The transferable tail: fusion of the N-terminal acidic extension of heparin cofactor II to alpha1-proteinase inhibitor M358R specifically increases the rate of thrombin inhibition.
The conversion of the reactive center bond of the serpin alpha1-proteinase inhibitor (alpha1-PI, also known as alpha1-antitrypsin) from Met-Ser to Arg-Ser decreases the rate at which it inhibits neutrophil elastase and endows it with the ability to inhibit thrombin and activated protein C (APC). Another serpin, heparin cofactor II (HCII), contains a unique N-terminal extension that binds thrombin exosite 1. We fused residues 1-75 of HCII to the N-terminus of alpha1-PI M358R, forming an HCII-alpha1-PI chimera (HAPI M358R). It inhibited alpha-thrombin 21-fold faster than alpha1-PI M358R, with second-order rate constants of 2.3 x 10(8) M(-1) min(-1) versus 1.1 x 10(7) M(-1) min(-1), respectively. When gammaT-thrombin, which lacks an intact exosite 1, was substituted for alpha-thrombin, the kinetic advantage of HAPI M358R over alpha1-PI M358R was reduced to 9-fold, whereas APC and trypsin, proteases lacking exosite 1-like regions, were inhibited only 1.3- and 2-fold more rapidly by HAPI M358R than by alpha1-PI M358R, respectively. Maximal enhancement of alpha1-PI M358R activity required the acidic residues found between HCII residues 55 and 75, because no enhancement was observed either by fusion of residues 1-54 alone or by fusion of a mutated HCII acidic extension in which all Glu and Asp residues between positions 55 and 75 were neutralized by mutation. Fusing residues 55-75 to alpha1-PI M358R yielded a relative rate enhancement of only 6-fold, suggesting a need for the full tail region to achieve maximal enhancement. Our results suggest that transfer of the N-terminal acidic extension of HCII to alpha1-PI M358R enhanced its inhibition of thrombin by conferring the ability to bind exosite 1 on HAPI M358R. This enhancement may aid in efforts to tailor this inhibitor for therapeutic use.


Massive expansion of Ubiquitination-related gene families within the Chlamydiae.
Gene loss, gain, and transfer play an important role in shaping the genomes of all organisms; however, the interplay of these processes in isolated populations, such as in obligate intracellular bacteria, is less understood. Despite a general trend towards genome reduction in these microbes, our phylogenomic analysis of the phylum Chlamydiae revealed that within the family Parachlamydiaceae, gene family expansions have had pronounced effects on gene content. We discovered that the largest gene families within the phylum are the result of rapid gene birth-and-death evolution. These large gene families are comprised of members harboring eukaryotic-like ubiquitination-related domains, such as F-box and BTB-box domains, marking the largest reservoir of these proteins found among bacteria. A heterologous type III secretion system assay suggests that these proteins function as effectors manipulating the host cell. The large disparity in copy number of members in these families between closely related organisms suggests that nonadaptive processes might contribute to the evolution of these gene families. Gene birth-and-death evolution in concert with genomic drift might represent a previously undescribed mechanism by which isolated bacterial populations diversify.


The role of arene-arene interactions in the folding of ortho-phenylenes.
The ortho-phenylenes are a simple class of helical oligomers and representative of the broader class of sterically congested polyphenylenes. Recent work has shown that o-phenylenes fold into well-defined helical conformations (in solution and, typically, in the solid state); however, the specific causes of this folding behavior have not been determined. Here, we report the effect of substituents on the conformational distributions of a series of o-phenylene hexamers. These experiments are complemented by dispersion-corrected DFT calculations on model oligomers (B97-D/TZV(2d,2p)). The results are consistent with a deterministic role for offset arene-arene stacking interactions on the folding behavior. On the basis of the experimental and computational results, we propose a model for o-phenylene folding with two simple rules. (1) Conformers are forbidden if they include a particular sequence of biaryl torsional states that causes excessive steric strain. These "ABA" states correspond to consecutive dihedral angles of -55°/+130°/-55° (or +55°/-130°/+55). (2) The stability of the remaining conformers is determined by offset arene-arene stacking interactions that are easily estimated as an additive function of the number of well-folded torsional states (±55°) along the backbone. For the parent, unsubstituted poly(o-phenylene), each interaction contributes roughly 0.5 kcal/mol to the helix stability (in chloroform), although their strength is sensitive to substituent effects. The behavior of the o-phenylenes as a class is discussed in the context of this model. They are analogous to α-helices, with axial aromatic stacking interactions in place of hydrogen bonding. The model predicts that the overall folding propensity should be quite sensitive to relatively small changes in the strength of the arene-arene stacking. In a broader sense, these results demonstrate that polyphenylenes may exhibit folding behavior that is amenable to simple models, and validate the use of diffusion-corrected DFT methods in predicting their three-dimensional structures.


Unzipping ion channels.
The functions of ion channels can be regulated by their phosphorylation state. Protein kinases and protein phosphatases tightly control the activity of channels, thereby regulating the flow of ions across cell membranes. Channel proteins and kinases or phosphatases can associate directly or through intermediate adaptor proteins. An interaction domain termed the leucine zipper (LZ), once thought to be unique to some families of transcription factors, has been identified in channel proteins and their cognate binding proteins. MacFarlane and Levitan discuss what roles LZ-containing proteins might have in controlling channel function.


Weight loss increases 11beta-hydroxysteroid dehydrogenase type 1 expression in human adipose tissue.
The global epidemic of obesity has heightened the need to understand the mechanisms that underpin its pathogenesis. Clinical observations in patients with Cushing's syndrome have highlighted the link between cortisol and central obesity. However, although circulating cortisol levels are normal or reduced in obesity, local regeneration of cortisol, from inactive cortisone, by 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) has been postulated as a pathogenic mechanism. Although levels of expression of 11betaHSD1 in adipose tissue in human obesity are debated in the literature, global inhibition of 11betaHSD1 improves insulin sensitivity. We have determined the effects of significant weight loss on cortisol metabolism and adipose tissue 11betaHSD1 expression after 10-wk ingestion of a very low calorie diet in 12 obese patients (six men and six women; body mass index, 35.9 +/- 0.9 kg/m2; mean +/- SE). All patients achieved significant weight loss (14.1 +/- 1.3% of initial body weight). Total fat mass fell from 41.8 +/- 1.9 to 32.0 +/- 1.7 kg (P < 0.0001). In addition, fat-free mass decreased (64.4 +/- 3.4 to 58.9 +/- 2.9 kg; P < 0.0001) and systolic blood pressure and total cholesterol also fell [systolic blood pressure, 135 +/- 5 to 121 +/- 5 mm Hg (P < 0.01); total cholesterol, 5.4 +/- 0.2 to 4.8 +/- 0.2 mmol/liter (P < 0.05)]. The serum cortisol/cortisone ratio increased after weight loss (P < 0.01). 11betaHSD1 mRNA expression in isolated adipocytes increased 3.4-fold (P < 0.05). Decreased 11betaHSD1 activity and expression in obesity may act as a compensatory mechanism to enhance insulin sensitivity through a reduction in tissue-specific cortisol concentrations. Inhibition of 11betaHSD1 may therefore be a novel, therapeutic strategy for insulin sensitization.


Measuring the benefits of the integration of health and social care: qualitative interviews with professional stakeholders and patient representatives.
Integrated care has the potential to ease the increasing pressures faced by health and social care systems, however, challenges around measuring the benefits for providers, patients, and service users remain. This paper explores stakeholders' views on the benefits of integrated care and approaches to measuring the integration of health and social care. Twenty-five semi-structured qualitative interviews were conducted with professional stakeholders (n = 19) and patient representatives (n = 6). Interviews focused on the benefits of integrated care and how it should be evaluated. Data was analysed using framework analysis. Three overarching themes emerged from the data: (1) integrated care and its benefits, with stakeholders defining it primarily from the patient's perspective; (2) potential measures for assessing the benefits of integration in terms of system effects, patient experiences, and patient outcomes; and (3) broader considerations around the assessment of integrated care, including the use of qualitative methods. There was consensus among stakeholders that patient experiences and outcomes are the best measures of integration, and that the main measures currently used to assess integration do not directly assess patient benefits. Validated health status measures are readily available, however, a substantial shift in practices is required before their use becomes commonplace.


Adenosquamous Carcinoma of the Stomach: A Population-based Study from the SEER Database.
Purpose: Gastric adenosquamous carcinoma (ASC) is a rare pathological type with poorly understood clinicopathological features. The purpose of this study is to identify the characteristics of gastric ASC patients. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database (2000 to 2014), patients with ASC (N=93) or adenocarcinoma (AC) (N=41794) of the stomach were included. The epidemiology, tumor features, treatment, and outcomes between these two groups were compared. Results: The incidences of ASC from 1983 to 2014 [annual percentage change (APC) = -3.5%, 95% confidence interval (CI) -4.9 to -2.1] and AC from 1973-2014 [APC = -1.8%, 95%CI -2.0 to -1.6] decreased over time. Compared to AC cases, patients with ASC were more likely to present poor differentiation (74.2% vs 52.4%) and later summary stage (distant: 46.2% vs 33.6%) or later T stage (T4: 15.1%% vs 9.0%). Besides, the proportion of patients with distant metastasis (33.3% vs 23.9%), and chemotherapy (44.1% vs 34.0%) in ASC group was higher. The Kaplan-Meier analyses showed ASC cases had worse overall survival (OS) (p=0.017) than that of AC after propensity score matching (PSM), but not the cancer-specific survival (CSS) (p=0.849). The further subgroup analyses suggested no statistical significance between gastric ASC patients and AC patients for CSS. The multivariate cox proportional hazard analyses indicated that patients with distant summary stage (HR=2.11, p=0.014), no surgery (HR=2.22, p=0.016), and no/unknown chemotherapy (HR=3.33, p<0.001) were associated with poor OS for ASC population alone. However, for CSS, only ASC cases with no/unknown chemotherapy (HR=2.22, p=0.018) indicated worse outcomes. Conclusions: Gastric ASC presented more aggressive clinicopathologic characteristics and poorer OS compared with AC. The localized/regional summary stages and undergoing surgery suggested favorable OS for gastric ASC patients. ASC cases receiving chemotherary showed both better OS and CSS.


Core-shell protein clusters comprising haemoglobin and recombinant feline serum albumin as an artificial O2 carrier for cats.
This report describes the synthesis and structure of core-shell protein clusters comprising haemoglobin (Hb) at the centre and recombinant feline serum albumin (rFSA) at the exterior, named as haemoglobin-albumin clusters (Hb-rFSA3). Specifically, we highlight their capability as an artificial O2 carrier that can be used as a red blood cell (RBC) substitute for cats, the most populous pet animal in the world. First, rFSA was expressed by genetic engineering using Pichia yeast. The proteins show identical features to the native FSA derived from feline plasma. Single crystals of rFSA were prepared under a microgravity environment on the international space station (ISS), from which the structure was first revealed at 3.4 Å resolution. Subsequently, bovine Hb was wrapped covalently by rFSA using an α-succinimidyl-ε-maleimide crosslinker, yielding Hb-rFSA3 clusters. Three rFSA entities enfolded the Hb nuclei satisfactorily, giving the protein clusters a negative surface net charge (pI = 4.7) and preventing an immunological response against anti-Hb antibodies. The O2 affinity was higher (P50 = 9 Torr) than that of the native Hb. The Hb-rFSA3 clusters are anticipated for use as an alternative material for RBC transfusion, and as an O2 therapeutic reagent that can be exploited in various veterinary medicine scenarios.


Ethnicity, traditional healing practices, and attitudes towards complementary medicine of a pediatric oncology population receiving healing touch in Hawaii.
Cultural competence among healthcare providers is becoming increasingly important. Hawai'i is an ethnically diverse island state that has a high rate of traditional and complementary medicine use. We previously reported on the feasibility of delivering Healing Touch (HT) to pediatric oncology patients, and its impact on pain, distress and fatigue. Our current objective is to examine the ethnic and cultural characteristics of this patient population, including traditional health related beliefs. Demographic data and feedback from subjects and their families from the 2009-2010 HT study conducted in Honolulu were analyzed. The majority of the participants were Asian American and/or Native Hawaiian or other Pacific Islander. Almost half of the participants were more than one race. Traditional cultural health related beliefs, as reported by patients and families, sometimes aligned with patient's experiences with HT, however, degree of acculturation/time living in the United States seemed to play a role as well, with younger generation perhaps being less "traditional". Common health related themes/values across the predominant cultures were 1) emphasis on family/clan and 2) mind/body connection. HT appeared to be well accepted by subjects from a variety of ethnic backgrounds. Several patients had attitudes/beliefs around healthcare that were rooted in their traditional cultural values, but this was not universal. Knowledge of different cultural attitudes on health, and traditional/complementary medicine, will improve patient care. Future areas of research could examine the acceptance of HT among pediatric oncology patients in geographic areas with differing cultural demographics (i.e., continentalUnited States or internationally).


The need to support students with autism at university.
Publicity surrounds the increased prevalence of autism. However, in contrast to support in primary and secondary schools, there exists little focus on supporting students with autism at university. Mental health nurses are well placed to facilitate support programmes for students with autism who have the capacity for higher education. This article examines the international literature around the support needs for these students and discusses opportunities that exist to support these students, their families, and higher education staff. Research is urgently needed to evaluate the success of such interventions, particularly in light of the low participation rates in study and work for people with autism.


An Unusual New Theropod with a Didactyl Manus from the Upper Cretaceous of Patagonia, Argentina.
Late Cretaceous terrestrial strata of the Neuquén Basin, northern Patagonia, Argentina have yielded a rich fauna of dinosaurs and other vertebrates. The diversity of saurischian dinosaurs is particularly high, especially in the late Cenomanian-early Turonian Huincul Formation, which has yielded specimens of rebacchisaurid and titanosaurian sauropods, and abelisaurid and carcharodontosaurid theropods. Continued sampling is adding to the known vertebrate diversity of this unit. A new, partially articulated mid-sized theropod was found in rocks from the Huincul Formation. It exhibits a unique combination of traits that distinguish it from other known theropods justifying erection of a new taxon, Gualicho shinyae gen. et sp. nov. Gualicho possesses a didactyl manus with the third digit reduced to a metacarpal splint reminiscent of tyrannosaurids, but both phylogenetic and multivariate analyses indicate that didactyly is convergent in these groups. Derived characters of the scapula, femur, and fibula supports the new theropod as the sister taxon of the nearly coeval African theropod Deltadromeus and as a neovenatorid carcharodontosaurian. A number of these features are independently present in ceratosaurs, and Gualicho exhibits an unusual mosaic of ceratosaurian and tetanuran synapomorphies distributed throughout the skeleton. Gualicho shinyae gen. et sp. nov. increases the known theropod diversity of the Huincul Formation and also represents the first likely neovenatorid from this unit. It is the most basal tetatanuran to exhibit common patterns of digit III reduction that evolved independently in a number of other tetanuran lineages. A close relationship with Deltadromaeus from the Kem Kem beds of Niger adds to the already considerable biogeographic similarity between the Huincul Formation and coeval rock units in North Africa.


Differential effects of vestibular processing on orienting exogenous and endogenous covert visual attention.
Recent research highlights the overwhelming role of vestibular information for higher order cognition. Central to body perception, vestibular cues provide information about self-location in space, self-motion versus object motion, and modulate the perception of space. Surprisingly, however, little research has dealt with how vestibular information combines with other senses to orient one's attention in space. Here we used passive whole body rotations as exogenous (Experiment 1) or endogenous (Experiment 2) attentional cues and studied their effects on orienting visual attention in a classical Posner paradigm. We show that-when employed as an exogenous stimulus-rotation impacts attention orienting only immediately after vestibular stimulation onset. However, when acting as an endogenous stimulus, vestibular stimulation provides a robust benefit to target detection throughout the rotation profile. Our data also demonstrate that vestibular stimulation boosts attentional processing more generally, independent of rotation direction, associated with a general improvement in performance. These data provide evidence for distinct effects of vestibular processing on endogenous and exogenous attention as well as alertness that differ with respect to the temporal dynamics of the motion profile. These data reveal that attentional spatial processing and spatial body perception as manipulated through vestibular stimulation share important brain mechanisms.


A candidate HIV/AIDS vaccine (MVA-B) lacking vaccinia virus gene C6L enhances memory HIV-1-specific T-cell responses.
The vaccinia virus (VACV) C6 protein has sequence similarities with the poxvirus family Pox_A46, involved in regulation of host immune responses, but its role is unknown. Here, we have characterized the C6 protein and its effects in virus replication, innate immune sensing and immunogenicity in vivo. C6 is a 18.2 kDa protein, which is expressed early during virus infection and localizes to the cytoplasm of infected cells. Deletion of the C6L gene from the poxvirus vector MVA-B expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (MVA-B ΔC6L) had no effect on virus growth kinetics; therefore C6 protein is not essential for virus replication. The innate immune signals elicited by MVA-B ΔC6L in human macrophages and monocyte-derived dendritic cells (moDCs) are characterized by the up-regulation of the expression of IFN-β and IFN-α/β-inducible genes. In a DNA prime/MVA boost immunization protocol in mice, flow cytometry analysis revealed that MVA-B ΔC6L enhanced the magnitude and polyfunctionality of the HIV-1-specific CD4+ and CD8+ T-cell memory immune responses, with most of the HIV-1 responses mediated by the CD8+ T-cell compartment with an effector phenotype. Significantly, while MVA-B induced preferentially Env- and Gag-specific CD8+ T-cell responses, MVA-B ΔC6L induced more Gag-Pol-Nef-specific CD8+ T-cell responses. Furthermore, MVA-B ΔC6L enhanced the levels of antibodies against Env in comparison with MVA-B. These findings revealed that C6 can be considered as an immunomodulator and that deleting C6L gene in MVA-B confers an immunological benefit by enhancing IFN-β-dependent responses and increasing the magnitude and quality of the T-cell memory immune responses to HIV-1 antigens. Our observations are relevant for the improvement of MVA vectors as HIV-1 vaccines.


Transient Depletion of Foxp3+ Regulatory T Cells Selectively Promotes Aggressive β Cell Autoimmunity in Genetically Susceptible DEREG Mice.
Type 1 diabetes (T1D) represents a hallmark of the fatal multiorgan autoimmune syndrome affecting humans with abrogated Foxp3+ regulatory T (Treg) cell function due to Foxp3 gene mutations, but whether the loss of Foxp3+ Treg cell activity is indeed sufficient to promote β cell autoimmunity requires further scrutiny. As opposed to human Treg cell deficiency, β cell autoimmunity has not been observed in non-autoimmune-prone mice with constitutive Foxp3 deficiency or after diphtheria toxin receptor (DTR)-mediated ablation of Foxp3+ Treg cells. In the spontaneous nonobese diabetic (NOD) mouse model of T1D, constitutive Foxp3 deficiency did not result in invasive insulitis and hyperglycemia, and previous studies on Foxp3+ Treg cell ablation focused on Foxp3DTR NOD mice, in which expression of a transgenic BDC2.5 T cell receptor (TCR) restricted the CD4+ TCR repertoire to a single diabetogenic specificity. Here we revisited the effect of acute Foxp3+ Treg cell ablation on β cell autoimmunity in NOD mice in the context of a polyclonal TCR repertoire. For this, we took advantage of the well-established DTR/GFP transgene of DEREG mice, which allows for specific ablation of Foxp3+ Treg cells without promoting catastrophic autoimmune diseases. We show that the transient loss of Foxp3+ Treg cells in prediabetic NOD.DEREG mice is sufficient to precipitate severe insulitis and persistent hyperglycemia within 5 days after DT administration. Importantly, DT-treated NOD.DEREG mice preserved many clinical features of spontaneous diabetes progression in the NOD model, including a prominent role of diabetogenic CD8+ T cells in terminal β cell destruction. Despite the severity of destructive β cell autoimmunity, anti-CD3 mAb therapy of DT-treated mice interfered with the progression to overt diabetes, indicating that the novel NOD.DEREG model can be exploited for preclinical studies on T1D under experimental conditions of synchronized, advanced β cell autoimmunity. Overall, our studies highlight the continuous requirement of Foxp3+ Treg cell activity for the control of genetically pre-installed autoimmune diabetes.


Volitional control of a prosthetic knee using surface electromyography.
This paper presents a method for providing volitional control of a powered knee prosthesis during nonweight-bearing activity such as sitting. The method utilizes an impedance framework, such that the joint can be programmed with a given stiffness and damping that reflects the nominal impedance properties of an intact joint. Volitional movement of the knee joint is commanded via the stiffness set-point angle of the joint impedance, which is commanded by the user as a function of the measured surface electromyogram (EMG) from the hamstring and quadriceps muscles of the residual limb. Rather than using the respective EMG measurements from these muscles to directly command the flexion or extension set point of the knee, the presented approach utilizes a combination of quadratic discriminant analysis and principal component analysis to align the user's intent to flex or extend the knee joint with the pattern of measured EMG. The approach was implemented on three transfemoral amputees, and their ability to control knee movement was characterized by a set of knee joint trajectory tracking tasks. Each amputee subject also performed the same set of trajectory tracking tasks with his sound side (intact) knee joint. The average root mean square trajectory tracking errors of the prosthetic knee employing the EMG-based volitional control and the intact knee of the three subjects were 6.2° and 5.2°, respectively.


Cryo-tomography tilt-series alignment with consideration of the beam-induced sample motion.
Recent evidence suggests that the beam-induced motion of the sample during tilt-series acquisition is a major resolution-limiting factor in electron cryo-tomography (cryoET). It causes suboptimal tilt-series alignment and thus deterioration of the reconstruction quality. Here we present a novel approach to tilt-series alignment and tomographic reconstruction that considers the beam-induced sample motion through the tilt-series. It extends the standard fiducial-based alignment approach in cryoET by introducing quadratic polynomials to model the sample motion. The model can be used during reconstruction to yield a motion-compensated tomogram. We evaluated our method on various datasets with different sample sizes. The results demonstrate that our method could be a useful tool to improve the quality of tomograms and the resolution in cryoET.


Dental RECUR Randomized Trial to Prevent Caries Recurrence in Children.
The purpose of this study was to determine the efficacy of a dental nurse-delivered intervention-the Dental RECUR Brief Negotiated Interview for Oral Health (DR-BNI)-in reducing the recurrence of dental caries in children who have a primary tooth extracted. It was based on a 2-arm multicenter randomized controlled trial with blinded outcome assessment. Participants were 5- to 7-y-old children (n = 241) scheduled to have primary teeth extracted in 12 UK centers. Test intervention parents (n = 119) received DR-BNI led by trained dental nurses. DR-BNI is a 30-min structured conversation informed by motivational interviewing with a forward focus to prevent future caries. Preventive goals are agreed, and a review appointment is made with child's general dental practitioner, who is advised to treat the child as being at high caries risk. The control intervention (n = 122) was a parent-nurse conversation about child's future tooth eruption, with advice given to visit a general dental practitioner as usual. At baseline, the DR-BNI group's mean dmft was 6.8, and the control group's was 6.3. A median of 5 teeth were extracted, mainly under general anesthesia. Final dental assessments were conducted by a single examiner visiting 189 schools 2 y after intervention; 193 (80%) of 241 children were examined. In the control group, 62% developed new caries in teeth that were caries-free or unerupted at baseline, as compared with 44% in the test group, a significant reduction (P = 0.021). The odds of new caries experience occurring were reduced by 51% in the DR-BNI group as compared with control. There was a 29% decrease in the relative risk of new caries experience in the DR-BNI group as compared with control. This single low-cost, low-intensity intervention was successful in significantly reducing the risk of recurrence of dental caries in children. This trial has implications for changing pediatric dental practice internationally. Training in and implementation of a motivational interviewing-informed brief intervention provides opportunities for dental nurses to facilitate behavior change improving the oral health of children at high caries risk (ISRCTN 24958829).


Building a home from foam--túngara frog foam nest architecture and three-phase construction process.
Frogs that build foam nests floating on water face the problems of over-dispersion of the secretions used and eggs being dangerously exposed at the foam : air interface. Nest construction behaviour of túngara frogs, Engystomops pustulosus, has features that may circumvent these problems. Pairs build nests in periodic bursts of foam production and egg deposition, three discrete phases being discernible. The first is characterized by a bubble raft without egg deposition and an approximately linear increase in duration of mixing events with time. This phase may reduce initial over-dispersion of foam precursor materials until a critical concentration is achieved. The main building phase is marked by mixing events and start-to-start intervals being nearly constant in duration. During the final phase, mixing events do not change in duration but intervals between them increase in an exponential-like fashion. Pairs joining a colonial nesting abbreviate their initial phase, presumably by exploiting a pioneer pair's bubble raft, thereby reducing energy and material expenditure, and time exposed to predators. Finally, eggs are deposited only in the centre of nests with a continuously produced, approximately 1 cm deep egg-free cortex that protectively encloses hatched larvae in stranded nests.


Systematic Review and Meta-Analysis of Randomized, Controlled Trials on Preoperative Physical Exercise Interventions in Patients with Non-Small-Cell Lung Cancer.
Preoperative physical exercise protocols prior to cancer surgery increased in popularity over recent years; however, the beneficial effect of such protocols is not well established, with conflicting results reported. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effects of different modalities or combinations of preoperative exercise interventions and/or prehabilitation multicomponent training in patients with non-small-cell lung cancer (NSCLC) after surgery on the outcomes related to functional capacity, mental wellness and medical care. We searched in OVID Embase, Pubmed, Cochrane Library, CINAHL, Scopus, and Web of Science. Characteristics of studies and program results and outcome data were extracted. Changes between the intervention and control groups, from baseline to follow-up (standardized mean difference (SMD) or relative risk (RR) with 95% confidence interval (CI) for each intervention was pooled using weighted random-effects models). A total of 676 participants from 10 RCTs were included in the final analysis (aerobic training + inspiratory muscle training, n = 5; aerobic training + strength training + inspiratory muscle training, n = 2; aerobic training + strength training, n = 1; multicomponent training, n = 1; aerobic training alone, n = 1). The results showed intervention-induced improvement in walking endurance (SMD = 0.27; 95% CI, 0.11 to 0.44; I2 = 0.0%), peak exercise capacity (SMD = 0.78; 95% CI, 0.35 to 1.21; I2 = 76.7%), dyspnoea (SMD = -0.30; 95% CI, -0.51 to -0.10; I2 = 0.0%), risk of hospitalization (SMD = -0.58; 95% CI, -0.97 to -0.20; I2 = 70.7%), and postoperative pulmonary complications (relative risk (RR) = 0.50; 95% CI, 0.39 to 0.66; I2 = 0.0%). For the functional capacity and medical care parameters, preoperative combined aerobic, resistance, and inspiratory muscle training was shown to be effective if comprising one to four weeks, performing 1-3 sessions per week, with moderate intensity (50% for endurance capacity). Further studies with larger samples and higher methodological quality are needed to clarify the potential benefits of preoperative exercise training for patients with NSCLC.


The comparison of bolus tracking and test bolus techniques for computed tomography thoracic angiography in healthy beagles.
Computed tomography thoracic angiography studies were performed on five adult beagles using the bolus tracking (BT) technique and the test bolus (TB) technique, which were performed at least two weeks apart. For the BT technique, 2 mL/kg of 300 mgI/mL iodinated contrast agent was injected intravenously. Scans were initiated when the contrast in the aorta reached 150 Hounsfield units (HU). For the TB technique, the dogs received a test dose of 15% of 2 mL/kg of 300 mgI/mL iodinated contrast agent, followed by a series of low dose sequential scans. The full dose of the contrast agent was then administered and the scans were conducted at optimal times as identified from time attenuation curves. Mean attenuation in HU was measured in the aorta (Ao) and right caudal pulmonary artery (rCPA). Additional observations included the study duration, milliAmpere (mA), computed tomography dose index volume (CTDI[vol]) and dose length product (DLP). The attenuation in the Ao (BT = 660 52 HU ± 138 49 HU, TB = 469 82 HU ± 199 52 HU, p = 0.13) and in the rCPA (BT = 606 34 HU ± 143 37 HU, TB = 413 72 HU ± 174.99 HU, p = 0.28) did not differ significantly between the two techniques. The BT technique was conducted in a significantly shorter time period than the TB technique (p = 0.03). The mean mA for the BT technique was significantly lower than the TB technique (p = 0.03), as was the mean CTDI(vol) (p = 0.001). The mean DLP did not differ significantly between the two techniques (p = 0.17). No preference was given to either technique when evaluating the Ao or rCPA but the BT technique was shown to be shorter in duration and resulted in less DLP than the TB technique.


Manual laterality and hitting performance in major league baseball.
Asymmetrical hand function was examined in the context of expert sports performance: hitting in professional baseball. An archival study was conducted to examine the batting performance of all Major League Baseball players from 1871 to 1992, focusing on those who batted left (n = 1,059) to neutralize the game asymmetry. Among them, left-handers (n = 421) were more likely to hit with power and to strike out than right-handers (n = 638). One possible account, based on the idea of hand dominance and an analogy to tennis, is that batting left involves a double-handed forehand for left-handers and a weaker and more reliable double-handed backhand for right-handers. The results are also interpretable in the light of Y. Guiard's (1987) kinematic chain model of a between-hands asymmetrical division of labor, which provides a detailed account of why left batting is optimal for left-handers.


Challenging sleep homeostasis in narcolepsy-cataplexy: implications for non-REM and REM sleep regulation.
We recently proposed insufficient non-rapid eye movement sleep (NREMS) intensity to contribute to disturbed nocturnal sleep in patients with narcolepsy-cataplexy (NC). To test this hypothesis, we investigated the effect of physiologically intensified NREMS in recovery sleep following sleep deprivation. Nocturnal baseline and recovery sleep architecture, and the sleep electroencephalogram (EEG) before and after 40 hours of sustained wakefulness were compared between 6 drug-free patients with NC (age range: 19-37 years) and 6 individually matched, healthy control subjects (18-43 years). Sleep and sleep EEG power spectra (C3A2 derivation). The dynamics of the homeostatic Process S were estimated from the time course of slow-wave activity (SWA, spectral power within 0.75-4.5 Hz) across consecutive NREMS episodes. Sleep research laboratory. In baseline, SWA decreased across consecutive NREMS episodes in patients with NC and control subjects. The build-up of SWA, however, was attenuated in NC in the second episode (P = 0.01) due to a higher number of short wake periods (P = 0.02). Prolonged wakefulness increased initial SWA in both groups (P = 0.003) and normalized the baseline differences between patients and control subjects in the time course of SWA in NREMS. The changed dynamics of SWA in the patients in recovery sleep when compared with baseline were associated with reduced numbers of intermittent wake periods in the first (P = 0.01) and second (P = 0.04) NREMS episodes. All patients, but no control subjects, showed a sleep-onset rapid eye movement period (SOREMP) in both baseline and recovery sleep. Sleep deprivation increased SOREMP duration (P = 0.03). Increased SWA after sleep deprivation indicates that sleep homeostasis is functional in NC. Increased NREMS intensity in recovery sleep postpones sleep fragmentation, supporting our concept that sleep fragmentation is directly related to insufficient NREMS intensity in NC. The persistence of SOREMP despite enhanced NREMS pressure suggests an abnormal interaction between NREMS and REMS regulatory processes.


Informed consent: study of quality of information given to participants in a clinical trial.
To determine whether the participants in a clinical trial had perceived adequate information about the trial according to the guidelines of the Declaration of Helsinki. About 18 months after the end of a gynaecological clinical trial the participants received a questionnaire by post, which focused on the quality of the information given to them before entering the trial. Neither researchers nor participants were aware in advance that the trial would become the subject of this follow up investigation. Eight different centres in Sweden. 43 women out of the 53 who completed the trial (mean (range) age 23 (16 to 35) years) returned the questionnaire. Adequacy of the information (based on requirements of the Declaration of Helsinki) to enable the following: understanding of the aims of the study; awareness of what participation meant; and awareness of the possibility of withdrawing from participation at any time. Motives for agreeing to participate, and a subjective evaluation of the given information were also recorded. All but one of the participants had been aware that they were taking part in a research project. Five women stated that they had not been aware that a second laparoscopy was performed only for research reasons. Seven women reported that they had not been aware of the meaning of participating in the project and 17 that they had had no information about the possibility of withdrawing from the study whenever they wanted. In the subjective rating 22 women considered the information given as good or very good. There was a systematic variation in the quality of the given information among the eight centres. Although all but one of the participants had been aware that they were taking part in a clinical trial, the quality of the information understood and recalled by participants varied, and in many cases clearly did not meet the guidelines of the Declaration of Helsinki. Variations among centres in participants' perception of information suggest that deficiencies in perception may be caused by informers rather than the participants.


Use of 2-hydroxypropyl-beta-cyclodextrin as an intrathecal drug vehicle with opioids.
2-Hydroxypropyl-beta-cyclodextrin (CDEX), a seven-membered glucose pyranose structure, forms reversible inclusion complexes with the lipophilic portion of a drug molecule by noncovalent bonding. This can increase the water solubility of lipid-soluble drugs and reduce the rate of clearance of such agents from the spinal cord into the vasculature after i.t. administration. In this study, opioids (morphine, lofentanil, alfentanil and sufentanil) with and without CDEX (20, 2, 0.2 and 0.02% w/v in sterile water) were administered spinally in rats prepared with chronic i.t. catheters. CDEX prolonged the duration of analgesia (52.5 degrees C hot plate) and reduced the incidence of catalepsy otherwise produced by a supermaximal i.t. dose of each of the opioids. The magnitude of the potentiating effect of CDEX on opioids was dependent upon concentration of the CDEX and varied with drug lipid partition coefficients. The highest concentration of CDEX alone (20%) had no effect upon the volume-evoked micturition reflex, blood pressure, heart rate, or spinal reflexes. Our data indicate that CDEX may be a useful i.t. vehicle for modifying the redistribution characteristics of highly diffusible molecules after their i.t. administration, and that for each drug there is an optimal CDEX concentration. In the present case, CDEX prolongs the spinal analgesic action and reduces the supraspinal actions of i.t. drugs.


Genetic Mosaicism in a Group of Patients With Cornelia de Lange Syndrome.
Background: Cornelia de Lange Syndrome (CdLS) is a heterogeneous disorder. Diverse expression of clinical symptoms can be caused by a variety of pathogenic variants located within the sequence of different genes correlated with the cohesin complex. Methods: Sixty-nine patients with confirmed clinical diagnosis of CdLS were enrolled in the study. Blood and buccal swab samples were collected for molecular studies. Mutational analysis was performed using the Next Generation (deep) Sequencing (NGS) covering 24 genes. In addition, the MLPA technique was applied to detect large rearrangements of NIPBL. Results: MLPA and NGS analysis were performed in 66 (95,7%) and 67 (97,1%) patients, respectively. Large rearrangements of NIPBL were not identified in the studied group. Germline pathogenic variants were detected in 18 (26,1%) patients. Fourteen variants (20,3%) were identified in NIPBL, two (2,9%) in SMC1A, and two (2,9%) in HDAC8. In total, 13 (18,8%) buccal swabs were suitable for deep sequencing. Mosaic variants were found in four (30,8%; 4/13) patients negative for germline alterations. Three mosaic substitutions were detected in NIPBL while one in KMT2A gene. Conclusions: Comprehensive and sensitive molecular techniques allow detecting novel pathogenic variants responsible for the molecular basis of CdLS. In addition, molecular testing of different tissues should be applied since such an approach allows detect mosaic variants specific for a subgroup of CdLS patients. Finally, to test possible pathogenicity of intronic variants, RNA analysis should be conducted.


Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis.
The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain. We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174374 deaths or major non-fatal vascular outcomes recorded among 1085949 people in 121 prospective studies. For people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators. Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.


Improving multilevel analyses: the integrated epidemiologic design.
Multilevel analysis has been widely used to allow the simultaneous examination of the effects of individual- and group-level variables on individual health outcomes. In spite of its utility, multilevel design can have some drawbacks in the estimation of risk factor effects when the within-group variation of variables of interest is small relative to between-group variation. An extreme case of this is a group-level risk factor, which by definition has no within-group variation. To improve the estimation of group-level and individual-level risk factor effects, we consider an integrated epidemiologic design using a population-based estimating equation approach that can be considered a further extension of the multilevel design. Although the integrated design uses the same individual-level and group-level data as the multilevel design, it includes aggregated health outcome data in each group as additional information. This paper explains differences between the 2 designs, describing advantages and disadvantages of the integrated design over the multilevel design. The 2 designs are applied to a real example of mortality following chronic kidney disease, illustrating differences that might be encountered in practice.


Conventional and real-time PCR targeting 16S ribosomal RNA for the detection of Mycobacterium tuberculosis complex.
Conventional diagnostic methods for tuberculosis (TB) have limited sensitivity and specificity or are time-consuming. 16S rDNA and 16S rRNA of Mycobacterium tuberculosis complex (MTC) were used as targets to develop sensitive and specific polymerase chain reactions (PCRs) to improve the diagnosis of MTC. We developed conventional and real-time PCRs targeting 16S rDNA and rRNA of MTC. PCRs targeting 16S rRNA had a 10-100 times lower limit of detection for M. tuberculosis than PCRs targeting 16S rDNA. The sensitivities of the 16S rDNA PCR, 16S rRNA reverse transcription PCR (RT-PCR), 16S rDNA real-time PCR and 16S rRNA real-time RT-PCR for sputum specimens were respectively 92%, 94.6%, 96% and 100%. Real-time PCR showed no cross-reactivity, but conventional PCR had cross-reactivity to M. avium, M. gastri and M. nonchromogenicum. PCRs targeting the 16S rRNA of MTC were more sensitive than those targeting 16S rDNA; 16S rRNA real-time RT-PCR showed the highest sensitivity and specificity for MTC.


Global regulator SATB1 recruits beta-catenin and regulates T(H)2 differentiation in Wnt-dependent manner.
In vertebrates, the conserved Wnt signalling cascade promotes the stabilization and nuclear accumulation of beta-catenin, which then associates with the lymphoid enhancer factor/T cell factor proteins (LEF/TCFs) to activate target genes. Wnt/beta -catenin signalling is essential for T cell development and differentiation. Here we show that special AT-rich binding protein 1 (SATB1), the T lineage-enriched chromatin organizer and global regulator, interacts with beta-catenin and recruits it to SATB1's genomic binding sites. Gene expression profiling revealed that the genes repressed by SATB1 are upregulated upon Wnt signalling. Competition between SATB1 and TCF affects the transcription of TCF-regulated genes upon beta-catenin signalling. GATA-3 is a T helper type 2 (T(H)2) specific transcription factor that regulates production of T(H)2 cytokines and functions as T(H)2 lineage determinant. SATB1 positively regulated GATA-3 and siRNA-mediated knockdown of SATB1 downregulated GATA-3 expression in differentiating human CD4(+) T cells, suggesting that SATB1 influences T(H)2 lineage commitment by reprogramming gene expression. In the presence of Dickkopf 1 (Dkk1), an inhibitor of Wnt signalling, GATA-3 is downregulated and the expression of signature T(H)2 cytokines such as IL-4, IL-10, and IL-13 is reduced, indicating that Wnt signalling is essential for T(H)2 differentiation. Knockdown of beta-catenin also produced similar results, confirming the role of Wnt/beta-catenin signalling in T(H)2 differentiation. Furthermore, chromatin immunoprecipitation analysis revealed that SATB1 recruits beta-catenin and p300 acetyltransferase on GATA-3 promoter in differentiating T(H)2 cells in a Wnt-dependent manner. SATB1 coordinates T(H)2 lineage commitment by reprogramming gene expression. The SATB1:beta-catenin complex activates a number of SATB1 regulated genes, and hence this study has potential to find novel Wnt responsive genes. These results demonstrate that SATB1 orchestrates T(H)2 lineage commitment by mediating Wnt/beta-catenin signalling. This report identifies a new global transcription factor involved in beta-catenin signalling that may play a major role in dictating the functional outcomes of this signalling pathway during development, differentiation, and tumorigenesis.


A dynamical-systems view of stem cell biology.
During development, cells undergo a unidirectional course of differentiation that progressively decreases the number of cell types they can potentially become. Stem cells, however, keep their potential to both proliferate and differentiate. A very important issue then is to understand the characteristics that distinguish stem cells from other cell types and allow them to conduct stable proliferation and differentiation. Here, we review relevant dynamical-systems approaches to describe the state transition between stem and differentiated cells, with an emphasis on fluctuating and oscillatory gene expression levels, as these represent the specific properties of stem cells. Relevance between recent experimental results and dynamical-systems descriptions of stem cell differentiation is also discussed.


Geriatric Emergency Medicine Fellowships: Current State of Specialized Training for Emergency Physicians in Optimizing Care for Older Adults.
Improving emergency department (ED) care for older adults is a critical issue in emergency medicine. Institutions throughout the United States and Canada have recognized the growing need for a workforce of emergency physician (EP) leaders focused on clinical innovation, education, and research and have developed specialized fellowship training in geriatric emergency medicine (GEM). We describe here the overview, structure, and curricula of these fellowships as well as successes and challenges they have encountered. Seven GEM fellowships are active in the United States and Canada, with five offering postresidency training only, one offering fellowship training during residency only, and one offering both. The backbone of the curriculum for all fellowships is the achievement of core competencies in various aspects of GEM, and each includes clinical rotations, teaching, and a research project. Evaluation strategies and feedback have allowed for significant curricular changes as well as customization of the fellowship experience for individual fellows. Key successes include an improved collaborative relationship with geriatrics faculty that has led to additional initiatives and projects and former fellows already becoming regional and national leaders in GEM. The most critical challenges have been ensuring adequate funding and recruiting new fellows each year who are interested in this clinical area. We believe that interest in GEM fellowships will grow and that opportunities exist to combine GEM fellowship training with a focus in research, administration, or health policy to create unique new types of highly impactful specialized training. Future research may include exploring former fellows' postfellowship experiences, careers, accomplishments, and contributions to GEM to better understand the impact of GEM fellowships.


Next Steps in Improving Healthcare Value: AHRQ Evidence-based Practice Center Program-Applying the Knowledge to Practice to Data Cycle to Strengthen the Value of Patient Care.
For more than 20 years, the Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) Program has been identifying and synthesizing evidence to inform evidence-based healthcare. Recognizing that many healthcare settings continue to face challenges in disseminating and implementing evidence into practice, AHRQ's EPC program has also embarked on initiatives to facilitate the translation of evidence into practice and to measure and monitor how practice changes impact health outcomes. The program has structured its efforts around the three phases of the Learning Healthcare System cycle: knowledge, practice, and data. Here, we use a topic relevant to the field of hospital medicine-Clostridium difficile colitis prevention and treatment-as an exemplar of how the EPC program has used this framework to move evidence into practice and develop systems to facilitate continuous learning in healthcare systems.


Purification and characterization of three members of the photolyase/cryptochrome family blue-light photoreceptors from Vibrio cholerae.
The sequence of Vibrio cholerae genome revealed three genes belonging to the photolyase/cryptochrome blue-light photoreceptor family. The proteins encoded by the three genes were purified and characterized. All three proteins contain folate and flavin cofactors and have absorption peaks in the range of 350-500 nm. Only one of the three, VcPhr, is a photolyase specific for cyclobutane pyrimidine dimers. The other two are cryptochromes and were designated VcCry1 and VcCry2, respectively. Mutation of phr abolishes photoreactivation of UV-induced killing, whereas mutations in cry1 and cry2 do not affect photorepair activity. VcCry1 exhibits some unique features. Of all cryptochromes characterized to date, it is the only one that contains stoichiometric amounts of both chromophores and retains its flavin cofactor in the two-electron reduced FADH2 form. In addition, VcCry1 exhibits RNA binding activity and co-purifies with an RNA of 60-70 nucleotides in length.


Canadian integrative oncology research priorities: results of a consensus-building process.
In Canada, many diverse models of integrative oncology care have emerged in response to the growing number of cancer patients who combine complementary therapies with their conventional medical treatments. The increasing interest in integrative oncology emphasizes the need to engage stakeholders and to work toward consensus on research priorities and a collaborative research agenda. The Integrative Canadian Oncology Research Initiative initiated a consensus-building process to meet that need and to develop an action plan that will implement a Canadian research agenda. A two-day consensus workshop was held after completion of a Delphi survey and stakeholder interviews. FIVE INTERRELATED PRIORITY RESEARCH AREAS WERE IDENTIFIED AS THE FOUNDATION FOR A CANADIAN RESEARCH AGENDA: EffectivenessSafetyResource and health services utilizationKnowledge translationDeveloping integrative oncology models Research is needed within each priority area from a range of different perspectives (for example, patient, practitioner, health system) and in a way that reflects a continuum of integration from the addition of a single complementary intervention within conventional cancer care to systemic change. Strategies to implement a Canadian integrative oncology research agenda were identified, and working groups are actively developing projects in line with those strategic areas. Of note is the intention to develop a national network for integrative oncology research and knowledge translation. The identified research priorities reflect the needs and perspectives of a spectrum of integrative oncology stakeholders. Ongoing stakeholder consultation, including engagement from new stakeholders, is needed to ensure appropriate uptake and implementation of a Canadian research agenda.


The impact of adenovirus infection on the immunocompromised host.
Adenovirus (Ad) infections in immunocompromised hosts have increased in frequency as the number of patients with transplants of bone marrow, liver, kidney, heart and other organs increase in number and survive longer. The numbers of such patients have also increased because of the emergence of the HIV epidemic. Ad infections with the 51 different serotypes recognised to date have few pathognomonic signs and symptoms, and thus require a variety of laboratory-based procedures to confirm infection. These viruses have the ability to target various organs with relative serotype specificity and can cause diverse manifestations including serious life-threatening diseases characteristic of the organs involved. Ads have cytolytic and immunoregulatory properties. The clinical dilemma remains the prompt recognition of Ad-related disease, the differentiation of Ad infection from Ad disease and the differentiation from other causative agents. Since the armamentarium of effective antiviral agents available to treat Ads is unproven by controlled trials and the virus is often not acquired de novo, it is difficult to prevent reactivation in immunodeficient hosts or new acquisition from donor organs. Timely discontinuation of immunosuppressive agents is necessary to prevent morbid outcomes. The clinical diseases, diagnostic tests, antiviral agents and biological aspects of the Ads as pathogens in immunocompromised patients are discussed in the context of this review. Some of the newer diagnostic tests are based on the well-studied molecular biology of Ads, which also have been attenuated by selective viral DNA deletions for use as vectors in numerous gene therapy trials in humans.


Expanded Endoscopic Endonasal Resection of Retrochiasmatic Craniopharyngioma.
This video abstract demonstrates the use of the expanded endoscopic endonasal approach for the resection of a retrochiasmatic craniopharyngioma. These tumors are notoriously difficult to treat, and many approaches have been tried to facilitate safe and effective resection. The endoscopic endonasal approach has been increasingly utilized for selected sellar/suprasellar pathology. We present the case of a 39-year-old man who was found to have a cystic, partially calcified suprasellar mass consistent with a craniopharyngioma. To facilitate robust skull base repair, a vascularized nasoseptal flap was harvested. A wide sphenoidotomy was performed and the sella and tuberculum were exposed. After the dural opening and arachnoid dissection, the stalk was identified, merging seamlessly with the tumor capsule. The lesion was then internally debulked with the use of an ultrasonic aspirator. The capsule was then dissected off of the optic chiasm, thalamus, and hypothalamus. The cavity was inspected with an angled endoscope to ensure complete resection. A multilayered reconstruction was performed using autologous fascia lata, the previously harvested nasoseptal flap, and dural sealant. Postoperatively, the patient did have expected panhypopituitarism but remained neurologically intact and had improvement in his vision. In conclusion, this video demonstrates how an expanded endonasal approach can be used to safely resect a craniopharyngioma, even when in close proximity to delicate structures such as the optic chiasm. The link to the video can be found at: https://youtu.be/tahjHmrXhc4 .


Long-acting injectable vs oral risperidone for schizophrenia and co-occurring alcohol use disorder: a randomized trial.
Alcohol use disorders worsen the course of schizophrenia. Although the atypical antipsychotic clozapine appears to decrease alcohol use in schizophrenia, risperidone does not. We have proposed that risperidone's relatively potent dopamine D2 receptor blockade may partly underlie its lack of effect on alcohol use. Since long-acting injectable (LAI) risperidone both results in lower average steady-state plasma concentrations than oral risperidone (with lower D2 receptor occupancy) and encourages adherence, it may be more likely to decrease heavy alcohol use (days per week of drinking 5 or more drinks per day) than oral risperidone. Ninety-five patients with DSM-IV-TR diagnoses of schizophrenia and alcohol use disorder were randomized to 6 months of oral or LAI risperidone between 2005 and 2008. Explanatory (efficacy) analyses were carried out to evaluate the potential benefits of LAI under suitably controlled conditions (in contrast to real-world settings), with intent-to-treat analyses being secondary. Explanatory analyses showed that heavy drinking in the oral group worsened over time (P = .024) and that there was a statistical trend toward significance in the difference between the changes in heavy drinking days in the oral and LAI groups (P = .054). Furthermore, the 2 groups differed in the mean number of drinking days per week (P = .035). The intent-to-treat analyses showed no difference in heavy drinking but did show a difference in average drinking days per week similar to that obtained from the explanatory analyses (P = .018). Neither explanatory nor intent-to-treat analyses showed any between-group differences in alcohol use as measured by intensity or the Alcohol Use Scale. The plasma concentrations of the active metabolite 9-hydroxyrisperidone were significantly lower in patients taking LAI (P < .05), despite their significantly (overall) better treatment adherence (P < .005). For the population considered here, schizophrenia patients with alcohol use disorder appear to continue drinking some alcohol while taking either form of risperidone. Nonetheless, our data suggest that injectable risperidone may be a better choice than the oral form for these dual diagnosis patients. ClinicalTrials.gov identifier: NCT00130923.


Vitamin D deficiency and periodontal clinical attachment loss in HIV-seropositive women: A secondary analysis conducted in the Women's Interagency HIV Study (WIHS).
The aim of this study was to test a hypothesized positive association between low vitamin D (VitD) serum levels and the severity of periodontal disease in women with HIV infection. This was a cross-sectional secondary analysis of data from an oral substudy conducted within the Chicago site of the Women's Interagency HIV Study. Serum VitD levels and clinical attachment loss (CAL) measurements were available for 74 women with HIV infection. VitD levels were treated as both continuous and categorical variables in bivariate and multivariate analyses. Mean clinical attachment loss (mCAL) was determined for each subject by obtaining the averages of measurements taken at 4 sites in each measured tooth. Average age of study participants (n = 74) was 39.6 years (standard deviation 7.2), and the majority were African Americans (70.3%) with VitD deficiency (58.1%). VitD deficiency was positively associated with higher mCAL (P = .012). After adjustment for race, age, smoking, and HIV viral load, an association was found between VitD deficiency and mCAL (Beta 0.438; P = .036). We identified a previously unreported association between VitD deficiency and mCAL in women with HIV infection. Larger and more inclusive, multisite, longitudinal studies are warranted to investigate whether these findings can be generalized to all individuals with HIV infection in the current treatment era and to determine causality.


Solid lipid nanoparticles: a modern formulation approach in drug delivery system.
Solid lipid nanoparticles are at the forefront of the rapidly developing field of nanotechnology with several potential applications in drug delivery, clinical medicine and research, as well as in other varied sciences. Due to their unique size-dependent properties, lipid nanoparticles offer the possibility to develop new therapeutics. The ability to incorporate drugs into nanocarriers offers a new prototype in drug delivery that could be used for secondary and tertiary levels of drug targeting. Hence, solid lipid nanoparticles hold great promise for reaching the goal of controlled and site specific drug delivery and hence have attracted wide attention of researchers. This review presents a broad treatment of solid lipid nanoparticles discussing their advantages, limitations and their possible remedies. The different types of nanocarriers which were based on solid lipid like solid lipid nanoparticles, nanostructured lipid carriers, lipid drug conjugates are discussed with their structural differences. Different production methods which are suitable for large scale production and applications of solid lipid nanoparticles are described. Appropriate analytical techniques for characterization of solid lipid nanoparticles like photon correlation spectroscopy, scanning electron microscopy, differential scanning calorimetry are highlighted. Aspects of solid lipid nanoparticles route of administration and their biodistribution are also incorporated. If appropriately investigated, solid lipid nanoparticles may open new vistas in therapy of complex diseases.


Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients.
Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.


Direct determination by 2H-NMR of the ionization state of phospholipids and of a local anaesthetic at the membrane surface.
Protonation and deprotonation of the primary amino group of phosphatidylethanolamine, and of the lipid phosphate groups of phosphatidylethanolamine with phosphatidylcholine, have been observed directly and isothermally in equimolar mixed fluid bilayers of the two phospholipids. In addition, the acid-base titration of the secondary amino group of the local anaesthetic, tetracaine, whilst partitioned into the bilayers, has also been determined. Here we show how studies by deuterium nuclear magnetic resonance of non-perturbing deuterons, specifically placed at the membrane polar-apolar interface, can give direct information about the electrostatics at a membrane surface.


Targeting phosphorylated p53 to elicit tumor-reactive T helper responses against head and neck squamous cell carcinoma.
The human T cell receptor is capable of distinguishing between normal and post-translationally modified peptides. Because aberrant phosphorylation of cellular proteins is a hallmark of malignant transformation, the expression of the phosphorylated epitope could be an ideal antigen to combat cancer without damaging normal tissues. p53 activates transcription factors to suppress tumors by upregulating growth arrest and apoptosis-related genes. In response to DNA damage, p53 is phosphorylated at multiple sites including Ser33 and Ser37. Here, we identified phosphorylated peptide epitopes from p53 that could elicit effective T helper responses. These epitope peptides, p5322-41/Phospho-S33 and p5322-41/Phospho-S37, induced T helper responses against tumor cells expressing the phosphorylated p53 protein. Moreover, chemotherapeutic agents augmented the responses of such CD4 T cells via upregulation of phosphorylated p53. The upregulation of phosphorylated p53 expression by chemotherapy was confirmed in in vitro and xenograft models. We evaluated phosphorylated p53 expression in the clinical samples of oropharyngeal squamous cell carcinoma and revealed that 13/24 cases (54%) were positive for phosphorylated p53. Importantly, the lymphocytes specific for the phosphorylated p53 peptide epitopes were observed in the head and neck squamous cell cancer (HNSCC) patients. These results reveal that a combination of phosphorylated p53 peptides and chemotherapy could be a novel immunologic approach to treat HNSCC patients.


Adaptation to sublethal environmental stresses protects Listeria monocytogenes against lethal preservation factors.
A sublethal dose of ethanol (5%, vol/vol), acid (HCl, pH 4.5 to 5.0), H2O2 (500 ppm), or NaCl (7%, wt/vol) was added to a Listeria monocytogenes culture at the exponential phase, and the cells were allowed to grow for 1 h. Exponential-phase cells also were heat shocked at 45 degrees C for 1 h. The stress-adapted cells were then subjected to the following factors at the indicated lethal levels--NaCl (25%, wt/vol), ethanol (17.5%, vol/vol), hydrogen peroxide (0.1%, wt/vol), acid (pH 3.5), and starvation on 0.1 M phosphate buffer at pH 7.0 (up to 300 h). Viable counts of the pathogen, after the treatment, were determined on Trypticase soy agar-yeast extract, and survivor plots were constructed. The area (h.log10 CFU/ml) between the control and treatment curves was calculated to represent the protective effect resulting from adaptation to the sublethal stress factor. Adaptation to pH 4.5 to 5.0 or 5% ethanol significantly (P < 0.05) increased the resistance of L. monocytogenes to lethal doses of acid, ethanol, and H2O2. Adaptation to ethanol significantly (P < 0.05) increased the resistance to 25% NaCl. When L. monocytogenes was adapted to 500 ppm of H2O2, 7% NaCl, or heat, resistance of the pathogen to 1% hydrogen peroxide increased significantly (P < 0.05). Heat shock significantly (P < 0.05) increased the resistance to ethanol and NaCl. Therefore, the occurrence of stress protection after adaptation of L. monocytogenes to environmental stresses depends on the type of stress encountered and the lethal factor applied. This "stress hardening" should be considered when current food processing technologies are modified or new ones are developed.


Impact of Breast Density Notification Legislation on Radiologists' Practices of Reporting Breast Density: A Multi-State Study.
Purpose To evaluate the impact of breast density notification legislation on breast density reporting by radiologists nationally. Materials and Methods The institutional review board exempted this HIPAA-compliant retrospective study from the requirement for informed consent. State-level data over a 5-year period on breast density categorization and breast cancer detection rate were collected from the National Mammography Database (NMD). Z tests were used to calculate differences in proportions. Results Facilities in 13 of 17 states that had breast density notification legislation as of 2014 submitted data to the NMD before and after law enactment. A total of 1 333 541 mammographic studies (hereafter called "mammograms") over a 30-month period, beginning 20 months before and continuing 10 months after law enactment, were included in the analysis. There was a small but statistically significant decrease in the percentage of mammograms reported as showing dense breast tissue (hereafter called "dense mammograms") in the month before law enactment compared with the month after (43.0% [22 338 of 52 000] vs 40.0% [18 604 of 46 464], P < .001). There was no statistically significant difference in the percentage of mammograms reported as dense in the month before law enactment compared with the 10th month after (43.0% [22 338 of 52 000] vs 42.8% [15 835 of 36 991], P = .65). There were no significant differences in the breast cancer detection rate between the month before and the month after law enactment (3.9 vs 3.8 cancers per 1000 mammograms, P = .79) or between the month before law enactment and the 10th month after (3.9 vs 4.2 cancers per 1000 mammograms, P = .55). In 21 analyzed states without breast density notification legislation, the percentage of mammograms reported as dense did not decrease below 42.8% (43 363 of 101 394) from 2010 to 2014, in contrast to 13 analyzed states with breast density notification legislation, which reached a nadir of 39.3% (20 965 of 53 360) (P < .001). Conclusion The percentage of mammograms reported as dense slightly decreased immediately after enactment of breast density notification legislation but then returned to prelegislation percentages within 10 months. (©) RSNA, 2016.


Anti-inflammatory ω-3 endocannabinoid epoxides.
Clinical studies suggest that diets rich in ω-3 polyunsaturated fatty acids (PUFAs) provide beneficial anti-inflammatory effects, in part through their conversion to bioactive metabolites. Here we report on the endogenous production of a previously unknown class of ω-3 PUFA-derived lipid metabolites that originate from the crosstalk between endocannabinoid and cytochrome P450 (CYP) epoxygenase metabolic pathways. The ω-3 endocannabinoid epoxides are derived from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to form epoxyeicosatetraenoic acid-ethanolamide (EEQ-EA) and epoxydocosapentaenoic acid-ethanolamide (EDP-EA), respectively. Both EEQ-EAs and EDP-EAs are endogenously present in rat brain and peripheral organs as determined via targeted lipidomics methods. These metabolites were directly produced by direct epoxygenation of the ω-3 endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) by activated BV-2 microglial cells, and by human CYP2J2. Neuroinflammation studies revealed that the terminal epoxides 17,18-EEQ-EA and 19,20-EDP-EA dose-dependently abated proinflammatory IL-6 cytokines while increasing anti-inflammatory IL-10 cytokines, in part through cannabinoid receptor-2 activation. Furthermore the ω-3 endocannabinoid epoxides 17,18-EEQ-EA and 19,20-EDP-EA exerted antiangiogenic effects in human microvascular endothelial cells (HMVEC) and vasodilatory actions on bovine coronary arteries and reciprocally regulated platelet aggregation in washed human platelets. Taken together, the ω-3 endocannabinoid epoxides' physiological effects are mediated through both endocannabinoid and epoxyeicosanoid signaling pathways. In summary, the ω-3 endocannabinoid epoxides are found at concentrations comparable to those of other endocannabinoids and are expected to play critical roles during inflammation in vivo; thus their identification may aid in the development of therapeutics for neuroinflammatory and cerebrovascular diseases.


Attitudes, subjective norms, and behavioral intentions of nurses toward dying patients and their families.
This investigation aimed to develop and validate an instrument, "Attitudes, Subjective Norms, and Behavioral Intentions of Nurses Toward the Care of Dying Patients and Their Families" (ASBID), and to examine the relationship among selected demographic variables, death anxiety, and social desirability response tendency on the behavioral intentions of nurses toward the dying. The Ajzen-Fishbein theory of reasoned action was used as the conceptual framework. Nursing behaviors toward the dying included in the ASBID were developed from interviews with bereaved family members. Three hundred seventy-two registered nurses caring for dying patients were used as the sample population for testing the ASBID. Internal consistency reliability coefficients for the ASBID achieved satisfactory standards. Factor analysis suggested three factors were being measured: general acute care measures for the dying, open communication with the dying, and continuing care for bereaved family members. Results supported the Ajzen-Fishbein theory that attitudes and subjective norms were major determinants of intentions. Findings indicate that educational programs planned to influence nursing care of the dying should focus on the consequences of specific behaviors of nurses rather than on death anxiety in nurses, and they should include nursing supervisors as well as nurses providing direct care for the dying.


Vertical extension of the subglacial drainage system into basal crevasses.
Water plays a first-order role in basal sliding of glaciers and ice sheets and is often a key constituent of accelerated glacier motion. Subglacial water is known to occupy systems of cavities and conduits at the interface between ice and the underlying bed surface, depending upon the history of water input and the characteristics of the substrate. Full understanding of the extent and configuration of basal water is lacking, however, because direct observation is difficult. This limits our ability to simulate ice dynamics and the subsequent impacts on sea-level rise realistically. Here we show that the subglacial hydrological system can have a large volume of water occupying basal crevasses that extend upward from the bed into the overlying ice. Radar and seismic imaging combined with in situ borehole measurements collected on Bench Glacier, Alaska, reveal numerous water-filled basal crevasses with highly transmissive connections to the bed. Some crevasses extend many tens of metres above the bed and together they hold a volume of water equivalent to at least a decimetre layer covering the bed. Our results demonstrate that the basal hydrologic system can extend high into the overlying ice mass, where basal crevasses increase water-storage capacity and could potentially modulate basal water pressure. Because basal crevasses can form under commonly observed glaciological conditions, our findings have implications for interpreting and modelling subglacial hydrologic processes and related sliding accelerations of glaciers and ice sheets.


Effects of tryptophan depletion in drug-free adults with autistic disorder.
The primary objective of this study was to investigate the behavioral and biochemical responses to acute tryptophan depletion in drug-free adult patients with autistic disorder. Twenty drug-free adults with autistic disorder (16 men and 4 women) (mean [+/- SD] age, 30.5 +/- 8.5 years) underwent short-term tryptophan depletion in a double-blind, placebo-controlled, randomized crossover design. Patients received a 24-hour, low-tryptophan diet followed the next morning by an amino acid drink. Behavioral ratings were obtained on the morning of the amino acid drink (baseline) and 180, 300, and 420 minutes after the drink. Plasma free and total tryptophan levels were obtained at baseline and 5 hours after the drink. The active and sham testing sessions were separated by 7 days. Eleven (65%) of the 17 patients who completed both test days showed a significant global worsening of behavioral symptoms with short-term tryptophan depletion, but none of the 17 patients showed any significant change in clinical status from baseline after sham depletion (P = .001). Tryptophan depletion led to a significant increase in behaviors such as whirling, flapping, pacing, banging and hitting self, rocking, and toe walking (P < .05). In addition, patients were significantly less calm and happy and more anxious. No significant change was observed in social relatedness or repetitive thoughts and behavior. Plasma total and free tryptophan levels were reduced 86% and 69%, respectively, 5 hours after the tryptophan-deficient amino acid drink. Patients who had a significant global exacerbation of symptoms had significantly higher baseline plasma total tryptophan levels (P < .001) and Autism Behavior Checklist scores (P = .005) than did patients who showed no significant change in symptoms after tryptophan depletion. The results of this study are consistent with previous research that has implicated a dysregulation in serotonin function in some patients with autism. These data suggest that the short-term reduction of serotonin precursor availability may exacerbate some symptoms characteristic of autism in some patients. Continued investigation into the role of serotonin in the pathogenesis and treatment of autistic disorder is warranted.


Beta-Blockers and Oxidative Stress in Patients with Heart Failure.
Oxidative stress has been implicated in the pathogenesis of heart failure. Reactive oxygen species (ROS) are produced in the failing myocardium, and ROS cause hypertrophy, apoptosis/cell death and intracellular Ca(2+) overload in cardiac myocytes. ROS also cause damage to lipid cell membranes in the process of lipid peroxidation. In this process, several aldehydes, including 4-hydroxy-2-nonenal (HNE), are generated and the amount of HNE is increased in the human failing myocardium. HNE exacerbates the formation of ROS, especially H₂O₂ and ·OH, in cardiomyocytes and subsequently ROS cause intracellular Ca(2+) overload. Treatment with beta-blockers such as metoprolol, carvedilol and bisoprolol reduces the levels of oxidative stress, together with amelioration of heart failure. This reduction could be caused by several possible mechanisms. First, the beta-blocking effect is important, because catecholamines such as isoproterenol and norepinephrine induce oxidative stress in the myocardium. Second, anti-ischemic effects and negative chronotropic effects are also important. Furthermore, direct antioxidative effects of carvedilol contribute to the reduction of oxidative stress. Carvedilol inhibited HNE-induced intracellular Ca(2+) overload. Beta-blocker therapy is a useful antioxidative therapy in patients with heart failure.


Silver nanoparticles (AgNPs) cause degeneration of cytoskeleton and disrupt synaptic machinery of cultured cortical neurons.
Silver nanoparticles (AgNPs), owing to their effective antimicrobial properties, are being widely used in a broad range of applications. These include, but are not limited to, antibacterial materials, the textile industry, cosmetics, coatings of various household appliances and medical devices. Despite their extensive use, little is known about AgNP safety and toxicity vis-à-vis human and animal health. Recent studies have drawn attention towards potential neurotoxic effects of AgNPs, however, the primary cellular and molecular targets of AgNP action/s remain to be defined. Here we examine the effects of ultra fine scales (20 nm) of AgNPs at various concentrations (1, 5, 10 and 50 μg/ml) on primary rat cortical cell cultures. We found that AgNPs (at 1-50 μg/ml) not only inhibited neurite outgrowth and reduced cell viability of premature neurons and glial cells, but also induced degeneration of neuronal processes of mature neurons. Our immunocytochemistry and confocal microscopy studies further demonstrated that AgNPs induced the loss of cytoskeleton components such as the β-tubulin and filamentous actin (F-actin). AgNPs also dramatically reduced the number of synaptic clusters of the presynaptic vesicle protein synaptophysin, and the postsynaptic receptor density protein PSD-95. Finally, AgNP exposure also resulted in mitochondria dysfunction in rat cortical cells. Taken together, our data show that AgNPs induce toxicity in neurons, which involves degradation of cytoskeleton components, perturbations of pre- and postsynaptic proteins, and mitochondrial dysfunction leading to cell death. Our study clearly demonstrates the potential detrimental effects of AgNPs on neuronal development and physiological functions and warns against its prolific usage.


Whistling shares a common tongue with speech: bioacoustics from real-time MRI of the human vocal tract.
Most human communication is carried by modulations of the voice. However, a wide range of cultures has developed alternative forms of communication that make use of a whistled sound source. For example, whistling is used as a highly salient signal for capturing attention, and can have iconic cultural meanings such as the catcall, enact a formal code as in boatswain's calls or stand as a proxy for speech in whistled languages. We used real-time magnetic resonance imaging to examine the muscular control of whistling to describe a strong association between the shape of the tongue and the whistled frequency. This bioacoustic profile parallels the use of the tongue in vowel production. This is consistent with the role of whistled languages as proxies for spoken languages, in which one of the acoustical features of speech sounds is substituted with a frequency-modulated whistle. Furthermore, previous evidence that non-human apes may be capable of learning to whistle from humans suggests that these animals may have similar sensorimotor abilities to those that are used to support speech in humans.


Enhanced stability of blood matrices using a dried sample spot assay to measure human butyrylcholinesterase activity and nerve agent adducts.
Dried matrix spots are safer to handle and easier to store than wet blood products, but factors such as intraspot variability and unknown sample volumes have limited their appeal as a sampling format for quantitative analyses. In this work, we introduce a dried spot activity assay for quantifying butyrylcholinesterase (BChE) specific activity which is BChE activity normalized to the total protein content in a sample spot. The method was demonstrated with blood, serum, and plasma spotted on specimen collection devices (cards) which were extracted to measure total protein and BChE activity using a modified Ellman assay. Activity recovered from dried spots was ∼80% of the initial spotted activity for blood and >90% for plasma and serum. Measuring total protein in the sample and calculating specific activity substantially improved quantification and reduced intraspot variability. Analyte stability of nerve agent adducts was also evaluated, and the results obtained via BChE-specific activity measurements were confirmed by quantification of BChE adducts using a previously established LC-MS/MS method. The spotted samples were up to 10 times more resistant to degradation compared to unspotted control samples when measuring BChE inhibition by the nerve agents sarin and VX. Using this method, both BChE activity and adducts can be accurately measured from a dried sample spot. This use of a dried sample spot with normalization to total protein is robust, demonstrates decreased intraspot variability without the need to control for initial sample volume, and enhances analyte stability.


Effects of physical activity counseling in primary care: the Activity Counseling Trial: a randomized controlled trial.
Physical activity is important for health, yet few studies have examined the effectiveness of physical activity patient counseling in primary care. To compare the effects of 2 physical activity counseling interventions with current recommended care and with each other in a primary care setting. The Activity Counseling Trial, a randomized controlled trial with recruitment in 1995-1997, with 24 months of follow-up. Eleven primary care facilities affiliated with 3 US clinical research centers. Volunteer sample of 395 female and 479 male inactive primary care patients aged 35 to 75 years without clinical cardiovascular disease. Participants were randomly assigned to 1 of 3 groups: advice (n = 292), which included physician advice and written educational materials (recommended care); assistance (n = 293), which included all the components received by the advice group plus interactive mail and behavioral counseling at physician visits; or counseling (n = 289), which included the assistance and advice group components plus regular telephone counseling and behavioral classes. Cardiorespiratory fitness, measured by maximal oxygen uptake (VO(2)max), and self-reported total physical activity, measured by a 7-day Physical Activity Recall, compared among the 3 groups and analyzed separately for men and women at 24 months. At 24 months, 91.4% of the sample had completed physical activity and 77.6% had completed cardiorespiratory fitness measurements. For women at 24 months, VO(2)max was significantly higher in the assistance group than in the advice group (mean difference, 80.7 mL/min; 99.2% confidence interval [CI], 8.1-153.2 mL/min) and in the counseling group than in the advice group (mean difference, 73.9 mL/min; 99.2% CI, 0.9-147.0 mL/min), with no difference between the counseling and assistance groups and no significant differences in reported total physical activity. For men, there were no significant between-group differences in cardiorespiratory fitness or total physical activity. Two patient counseling interventions differing in type and number of contacts were equally effective in women in improving cardiorespiratory fitness over 2 years compared with recommended care. In men, neither of the 2 counseling interventions was more effective than recommended care.


Prediction of Improved Antimalarial Chemoprevention with Weekly Dosing of Dihydroartemisinin-Piperaquine.
Intermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women. IPT with the fixed dose combination of piperaquine (PQ) and dihydroartemisinin (DHA) is being evaluated as a potential mass treatment to control and eliminate artemisinin-resistant falciparum malaria. This study explored alternative DHA-PQ adult dosing regimens compared to the monthly adult dosing regimen currently being studied in clinical trials. A time-to-event model describing the concentration-effect relationship of preventive DHA-PQ administration was used to explore the potential clinical efficacy of once-weekly adult dosing regimens. Loading dose strategies were evaluated and the advantage of weekly dosing regimen was tested against different degrees of adherence. Assuming perfect adherence, three tablets weekly dosing regimen scenarios maintained malaria incidence of 0.2 to 0.3% per year compared to 2.1 to 2.6% for all monthly dosing regimen scenarios and 52% for the placebo. The three tablets weekly dosing regimen was also more forgiving (i.e., less sensitive to poor adherence), resulting in a predicted ∼4% malaria incidence per year compared to ∼8% for dosing regimen of two tablets weekly and ∼10% for monthly regimens (assuming 60% adherence and 35% interindividual variability). These results suggest that weekly dosing of DHA-PQ for malaria chemoprevention would improve treatment outcomes compared to monthly administration by lowering the incidence of malaria infections, reducing safety concerns about high PQ peak plasma concentrations and being more forgiving. In addition, weekly dosing is expected to reduce the selection pressure for PQ resistance.


Implementation of a basement membrane invasion assay using mesenteric tissue.
Metastasis accounts for nearly 90% of all cancer associated mortalities. A hallmark of metastasis in malignancies of epithelial origin such as in the pancreas and breast, is invasion of the basement membrane (BM). While various in vitro assays have been developed to address questions regarding the invasiveness of tumors with relation to the BM, most fail to recapitulate a physiologically accurate cell-membrane interface. Here, we introduce a new 3D in vitro assay that uses the mouse mesenteric tissue as a mimic for the epithelial BM. We describe a simple, cost-effective protocol for extraction and setup of the assay, and show that the mesentery is a physiologically accurate model of the BM in its key components-type IV collagen, laminin-1 and perlecan. Furthermore, we introduce a user-friendly quantification tool, Q-Pi, which allows the 3D reconstruction, visualization and quantification of invasion at a cellular level. Overall, we demonstrate that this invasion assay provides a physiologically accurate tool to investigate BM invasion.


An Exploratory Survey of Mental Health Social Work in Europe.
This article reports on an exploratory study comparing mental health social work (MHSW) in Europe. There has been very limited previous research comparing approaches to MHSW in Europe and so the aim of the study was to develop a better understanding of the similarities and differences between and, where relevant, within countries (referred to as jurisdictions). An online survey was distributed mainly through existing European networks and social media to seek information on the role, nature, extent and context of MHSW in a range of European jurisdictions. Conducted during the COVID-19 pandemic, there were 158 responses from 10 jurisdictions. Data were analyzed using thematic analysis. From this analysis, four main themes were identified, relating to: role; law, policy and education; the distinctive contribution made by MHSW; and the key challenges for MHSW. The study demonstrates that MHSW, although it is described and provided in different ways and is confined by a range of factors, plays an important role in mental health services across jurisdictions. There are also interesting differences between contexts, especially in the balance of therapeutic, legal and specialist/generic approaches, some of which reflect the World Health Organisation's vision and objectives for mental health. Lastly, the study illustrates a need and provides a valuable basis for further comparative and collaborative work to define MHSW and enhance the contributions it makes.


Body shape shifting during growth permits tests that distinguish between competing geometric theories of metabolic scaling.
Metabolism fuels all of life's activities, from biochemical reactions to ecological interactions. According to two intensely debated theories, body size affects metabolism via geometrical influences on the transport of resources and wastes. However, these theories differ crucially in whether the size dependence of metabolism is derived from material transport across external surfaces, or through internal resource-transport networks. We show that when body shape changes during growth, these models make opposing predictions. These models are tested using pelagic invertebrates, because these animals exhibit highly variable intraspecific scaling relationships for metabolic rate and body shape. Metabolic scaling slopes of diverse integument-breathing species were significantly positively correlated with degree of body flattening or elongation during ontogeny, as expected from surface area theory, but contradicting the negative correlations predicted by resource-transport network models. This finding explains strong deviations from predictions of widely adopted theory, and underpins a new explanation for mass-invariant metabolic scaling during ontogeny in animals and plants.


Diabetes Australia position statement. A new language for diabetes: improving communications with and about people with diabetes.
Diabetes is the fastest growing chronic condition in Australia, affecting 1.7 million Australians, requiring daily self-care, and known to reduce quantity and quality of life. On average, people with diabetes experience greater emotional distress than those without diabetes. One source of distress can be the language used to refer to diabetes, its management and the person with diabetes. The way verbal and written language is used reflects and shapes people's thoughts, beliefs and behaviours. Language has the power to persuade, change or reinforce beliefs and stereotypes - for better or worse. Words do more than reflect people's reality: they create reality and affect how people view the world and their diabetes. Language needs to engage people with diabetes and support their self-care efforts. Importantly, language that de-motivates or induces fear, guilt or distress needs to be avoided and countered. Diabetes Australia believes optimal communication increases the motivation, health and well-being of people with diabetes, and that careless or negative language can be de-motivating, is often inaccurate, and can be harmful. Diabetes Australia developed this position statement to encourage greater awareness of the language surrounding diabetes and provide recommendations for more careful and positive language use.


Long-term survival after radical prostatectomy for men with high Gleason sum in pathologic specimen.
To evaluate the long-term outcomes of patients with high Gleason sum 8-10 at radical prostatectomy (RP) and to identify the predictors of prostate cancer-specific survival (CSS) in this cohort. The institutional RP database was queried. A total of 9381 patients with complete follow-up underwent RP from 1982 to 2008. Of these 9381 patients, 1061 had pathologic Gleason sum 8-10 cancer. The patient and prostate cancer characteristics were evaluated. Survival analyses were performed using the Kaplan-Meier method. Univariate and multivariate proportional hazard regression models were created to evaluate the pertinent predictors of CSS (death from, or attributed to, prostate cancer). The median preoperative prostate-specific antigen level was 7.6 ng/mL; 435 men had clinical Stage T1 tumor, 568 had Stage T2, and 36 had Stage T3. The biopsy Gleason sum was <7, 7, and >7 in 244 (22.3%), 406 (37.2%), and 425 (38.9%) patients, respectively. The median follow-up was 5 years (range 1-23). The actuarial 15-year recurrence-free survival, CSS, and overall survival rate was 20.7%, 57.4%, and 45.4%, respectively. On multivariate analysis, the predictors of poor CSS were pathologic Gleason sum 9-10 and seminal vesicle and lymph node involvement. Patients with pathologic Gleason sum 8 and organ-confined disease had a CSS rate of 89.9% at 15 years. The results of our study have shown that 80% of the men with Gleason sum 8-10 who undergo RP will have experienced biochemical recurrence by 15 years. However, the CSS rate approached 90% for men with pathologic organ-confined disease. Higher pathologic Gleason sum 9-10 and seminal vesicle and lymph node involvement were independent predictors of worse CSS.