (control, p = 0.002), for renal arteries it was 6.71 +/- 0.33 (endotoxin) versus 7.81 +/- 0.18 (control, p = 0.019), and for mesenteric arteries it was 7.27 +/- 0.03 (endotoxin) versus 7.95 +/- 0.15 (control, p = 0.002). These results demonstrate that endotoxin treatment impairs endothelium-dependent relaxation of canine arteries in vitro. The data suggest that vascular changes in endotoxemia are accompanied by alteration in endothelial cell function, perhaps through altered endothelial production of vasodilatory mediators.


A sensitive liquid chromatography method for analysis of propofol in small volumes of neonatal blood.
Sampling volumes of blood from neonates is necessarily limited. However, most of the published propofol analysis assays require a relatively large blood sample volume (typically ≥0.5 mL). Therefore, the aim of the present study was to develop and validate a sensitive method requiring a smaller sample volume (0.2 mL) to fulfill clinically relevant research requirements. Following simple protein precipitation and centrifugation, the supernatant was injected into the HPLC-fluorescence system and separated with a reverse phase column. Propofol and the internal standard (thymol) were detected and quantified using fluorescence at excitation and emission wavelengths of 270 nm and 310 nm, respectively. The method was validated with reference to the Food and Drug Administration (FDA) guidance for industry. Accuracy (CV, %) and precision (RSD, %) were evaluated at three quality control concentration levels (0.05, 0.5 and 5 µg/mL). Calibration curves were linear in the range of 0.005-20 µg/mL. Intra- and interday accuracy (-4.4%-13.6%) and precision (0.2%-5.8%) for propofol were below 15%. The calculated LOD (limit of detection) and LLOQ (lower limit of quantification) were 0.0021 µg/mL and 0.0069 µg/mL, respectively. Propofol samples were stable for 4 months at -20°C after the sample preparation. This method was applied for analyzing blood samples from 41 neonates that received propofol, as part of a dose-finding study. The measured median (range) concentration was 0.14 (0.03-1.11) µg/mL, which was in the range of the calibration curve. The calculated median (range) propofol half-life of the gamma elimination phase was 10.4 (4.7-26.7) hours. A minimal volume (0.2 mL) of blood from neonates is required for the determination of propofol with this method. The method can be used to support the quantification of propofol drug concentrations for pharmacokinetic studies in the neonatal population.


Recurring two-stage evolutionary programming: a novel approach for numeric optimization.
In the application of evolutionary algorithms (EAs) to complex problem solving, it is essential to maintain proper balance between global exploration and local exploitation to achieve a good near-optimum solution to the problem. This paper presents a recurring two-stage evolutionary programming (RTEP) to balance the explorative and exploitative features of the conventional EAs. Unlike most previous works, RTEP is based on repeated and alternated execution of two different stages, namely, the exploration and exploitation stages, each with its own mutation operator, selection strategy, and explorative/exploitative objective. Both analytical and empirical studies have been carried out to understand the necessity of repeated and alternated exploration and exploitation operations in EAs. A suite of 48 benchmark numerical optimization problems has been used in the empirical studies. The experimental results show the remarkable effectiveness of the repeated exploration and exploitation operations employed by RTEP.


Conditioned place preference reveals ongoing pain in calves 3 weeks after disbudding.
Hot-iron disbudding, a routine procedure that prevents horn bud growth through cauterization, is painful for calves. The resulting burns remain sensitive to touch for weeks, but it is unknown whether calves experience ongoing, non-evoked pain. We evaluated conditioned place preference for analgesia in 44 calves disbudded or sham-disbudded 6 hours (Day 0) or 20 days (Day 20) before testing (n = 11/treatment). Calves were conditioned to associate the effects of a lidocaine cornual nerve block with the location and pattern of a visual stimulus, and a control injection of saline with the contrasting stimulus. On Day 0, disbudded calves tended to prefer the lidocaine-paired stimulus over the saline-paired one, suggesting that they found analgesia rewarding. On Day 20, sham calves avoided the lidocaine-paired stimulus, consistent with humans' experience of this drug being painful. Disbudded calves on Day 20 did not show this aversion, suggesting that they traded off the short-term pain of the lidocaine with the longer-term analgesia provided. Day 0 sham calves did not avoid the lidocaine-paired stimulus, likely because they received less than half the dose of Day 20 calves during conditioning. Thus, higher doses of lidocaine are aversive to uninjured animals, but disbudded calves are willing to engage in this cost. We conclude that calves experience ongoing pain 3 weeks after disbudding, raising additional welfare concerns about this procedure.


APG350 induces superior clustering of TRAIL receptors and shows therapeutic antitumor efficacy independent of cross-linking via Fcγ receptors.
Cancer cells can be specifically driven into apoptosis by activating Death-receptor-4 (DR4; TRAIL-R1) and/or Death-receptor-5 (DR5; TRAIL-R2). Albeit showing promising preclinical efficacy, first-generation protein therapeutics addressing this pathway, especially agonistic anti-DR4/DR5-monoclonal antibodies, have not been clinically successful to date. Due to their bivalent binding mode, effective apoptosis induction by agonistic TRAIL-R antibodies is achieved only upon additional events leading to antibody-multimer formation. The binding of these multimers to their target subsequently leads to effective receptor-clustering on cancer cells. The research results presented here report on a new class of TRAIL-receptor agonists overcoming this intrinsic limitation observed for antibodies in general. The main feature of these agonists is a TRAIL-mimic consisting of three TRAIL-protomer subsequences combined in one polypeptide chain, termed the single-chain TRAIL-receptor-binding domain (scTRAIL-RBD). In the active compounds, two scTRAIL-RBDs with three receptor binding sites each are brought molecularly in close proximity resulting in a fusion protein with a hexavalent binding mode. In the case of APG350-the prototype of this engineering concept-this is achieved by fusing the Fc-part of a human immunoglobulin G1 (IgG1)-mutein C-terminally to the scTRAIL-RBD polypeptide, thereby creating six receptor binding sites per drug molecule. In vitro, APG350 is a potent inducer of apoptosis on human tumor cell lines and primary tumor cells. In vivo, treatment of mice bearing Colo205-xenograft tumors with APG350 showed a dose-dependent antitumor efficacy. By dedicated muteins, we confirmed that the observed in vivo efficacy of the hexavalent scTRAIL-RBD fusion proteins is-in contrast to agonistic antibodies-independent of FcγR-based cross-linking events.


A dilemma of hemorrhage vs thrombosis: a case of watchman device thrombus in a patient with intracranial hemorrhage history.
Recently updated guidelines for Atrial Fibrillation (AF) outline that percutaneous left atrial appendage (LAA) occlusion with the Watchman device may be a reasonable alternative for those who have contraindications to long-term oral anticoagulation. However, optimal periprocedural antithrombotic therapy remains disputable, particularly in patients who are ineligible for oral anticoagulation or those with history of intracranial hemorrhage (ICH). We present the case of a 67-year-old male with a history of ischemic stroke with hemorrhagic conversion and permanent AF, who was treated with the Watchman device and subsequently developed device related thrombus and recurrent ischemic stroke. We discuss the dilemma and review the literature regarding anticoagulation for device related thrombus in this patient with increased bleeding risk, given his history of ICH. His course and antithrombotic strategy are described and despite the use of anticoagulation with warfarin in the setting of recurrent ischemic stroke, he did not develop hemorrhagic transformation. He also did, ultimately, achieve device related thrombus resolution on repeat Transesophageal Echocardiogram (TEE). This case supported the use of warfarin for device related thrombus in the setting of ischemic stroke and history of ICH. However, evidence-based guidelines for periprocedural antithrombotic regimens in patients with high bleeding risk have yet to be released and further research is needed.


Extracorporeal cardiopulmonary resuscitation: a national study on the association between favourable neurological status and biomarkers of hypoperfusion, inflammation, and organ injury.
In refractory out-of-hospital cardiac arrest (OHCA) with prolonged whole-body ischaemia, global tissue injury proceeds even after establishment of circulation with extracorporeal cardiopulmonary resuscitation (ECPR). We aimed to investigate the role of biomarkers reflecting hypoperfusion, inflammation, and organ injury in prognostication of patients with refractory OHCA managed with ECPR. This nationwide retrospective study included 226 adults with refractory OHCA managed with ECPR in Denmark (2011-2020). Biomarkers the first days after ECPR-initiation were assessed. Odds ratio of favourable neurological status (Cerebral Performance Category 1-2) at hospital discharge was estimated by logistic regression analyses. Cut-off values were calculated using the Youden's index. Fifty-six patients (25%) survived to hospital discharge, 51 (91%) with a favourable neurological status. Factors independently associated with favourable neurological status were low flow time <81 min, admission leukocytes ≥12.8 × 109/L, admission lactate <13.2 mmol/L, alkaline phosphatase (ALP) < 56 (day1) or <55 U/L (day2), and day 1 creatine kinase MB (CK-MB) < 500 ng/mL. Selected biomarkers (leukocytes, C-reactive protein, and lactate) were significantly better predictors of favourable neurological status than classic OHCA-variables (sex, age, low-flow time, witnessed arrest, shockable rhythm) alone (P = 0.001) after hospital admission. Biomarkers of hypoperfusion (lactate), inflammation (leucocytes), and organ injury (ALP and CK-MB) were independently associated with neurological status at hospital discharge. Biomarkers of hypoperfusion and inflammation (at hospital admission) and organ injury (days 1 and 2 after ECPR) may aid in the clinical decision of when to prolong or terminate ECPR in cases of refractory OHCA.


Banning shisha smoking in public places in Iran: an advocacy coalition framework perspective on policy process and change.
Shisha smoking is a widespread custom in Iran with a rapidly growing prevalence especially among the youth. In this article, we analyze the policy process of enforcing a federal/state ban on shisha smoking in all public places in Kerman Province, Iran. Guided by the Advocacy Coalition Framework (ACF), we investigate how a shisha smoking ban reached the political agenda in 2011, how it was framed by different policy actors, and why no significant breakthrough took place despite its inclusion on the agenda. We conducted a qualitative study using a case study approach. Two main sources of data were employed: face-to-face in-depth interviews and document analysis of key policy texts. We interviewed 24 policy actors from diverse sectors. A qualitative thematic framework, incorporating both inductive and deductive analyses, was employed to analyze our data. We found that the health sector was the main actor pushing the issue of shisha smoking onto the political agenda by framing it as a public health risk. The health sector and its allies advocated enforcement of a federal law to ban shisha smoking in all public places including teahouses and traditional restaurants whereas another group of actors opposed the ban. The pro-ban group was unable to neutralize the strategies of the anti-ban group and to steer the debate towards the health harms of shisha smoking. Our analysis uncovers three main reasons behind the policy stasis: lack of policy learning due to lack of agreement over evidence and related analytical conflicts between the two groups linked to differences in core and policy beliefs; the inability of the pro-ban group to exploit opportunities in the external policy subsystem through generating stronger public support for enforcement of the shisha smoking ban; and the nature of the institutional setting, in particular the autocratic governance of CHFS which contributed to a lack of policy learning within the policy subsystem. Our research demonstrated the utility of ACF as a theoretical framework for analyzing the policy process and policy change to promote tobacco control. It shows the importance of accounting for policy actors' belief systems and issue-framing in understanding how some issues get more prominence in the policy-making process than others. Our findings further indicate a need for significant resources employed by the state through public awareness campaigns to change public perceptions of shisha smoking in Iran which is a deeply anchored cultural practice.


Intraarterial abciximab for treatment of thromboembolism during coil embolization of intracranial aneurysms: outcome and fatal hemorrhagic complications.
Experience with intraarterial abciximab for the treatment of thromboembolism during endovascular coil embolization is limited. The authors report the outcome of intraarterial abciximab use, with an emphasis on fatal hemorrhagic complications. Between March 2003 and May 2006, the authors treated 606 aneurysms by using endovascular coil embolization, and in 32 (5.3%) of these aneurysms (31 patients) an intraarterial thrombus developed. Sixteen of these aneurysms were ruptured and the other 16 were unruptured. Arterial thrombi were totally occlusive in 3 and partially occlusive in the remaining 29 cases. Intraarterial abciximab was administered at a concentration of 0.2 mg/ml as a bolus of 4-15 mg over a period of 15-30 minutes. Complete thrombolysis was achieved in 17 (53%) and partial thrombolysis in 15 (47%) of 32 lesions. Twenty-eight patients (90.3%) were asymptomatic after abciximab thrombolysis, but 3 had postprocedural rebleeding that occurred after abciximab treatment; all of these patients had recently experienced an aneurysm rupture. Of these patients, 1 displayed severe thrombocytopenia and the other 2 showed a > 25% reduction in platelet count after abciximab treatment. Intraarterial abciximab is effective for the treatment of thromboembolic complications that occur during intracranial aneurysm coil insertion. Nevertheless, attention should be paid to prevent potentially fatal complications such as thrombocytopenia and hemorrhage, especially in patients with a ruptured aneurysm.


12q24 locus association with type 1 diabetes: SH2B3 or ATXN2?
Genetic linkage analyses, genome-wide association studies of single nucleotide polymorphisms, copy number variation surveys, and mutation screenings found the human chromosomal 12q24 locus, with the genes SH2B3 and ATXN2 in its core, to be associated with an exceptionally wide spectrum of disease susceptibilities. Hematopoietic traits of red and white blood cells (like erythrocytosis and myeloproliferative disease), autoimmune disorders (like type 1 diabetes, coeliac disease, juvenile idiopathic arthritis, rheumatoid arthritis, thrombotic antiphospholipid syndrome, lupus erythematosus, multiple sclerosis, hypothyroidism and vitiligo), also vascular pathology (like kidney glomerular filtration rate deficits, serum urate levels, plasma beta-2-microglobulin levels, retinal microcirculation problems, diastolic and systolic blood pressure and hypertension, cardiovascular infarction), furthermore obesity, neurodegenerative conditions (like the polyglutamine-expansion disorder spinocerebellar ataxia type 2, Parkinson's disease, the motor-neuron disease amyotrophic lateral sclerosis, and progressive supranuclear palsy), and finally longevity were reported. Now it is important to clarify, in which ways the loss or gain of function of the locally encoded proteins SH2B3/LNK and ataxin-2, respectively, contribute to these polygenic health problems. SH2B3/LNK is known to repress the JAK2/ABL1 dependent proliferation of white blood cells. Its null mutations in human and mouse are triggers of autoimmune traits and leukemia (acute lymphoblastic leukemia or chronic myeloid leukemia-like), while missense mutations were found in erythrocytosis-1 patients. Ataxin-2 is known to act on RNA-processing and trophic receptor internalization. While its polyglutamine-expansion mediated gain-of-function causes neuronal atrophy in human and mouse, its deletion leads to obesity and insulin resistance in mice. Thus, it is conceivable that the polygenic pathogenesis of type 1 diabetes is enhanced by an SH2B3-dysregulation-mediated predisposition to autoimmune diseases that conspires with an ATXN2-deficiency-mediated predisposition to lipid and glucose metabolism pathology.


Using Methyl Bromide for Interspecies Cell-Cell Signaling and As a Reporter in a Model Soil Consortium.
Soil microbial communities with reduced complexity are emerging as model systems for studying consortia-scale phenotypes. To establish synthetic biology tools for studying these communities in hard-to-image environmental materials, we evaluated whether a single member of a model soil consortium (MSC) can be programmed to report on gene expression without requiring matrix disruption. For these studies, we targeted a five-membered MSC that includes Dyadobacter fermentans, Ensifer adhaerens, Rhodococcus sp003130705, Streptomyces sp001905665, and Variovorax beijingensis. By coupling the expression of a methyl halide transferase to a constitutive promoter, we show that V. beijingensis can be programmed to synthesize methyl halides that accumulate in the soil headspace at levels that are ≥24-fold higher than all other MSC members across a range of environmentally relevant hydration conditions. We find that methyl halide production can report on an MSC promoter that is activated by changes in water potential, and we demonstrate that a synthetic gas signal can be read out directly using gas chromatography and indirectly using a soil-derived Methylorubrum that is programmed to produce a visual output in response to methyl halides. These tools will be useful for future studies that investigate how MSC responds to dynamic hydration conditions, such as drought and flood events induced by climate change, which can alter soil water potential and induce the release of stored carbon.


Mechanistic insights into artificial metalloenzymes towards imine reduction.
In the field of artificial metalloenzyme (ArM) catalysis, how to identify the critical factors affecting the catalytic activity and enantioselectivity remains a challenge. In this work, the mechanism of enantioselective reduction of imine catalyzed by using [Rh(Me4Cpbiot)Cl2]·S112H Sav (denoted as S112H) and [Rh(Me4Cpbiot)Cl2]·K121H Sav (denoted as K121H) was studied by using molecular dynamics (MD) simulations combined with density functional theory (DFT) calculations. Four binding modes of imine, two proton sources (hydronium ion and lysine) and eight proposed reaction pathways were systematically discussed. The results showed that due to the anchoring effect of the mutation site of ArMs, the rhodium complex which oscillated like a pendulum was bound to a specific conformation, which further determined the chirality of the reduced product. C-Hπ, cation-π and ππ weak interactions played an important role in imine binding, and the favorable binding mode of imine was catalyzed by S112H in landscape orientation and catalyzed by K121H in portrait orientation, respectively. LYS121 is the most possible proton source in the S112H catalytic process while the proton source in the K121H catalytic process is the hydronium ion of the active sites. Furthermore, based on the reaction mechanism, modification of Rh(Me4Cpbiot)Cl2 was carried out in S112H and K121H, and the results suggested that the reaction barrier could be effectively reduced by replacing the methyl groups on Cp* with an amino group. This work gives a fundamental understanding of the mechanism of ArMs toward the imine reduction reaction, in the hope of providing a strategy for reasonable designs of ArMs with high enantioselectivity.


A 16S rDNA-based nested PCR protocol to detect Campylobacter gracilis in oral infections.
The aim of this study was to describe a 16S rDNA-based nested polymerase chain reaction (nPCR) assay to investigate the occurrence of Campylobacter gracilis in oral infections. Samples were collected from ten infected root canals, ten cases of acute periradicular abscesses and eight cases of adult marginal periodontitis. DNA extracted from the samples was initially amplified using universal 16S rDNA primers. A second round of amplification used the first PCR products to detect C. gracilis using oligonucleotide primers designed from species-specific 16S rDNA signature sequences. The nPCR assay used in this study showed a detection limit of 10 C. gracilis cells and no cross-reactivity was observed with nontarget bacteria. C. gracilis was detected in the three types of oral infections investigated - 4/10 infected root canals; 2/10 acute periradicular abscesses; and 1/8 subgingival specimens from adult periodontitis. The method proposed in this study showed both high sensitivity and high specificity to directly detect C. gracilis in samples from root canal infections, abscesses, and subgingival plaque. Our findings confirmed that C. gracilis may be a member of the microbiota associated with distinct oral infections, and its specific role in such diseases requires further clarification.


Identification and expression analysis of Oxfibrillin gene involved in the regeneration process of Ophryotrocha xiamen (Annelida, Dorcilleidae).
Regeneration of lost body parts is a widespread phenomenon across annelids. However, the molecular inducers of the cell sources for this reparative morphogenesis have not been identified. We have identified a regeneration-related gene Oxfibrillin from the transcriptome analysis of a polychaeta, Ophryotrocha xiamen, which is found to be a well-suited model to study the mechanisms of regeneration. Fibrillins are large glycoproteins that assemble to form the microfibrils and regulate growth factors or other transfer processes. Here, we obtained the 31,274 bp genomic DNA sequences of Oxfibrillin. The coding sequence length was 5784 bp encoding 1927 amino acids with a VWD domain, EGF/cb-EGF domains, a TR domain, and a transmembrane domain. Oxfibrillin was positioned within the subgroup of invertebrates and showed low scores for homology to mammalian fibrillin. In gene expression analysis, Oxfibrillin genes were constantly upregulated during the early regeneration process and then remained stable until the formation of the complete tail which indicated that it might be a vital factor to affect posterior regeneration process. Therefore, the Oxfibrillin of O. xiamen might play important roles in the regeneration process.


Development of nutrition standards and therapeutic diet specifications for public hospitals in New South Wales.
In New South Wales (NSW), a new suite of nutrition standards for menus and specifications for therapeutic diets to be used in hospitals has been developed. These standards were required to facilitate centralised menu planning and food production, with the move to management of most hospital food services by HealthShare NSW, a state-wide business unit of NSW Health. The standards also aim to improve communication between health professionals, particularly with the increasing use of computerised meal-ordering systems. Nutrition standards have been developed for adult, paediatric and mental health inpatients, and specifications for 147 different adult and paediatric therapeutic diets. There is still significant variation in the nutrition standards for nutrition and therapeutic diets in hospitals across the Australian states, and a move to a more nationally harmonised approach would be welcome. Further research is required to examine the impact of these standards on operating efficiency and patient care outcomes.


Genomic structure and functional expression of a human alpha(2)/delta calcium channel subunit gene (CACNA2).
CACNA2 encodes the alpha(2)/delta subunit of the human voltage-gated calcium channels and is located in the candidate region of malignant hyperthermia susceptibility type 3 (MHS3). We determined the structural organization of CACNA2 by isolation of overlapping genomic DNA clones from a human phage library. The gene consists of at least 40 exons, 2 of which are alternatively spliced, spanning more than 150 kb of genomic DNA. Exons range from 21 to 159 bp, and introns range from 98 bp to at least more than 20 kb. We constructed a full-length cDNA and cloned it into a mammalian expression vector. Cotransfection of the CACNA2 cDNA with alpha(1A) and beta(4) cDNA into HEK293 cells led to the expression of Q-type calcium currents. The alpha(2)/delta subunit enhanced the current density 18-fold compared to cells transfected with only alpha(1A) and beta(4) cDNA. The sequence analysis provides the basis for comprehensive mutation screening of CACNA2 for putative MHS3 individuals and patients with other channelopathies.


Effect of Statins on the Risk of Extrahepatic Cholangiocarcinoma.
Statins have been proven to be cytotoxic to human cholangiocarcinoma cells by inhibiting cell division and inducing apoptosis. We aimed to determine the effect of statin use on the risk of cancer development and survival in patients with extrahepatic cholangiocarcinoma (ECC), including perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). A total of 394 patients with ECC and hyperlipidemia who received care at Mayo Clinic Rochester between 2005 and 2015 were matched by age, sex, race, ethnicity, and residency to 788 controls with hyperlipidemia. Clinical and outcome data were abstracted. The odds ratios (ORs) for risk and hazard ratios for outcomes were calculated. The mean age and standard deviation (SD) for cases and controls was 65.6 years (13.8). The number of statin users in cases and controls was 73 (19%) and 403 (51%), respectively. Hepatitis C virus infection (OR, 15.84; 95% confidence interval [CI], 4.06-61.87; P < 0.001) was the most significant risk factor for pCCA followed by inflammatory bowel disease and cirrhosis, whereas other liver disease, including biliary stone disease (OR, 4.06; CI, 2.24-7.36; P < 0.001), was the only significant risk factor for dCCA. Statin use was associated with significantly reduced risk for all ECC (OR, 0.22; CI, 0.16-0.29) as well as for the subtypes pCCA (OR, 0.3; CI, 0.21-0.41) and dCCA (OR, 0.06; CI, 0.03-0.14), all P < 0.0001. Moderate-intensity dosage was found to decrease the risk of ECC (OR, 0.48; CI, 0.34-0.67; P < 0.001). Comparing statin ever users to nonusers, patients with dCCA who used statins had significantly overall better survival (hazard ratio = 0.53; CI, 0.29-0.97; P = 0.04). This case-control study suggests that statins decrease the risk of ECC and may improve survival in patients with dCCA. Additional validation studies are warranted.


Cardiovascular and endocrine effects of potassium in spontaneously hypertensive rats.
Although potassium is known to lower blood pressure in a number of forms of experimental and human hypertension, the mechanism for this effect remains unclear. We studied several possible mechanisms for this effect in the spontaneously hypertensive rat (SHR). Fourteen-week-old SHR were given 0.5% KCl in the drinking water. This potassium supplement resulted in a 16-mmHg fall in mean arterial pressure and a 22% decrease in peripheral vascular resistance. Plasma potassium increased 0.4 meq/l, while muscle potassium was unchanged. Potassium supplementation resulted in no change in plasma renin activity, plasma aldosterone, or plasma norepinephrine. Urinary excretion of prostaglandin (PG) E2 and 6-keto-PGF1 alpha was also not altered by potassium supplementation. Potassium-supplemented SHR were found to have no difference in sodium excretion compared with control SHR, and plasma volume was similar in both groups. The pressor response to angiotensin II and norepinephrine was not substantially affected by potassium supplementation. Furthermore, baroreflex control of heart rate was not altered by potassium supplementation. Finally, potassium supplementation resulted in no change in mesenteric artery angiotensin II receptor number or receptor affinity. Therefore, although potassium lowers blood pressure in the SHR by decreasing peripheral vascular resistance, the mechanism of this effect on vascular resistance remains unknown.


TSG-6 inhibits osteoclast activity via an autocrine mechanism and is functionally synergistic with osteoprotegerin.
TSG-6 (the product of tumor necrosis factor [TNF]-stimulated gene 6) has a potent inhibitory effect on RANKL-mediated bone erosion. The aim of this study was to compare the activity of TSG-6 with that of osteoprotegerin (OPG) and to investigate its role as an autocrine modulator of cytokine-mediated osteoclast formation/activation. We also determined TSG-6 expression in inflammatory joint disease. The effects of TSG-6, OPG, and the inflammation mediators TNFα, interleukin-1 (IL-1), and IL-6 on the formation of osteoclasts from peripheral blood mononuclear cells and synovial fluid (SF) macrophages were determined by tartrate-resistant acid phosphatase staining. Lacunar resorption and filamentous actin ring formation were measured as indicators of osteoclast activity. The amount of TSG-6 in culture media or SF was quantified by enzyme-linked immunosorbent assay, and expression of TSG-6 in synovial tissue was assessed by immunohistochemistry. TSG-6 acted in synergy with OPG to inhibit RANKL-mediated bone resorption and was produced by osteoclast precursors and mature osteoclasts in response to TNFα, IL-1, and IL-6. Expression of TSG-6 correlated with inhibition of lacunar resorption; this effect was ameliorated by an anti-TSG-6 antibody. The level of TSG-6 protein was determined in SF from patients with various arthritides; it was highest in patients with inflammatory conditions such as rheumatoid arthritis, in which it correlated with the amount of TSG-6 immunostaining in the synovium. TSG-6 inhibited the activation but not the formation of osteoclasts from SF macrophages. In the presence of inflammatory cytokines, osteoclasts produced TSG-6 at concentrations that are sufficient to inhibit lacunar resorption. This may represent an autocrine mechanism to limit the degree of bone erosion during joint inflammation.


Aqueous root extract of Asparagus cochinchinensis (Lour.) Merr. Has antioxidant activity in D-galactose-induced aging mice.
Extracts of plants have been considered as sources of natural antioxidant agents. In this study, we aimed to explore the antioxidant capacity of the aqueous root extract of Asparagus cochinchinensis (Lour.) Merr. Using vitamin C (Vc) as a positive control, we analyzed the aqueous root extract of A. cochinchinensis free radical scavenging ability in vitro. We also established a mouse aging model using D-galactose and then treated it with aqueous root extract or Vc. The blood cell count and superoxide dismutase (SOD), catalase (CAT), and nitric oxide synthase (NOS) activities as well as malondialdehyde (MDA) and nitric oxide (NO) contents were measured; pathological examination of tissues was performed; and SOD, glutathione peroxidase (GPX), and NOS expression levels in the serum, liver, and brain tissues were investigated. In vitro, compared with the antioxidant Vc, the aqueous root extract showed similar 1,1-Diphenyl-2-picrylhydrazyl radical and 3-ethylbenzothiazoline-6-sulfonic·scavenging activities and even significantly increased superoxide anion (p < 0.05) and hydroxyl radical (OH) (p < 0.01) scavenging activities. The aqueous extract significantly increased the white blood cell count as well as enhanced SOD, CAT, and NOS activities (p < 0.01) in aging mice. In addition, the aqueous extract increased the NO content (p < 0.05) and reduced the MDA content (p < 0.05). The aqueous root extract of A. cochinchinensis showed as strong antioxidant ability as Vc and might prevent aging by reducing radicals.


Lung transplantation for patients with cystic fibrosis and Burkholderia cepacia complex infection: a single-center experience.
Pre-operative infection with organisms from the Burkholderia cepacia complex (BCC), particularly B cenocepacia, has been linked with a poorer prognosis after transplantation compared to patients with cystic fibrosis (CF) without this infection. Therefore, many transplant centers do not list these patients for transplantation. We report the early and long-term results of a cohort of lung transplant recipients with CF and pre-operative BCC infection. Patients with pre-transplantation BCC infection were identified by case-note review. BCC species status was assigned by polymerase chain reaction (PCR)-based techniques. Survival rates were compared to recipients with CF without BCC infection. Survival rates in BCC subgroups were also compared, and then further analyzed pre- and post-2001, when a new immunosuppressive and antibiotic regime was introduced for such patients. Two hundred sixteen patients with CF underwent lung transplantation and 22 had confirmed pre-operative BCC infection, with 12 of these being B cenocepacia. Nine B cenocepacia-infected recipients died within the first year, and in 8 BCC sepsis was considered to be the cause of death. Despite instituting a tailored peri-operative immunosuppressive and microbiologic care approach for such patients, post-transplantation BCC septic deaths occurred frequently in those with pre-transplantation B cenocepacia infection. In contrast, recipients infected with other BCC species had significantly better outcomes, with post-transplantation survival comparable to other recipients with CF. Mortality in patients with B cenocepacia infection was unacceptably high and has led to our center no longer accepting patients with this condition onto the lung transplant waiting list. Long-term survival in the non-B cenocepacia BCC group was excellent, without high rates of acute rejection or bronchiolitis obliterans syndrome (BOS) longer term, and these patients continue to be considered for lung transplantation.


Diffusion-weighted MR imaging of subdural empyemas in children.
Subdural empyema (SDE), an infection of the subdural space, occurs most often in pediatric patients as a complication of meningitis, sinusitis, or otitis media. Diffusion-weighted imaging (DWI) has been used in the past to investigate intracerebral infections. The purpose of this study was to determine the signal intensity characteristics of SDE on DWIs as well as the corresponding apparent diffusion coefficient (ADC) maps. MR studies of 10 patients with SDEs were retrospectively reviewed. Included were routine sequences and DWI, which consisted of an axial single-shot echo-planar spin-echo sequence (TR/TE, 4000/110) with b values of 0, 500, and 1000 s/mm(2). Signal-intensity characteristics on routine MR images and DWIs were evaluated. In seven patients, ADC values of the lesions were calculated by using two b values. Follow-up imaging study was performed in seven patients. In nine patients, the empyema was hyperintense on DWIs. In the remaining patient, the empyema showed mixed hyperintensity and hypointensity. ADC values were lower than those of normal cortical gray matter and much lower than those of reactive subdural effusions. In all seven patients with persistent clinical signs of infection, the empyemas were hyperintense on follow-up DWIs. SDE had high signal intensity on DWIs and low signal intensity on ADC maps, with an ADC value lower than that of the normal cortical gray matter. Diffusion MR imaging can be valuable in distinguishing SDE from effusion and in the follow-up of subdural collections.


The Effects of Age on the Neural Correlates of Recollection Success, Recollection-Related Cortical Reinstatement, and Post-Retrieval Monitoring.
Functional magnetic resonance imaging (fMRI) was used to investigate whether age-related differences in episodic memory performance are accompanied by a reduction in the specificity of recollected information. We addressed this question by comparing recollection-related cortical reinstatement in young and older adults. At study, subjects viewed objects and concrete words, making 1 of 2 different semantic judgments depending on the study material. Test items were words that corresponded to studied words or the names of studied objects. Subjects indicated whether each test item was recollected, familiar, or novel. Reinstatement of information differentiating the encoding tasks was quantified both with a univariate analysis of the fMRI signal and with a multivoxel pattern analysis, using a classifier that had been trained to discriminate between the 2 classes of study episode. The results of these analyses converged to suggest that reinstatement did not differ according to age. Thus, there was no evidence that specificity of recollected information was reduced in older individuals. Additionally, there were no age effects in the magnitude of recollection-related modulations in regional activity or in the neural correlates of post-retrieval monitoring. Taken together, the findings suggest that the neural mechanisms engaged during successful episodic retrieval can remain stable with advancing age.


Convergent antibody responses to the SARS-CoV-2 spike protein in convalescent and vaccinated individuals.
Unrelated individuals can produce genetically similar clones of antibodies, known as public clonotypes, which have been seen in responses to different infectious diseases, as well as healthy individuals. Here we identify 37 public clonotypes in memory B cells from convalescent survivors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or in plasmablasts from an individual after vaccination with mRNA-encoded spike protein. We identify 29 public clonotypes, including clones recognizing the receptor-binding domain (RBD) in the spike protein S1 subunit (including a neutralizing, angiotensin-converting enzyme 2 [ACE2]-blocking clone that protects in vivo) and others recognizing non-RBD epitopes that bind the S2 domain. Germline-revertant forms of some public clonotypes bind efficiently to spike protein, suggesting these common germline-encoded antibodies are preconfigured for avid recognition. Identification of large numbers of public clonotypes provides insight into the molecular basis of efficacy of SARS-CoV-2 vaccines and sheds light on the immune pressures driving the selection of common viral escape mutants.


Transgenerational plasticity and climate change experiments: Where do we go from here?
Phenotypic plasticity, both within and across generations, is an important mechanism that organisms use to cope with rapid climate change. While an increasing number of studies show that plasticity across generations (transgenerational plasticity or TGP) may occur, we have limited understanding of key aspects of TGP, such as the environmental conditions that may promote it, its relationship to within-generation plasticity (WGP) and its role in evolutionary potential. In this review, we consider how the detection of TGP in climate change experiments is affected by the predictability of environmental variation, as well as the timing and magnitude of environmental change cues applied. We also discuss the need to design experiments that are able to distinguish TGP from selection and TGP from WGP in multigenerational experiments. We conclude by suggesting future research directions that build on the knowledge to date and admit the limitations that exist, which will depend on the way environmental change is simulated and the type of experimental design used. Such an approach will open up this burgeoning area of research to a wider variety of organisms and allow better predictive capacity of the role of TGP in the response of organisms to future climate change.


MR myelography for identification of spinal CSF leak in spontaneous intracranial hypotension.
CT myelography has historically been the test of choice for localization of CSF fistula in patients with spontaneous intracranial hypotension. This study evaluates the additional benefits of intrathecal gadolinium MR myelography in the detection of CSF leak. We performed a retrospective review of patients with spontaneous intracranial hypotension who underwent CT myelography followed by intrathecal gadolinium MR myelography. All patients received intrathecal iodine and off-label gadolinium-based contrast followed by immediate CT myelography and subsequent intrathecal gadolinium MR myelography with multiplanar T1 fat-suppressed sequences. CT myelography and intrathecal gadolinium MR myelography images were reviewed by an experienced neuroradiologist to determine the presence of CSF leak. Patient records were reviewed for demographic data and adverse events following the procedure. Twenty-four patients met both imaging and clinical criteria for spontaneous intracranial hypotension and underwent CT myelography followed by intrathecal gadolinium MR myelography. In 3/24 patients (13%), a CSF leak was demonstrated on both CT myelography and intrathecal gadolinium MR myelography, and in 9/24 patients (38%), a CSF leak was seen on intrathecal gadolinium MR myelography (P = .011). Four of 6 leaks identified independently by intrathecal gadolinium MR myelography related to meningeal diverticula. CT myelography did not identify any leaks independently. There were no reported adverse events. Present data demonstrate a higher rate of leak detection with intrathecal gadolinium MR myelography when investigating CSF leaks in our cohort of patients with spontaneous intracranial hypotension. Although intrathecal gadolinium is an FDA off-label use, all patients tolerated the medication without evidence of complications. Our data suggest that intrathecal gadolinium MR myelography is a well-tolerated examination with significant benefit in the evaluation of CSF leak, particularly for patients with leak related to meningeal diverticula.


Commerce in drugs and chemicals and the detection of clandestine laboratories.
There were 225 clandestine laboratories seized in the United States of America in 1982, an increase of 23 per cent over 1981. These laboratories most commonly produced methamphetamines, phencyclidine (PCP), lysergic acid diethylamide (LSD), amphetamine and methaqualone. In order to determine whether a seized drug has been clandestinely manufactured and to identify the source of the drug, special techniques are used, involving detailed physical and chemical examinations. The results of such examinations are computerized and compared with reference samples to provide indications of the drug source. Undercover techniques are also effectively used for the detection of clandestine laboratories. Chemicals necessary for the illegal production of drugs of abuse were often diverted from legitimate sources through international commerce, which, together with clandestine laboratories, are recognized as an international problem that requires monitoring through international co-operation.


Microbiota-Propelled T Helper 17 Cells in Inflammatory Diseases and Cancer.
Technologies allowing genetic sequencing of the human microbiome are opening new realms to discovery. The host microbiota substantially impacts immune responses both in immune-mediated inflammatory diseases (IMIDs) and in tumors affecting tissues beyond skin and mucosae. However, a mechanistic link between host microbiota and cancer or IMIDs has not been well established. Here, we propose T helper 17 (TH17) lymphocytes as the connecting factor between host microbiota and rheumatoid or psoriatic arthritides, multiple sclerosis, breast or ovarian cancer, and multiple myeloma. We theorize that similar mechanisms favor the expansion of gut-borne TH17 cells and their deployment at the site of inflammation in extraborder IMIDs and tumors, where TH17 cells are driving forces. Thus, from a pathogenic standpoint, tumors may share mechanistic routes with IMIDs. A review of similarities and divergences in microbiota-TH17 cell interactions in IMIDs and cancer sheds light on previously ignored pathways in either one of the two groups of pathologies and identifies novel therapeutic avenues.


A study of the relationship between performance and dietary component digestibilities by swine fed different levels of dietary fiber.
A 49-d feeding trial, using 192 growing-finishing pigs (avg initial wt, 32 kg), was conducted to identify pigs of widely differing average daily gains (ADG) when fed 16% crude protein diets containing either 0, 7.5 or 15% corn cobs. There were linear decreases in both ADG (P less than .01) and gain/feed (P less than .001) with increasing levels of dietary corn cobs. Average daily feed intake increased linearly (P less than .001), but average daily digestible energy (DE) intake tended to decrease (P less than .08) with increasing dietary fiber level. Gain/DE was not apparently affected by dietary treatment. At the end of the feeding trial, 27 pigs, nine from each dietary treatment, were selected on the basis of ADG to represent pigs of above average, average and below average performance during the feeding trial. Previous ADG of the pigs selected for these were .93, .81 and .69 kg, respectively. In these pigs, plasma levels of glucose decreased (P less than .01) linearly, but urea N tended to increase (P less than .08) linearly with increasing level of dietary corn cobs. A digestion trial was conducted to determine if previous performance of the selected pigs could be related to the digestibilities of dietary components and the retention of N by these pigs. Nitrogen and dry matter (DM) digestibilities and dietary DE decreased linearly with increasing level of dietary corn cobs. The digestibilities of dietary neutral detergent fiber (NDF) and acid detergent fiber (ADF) decreased both linearly and quadratically with increasing level of corn cobs. Regardless of dietary treatment, no significant differences in any of these criteria were observed among pigs selected on the basis of widely differing ADG during the feeding trial.


[Breast cancer mortality. Trend and geographical distribution, 1981-2001].
to describe trend and geographical distribution of breast cancer mortality, in Mexico. it was done an ecological and tendency study from 1981 to 2001, 52,739 deaths by breast cancer in women > or = 20-year-old. Mortality was studied according to the International Classification of Diseases. The data were obtained from the National Institute of Statistics, Geography and Informatics and from the General Census of Population. The period studied was three-yearly. Adjusted rates were calculated with the direct method. It was utilized a lineal regression model for the analysis of mortality tendencies. Map was built from the distribution of the mortality along the country. the mortality tendency was increased in the first decade and in the second it was maintained stable, with an important drop in four states (p<0.05). The 66% of the states had rates over the national adjusted rate, all of them in the north of the country. Nayarit, Guerrero, and Mexico State had an increment of 300%. the ascending tendency and stabilization of the mortality is similar to other countries. The north states had the greater rate of mortality, intermediate rates in the middle of country and drops in the south. It is possible that these changes were secondary to environmental, social and medical care factors.


Hyperglycemia enhances the proliferation of non-tumorigenic and malignant mammary epithelial cells through increased leptin/IGF1R signaling and activation of AKT/mTOR.
Obesity and diabetes are associated with increased breast cancer risk and worse disease progression once cancer is diagnosed; however, the exact etiology behind these observations remains to be fully elucidated. Due to the global obesity/diabetes pandemic, it is imperative to understand how these diseases promote and enhance breast cancer and other common cancers. In this study we demonstrate that hyperglycemia promotes breast cancer by altering leptin/IGF1R and AKT/mTOR signaling. To our knowledge, we show for the first time that in breast epithelial cells, hyperglycemia alone directly impacts leptin signaling. Hyperglycemia increased proliferation of both non-tumorigenic and malignant mammary epithelial cells. These observations coincided with increased leptin receptor and IGF1R receptor, as well as, increased levels of GRB2, pJAK2, pSTAT3, pIRS1/2, pAKT, and p-mTOR. Moreover, pJAK2 was almost completely colocalized with leptin receptor under high glucose conditions. These results demonstrate how hyperglycemia can potentially increase the risk of breast cancer in premalignant lesions and enhance cancer progression in malignant cells.


Report from the OMERACT Hand Osteoarthritis Special Interest Group: advances and future research priorities.
Osteoarthritis (OA) is one of the most common musculoskeletal disorders, frequently affecting the hands. In the last decade there has been increased awareness concerning this disorder because of its clinical burden. Unfortunately, only limited treatments for symptom alleviation are available, and no effective treatment for disease modification exists. The lack of treatment is due not only to a lack of understanding of the disease process, but also to poor outcome measures to assess the condition. The OMERACT Hand OA Special Interest Group (SIG) has started to develop a core set of outcome measures for hand OA clinical trials, observational studies, and clinical record keeping. At OMERACT 11, results from a Delphi exercise were presented, and a preliminary set of core domains was discussed. The group attempted to adopt the new OMERACT Filter 2.0 in the process, and literature overviews of conventional radiographs, ultrasonography, and magnetic resonance imaging as outcome measures in hand OA were presented. Discussions that followed highlighted further suggestions for core domains, the heterogeneity of hand OA, and future research priorities.


Cross-linker design determines microtubule network organization by opposing motors.
During cell division, cross-linking motors determine the architecture of the spindle, a dynamic microtubule network that segregates the chromosomes in eukaryotes. It is unclear how motors with opposite directionality coordinate to drive both contractile and extensile behaviors in the spindle. Particularly, the impact of different cross-linker designs on network self-organization is not understood, limiting our understanding of self-organizing structures in cells but also our ability to engineer new active materials. Here, we use experiment and theory to examine active microtubule networks driven by mixtures of motors with opposite directionality and different cross-linker design. We find that although the kinesin-14 HSET causes network contraction when dominant, it can also assist the opposing kinesin-5 KIF11 to generate extensile networks. This bifunctionality results from HSET's asymmetric design, distinct from symmetric KIF11. These findings expand the set of rules underlying patterning of active microtubule assemblies and allow a better understanding of motor cooperation in the spindle.


Protein and amino acid metabolism in posterior hemicorpus of acutely uremic rats.
Protein synthesis and degradation and net uptake and release of amino acids and minerals were examined in the perfused hemicorpus of bilaterally nephrectomized and sham-operated control rats. Animals were studied 30 h after surgery. In comparison with controls, uremic rats had greater urea N appearance (net urea generation) and lower plasma and muscle concentrations of most amino acids. Muscle protein synthesis was not altered, but protein degradation was greater in uremic versus sham rats. There was greater net release of phenylalanine, tyrosine, alanine, total nonessential amino acids, total amino acids, potassium, and phosphorus from the perfused hemicorpus of uremic rats and greater release of citrulline from sham rats. ATP, creatine phosphate, cAMP, and activities of cathepsin B1, cathepsin D, and alkaline protease were not different in muscles of the uremic versus sham rats. Thus, in acutely uremic rats there is increased protein wasting in the hemicorpus due to enhanced protein degradation. The enhanced protein degradation does not appear to be due to increased muscle cathepsin B1, cathepsin D, or alkaline protease activities.


Endogenous 17β-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system.
17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic interneurons (ChIs). Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson's disease.


Crystal structure of Mycobacterium tuberculosis FadB2 implicated in mycobacterial β-oxidation.
The intracellular pathogen Mycobacterium tuberculosis is the causative agent of tuberculosis, which is a leading cause of mortality worldwide. The survival of M. tuberculosis in host macrophages through long-lasting periods of persistence depends, in part, on breaking down host cell lipids as a carbon source. The critical role of fatty-acid catabolism in this organism is underscored by the extensive redundancy of the genes implicated in β-oxidation (∼100 genes). In a previous study, the enzymology of the M. tuberculosis L-3-hydroxyacyl-CoA dehydrogenase FadB2 was characterized. Here, the crystal structure of this enzyme in a ligand-free form is reported at 2.1 Å resolution. FadB2 crystallized as a dimer with three unique dimer copies per asymmetric unit. The structure of the monomer reveals a dual Rossmann-fold motif in the N-terminal domain, while the helical C-terminal domain mediates dimer formation. Comparison with the CoA- and NAD+-bound human orthologue mitochondrial hydroxyacyl-CoA dehydrogenase shows extensive conservation of the residues that mediate substrate and cofactor binding. Superposition with the multi-catalytic homologue M. tuberculosis FadB, which forms a trifunctional complex with the thiolase FadA, indicates that FadB has developed structural features that prevent its self-association as a dimer. Conversely, FadB2 is unable to substitute for FadB in the tetrameric FadA-FadB complex as it lacks the N-terminal hydratase domain of FadB. Instead, FadB2 may functionally (or physically) associate with the enoyl-CoA hydratase EchA8 and the thiolases FadA2, FadA3, FadA4 or FadA6 as suggested by interrogation of the STRING protein-network database.


Deformable templates using large deformation kinematics.
A general automatic approach is presented for accommodating local shape variation when mapping a two-dimensional (2-D) or three-dimensional (3-D) template image into alignment with a topologically similar target image. Local shape variability is accommodated by applying a vector-field transformation to the underlying material coordinate system of the template while constraining the transformation to be smooth (globally positive definite Jacobian). Smoothness is guaranteed without specifically penalizing large-magnitude deformations of small subvolumes by constraining the transformation on the basis of a Stokesian limit of the fluid-dynamical Navier-Stokes equations. This differs fundamentally from quadratic penalty methods, such as those based on linearized elasticity or thin-plate splines, in that stress restraining the motion relaxes over time allowing large-magnitude deformations. Kinematic nonlinearities are inherently necessary to maintain continuity of structures during large-magnitude deformations, and are included in all results. After initial global registration, final mappings are obtained by numerically solving a set of nonlinear partial differential equations associated with the constrained optimization problem. Automatic regridding is performed by propagating templates as the nonlinear transformations evaluated on a finite lattice become singular. Application of the method to intersubject registration of neuroanatomical structures illustrates the ability to account for local anatomical variability.


The Nucleophilicity of Persistent α-Monofluoromethide Anions.
α-Fluorocarbanions are key intermediates in nucleophilic fluoroalkylation reactions. Although frequently discussed, the origin of the fluorine effect on the reactivity of α-fluorinated CH acids has remained largely unexplored. We have now investigated the kinetics of a series of reactions of α-substituted carbanions with reference electrophiles to elucidate the effects of α-F, α-Cl, and α-OMe substituents on the nucleophilic reactivities of carbanions.


[Phenotype of blast cells in acute lymphoblastic leukemia].
The complex morphocytochemical, immunological and cytogenetic investigation of the blast cells in acute lymphoblastic leukemia showed their considerable heterogeneity. There were several kinds of cells: typical blast cells, Ph'-positive blast cells expressing only Ia-like antigen and anaplastic blast cells with myeloid and erythroid differentiation.


The Scapula: The Greater Masquerader of Shoulder Pathologies.
A comprehensive review of scapular pathologies and their effect on shoulder function is necessary to determine the best treatment options. The coordinated motion between the scapulothoracic and glenohumeral joints is essential for shoulder motion and depends on the balanced activity of the periscapular muscles. Disruption in these muscles can cause abnormal scapular motion and compensatory glenohumeral movements, leading to misdiagnosis or delayed diagnosis. Scapular pathologies can arise from muscle overactivity or underactivity/paralysis, resulting in a range of scapulothoracic abnormal motion (STAM). STAM can lead to various glenohumeral pathologies, including instability, impingement, or nerve compression. It is important to highlight the critical periscapular muscles involved in scapulohumeral rhythm (such as the upper, middle, and lower trapezius; rhomboid major and minor; serratus anterior; levator scapulae; and pectoralis minor). A discussion of the different etiologies of STAM should include examples of muscle dysfunction, such as overactivity of the pectoralis minor, underactivity or paralysis of the serratus anterior or trapezius muscles, and dyskinesis resulting from compensatory mechanisms in patients with recurrent glenohumeral instability due to Ehlers-Danlos syndrome. The evaluation and workup of STAM has shown that patients typically present with radiating shoulder pain, especially in the posterior aspect of the shoulder and scapula, and limitations in active shoulder overhead motion associated with glenohumeral pain, instability, or rotator cuff pathologies.


A Randomized Trial Investigating the Influence of Strength Training on Quality of Life in Ischemic Stroke.
Strength training post stroke is widely acknowledged as an important part of a rehabilitation program. Muscle strength has been shown to be a significant contributor to physical disability after stroke, which in turn has an immense impact on the reintegration of patients into society, affecting their quality of life. This was a randomized intervention trial to determine the effect of a resistance training program on the quality of life in patients with stroke. An experimental group (EG), consisting of 11 subjects aged 51.7 ± 8.0 years, and a control group (CG), consisting of 13 subjects aged 52.5 ± 7.7 years, were studied before and after 12 weeks. EG underwent 12 weeks of strength training three times a week. The CG did not undergo strength training during the 12-week study period. There was a significant increase in quality of life from pre-test to post-test (Δ% = 21.47%; p = 0.021) in EG. There were significant differences in all indicators of quality of life between groups at 12 weeks. There were greater gains in strength in EG than in CG (p ≤ 0.05). There was a negative correlation between the strength gains as determined with the 1RM test and the quality of life, especially in lower limb exercises. The results of this study indicate that there was an improvement in the measures of strength in EG, and that there was a correlation between improvements in strength and quality of life in these patients who had previously suffered a stroke at least one year prior to study.


Motives for weight loss and weight loss maintenance: results from the MedWeight study.
The relationship of weight loss motives with long-term outcomes is equivocal. We aimed to examine differences in weight loss motives of maintainers and regainers, as well as explore associations between motives and successful maintenance. The study sample includes 607 adults, with a history of overweight/obesity and self-reported ≥10% voluntary weight loss, 12 months before study entry. Participants were classified as maintainers (weighing ≤90% maximum weight) or regainers. Volunteers identified possible motives for weight loss and maintenance (maintainers only), from a specific list. Both maintainers and regainers were predominantly motivated by physical appearance (38.6% versus 39.9%, P > 0.05) and self-esteem (26.8% versus 32.0%, P > 0.05) for weight loss. Compared to regainers, more maintainers reported weight reduction driven by social purposes (16.6% versus 9.4%, P = 0.022) and less were prompted by friends/family to lose weight (21.1% versus 31.7%, P = 0.005). In maintainers, shifts in motives from weight loss to maintenance phase were found, including an increased prevalence of health motives (6.4% versus 9.6%, P < 0.001) and decreased physical appearance motives (38.6% versus 30.3%, P < 0.001). Reporting physical appearance as main maintenance motive was inversely associated with maintained weight loss, after adjusting for age, sex and years of education (B = -3.49 [1.07], P = 0.001); maintainers reporting physical appearance as the main motive maintained 3.5% less weight loss compared to those who did not (P = 0.001). The present study has highlighted motivational influences associated with weight loss outcomes. Future studies should explore the ability of people with overweight/obesity to act upon motives for long-term weight management, as well as the impact of shifting through motives on the magnitude of maintenance.


An evaluation of a partial-walled laminar-flow operating room.
This paper contains an assessment of the physical performance of a permanently installed down-flow laminar-flow operating room at the London Hospital. This system employs partial walls extending 0.76 m (2.5 ft.) from the ceiling, from which the air is allowed to issue freely downwards at an initial velocity of about 0.4 m./sec. (80 ft./min.).The usefulness of the partial wall, as compared with a free issuing system, was demonstrated and a comparison made with a fully walled system. It was shown that a fully walled system would be more efficient than a partial-walled system as there was a loss in air velocity of about 20-25% with the partial wall due to the nonconstrained flow of air. This loss would be reflected in an increase in airborne bacterial count and would mean that an increase of 20-25% in the air volume would be required to obtain the same conditions as with the full-walled system. Entrainment of contaminated air was demonstrated but it was concluded that this would be of little consequence in the centre of the clean area, i.e. at the wound site. Sterile instruments, etc., however, on the outside of the clean area, would be more liable to airborne contamination.Bacterial and dust airborne counts taken during total hip operations gave a very low average figure (0.3 bacteria/ft.(3) or 10.5/m.(3)) from which we conclude that the system was about 30 times cleaner in terms of airborne bacteria than a well ventilated conventional operating-room. We concluded that although the partial-walled system was slightly less efficacious than a normal full-walled system, the freedom of movement and of communication for the operating team could in some circumstances outweigh this disadvantage.Sound levels were such that normal conversation was possible with little or no awareness of background noise.


Breeding services and the factors influencing their use on smallholder dairy farms in central Uganda.
Dairy cattle breeding is an important technology in the enhancement and promotion of dairy production in Uganda. The introduction of germplasm through AI is crucial to enhance the production potential of the local breeds. A study was conducted in six districts of Uganda in the central region using a questionnaire survey involving 450 randomly selected households to profile the dairy breeding services in use and investigate the factors that affect the success of dairy breeding focusing on AI. Adoption of the AI service was highly (P < 0.05) dependent on ava ilability of extension services, record keeping practice (P < 0.05), and availability of milk markets (P < 0.05). On the other hand AI adoption was independent of formal education, age of farmer, labor availability, and feed/water availability (P > 0.05). Use or nonuse of AI did not significantly (P > 0.05) influence the sex of the calf born. While preference for AI was marked, very few farmers actually used it. This implies that focus should be put on improved AI service delivery alongside improved extension services.


Therapy for hyperthermia-induced seizures in Scn1a mutant rats.
Mutations in the SCN1A gene, which encodes the α1 subunit of voltage-gated sodium channels, cause generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). N1417H-Scn1a mutant rats are considered to be an animal model of human FS+ or GEFS+. To assess the pharmacologic validity of this model, we compared the efficacies of eight different antiepileptic drugs (AEDs) for the treatment of hyperthermia-induced seizures using N1417H-Scn1a mutant rats. AEDs used in this study included valproate, carbamazepine (CBZ), phenobarbital, gabapentin, acetazolamide, diazepam (DZP), topiramate, and potassium bromide (KBr). The effects of these AEDs were evaluated using the hot water model, which is a model of experimental FS. Five-week-old rats were pretreated with each AED and immersed in water at 45°C to induce hyperthermia-induced seizures. The seizure manifestations and video-electroencephalographic recordings were evaluated. Furthermore, the effects of each AED on motor coordination and balance were assessed using the balance-beam test. KBr significantly reduced seizure durations, and its anticonvulsant effects were comparable to those of DZP. On the other hand, CBZ decreased the seizure threshold. In addition, DZP and not KBr showed significant impairment in motor coordination and balance. DZP and KBr showed potent inhibitory effects against hyperthermia-induced seizures in the Scn1a mutant rats, whereas CBZ exhibited adverse effects. These responses to hyperthermia-induced seizures were similar to those in patients with GEFS+ and SMEI. N1417H-Scn1a mutant rats may, therefore, be useful for testing the efficacy of new AEDs against FS in GEFS+ and SMEI patients.


Modelling homing suppression gene drive in haplodiploid organisms.
Gene drives have shown great promise for suppression of pest populations. These engineered alleles can function by a variety of mechanisms, but the most common is the CRISPR homing drive, which converts wild-type alleles to drive alleles in the germline of heterozygotes. Some potential target species are haplodiploid, in which males develop from unfertilized eggs and thus have only one copy of each chromosome. This prevents drive conversion, a substantial disadvantage compared to diploids where drive conversion can take place in both sexes. Here, we study homing suppression gene drives in haplodiploids and find that a drive targeting a female fertility gene could still be successful. However, such drives are less powerful than in diploids and suffer more from functional resistance alleles. They are substantially more vulnerable to high resistance allele formation in the embryo owing to maternally deposited Cas9 and guide RNA and also to somatic cleavage activity. Examining spatial models where organisms move over a continuous landscape, we find that haplodiploid suppression drives surprisingly perform nearly as well as in diploids, possibly owing to their ability to spread further before inducing strong suppression. Together, these results indicate that gene drive can potentially be used to effectively suppress haplodiploid populations.


Degradation of MAC13243 and studies of the interaction of resulting thiourea compounds with the lipoprotein targeting chaperone LolA.
The discovery of novel small molecules that function as antibacterial agents or cellular probes of biology is hindered by our limited understanding of bacterial physiology and our ability to assign mechanism of action. We previously employed a chemical genomic strategy to identify a novel small molecule, MAC13243, as a likely inhibitor of the bacterial lipoprotein targeting chaperone, LolA. Here, we report on the degradation of MAC13243 into the active species, S-(4-chlorobenzyl)isothiourea. Analogs of this compound (e.g., A22) have previously been characterized as inhibitors of the bacterial actin-like protein, MreB. Herein, we demonstrate that the antibacterial activity of MAC13243 and the thiourea compounds are similar; these activities are suppressed or sensitized in response to increases or decreases of LolA copy number, respectively. We provide STD NMR data which confirms a physical interaction between LolA and the thiourea degradation product of MAC13243, with a Kd of ~150 μM. Taken together, we conclude that the thiourea series of compounds share a similar cellular mechanism that includes interaction with LolA in addition to the well-characterized target MreB.


Addition of dose-intensified doxorubicin to standard chemotherapy for rhabdomyosarcoma (EpSSG RMS 2005): a multicentre, open-label, randomised controlled, phase 3 trial.
Rhabdomyosarcoma is an aggressive tumour that can develop in almost any part of the body. Doxorubicin is an effective drug against rhabdomyosarcoma, but its role in combination with an established multidrug regimen remains controversial. Therefore, we aimed to evaluate the possible benefit of early dose intensification with doxorubicin in patients with non-metastatic rhabdomyosarcoma. We did a multicentre, open-label, randomised controlled, phase 3 trial involving 108 hospitals from 14 countries. We included patients older than 6 months but younger than 21 years with a pathologically proven diagnosis of rhabdomyosarcoma. We assigned each patient to a specific subgroup according to the EpSSG stratification system. Those with embryonal rhabdomyosarcoma incompletely resected and localised at unfavourable sites with or without nodal involvement, or those with alveolar rhabdomyosarcoma without nodal involvement were considered at high risk of relapse. These high-risk patients were randomly assigned (1:1) to receive either nine cycles of IVA (ifosfamide 3 g/m2 given as a 3-h intravenous infusion on days 1 and 2, vincristine 1·5 mg/m2 weekly during the first 7 weeks then only on day 1 of each cycle [given as a single intravenous injection], and dactinomycin 1·5 mg/m2 on day 1 given as a single intravenous injection) or four cycles of IVA with doxorubicin 30 mg/m2 given as a 4-h intravenous infusion on days 1 and 2 followed by five cycles of IVA. The interval between cycles was 3 weeks. Randomisation was done using a web-based system and was stratified (block sizes of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary endpoint was 3-year event-free survival assessed by the investigator at each centre in the intention-to-treat population. Patients who received at least one dose of study treatment were considered in the safety analysis. In agreement with the independent data monitoring committee, the study was closed to patient entry on Dec 16, 2013, after futility analysis. This trial is registered with EudraCT, number 2005-000217-35, and is currently in follow-up. Between Oct 1, 2005, and Dec 16, 2013, 484 patients were randomly assigned to receive each chemotherapy regimen (242 in the IVA group and 242 in the IVA plus doxorubicin group). Median follow-up was 63·9 months (IQR 44·6-78·9). The 3-year event-free survival was 67·5% (95% CI 61·2-73·1) in the IVA plus doxorubicin group and 63·3% (56·8-69·0) in the IVA group (hazard ratio 0·87, 95% CI 0·65-1·16; p=0·33). Grade 3-4 leucopenia (232 [93%] of 249 patients in the IVA plus doxorubicin group vs 194 [85%] of 227 in the IVA group; p=0·0061), anaemia (195 [78%] vs 111 [49%]; p<0·0001), thrombocytopenia (168 [67%] vs 59 [26%]; p<0.0001), and gastrointestinal adverse events (78 [31%] vs 19 [8%]; p<0·0001) were significantly more common in the IVA plus doxorubicin group than in the IVA group. Grade 3-5 infections (198 [79%] vs 128 [56%]; p<0·0001) were also significantly more common in the IVA plus doxorubicin group than in the IVA group, in which one patient had grade 5 infection. Two treatment-related deaths were reported (one patient developed septic shock and one affected by Goldenhar syndrome developed intractable seizures) in the IVA plus doxorubicin group, both occurring after the first cycle of treatment, and none were reported in the IVA group. The addition of dose-intensified doxorubicin to standard IVA chemotherapy did not show a significant improvement in the outcome of patients with high-risk non-metastatic rhabdomyosarcoma. Therefore, the IVA chemotherapy regimen should remain the standard of care for patients with localised rhabdomyosarcoma in Europe. Fondazione Città della Speranza, Italy, and the Association Léon Berard Enfant Cancéreux, France.


[efficacy and safety of salmeterol in long-term therapy in patients with chronic obstructive airway diseases].
Salmeterol is a long-acting inhaled beta 2-agonist with a bronchodilating effect lasting over 10 to 12 hours. A prospective, open, multi-centre study was performed to evaluate the efficacy and safety of inhaled salmeterol (50 micrograms BID) over a mean treatment period of 29 months (range: 4-1145 days) in 634 patients (54% male, age 45 +/- 15 years) with mild to moderate asthma or chronic obstructive pulmonary disease (COPD). Peak expiratory flow rates, rescue use of short acting beta 2-agonists and safety were study objectives. Patients were critically monitored for a possible loss of bronchodilator efficacy of salmeterol during long-term treatment. During the first month of salmeterol therapy, morning peak flow improved from 384 +/- 104 l/min to 413 +/- 112 l/min (p < 0.001), and use of rescue salbutamol was significantly reduced (21 +/- 21 to 8 +/- 14 puffs/week during daytime and 9 +/- 12 to 4.5 +/- 9 puffs/week during nighttime, p < 0.001 both comparisons). Peak flow improvement and reduction of short-acting beta 2-agonist use was maintained during the whole study period. Frequent adverse events were exacerbations of the underlying airway disease (24%) and infections (12%), while typical pharmacological side-effects like tremor or tachycardia where reported in less than 1% of all patients. These results confirm the persistent efficacy and favourable safety profile of salmeterol during long-term therapy over more than two years. No clinical signs of a decreasing bronchodilator potency indicating tachyphylaxis were observed. Salmeterol treatment provides a therapeutic option to further improve the management and care of patients with moderate obstructive airway diseases.


Gunslingers, poker players, and chickens 3: Decision making under mental performance pressure in junior elite athletes.
Having investigated the decision making of world class elite and subelite athletes (see Parkin and Walsh, 2017; Parkin et al., 2017), here the abilities of those at the earliest stage of entry to elite sport are examined. Junior elite athletes have undergone initial national selection and are younger than athletes examined previously (mean age 13 years). Decision making under mental pressure is explored in this sample. During performance an athlete encounters a wide array of mental pressures; these include the psychological impact of errors, negative feedback, and requirements for sustained attention in a dynamic environment (Anshel and Wells, 2000; Mellalieu et al., 2009). Such factors increase the cognitive demands of the athletes, inducing distracting anxiety-related thoughts known as rumination (Beilock and Gray, 2007). Mental pressure has been shown to reduce performance of decision-making tasks where reward and loss contingencies are explicit, with a shift toward increased risk taking (Pabst et al., 2013; Starcke et al., 2011). Mental pressure has been shown to be detrimental to decision-making speed in comparison to physical stress, highlighting the importance of considering a range of different pressures encountered by athletes (Hepler, 2015). To investigate the influence of mental pressure on key indicators of decision making in junior elite athletes. This chapter concludes a wider project examining decision making across developmental stages in elite sport. The work further explores how psychological insights can be applied in an elite sporting environment and in particular tailored to the requirements of junior athletes. Seventeen junior elite athletes (10 males, mean age: 13.80 years) enrolled on a national youth athletic development program participated in the study. Performance across three categories of decision making was assessed under conditions of low and high mental pressure. Decision making under risk was measured via the Cambridge Gambling Task (CGT; Rogers et al., 1999), decision making under uncertainty via the Balloon Analogue Risk Task (BART; Lejuez et al., 2002), and fast reactive responses to perceptual stimuli via the Visual Search Task (Treisman, 1982). Mental pressure was induced with the addition of a concurrent verbal memory task, used to increase cognitive load and mimic the distracting effects of anxiety-related rumination. In junior elite athletes, fast reactive responses to perceptual stimuli (on the Visual Search Task) were slower under conditions of mental pressure. For decision making under risk there was an interaction of mental pressure and gender on the amount of points gambled, under pressure there was a higher level of risk taking in male athletes compared to females. There was no influence of mental pressure on decision making under uncertainity. There were no significant correlations in the degree to which individual's responses changed under pressure across the three measures of decision making. When assessing the applicability of results based on group averages there were no junior elite athletes who showed an "average" response (within 1SD of the mean) to mental pressure across all the three decision-making tasks. Mental pressure affects decision making in a sample of junior elite athletes, with a slowing of response times, and modulations to performance of decision making under risk that have a high requirement for working memory. In relation to sport, these findings suggest that novel situations that place high cognitive demands on the athlete may be particularly influenced by mental pressure. The application of this work in junior elite athletes included the feedback of individual results and the implementation of a decision-making taxonomy.


Changing attitude to mental illness among community mental health volunteers in south-western Nigeria.
Community-based mental health services may be impaired by stigmatization and social distance towards persons with mental illness. Little is known about the impact of education on the attitude of volunteers for mental health programmes. This study aimed to examine the effect of an educational programme on the attitude of community volunteers towards mental illness. Thirty-one volunteers for a community mental health programme completed the Familiarity with Mental Illness Questionnaire and a modified version of the Bogardus Social Distance Scale (Bogardus, 1925) before and after an educational programme. At the end of the educational session, perceived dangerousness was significantly reduced and attitude (social distance) towards persons with mental illness showed significant improvement. Attitudes of community volunteers towards persons with mental illness improve with educational programmes. This may lead to improved treatment and care of individuals who are mentally ill.


Hip joint biomechanics in those with and without post-traumatic knee osteoarthritis after anterior cruciate ligament injury.
Anterior cruciate ligament injury results in altered kinematics and kinetics in the knee and hip joints that persist despite surgical reconstruction and rehabilitation. Abnormal movement patterns and a history of osteoarthritis are risk factors for articular cartilage degeneration in additional joints. The purpose of this study was to determine if hip joint biomechanics early after anterior cruciate ligament injury and reconstruction differ between patients with and without post-traumatic knee osteoarthritis 5years after reconstruction. The study's rationale was that individuals who develop knee osteoarthritis after anterior cruciate ligament injury may also demonstrate large alterations in hip joint biomechanics. Nineteen athletes with anterior cruciate ligament injury completed standard gait analysis before (baseline) and after (post-training) extended pre-operative rehabilitation and at 6months, 1year, and 2years after reconstruction. Weightbearing knee radiographs were completed 5years after reconstruction to identify medial compartment osteoarthritis. Five of 19 patients had knee osteoarthritis at 5years after anterior cruciate ligament reconstruction. Patients with knee osteoarthritis at 5years walked with smaller sagittal plane hip angles (P: 0.043) and lower sagittal (P: 0.021) and frontal plane (P: 0.042) external hip moments in the injured limb before and after reconstruction compared to those without knee osteoarthritis. The current findings suggest hip joint biomechanics may be altered in patients who develop post-traumatic knee osteoarthritis. Further study is needed to confirm whether the risk of non-traumatic hip pathology is increased after anterior cruciate ligament injury and if hip joint biomechanics influence its development.