Investigating the effects of antipsychotics and schizotypy on the N400 using event-related potentials and semantic categorization.
Within the field of cognitive neuroscience, functional magnetic resonance imaging (fMRI) is a popular method of visualizing brain function. This is in part because of its excellent spatial resolution, which allows researchers to identify brain areas associated with specific cognitive processes. However, in the quest to localize brain functions, it is relevant to note that many cognitive, sensory, and motor processes have temporal distinctions that are imperative to capture, an aspect that is left unfulfilled by fMRI's suboptimal temporal resolution. To better understand cognitive processes, it is thus advantageous to utilize event-related potential (ERP) recording as a method of gathering information about the brain. Some of its advantages include its fantastic temporal resolution, which gives researchers the ability to follow the activity of the brain down to the millisecond. It also directly indexes both excitatory and inhibitory post-synaptic potentials by which most brain computations are performed. This sits in contrast to fMRI, which captures an index of metabolic activity. Further, the non-invasive ERP method does not require a contrast condition: raw ERPs can be examined for just one experimental condition, a distinction from fMRI where control conditions must be subtracted from the experimental condition, leading to uncertainty in associating observations with experimental or contrast conditions. While it is limited by its poor spatial and subcortical activity resolution, ERP recordings' utility, relative cost-effectiveness, and associated advantages offer strong rationale for its use in cognitive neuroscience to track rapid temporal changes in neural activity. In an effort to foster increase in its use as a research imaging method, and to ensure proper and accurate data collection, the present article will outline - in the framework of a paradigm using semantic categorization to examine the effects of antipsychotics and schizotypy on the N400 - the procedure and key aspects associated with ERP data acquisition.


Fast oxidation of sulfur dioxide by hydrogen peroxide in deliquesced aerosol particles.
Atmospheric sulfate aerosols have important impacts on air quality, climate, and human and ecosystem health. However, current air-quality models generally underestimate the rate of conversion of sulfur dioxide (SO2) to sulfate during severe haze pollution events, indicating that our understanding of sulfate formation chemistry is incomplete. This may arise because the air-quality models rely upon kinetics studies of SO2 oxidation conducted in dilute aqueous solutions, and not at the high solute strengths of atmospheric aerosol particles. Here, we utilize an aerosol flow reactor to perform direct investigation on the kinetics of aqueous oxidation of dissolved SO2 by hydrogen peroxide (H2O2) using pH-buffered, submicrometer, deliquesced aerosol particles at relative humidity of 73 to 90%. We find that the high solute strength of the aerosol particles significantly enhances the sulfate formation rate for the H2O2 oxidation pathway compared to the dilute solution. By taking these effects into account, our results indicate that the oxidation of SO2 by H2O2 in the liquid water present in atmospheric aerosol particles can contribute to the missing sulfate source during severe haze episodes.


Rural gifted students who are deaf or hard of hearing: how electronic technology can help.
Electronic technology can be used to overcome many of the barriers and other factors that restrict delivery of services to rural schools; it can also expand the world of rural gifted students who are deaf or hard of hearing. Online college and high school Web sites that offer courses are listed, as well as a Web site for tutoring and one offering help for teachers of rural gifted students who are deaf or hard of hearing. Recommendations are made for ways that legislatures and rural school districts can make Internet resources and assistive technology more widely available in rural educational settings.


Pregnancy And Neonatal Diabetes Outcomes in Remote Australia: the PANDORA study-an observational birth cohort.
In Australia's Northern Territory, 33% of babies are born to Indigenous mothers, who experience high rates of hyperglycemia in pregnancy. We aimed to determine the extent to which pregnancy outcomes for Indigenous Australian women are explained by relative frequencies of diabetes type [type 2 diabetes (T2DM) and gestational diabetes (GDM)]. This prospective birth cohort study examined participants recruited from a hyperglycemia in pregnancy register. Baseline data collected were antenatal and perinatal clinical information, cord blood and neonatal anthropometry. Of 1135 women (48% Indigenous), 900 had diabetes: 175 T2DM, 86 newly diagnosed diabetes in pregnancy (DIP) and 639 had GDM. A group of 235 women without hyperglycemia in pregnancy was also recruited. Diabetes type differed for Indigenous and non-Indigenous women (T2DM, 36 vs 5%; DIP, 15 vs 7%; GDM, 49 vs 88%, p < 0.001). Within each diabetes type, Indigenous women were younger and had higher smoking rates. Among women with GDM/DIP, Indigenous women demonstrated poorer birth outcomes than non-Indigenous women: large for gestational age, 19 vs 11%, p = 0·002; neonatal fat 11.3 vs 10.2%, p < 0.001. In the full cohort, on multivariate regression, T2DM and DIP were independently associated (and Indigenous ethnicity was not) with pregnancy outcomes. Higher rates of T2DM among Indigenous women predominantly contribute to absolute poorer pregnancy outcomes among Indigenous women with hyperglycemia. As with Indigenous and minority populations globally, prevention or delay of type 2 diabetes in younger women is vital to improve pregnancy outcomes and possibly to improve the long-term health of their offspring.


Angiogenic and Immunologic Proteins Identified by Deep Proteomic Profiling of Human Retinal and Choroidal Vascular Endothelial Cells: Potential Targets for New Biologic Drugs.
Diseases that involve retinal or choroidal vascular endothelial cells are leading causes of vision loss: age-related macular degeneration, retinal ischemic vasculopathies, and noninfectious posterior uveitis. Proteins differentially expressed by these endothelial cell populations are potential drug targets. We used deep proteomic profiling to define the molecular phenotype of human retinal and choroidal endothelial cells at the protein level. Retinal and choroidal vascular endothelial cells were separately isolated from 5 human eye pairs by selection on CD31. Total protein was extracted and digested, and peptide fractions were analyzed by reverse-phase liquid chromatography tandem mass spectrometry. Peptide sequences were assigned to fragment ion spectra, and proteins were inferred from openly accessible protein databases. Protein abundance was determined by spectral counting. Publicly available software packages were used to identify proteins that were differentially expressed between human retinal and choroidal endothelial cells, and to classify proteins that were highly abundant in each endothelial cell population. Human retinal and/or choroidal vascular endothelial cells expressed 5042 nonredundant proteins. Setting the differential expression false discovery rate at 0.05, 498 proteins of 3454 quantifiable proteins (14.4%) with minimum mean spectral counts of 2.5 were differentially abundant in the 2 cell populations. Retinal and choroidal endothelial cells were enriched in angiogenic proteins, and retinal endothelial cells were also enriched in immunologic proteins. This work describes the different protein expression profiles of human retinal and choroidal vascular endothelial cells, and provides multiple candidates for further study as novel treatments or drug targets for posterior eye diseases. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.


Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells.
Transposable elements comprise roughly 40% of mammalian genomes. They have an active role in genetic variation, adaptation and evolution through the duplication or deletion of genes or their regulatory elements, and transposable elements themselves can act as alternative promoters for nearby genes, resulting in non-canonical regulation of transcription. However, transposable element activity can lead to detrimental genome instability, and hosts have evolved mechanisms to silence transposable element mobility appropriately. Recent studies have demonstrated that a subset of transposable elements, endogenous retroviral elements (ERVs) containing long terminal repeats (LTRs), are silenced through trimethylation of histone H3 on lysine 9 (H3K9me3) by ESET (also known as SETDB1 or KMT1E) and a co-repressor complex containing KRAB-associated protein 1 (KAP1; also known as TRIM28) in mouse embryonic stem cells. Here we show that the replacement histone variant H3.3 is enriched at class I and class II ERVs, notably those of the early transposon (ETn)/MusD family and intracisternal A-type particles (IAPs). Deposition at a subset of these elements is dependent upon the H3.3 chaperone complex containing α-thalassaemia/mental retardation syndrome X-linked (ATRX) and death-domain-associated protein (DAXX). We demonstrate that recruitment of DAXX, H3.3 and KAP1 to ERVs is co-dependent and occurs upstream of ESET, linking H3.3 to ERV-associated H3K9me3. Importantly, H3K9me3 is reduced at ERVs upon H3.3 deletion, resulting in derepression and dysregulation of adjacent, endogenous genes, along with increased retrotransposition of IAPs. Our study identifies a unique heterochromatin state marked by the presence of both H3.3 and H3K9me3, and establishes an important role for H3.3 in control of ERV retrotransposition in embryonic stem cells.


Active vacuum brazing of CNT films to metal substrates for superior electron field emission performance.
The joining of macroscopic films of vertically aligned multiwalled carbon nanotubes (CNTs) to titanium substrates is demonstrated by active vacuum brazing at 820 °C with a Ag-Cu-Ti alloy and at 880 °C with a Cu-Sn-Ti-Zr alloy. The brazing methodology was elaborated in order to enable the production of highly electrically and thermally conductive CNT/metal substrate contacts. The interfacial electrical resistances of the joints were measured to be as low as 0.35 Ω. The improved interfacial transport properties in the brazed films lead to superior electron field-emission properties when compared to the as-grown films. An emission current of 150 μA was drawn from the brazed nanotubes at an applied electric field of 0.6 V μm-1. The improvement in electron field-emission is mainly attributed to the reduction of the contact resistance between the nanotubes and the substrate. The joints have high re-melting temperatures up to the solidus temperatures of the alloys; far greater than what is achievable with standard solders, thus expanding the application potential of CNT films to high-current and high-power applications where substantial frictional or resistive heating is expected.


Effects of body mass on microstructural features of the osteochondral unit: A comparative analysis of 37 mammalian species.
Since Galileo's days the effect of size on the anatomical characteristics of the structural elements of the body has been a subject of interest. However, the effects of scaling at tissue level have received little interest and virtually no data exist on the subject with respect to the osteochondral unit in the joint, despite this being one of the most lesion-prone and clinically relevant parts of the musculoskeletal system. Imaging techniques, including Fourier transform infrared imaging, polarized light microscopy and micro computed tomography, were combined to study the response to increasing body mass of the osteochondral unit. We analyzed the effect of scaling on structural characteristics of articular cartilage, subchondral plate and the supporting trabecular bone, across a wide range of mammals at microscopic level. We demonstrated that, while total cartilage thickness scales to body mass in a negative allometric fashion, thickness of different cartilage layers did not. Cartilage tissue layers were found to adapt to increasing loads principally in the deep zone with the superficial layers becoming relatively thinner. Subchondral plate thickness was found to have no correlation to body mass, nor did bone volume fraction. The underlying trabecular bone was found to have thicker trabeculae (r=0.75, p<0.001), as expected since this structure carries most loads and plays a role in force mitigation. The results of this study suggest that the osteochondral tissue structure has remained remarkably preserved across mammalian species during evolution, and that in particular, the trabecular bone carries the adaptation to the increasing body mass.


Toward a meaningful spirituality for people of color: lessons for the counseling practitioner.
This article attempts to capture a significant aspect of the counseling process for people of color: the spiritual dimension. It is argued that spirit and spirituality are relevant dimensions that should be integrated in counseling because spirituality is a key ingredient in the cultural upbringing and socialization of many people of color. Further, religious and spiritual beliefs are affected by experiences of racism and oppression, which then affects psychological coping. Reflective guidelines are offered to understand the essence of spirituality and cultural diversity, and lessons for the practitioner are recommended.


Marine heatwaves and the collapse of marginal North Atlantic kelp forests.
Extreme climatic events including marine heatwaves (MHWs) are becoming more frequent and severe in the Anthropocene. However, our understanding of how these events affect population dynamics of ecologically important species is limited, in part because extreme events are rare and difficult to predict. Here, we quantified the occurrence and severity of MHWs over 60 years in warm range edge kelp forests on both sides of the North Atlantic. The cumulative annual intensity of MHWs increased two- to four-fold during this period, coinciding with the disappearance of kelps. We experimentally demonstrated a relationship between strong and severe 2018 heatwaves and high kelp mortality in both regions. Patterns of kelp mortality were strongly linked to maximum temperature anomalies, which crossed lethal thresholds in both regions. Translocation and tagging experiments revealed similar kelp mortality rates on reefs dominated by healthy kelp forests and degraded sediment-laden algal 'turfs', indicating equal vulnerability to extreme events. These results suggest a mechanistic link between MHWs and broad-scale kelp loss, and highlight how warming can make ecosystem boundaries unstable, forcing shifts to undesirable ecosystem states under episodically extreme climatic conditions.


Vaccines, adjuvants and autoimmunity.
Vaccines and autoimmunity are linked fields. Vaccine efficacy is based on whether host immune response against an antigen can elicit a memory T-cell response over time. Although the described side effects thus far have been mostly transient and acute, vaccines are able to elicit the immune system towards an autoimmune reaction. The diagnosis of a definite autoimmune disease and the occurrence of fatal outcome post-vaccination have been less frequently reported. Since vaccines are given to previously healthy hosts, who may have never developed the disease had they not been immunized, adverse events should be carefully accessed and evaluated even if they represent a limited number of occurrences. In this review of the literature, there is evidence of vaccine-induced autoimmunity and adjuvant-induced autoimmunity in both experimental models as well as human patients. Adjuvants and infectious agents may exert their immune-enhancing effects through various functional activities, encompassed by the adjuvant effect. These mechanisms are shared by different conditions triggered by adjuvants leading to the autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). In conclusion, there are several case reports of autoimmune diseases following vaccines, however, due to the limited number of cases, the different classifications of symptoms and the long latency period of the diseases, every attempt for an epidemiological study has so far failed to deliver a connection. Despite this, efforts to unveil the connection between the triggering of the immune system by adjuvants and the development of autoimmune conditions should be undertaken. Vaccinomics is a field that may bring to light novel customized, personalized treatment approaches in the future.


Self-reported help-seeking behaviors and treatment choices of adolescents regarding acne.
Acne vulgaris is a common condition affecting adolescents that they often choose to treat on their own rather than seek out and follow medical advice. Using data from an anonymous survey administered to 1,214 students in public middle and high schools in New Jersey, we compared the self-reported acne frequency, severity, and beliefs of students based on their help-seeking behaviors, treatment choices, and treatment adherence. Chi-square analyses were performed for data comparison. A large proportion of students in this sample (57%) treated their own acne, and a much smaller proportion (17%) have sought medical care. Students who saw a health professional reported acne of higher frequency and severity than those who did not (p = 0.01). Severity also appeared to affect treatment adherence, with students who adhered to recommended treatments reporting more frequent (p < 0.001) and more severe (p = 0.02) acne than those who chose to self-treat. Beliefs and knowledge varied most significantly according to treatment adherence. In conclusion, most adolescent students treat their own acne. Self-assessment of acne severity plays a significant role in the tendency to seek out and adhere to medical treatment. Beliefs and knowledge may also affect adherence, suggesting a role for physicians to influence adherence rates through patient education. Because the majority of students are getting information from nonphysician sources, there may be a need to evaluate the resources they are using to make sure they are receiving appropriate, helpful information.


Port site recurrence diagnosed by positron emission tomography after laparoscopic surgery for colon cancer.
Port site recurrence after laparoscopic surgery for colorectal cancer patients is a rare complication. We report a case of port site recurrence in a 46-year-old woman that was detected by positron emission tomography (PET) using 18[F]-fluoro-deoxyglucose (FDG). Surgical treatment consisted of laparoscopic ileo-cecal resection and lymph node dissection. At her nine months postoperative follow-up examination, her serum carcinoembryonic antigen (CEA) levels had raised to 15.8ng/mL. Although computed tomography and colonoscopic examination were performed, lung, liver and local recurrence in the colon were not detected. FDG-PET was then performed and detected a higher concentration of FDG at the port site in the abdominal wall. Port site recurrence was diagnosed clinically and surgical resection of tumor at the port site was performed. Pathology revealed a moderately differentiated adenocarcinoma diagnosed as port site recurrence. This case suggests that FDG-PET is an important examination for the detection of port site recurrence when serum CEA levels are rising and routinely radiographic examinations are unable to detect the site of recurrence.


[Global health 2035: a world converging within a generation].
Prompted by the 20th anniversary of the 1993 World Development Report, a Lancet Commission revisited the case for investment in health and developed a new investment framework to achieve dramatic health gains by 2035. The Commission's report has four key messages, each accompanied by opportunities for action by national governments of low-income and middle-income countries and by the international community. First, there is an enormous economic payoff from investing in health. The impressive returns make a strong case for both increased domestic financing of health and for allocating a higher proportion of official development assistance to development of health. Second, modeling by the Commission found that a "grand convergence" in health is achievable by 2035-that is, a reduction in infectious, maternal, and child mortality down to universally low levels. Convergence would require aggressive scale up of existing and new health tools, and it could mostly be financed from the expected economic growth of low- and middle-income countries. The international community can best support convergence by funding the development and delivery of new health technologies and by curbing antibiotic resistance. Third, fiscal policies -such as taxation of tobacco and alcohol- are a powerful and underused lever that governments can use to curb non-communicable diseases and injuries while also raising revenue for health. International action on NCDs and injuries should focus on providing technical assistance on fiscal policies, regional cooperation on tobacco, and funding policy and implementation research on scaling-up of interventions to tackle these conditions. Fourth, progressive universalism, a pathway to universal health coverage (UHC) that includes the poor from the outset, is an efficient way to achieve health and financial risk protection. For national governments, progressive universalism would yield high health gains per dollar spent and poor people would gain the most in terms of health and financial protection. The international community can best support countries to implement progressive UHC by financing policy and implementation research, such as on the mechanics of designing and implementing evolution of the benefits package as the resource envelope for public finance grows.


High-fat diet alters PP2A, TC10, and CIP4 expression in visceral adipose tissue of rats.
The aim of this study was to investigate a possible link between high-fat diet (HFD)-induced obesity and the expression of protein phosphatase 2A (PP2A) and Cdc42-interacting protein 4 (CIP4) proteins, potential downstream components of the IRS/PI3K/AKT and CAP/Cbl/TC10 pathway, respectively, in the visceral adipose tissue. Twenty male Sprague-Dawley rats were randomly divided into two groups and were given either HFD or the normal diet (ND) for 8 weeks. The HFD-induced changes in the expression of the epididymal adipose tissue genes involved in the insulin-signaling pathways were evaluated using real-time reverse-transcription PCR and western blot analysis. The exposure of rats to HFD for 8 weeks resulted in a significant increase in the expression of PP2A at both the transcriptional and translational levels, along with a marked reduction in the levels of phosphorylated AKT and insulin receptor substrate-1 (IRS-1) in the cytosol of visceral adipocytes, compared with the ND rats. Besides, there were significant HFD-induced decreases in the mRNA and protein levels of CIP4 and TC10 in the adipose tissue of rats. These data suggest that HFD might have a relevance to insulin resistance by increasing the expression of PP2A, an inhibitor of AKT activity in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, and also by suppressing the expression of TC10 and CIP4, downstream effectors of the Cbl/CAP/TC10 insulin-signaling cascade in the visceral adipose tissue.


A new method for osteotomies in oncologic nasal surgery: Piezosurgery.
Piezosurgery is a recently developed system for cutting bone without necrosis and nonmineralized tissues damage. The aim of this work has been to test Piezosurgery as a new bony scalpel in nasal surgery. In this nonrandomized study, we have performed Piezosurgery in the excision of malignant nasal tumors through a paralateronasal approach. We have used Piezosurgery on 10 patients affected by nasal adenocarcinoma. The piezoelectric device uses low-frequency ultrasonic waves (24.7-29.5 kHz); the applied power can be modulated between 2.8 and 16 W and is programmed in accordance to the density of the bone. The equipment consists of 2 hand pieces, 2 inserts, and 2 peristaltic pumps; the microvibrations that are created in the piezoelectric hand piece cause the inserts to vibrate linearly between 60 and 210 mum. In all the patients, Piezosurgery provided excellent control without bleeding and harming effects on the adjacent structures. No patients experienced adverse effects. Piezosurgery is a new and revolutionary osteotomy technique using the microvibrations of scalpels at ultrasonic frequency, so that soft tissue will not be damaged even upon accidental contact with the cutting tip. The safety of Piezosurgery as regards soft tissues was confirmed. No adverse effects were detected during unintentional contact with the tumor, nerve, vessel, and mucoperiosteum; this renders the piezoelectric device ideal for this application.


Effects of potato fiber and potato-resistant starch on biomarkers of colonic health in rats fed diets containing red meat.
The effects of red meat consumption with and without fermentable carbohydrates on indices of large bowel health in rats were examined. Sprague-Dawley rats were fed cellulose, potato fiber, or potato-resistant starch diets containing 12% casein for 2 wk, then similar diets containing 25% cooked beef for 6 wk. After week 8, cecal and colonic microbiota composition, fermentation end-products, colon structure, and colonocyte DNA damage were analyzed. Rats fed potato fiber had lower Bacteroides-Prevotella-Porphyromonas group compared to other diet groups. Colonic Bifidobacterium spp. and/or Lactobacillus spp. were higher in potato fiber and potato-resistant starch diets than in the cellulose diet. Beneficial changes were observed in short-chain fatty acid concentrations (acetic, butyric, and propionic acids) in rats fed potato fiber compared with rats fed cellulose. Phenol and p-cresol concentrations were lower in the cecum and colon of rats fed potato fiber. An increase in goblet cells per crypt and longer crypts were found in the colon of rats fed potato fiber and potato-resistant starch diets. Fermentable carbohydrates had no effect on colonic DNA damage. Dietary combinations of red meat with potato fiber or potato-resistant starch have distinctive effects in the large bowel. Future studies are essential to examine the efficacy of different types of nondigestible carbohydrates in maintaining colonic health during long-term consumption of high-protein diets. Improved understanding of interactions between the food consumed and gut microbiota provides knowledge needed to make healthier food choices for large bowel health. The impact of red meat on large bowel health may be ameliorated by consuming with fermentable dietary fiber, a colonic energy source that produces less harmful by-products than the microbial breakdown of colonic protein for energy. Developing functional red meat products with fermentable dietary fiber could be one way to promote a healthy and balanced macronutrient diet.


Evaluation of matrix metalloproteinase 7 in plasma and pancreatic juice as a biomarker for pancreatic cancer.
Differentiating between periampullary carcinoma and chronic pancreatitis with an inflammatory mass is difficult. Consequently, 6% to 9% of pancreatic resections for suspected carcinoma are done inappropriately for chronic pancreatitis. Here, we test if matrix metalloproteinase 7 (MMP-7), a secreted protease frequently expressed in pancreatic carcinoma, can be measured in plasma, pancreatic, and duodenal juice, and if it can distinguish between periampullary carcinoma and chronic pancreatitis. Ninety-four patients who underwent pancreatic surgery for a (peri)pancreatic neoplasm (n = 63) or chronic pancreatitis (n = 31) were analyzed. Median plasma MMP-7 levels were significantly higher in carcinoma (1.95 ng/mL; interquartile range, 0.81-3.22 ng/mL) compared with chronic pancreatitis and benign disease (0.83 ng/mL; interquartile range, 0.25-1.21 ng/mL; P < 0.01). MMP-7 levels in pancreatic juice were higher, although not significantly, in carcinoma (62 ng/mg protein; interquartile range, 18-241 ng/mg protein) compared with chronic pancreatitis and benign disease (23 ng/mg protein; interquartile range, 8.5-99 ng/mg protein; P = 0.17). MMP-7 levels in duodenal juice were universally low. At an arbitrary cutoff of 1.5 ng/mL in plasma, positive and negative predictive values were 83% and 57%, respectively, values comparable to those of today's most common pancreatic tumor marker, carbohydrate antigen 19-9 (CA19-9; 83% and 53%, respectively). Positive and negative likelihood ratios for plasma MMP-7 were 3.35 and 0.52, respectively. The area under the receiver operating characteristic curve for MMP-7 was 0.73 (95% confidence interval, 0.63-0.84) and for CA19-9, 0.75 (95% confidence interval, 0.64-0.85). Combined MMP-7 and CA19-9 assessment gave a positive predictive value of 100%. Thus, plasma MMP-7 levels discriminated between patients with carcinoma and those with chronic pancreatitis or benign disease. The diagnostic accuracy of plasma MMP-7 alone is not sufficient to determine treatment strategy in patients with a periampullary mass, but combined evaluation of plasma MMP-7 with CA19-9 and other markers may be clinically useful.


Extra forces evoked during electrical stimulation of the muscle or its nerve are generated and modulated by a length-dependent intrinsic property of muscle in humans and cats.
Extra forces or torques are defined as forces or torques that are larger than would be expected from the input or stimuli, which can be mediated by properties intrinsic to motoneurons and/or to the muscle. The purpose of this study was to determine whether extra forces/torques evoked during electrical stimulation of the muscle or its nerve with variable frequency stimulation are modulated by muscle length/joint angle. A secondary aim was to determine whether extra forces/torques are generated by an intrinsic neuronal or muscle property. Experiments were conducted in 14 able-bodied human subjects and in eight adult decerebrate cats. Torque and force were measured in human and cat experiments, respectively. Extra forces/torques were evoked by stimulating muscles with surface electrodes (human experiments) or by stimulating the nerve with cuff electrodes (cat experiments). In humans and cats, extra forces/torques were larger at short muscle lengths, indicating that a similar regulatory mechanism is involved. In decerebrate cats, extra forces and length-dependent modulation were unaffected by intrathecal methoxamine injections, despite evidence of increased spinal excitability, and by transecting the sciatic nerve proximal to the nerve stimulations. Anesthetic nerve block experiments in two human subjects also failed to abolish extra torques and the length-dependent modulation. Therefore, these data indicate that extra forces/torques evoked during electrical stimulation of the muscle or nerve are muscle length-dependent and primarily mediated by an intrinsic muscle property.


Shared Blood: Expeditionary Resuscitative Surgical Team (ERST-5) Use of Local Whole Blood to Improve Resuscitation of Host Nation Partner Forces.
US Special Operations Forces work by, with, and through partner forces (PFs) to accomplish mutual objectives. Surgical teams support these forces directly and may assist in treating injuries sustained by PF, based on established medical rules of engagement. These surgical operations are often conducted in austere conditions, with limited access to blood products. Limited blood product availability decreases US medical capacity to resuscitate injured PFs and augment the local trauma system. We present an innovative solution used by an expeditionary resuscitative surgical team (ERST) and Special Operations civil affairs team to partner with host nation (HN) medical personnel to improve PF access to damage control resuscitation and surgery. Whole blood obtained through a local HN hospital was provided to the ERST to allow for increased capacity to resuscitate PF casualties and augment the local trauma system. The ERST subsequently used this blood to resuscitate two PF surgical casualties.


Antidepressants for pain management in adults with chronic pain: a network meta-analysis.
Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients' global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions. To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache). We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022. We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm. DATA COLLECTION AND ANALYSIS: Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal. This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel-armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Primary efficacy outcomes Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) -0.31, 95% CI -0.39 to -0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD -0.22, 95% CI -0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD -0.5, 95% CI -0.78 to -0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD -0.16, 95% CI -0.22 to -0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes. Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.


Efficacy of rabbit anti-thymocyte globulin in severe aplastic anemia.
A combination of horse anti-thymocyte globulin and cyclosporine produces responses in 60-70% of patients with severe aplastic anemia. We performed a phase II study of rabbit anti-thymocyte globulin and cyclosporine as first-line therapy for severe aplastic anemia. Twenty patients with severe aplastic anemia treated with rabbit anti-thymocyte globulin were compared to 67 historical control cases with matched clinical characteristics treated with horse anti-thymocyte globulin. Response rates at 3, 6 and 12 months were similar for patients treated with rabbit anti-thymocyte globulin or horse anti-thymocyte globulin: 40% versus 55% (P=0.43), 45% versus 58% (P=0.44) and 50% versus 58% (P=0.61), respectively. No differences in early mortality rates or overall survival were observed. We then performed multivariable analyses of response at 6 months and overall survival and identified the presence of a paroxysmal nocturnal hemoglobinuria clone (P=0.01) and a pretreatment absolute reticulocyte count greater than 30×10(9)/L (P=0.007) as independent predictors of response and younger age (P=0.003), higher pretreatment absolute neutrophil (P=0.02) and absolute lymphocyte counts (P=0.03) as independent predictors of overall survival. None of the immunogenetic polymorphisms studied was predictive of response to immunosupressive therapy. Despite reports suggesting differences in biological activity of different anti-thymocyte globulin preparations, rabbit and horse anti-thymocyte globulin appear to have a similar efficacy for up-front treatment of severe aplastic anemia. Clinicaltrial.gov: NCT01231841).


Cost-effectiveness of indwelling pleural catheter compared with talc in malignant pleural effusion.
Malignant pleural effusion is associated with morbidity and mortality. A randomized controlled trial previously compared clinical outcomes and resource use with indwelling pleural catheter (IPC) and talc pleurodesis in this population. Using unpublished quality of life data, we estimate the cost-effectiveness of IPC compared with talc pleurodesis. Healthcare utilization and costs were captured during the trial. Utility weights produced by the EuroQol Group five-dimensional three-level questionnaire and survival were used to determine quality-adjusted life-years (QALYs) gained. The incremental cost-effectiveness ratio (ICER) was calculated over the 1-year trial period. Sensitivity analysis used patient survival data and modelled additional nursing time required per week for catheter drainage. Utility scores, cost and QALYs gained did not differ significantly between groups. The ICER for IPC compared with talc was favorable at $US10 870 per QALY gained. IPC was less costly with a probability exceeding 95% of being cost-effective when survival was <14 weeks, and was more costly when 2-h nursing time per week was assumed for catheter drainage. IPC is cost-effective when compared with talc, although substantial uncertainty exists around this estimate. IPC appears most cost-effective in patients with limited survival. If significant nursing time is required for catheter drainage, IPC becomes less likely to be cost-effective. Either therapy may be considered as a first-line option in treating malignant pleural effusion in patients without history of prior pleurodesis, with consideration for patient survival, support and preferences.


Erectile function in two-kidney, one-clip hypertensive rats is maintained by a potential increase in nitric oxide production.
Hypertension is closely associated with erectile dysfunction (ED) as it has been observed in many experimental models of hypertension. Additionally, epidemiological studies show that approximately a third of hypertensive patients have ED. To test the hypothesis that the two-kidney, one-clip (2K-1C) rat model of hypertension displays normal erectile function due to increased nitric oxide (NO) production in the penis. Ganglionic-induced increase in intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio was used as an index of erectile function in 2K-1C and in normotensive sham-operated (SHAM) anesthetized rats. Cavernosal strips from hypertensive and normotensive rats were used for isometric tension measurement. The contraction induced by alpha-adrenergic agonist phenylephrine and the relaxation induced by the NO donor sodium nitroprusside (SNP) and by the Rho-kinase inhibitor Y-27632 were performed in the absence and in the presence of the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA). Changes in ICP/MAP induced by ganglionic stimulation were not different between 2K-1C and SHAM rats. The contractile response induced by phenylephrine as well as the relaxation induced by SNP or the Y-27632 were similar in cavernosal strips from both groups. However, in the presence of L-NNA, the relaxation induced by Y-27632 was significantly impaired in 2K-1C compared to SHAM. These data suggest that hypertension and ED could be dissociated from high levels of blood pressure in some animal models of hypertension. Erectile function in 2K-1C hypertensive rats is maintained in spite of the increased Rho-kinase activity by increased NO signaling.


Global sea level and Earth rotation.
Recent analyses of long time scale secular variations of sea level, based on tide gauge observations, have established that sea level is apparently rising at a globally averaged rate somewhat in excess of 1 millimeter per year. It has been suggested that the nonsteric component of this secular rate might be explicable in terms of ongoing mass loss from the small ice sheets and glaciers of the world. Satellite laser ranging and very long baseline interferometry data may be used to deliver strong constraints on this important scenario because of the information that these systems provide on variations of the length of day and of the position of the rotation pole with respect to the earth's surface geography. These data demonstrate that the hypothesis of mass loss is plausible if the Barents Sea was covered by a substantial ice sheet at the last maximum of the current ice age 18,000 years ago.


Earthquake-Related Changes in Species Spatial Niche Overlaps in Spring Communities.
Species interactions between stygobites (obligate groundwater organisms) are poorly known, reflecting the difficulty in studying such organisms in their natural environments. Some insight can be gained from the study of the spatial variability in microcrustacean communities in groundwater-fed springs. Earthquakes can increase hydraulic conductivity in the recharge area of karstic aquifers and flow rates in discharge zones, thus dislodging stygobites from their original habitats to the spring outlets. Earthquakes are expected to alter species spatial niche overlap at the spring outlets, where stygobites coexist with non-stygobites living in benthic and subsurface habitats. We compared the abundance of stygobiotic and non-stygobiotic microcrustaceans in groundwater-fed springs before and after the 6.3-Mw earthquake that hit the karstic Gran Sasso Aquifer (Italy) in 2009. Pre-seismic (1997, 2005) overall niche overlaps were not different from null expectations, while post-seismic (2012) species mean niche overlaps were higher, following the redistribution of animals caused by the earthquake-triggered discharge. The reduced abundance of stygobites following their dislodgement from the aquifer and the concomitant displacement of non-stygobites led to a higher post-seismic co-occurrence of stygobites and non-stygobites. Changes in aquifer structure destroyed pre-seismic species segregation patterns by creating new or strengthening already existing interactions.


Spontaneous Acute Mesenteric Thrombosis in a Patient With Hemoglobin E Thalassemia.
Acute mesenteric vein thrombosis (MVT) is an uncommon cause of mesenteric ischemia and portal hypertension. The common risk factors for the development of MVT include surgery, acute-intraabdominal inflammatory disorders, malignancies, and other prothrombotic states. However, MVT can occur in the absence of these risk factors. We describe the case of a 40-year-old man with a new diagnosis of hemoglobin E thalassemia and MVT and discuss the relationship between the hemoglobinopathy and thrombosis based on evidence from existing literature. The case emphasizes the importance of a high index of suspicion in the diagnosis of MVT in other to reduce complications and improve overall outcomes.


Public health infrastructure system change: outcomes from the turning point initiative.
The Robert Wood Johnson and W.K. Kellogg Foundations created the Turning Point initiative to transform and strengthen the public health infrastructure. This study examined 135 public health system changes for their links to multiple sector collaborative engagement, essential public health services, health outcomes, and infrastructure building strategies. An on-line documentation system developed by the University of Kansas was used to record and analyze these linkages. The results showed that each state accomplished notable system changes; the majority involved more than one sector and primarily related to increasing local public health system capacity and organizational change.


Exercise training induces similar elevations in the activity of oxoglutarate dehydrogenase and peak oxygen uptake in the human quadriceps muscle.
During exercise involving a small muscle mass, peak oxygen uptake is thought to be limited by peripheral factors, such as the degree of oxygen extraction from the blood and/or mitochondrial oxidative capacity. Previously, the maximal activity of the Krebs cycle enzyme oxoglutarate dehydrogenase has been shown to provide a quantitative measure of maximal oxidative metabolism, but it is not known whether the increase in this activity after a period of training reflects the elevation in peak oxygen consumption. Fourteen subjects performed one-legged knee extension exercise for 5-7 weeks, while the other leg remained untrained. Thereafter, the peak oxygen uptake by the quadriceps muscle was determined for both legs, and muscle biopsies were taken for assays of maximal enzyme activities (at 25°C). The peak oxygen uptake was 26% higher in the trained than in the untrained muscle (395 vs. 315 ml min(-1) kg(-1), respectively; P<0.01). The maximal activities of the Krebs cycle enzymes in the trained and untrained muscle were as follows: citrate synthase, 22.4 vs. 18.2 μmol min(-1) g(-1) (23%, P<0.05); oxoglutarate dehydrogenase, 1.88 vs. 1.54 μmol min(-1) g(-1) (22%, P<0.05); and succinate dehydrogenase, 3.88 vs. 3.28 μmol min(-1) g(-1) (18%, P<0.05). The difference between the trained and untrained muscles with respect to peak oxygen uptake (80 ml min(-1) kg(-1)) corresponded to a flux through the Krebs cycle of 1.05 μmol min(-1) g(-1), and the corresponding difference in oxoglutarate dehydrogenase activity (at 38°C) was 0.83 μmol min(-1) g(-1). These parallel increases suggest that there is no excess mitochondrial capacity during maximal exercise with a small muscle mass.


Is penile block better than caudal epidural block for postcircumcision analgesia?
To compare caudal and penile block for post-operative analgesia in children undergoing circumcision with respect to efficacy, complication rates, and parental satisfaction. The study population consisted of 100 ASA 1 and 2 boys aged 3 to 8 years who were undergoing circumcision for religious reasons. In all participants, inhalation anesthesia was administered with oxygen : nitrous oxide (1 : 2) and halothane. The participants were allocated randomly into two groups of 50 children each. Group 1 received penile block and Group 2 caudal block. The penile block was achieved by injecting bupivacaine into the two compartments of the subpubic space, with an additional ventral infiltration of a small volume of bupivacaine along the raphe of the penis. For caudal block, 1 ml.kg(-1) body weight of 0.25% bupivacaine was administered. Penile block shortened the induction-incision time and enabled earlier discharge home compared with caudal block. One patient undergoing penile block and nine patients undergoing caudal block vomited. Penile and caudal block are equally effective for postcircumcision analgesia and neither is associated with serious complications. Anesthesiologist preference should be the deciding factor in choosing one technique over the other.


Multiple and concurrent sexual partnerships among men who have sex with men in Viet Nam: results from a National Internet-based Cross-sectional Survey.
Men who have sex with men (MSM) are one of the largest HIV risk groups in Viet Nam and have been understudied. Sexual concurrency and multiple sex partnerships may contribute to high HIV incidence among MSM in Viet Nam. Limited information is available on concurrency and multiple sexual partnerships among MSM in Viet Nam or on the extent to which this population engages in concurrent and multiple unprotected anal intercourse. Data are from a self-administered Internet-based survey of Vietnamese MSM aged 18 years or older, having sex with male partner(s) in the last 12 months and recruited from social networking MSM-specific websites in Viet Nam. Multiple partnerships and concurrency were measured using the UNAIDS-recommended sexual partner matrix, a key component in the questionnaire. Concurrent and multiple sexual partnerships were analyzed at the individual level. Logistic regression analyses were conducted to assess the demographic characteristics and behaviors associated with multiple sexual partnerships. A total of 1695 MSM reported on multiple sexual partnerships; 69.5% indicated multiple sexual partnerships in the last 6 months. A total of 257 MSM reported on concurrent sexual partnerships, with 51.0% reporting penetrative sex with concurrent partners in the last 6 months. Respondents were more likely to engage in multiple sexual partnerships if they were no longer a student, consumed alcohol before and/or during sex, used the Internet to meet casual sex partners and had never participated in a behavioral HIV intervention. Multiple sexual partnerships in the previous 6 months were common among MSM surveyed, as was sexual concurrency. High levels of multiple and concurrent sexual partnerships may be catalyzing the transmission of HIV among MSM in Viet Nam. Given the high prevalence of this high-risk sexual behavior, our findings underscore the urgent need for targeted prevention efforts, focusing on the reduction of multiple and concurrent sexual partners among this key population.


Winter chilling speeds spring development of temperate butterflies.
Understanding and predicting phenology has become more important with ongoing climate change and has brought about great research efforts in the recent decades. The majority of studies examining spring phenology of insects have focussed on the effects of spring temperatures alone. Here we use citizen-collected observation data to show that winter cold duration, in addition to spring temperature, can affect the spring emergence of butterflies. Using spatial mixed models, we disentangle the effects of climate variables and reveal impacts of both spring and winter conditions for five butterfly species that overwinter as pupae across the UK, with data from 1976 to 2013 and one butterfly species in Sweden, with data from 2001 to 2013. Warmer springs lead to earlier emergence in all species and milder winters lead to statistically significant delays in three of the five investigated species. We also find that the delaying effect of winter warmth has become more pronounced in the last decade, during which time winter durations have become shorter. For one of the studied species, Anthocharis cardamines (orange tip butterfly), we also make use of parameters determined from previous experiments on pupal development to model the spring phenology. Using daily temperatures in the UK and Sweden, we show that recent variation in spring temperature corresponds to 10-15 day changes in emergence time over UK and Sweden, whereas variation in winter duration corresponds to 20 days variation in the south of the UK versus only 3 days in the south of Sweden. In summary, we show that short winters delay phenology. The effect is most prominent in areas with particularly mild winters, emphasising the importance of winter for the response of ectothermic animals to climate change. With climate change, these effects may become even stronger and apply also at higher latitudes.


Successional changes in bacterial communities during the development of black band disease on the reef coral, Montipora hispida.
Black band disease (BBD) consists of a mat-forming microbial consortium that migrates across coral colonies causing rapid tissue loss. Although BBD-associated microbial communities have been well characterized, little is known regarding how these complex bacterial consortia develop. This study analyzed successional changes in microbial communities leading to the development of BBD. Long-term monitoring of tagged corals throughout outbreaks of BBD in the central Great Barrier Reef documented cyanobacterium-infected lesions, herein termed cyanobacterial patch(es) (CP), which were macroscopically distinct from BBD and preceded the onset of BBD in 19% of the cases. Dominant cyanobacteria within CP lesions were morphologically distinct from ones dominating BBD lesions. Clone libraries and terminal restriction fragment length polymorphism analysis confirmed shifts within cyanobacterial assemblages, from Blennothrix sp.-affiliated sequences dominating CP lesions, to Oscillatoria sp.-affiliated sequences, similar to those retrieved from other BBD samples worldwide, dominating BBD lesions. Bacterial 16S ribosomal RNA clone libraries also showed shifts in bacterial ribotypes during transitions from CP to BBD, with Alphaproteobacteria-affiliated sequences dominant in CP libraries, whereas gammaproteobacterial and cyanobacterial ribotypes were more abundant in BBD clone libraries. Sequences affiliated with organisms identified in sulfur cycling were commonly retrieved from lesions showing characteristic field signs of BBD. As high sulfide concentrations have been implicated in BBD-mediated coral tissue degradation, proliferation of a microbial community actively involved in sulfur cycling potentially contributes to the higher progression rates found for BBD compared with CP lesions. Results show how microbial colonization of indistinct lesions may facilitate a common coral disease with proven ecological effects on coral populations.


Anti-muscarinic adjunct therapy accelerates functional human oligodendrocyte repair.
Therapeutic repair of myelin disorders may be limited by the relatively slow rate of human oligodendrocyte differentiation. To identify appropriate pharmacological targets with which to accelerate differentiation of human oligodendrocyte progenitors (hOPCs) directly, we used CD140a/O4-based FACS of human forebrain and microarray to hOPC-specific receptors. Among these, we identified CHRM3, a M3R muscarinic acetylcholine receptor, as being restricted to oligodendrocyte-biased CD140a(+)O4(+) cells. Muscarinic agonist treatment of hOPCs resulted in a specific and dose-dependent blockade of oligodendrocyte commitment. Conversely, when hOPCs were cocultured with human neurons, M3R antagonist treatment stimulated oligodendrocytic differentiation. Systemic treatment with solifenacin, an FDA-approved muscarinic receptor antagonist, increased oligodendrocyte differentiation of transplanted hOPCs in hypomyelinated shiverer/rag2 brain. Importantly, solifenacin treatment of engrafted animals reduced auditory brainstem response interpeak latency, indicative of increased conduction velocity and thereby enhanced functional repair. Therefore, solifenacin and other selective muscarinic antagonists represent new adjunct approaches to accelerate repair by engrafted human progenitors.


Determinants of adherence to delayed-release doxylamine and pyridoxine in patients with nausea and vomiting of pregnancy.
Women often hesitate to take medications in pregnancy due to fears of perceived potential fetal damage. The authors' objective is to identify the determinants of adherence to delayed-release doxylamine-pyridoxine (Diclectin) in patients with nausea and vomiting of pregnancy (NVP). The authors performed a prespecified secondary analysis of a multicenter double-blind randomized controlled trial of Diclectin versus placebo for the treatment of NVP. Data on adherence to study medication were collected in all patients. The primary outcome of this analysis was adherence to study medication, which was determined by pill counting and patient diaries. The treatment regimen in the original trial was not fixed and depended on patient's symptoms. There was no difference in the adherence rates between subjects in the Diclectin or placebo arms of the study, so the 2 arms were analyzed as one cohort. The degree of adherence was analyzed in the various subgroups. Subsequently, a multiple linear regression model was constructed to identify predictors to adherence. Two hundred fifty-eight women were included in this analysis. There were no differences in adherence rates according to ethnicity, race, or the presence of adverse events. Gravidity, average number of prescribed tablets per day, site of enrollment, and change in NVP severity measured by the pregnancy unique-quantification of emesis score were associated with adherence. In multivariable analysis, average number of tablets per day, change in pregnancy unique-quantification of emesis, number of treatment days, site of enrollment were significantly predictive of adherence, with the former being negatively correlated. Adherence to antinauseants for NVP is affected by number of tablets prescribed per day, and treatment duration and effectiveness.


Increased recruitment of endogenous stem cells and chondrogenic differentiation by a composite scaffold containing bone marrow homing peptide for cartilage regeneration.
Even small cartilage defects could finally degenerate to osteoarthritis if left untreated, owing to the poor self-healing ability of articular cartilage. Stem cell transplantation has been well implemented as a common approach in cartilage tissue engineering but has technical complexity and safety concerns. The stem cell homing-based technique emerged as an alternative promising therapy for cartilage repair to overcome traditional limitations. In this study, we constructed a composite hydrogel scaffold by combining an oriented acellular cartilage matrix (ACM) with a bone marrow homing peptide (BMHP)-functionalized self-assembling peptide (SAP). We hypothesized that increased recruitment of endogenous stem cells by the composite scaffold could enhance cartilage regeneration. Methods: To test our hypothesis, in vitro proliferation, attachment and chondrogenic differentiation of rabbit mesenchymal stem cells (MSCs) were tested to confirm the bioactivities of the functionalized peptide hydrogel. The composite scaffold was then implanted into full-thickness cartilage defects on rabbit knee joints for cartilage repair, in comparison with microfracture or other sample groups. Stem cell recruitment was monitored by dual labeling with CD29 and CD90 under confocal microcopy at 1 week after implantation, followed by chondrogenic differentiation examined by qRT-PCR. Repaired tissue of the cartilage defects was evaluated by histological and immunohistochemistry staining, microcomputed tomography (micro-CT) and magnetic resonance imaging (MRI) at 3 and 6 months post-surgery. Macroscopic and histological scoring was done to evaluate the optimal in vivo repair outcomes of this composite scaffold. Results: The functionalized SAP hydrogels could stimulate rabbit MSC proliferation, attachment and chondrogenic differentiation during in vitro culture. At 7 days after implantation, increased recruitment of MSCs based on CD29+ /CD90+ double-positive cells was found in vivo in the composite hydrogel scaffold, as well as upregulation of cartilage-associated genes (aggrecan, Sox9 and type II collagen). After 3 and 6 months post-surgery, the articular cartilage defect in the composite scaffold-treated group was fully covered with cartilage-like tissue with a smooth surface, which was similar to the surrounding native cartilage, according to the results of histological and immunohistochemistry staining, micro-CT and MRI analysis. Macroscopic and histological scoring confirmed that the quality of cartilage repair was significantly improved with implantation of the composite scaffold at each timepoint, in comparison with microfracture or other sample groups. Conclusion: Our findings demonstrated that the composite scaffold could enhance endogenous stem cell homing and chondrogenic differentiation and significantly improve the therapeutic outcome of chondral defects. The present study provides a promising approach for in vivo cartilage repair without cell transplantation. Optimization of this strategy may offer great potential and benefits for clinical application in the future.


A systematic review of the organizational, environmental, professional and child and family factors influencing the timing of admission to hospital for children with serious infectious illness.
Infection, particularly in the first 5 years of life, is a major cause of childhood deaths globally, many deaths from infections such as pneumonia and meningococcal disease are avoidable, if treated in time. Some factors that contribute to morbidity and mortality can be modified. These include organisational and environmental factors as well as those related to the child, family or professional. Examine what organizational and environmental factors and individual child, family and professional factors affect timing of admission to hospital for children with a serious infectious illness. Systematic review. Key search terms were identified and used to search CINAHL Plus, Medline, ASSIA, Web of Science, The Cochrane Library, Joanna Briggs Institute Database of Systematic Review. Primary research (e.g. quantitative, qualitative and mixed methods studies) and literature reviews (e.g., systematic, scoping and narrative) were included if participants included or were restricted to children under 5 years of age with serious infectious illnesses, included parents and/or first contact health care professionals in primary care, urgent and emergency care and where the research had been conducted in OECD high income countries. The Mixed Methods Appraisal Tool was used to review the methodological quality of the studies. Thirty-six papers were selected for full text review; 12 studies fitted the inclusion criteria. Factors influencing the timing of admission to hospital included the variability in children's illness trajectories and pathways to hospital, parental recognition of symptoms and clinicians non-recognition of illness severity, parental help-seeking behaviour and clinician responses, access to services, use and non-use of 'gut feeling' by clinicians, and sub-optimal management within primary, secondary and tertiary services. The pathways taken by children with a serious infectious illness to hospital are complex and influenced by a variety of potentially modifiable individual, organisational, environmental and contextual factors. Supportive, accessible, respectful services that provide continuity, clear communication, advice and safety-netting are important as is improved training for clinicians and a mandate to attend to 'gut feeling'. Relatively simple interventions such as improved communication have the potential to improve the quality of care and reduce morbidity and mortality in children with a serious infectious illness.


Alcohol and Obesity: A Dangerous Association for Fatty Liver Disease.
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the most frequent chronic liver disorders, and their advanced forms - alcoholic steatohepatitis and nonalcoholic steatohepatitis - are the most frequent conditions leading to liver cirrhosis and hepatocellular carcinoma worldwide. NAFLD is considered as the hepatic manifestation of the metabolic syndrome. With the pandemic rise of obesity, the incidence of NAFLD is also further increasing, and considering the life style in modern societies, there is a significant overlap of (risk factors causing) NAFLD and (alcohol consumption predisposing for) ALD at least in Western countries. Epidemiological studies propose a causative link between chronic alcohol consumption and progressive liver disease in obese individuals. Furthermore, experimental studies indicate combined pathological effects of alcohol and obesity or fatty acid levels, respectively, on hepatocellular lipid accumulation and injury as well as hepatic inflammation, fibrosis and cancerogenesis. Notably, these combined pathological effects are in part additive but partly even synergistic. And importantly, alcohol does already exhibit synergistic pathological effects with obesity at moderate doses. This indicates significant differences in the dose threshold for hepatotoxic alcohol effects in lean and obese subjects and herewith also has important implications for recommendations for 'safe' alcohol consumption. The purpose of this brief review is to update the knowledge on the combined effects of alcohol and obesity on the development and progression of liver disease. Undoubtedly, alcohol and the metabolic syndrome appear as a dangerous mix, and there are important interactive effects of either condition with regard to crucial triggers of liver injury.


Statistical and Computational Methods for High-Throughput Sequencing Data Analysis of Alternative Splicing.
The burgeoning field of high-throughput sequencing significantly improves our ability to understand the complexity of transcriptomes. Alternative splicing, as one of the most important driving forces for transcriptome diversity, can now be studied at an unprecedent resolution. Efficient and powerful computational and statistical methods are in urgent need to facilitate the characterization and quantification of alternative splicing events. Here we discuss methods in splice junction read mapping, and methods in exon-centric or isoform-centric quantification of alternative splicing. In addition, we discuss HITS-CLIP and splicing QTL analyses which are novel high-throughput sequencing based approaches in the dissection of splicing regulation.


αTAT1 catalyses microtubule acetylation at clathrin-coated pits.
In most eukaryotic cells microtubules undergo post-translational modifications such as acetylation of α-tubulin on lysine 40, a widespread modification restricted to a subset of microtubules that turns over slowly. This subset of stable microtubules accumulates in cell protrusions and regulates cell polarization, migration and invasion. However, mechanisms restricting acetylation to these microtubules are unknown. Here we report that clathrin-coated pits (CCPs) control microtubule acetylation through a direct interaction of the α-tubulin acetyltransferase αTAT1 (refs 8, 9) with the clathrin adaptor AP2. We observe that about one-third of growing microtubule ends contact and pause at CCPs and that loss of CCPs decreases lysine 40 acetylation levels. We show that αTAT1 localizes to CCPs through a direct interaction with AP2 that is required for microtubule acetylation. In migrating cells, the polarized orientation of acetylated microtubules correlates with CCP accumulation at the leading edge, and interaction of αTAT1 with AP2 is required for directional migration. We conclude that microtubules contacting CCPs become acetylated by αTAT1. In migrating cells, this mechanism ensures the acetylation of microtubules oriented towards the leading edge, thus promoting directional cell locomotion and chemotaxis.


[Education within the Dutch National Care for the Elderly Programme].
The Netherlands Organisation of Health Research and Development started in 2008 the Dutch National Care for the Elderly Programme (in Dutch abbreviated as NPO) with the aim to improve the quality of life for the frail older people through better quality of care (health, social, community) which is tailored to the needs and wants of older people. The delivery of good care is related with competent professional behaviour which is inextricably linked to the education of professionals. This article presents an overview of 32 educational programmes developed within the NPO. Within the NPO different educational programmes were developed on relevant themes to improve elderly care. However, the programmes focused mainly on professionals in health care, especially those working in primary care. For nurses and nursing assistants and more or less for physicians also different educational programmes were developed. Educational programmes for paramedics or professionals working in social care, housing or in the municipalities were scarce. This is also the case for specific themes in elderly care like loneliness or (domestic) violence. Moreover, none of the experiments focused on older people or informal care givers. Although 22 of the 32 projects developed educational programmes for different groups, multi - or interdisciplinary education is rare in these programmes. Based on the overview we advise the development of more educational programmes on: target groups which were less or not addressed in the NPO, like professionals in social care and paramedics; multi- or interdisciplinary collaboration; and themes, like loneliness in older people and elder abuse.


Planar photonic crystal structure with inherently single-mode waveguides.
A planar photonic crystal that allows inherently gap-guided single-mode waveguides is proposed and discussed. This novel structure consists of a two-dimensional lattice of silicon rods embedded on a thin silica slab sandwiched between two silica claddings whose refractive indices are slightly lower than the index of the silica core. The physical parameters of the structure, i.e., rod radius and core thickness, are optimized to maximize the bandgap width for odd modes. Lossless guided modes inside the bandgap and below the claddings' light cone are obtained by reducing the radius of a row of rods. The waveguide bandwidth can be increased by inserting a thin silicon dielectric waveguide instead of the row of rods. The proposed approach may overcome many of the common drawbacks in conventional holes-on-dielectric planar photonic crystal waveguides.


ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy--a genome-wide study of Japanese HCV virus patients.
Ribavirin-induced anemia is one of the major causes of discontinuation and dose reduction during anti-hepatitis C virus therapy. Factors influencing this anemia, especially host genetic factors, are poorly understood. In this study we investigated predictive factors in hepatitis C virus patients treated with combination therapy. We performed a 2-step genome-wide screening followed by replication analysis and fine-mapping using a total of 923 Japanese hepatitis C virus 1b-infected patients treated with pegylated-interferon plus ribavirin. We also applied logistic regression analysis to search for possible independent associations of clinical parameters and genetic variants with treatment-induced hemoglobin (Hb) decline as well as treatment outcomes. We identified a variant, located upstream of the inosine triphosphate pyrophosphatase gene on chromosome 20p13 that is significantly associated with treatment-induced anemia (combined P = 6.0 × 10(-14)). Resequencing and fine-mapping revealed several single nucleotide polymorphisms (SNPs) strongly associated with Hb decline, including the nonsynonymous SNP rs1127354 (P = 3.5 × 10(-44)), which was recently reported for other ethnic groups. Another reported SNP, the splicing variant-related SNP rs7270101, was not polymorphic in the Japanese population. Stratified analysis based on rs1127354 genotype revealed that inosine triphosphate pyrophosphatase expression is not correlated with Hb decline, suggesting that rs1127354 is a direct causal variant in the Japanese population. Multivariate analysis demonstrated that age, baseline Hb, baseline platelet count, and rs1127354 were independently associated with severe anemia (Hb <10 g/dL). A missense substitution in inosine triphosphate pyrophosphatase gene affects ribavirin-induced anemia in hepatitis C virus-infected Japanese patients.


Electrocatalytic reduction of nitrate and selenate by NapAB.
Bacterial cellular metabolism is renowned for its metabolic diversity and adaptability. However, certain environments present particular challenges. Aerobic metabolism of highly reduced carbon substrates by soil bacteria such as Paracoccus pantotrophus presents one such challenge since it may result in excessive electron delivery to the respiratory redox chain when compared with the availability of terminal oxidant, O2. The level of a periplasmic ubiquinol-dependent nitrate reductase, NAP, is up-regulated in the presence of highly reduced carbon substrates. NAP oxidizes ubiquinol at the periplasmic face of the cytoplasmic membrane and reduces nitrate in the periplasm. Thus its activity counteracts the accumulation of excess reducing equivalents in ubiquinol, thereby maintaining the redox poise of the ubiquinone/ubiquinol pool without contributing to the protonmotive force across the cytoplasmic membrane. Although P. pantotrophus NapAB shows a high level of substrate specificity towards nitrate, the enzyme has also been reported to reduce selenate in spectrophotometric solution assays. This transaction draws on our current knowledge concerning the bacterial respiratory nitrate reductases and extends the application of PFE (protein film electrochemistry) to resolve and quantify the selenate reductase activity of NapAB.


Characterization of tccP2 carried by atypical enteropathogenic Escherichia coli.
Atypical enteropathogenic Escherichia coli (EPEC) comprise an important group of paediatric pathogens. Atypical EPEC have reservoirs in farm and domestic animals where they can be either commensal or pathogenic; serogroup O26 is dominant in humans and animals. Central to intestinal colonization by EPEC is the translocation of the type III secretion system effector Tir into enterocytes, which following phosphorylation (Tir-Yp) recruits Nck to activate the N-WASP actin signalling cascade. The authors have recently shown that typical EPEC strains, belonging to the EPEC-2 lineage, carry a tir gene encoding Tir-Yp and can also use the alternative TccP2 actin-signalling cascade. The aim of this study was to determine if tccP2 is found in atypical EPEC isolated from human and farm animals. tccP2 was found at a frequency of 41% in non-O26 EPEC isolates and in 82.3% of the O26 strains. TccP2 of human and animal strains show high level of sequence identity. It is shown that most strains carry a tir gene encoding Tir-Yp. In addition the authors identified two new variants of tir genes in EPEC O104:H12 and NT:H19 strains.


Configurational temperatures and interactions in charge-stabilized colloid.
A system's temperature can be expressed in terms of its constituents' instantaneous positions rather than their momenta. Such configurational temperature definitions offer substantial benefits for experimental studies of soft condensed matter systems, most notably their applicability to overdamped systems whose instantaneous momenta may not be accessible. We demonstrate that the configurational temperature formalism can be derived from the classical hypervirial theorem, and introduce a hierarchy of hyperconfigurational temperature definitions, which are particularly well suited for experimental studies. We then use these analytical tools to probe the electrostatic interactions in monolayers of charge-stabilized colloidal spheres confined by parallel glass surfaces. The configurational and hyperconfigurational temperatures, together with a thermodynamic sum rule, provide previously lacking self-consistency tests for interaction measurements based on digital video microscopy, and thereby cast light on controversial reports of confinement-induced like-charge attractions. We further introduce a method to determine unknown parameters in a model potential by using consistency of the configurational and hyperconfigurational temperatures as a set of constraints. This approach, in principle, also should provide the basis for a model-free estimation of the pair potential.


Transcriptional profiling endometrial carcinomas microdissected from DES-treated mice identifies changes in gene expression associated with estrogenic tumor promotion.
Exposure to unopposed estrogen is a potent risk factor for developing human endometrial cancer. However, little is known about the transcriptional changes elicited by estrogens in endometrial carcinogenesis, in part, because of genetic and environmental heterogeneity of human tumors. We have begun to chart the expression signatures of endometrial tumors promoted with the synthetic estrogen, diethylstilbestrol (DES), in inbred mice. As expected, laser-capture-microdissected endometrial cancers from DES-treated mice displayed a large number of transcriptional changes when compared to uninvolved endometrial epithelium. Genes differentially expressed in carcinomas included cell adhesion and extracellular matrix genes (Decorin as 1 example), developmental genes (Hoxa11), and cytokine signaling genes (Socs3). The DES-promoted carcinomas appeared to fall into 2 distinct transcriptional classes, and expression of the tumor suppressor Pten was among the top discriminators between the 2 cancer groups. Pten was down regulated in the majority of the DES-promoted carcinomas, which is analogous to the frequent loss of PTEN expression in human endometrial tumors. Although preliminary, these observations suggest that the cancers that arise in the DES model bear similarities to human endometrial cancers and provide insights into transcriptional alterations that accompany estrogen-driven endometrial carcinogenesis.


In-house HIV-1 RNA real-time RT-PCR assays: principle, available tests and usefulness in developing countries.
The principle of currently available licensed HIV-1 RNA assays is based on real-time technologies that continuously monitor the fluorescence emitted by the amplification products. Besides these assays, in-house quantitative (q) real-time reverse transcription (RT)-PCR (RT-qPCR) tests have been developed and evaluated particularly in developing countries, for two main reasons. First, affordable and generalized access to HIV-1 RNA viral load is urgently needed in the context of expected universal access to prevention and antiretroviral treatment programs in these settings. Second, since many non-B subtypes, circulating recombinant forms and unique recombinant forms circulate in these areas, in-house HIV-1 RNA RT-qPCR assays are ideal academic tools to thoroughly evaluate the impact of HIV-1 genetic diversity on the accuracy of HIV-1 RNA quantification, as compared with licensed techniques. To date, at least 15 distinct in-house assays have been designed. They differ by their chemistry and the HIV-1 target sequence (located in gag, Pol-IN or LTR gene). Analytical performances of the tests that have been extensively evaluated appear at least as good as (or even better than) those of approved assays, with regard to HIV-1 strain diversity. Their clinical usefulness has been clearly demonstrated for early diagnosis of pediatric HIV-1 infection and monitoring of highly active antiretroviral therapy efficacy. The LTR-based HIV-1 RNA RT-qPCR assay has been evaluated by several groups under the auspices of the Agence Nationale de Recherches sur le SIDA et les hépatites virales B et C. It exists now as a complete standardized commercial test.


Genetic interactions between Hsp90 and the Cdc2 mitotic machinery in the fission yeast Schizosaccharomyces pombe.
In Schizosaccharomyces pombe, wee1 encodes a tyrosine kinase that inhibits entry into mitosis by phophorylating Cdc2, the universal cyclin-dependent kinase (Cdk) that regulates the G2/M transition in all eukaryotic cells. A search for suppressors of the G2 arrest caused by overexpression of weel led to the isolation of a new allele of swo1 (named swo1-w1), the gene coding for chaperone Hsp90, which is required to stabilise Weel. The swo1-w1 allele carries a glycine to aspartic acid substitution at amino acid 155 that results in a partial loss of Hsp90 function. Cells bearing the swo1-w1 mutation in combination with the point mutation cdc2-33 or cdc2-M26 showed severe mitotic defects. Genetic interactions were not observed in combination with point mutations in other cdc genes, suggesting that Cdc2 specifically interacts with Hsp90. This synthetic lethal swo1-w1 cdc2-33 (or cdc2-M26) strain had normal levels of Cdc2 protein and histone H1 phosphorylation activity, indicating that Hsp90 is required to enable Cdc2 to interact with its mitotic substrates or regulators, rather than for its proper folding or stabilisation. In a wild-type background, swo1-w1 mutant cells were sensitive to temperature as well as to other stress agents, such as KCI, ethanol and formamide. Under these stressful growth conditions, the swo1-w1 cells displayed anaphase B arrest and aberrant septation patterns, indicating that a subset of proteins involved in mitosis and cytokinesis is highly dependent on chaperone Hsp90 for function.


Five-year experience with triple-drug immunosuppressive therapy in cardiac transplantation.
Although triple-drug immunosuppression with a combination of cyclosporine, prednisone, and azathioprine has been shown to improve short-term survival after cardiac transplantation, its long-term effects still are unknown. From December 1983 through December 1988, all patients (N = 139) who underwent orthotopic cardiac transplant at our institution received triple-drug immunosuppressant therapy. Follow-up averaged 32.2 +/- 15.8 months. Twenty-one patients died; 134 survived more than 30 days. Actuarial survival was 92% at 1 year, 85% at 3 years, and 78% at 5 years. Twenty-five episodes of acute graft rejection were diagnosed in 21 of the 139 recipients (0.18 episode per patient). In patients, the incidence of infection was 0.82 episode; 72% of infections were viral, with 10% due to cytomegalovirus. The incidence of coronary artery disease was 10% at 1 year, 25% at 3 years, and 36% at 5 years. Coronary artery disease was responsible for 60% of late deaths. Arterial hypertension developed in 81% of patients, despite relatively well-maintained renal function (serum creatinine, 1.7 +/- 0.3 mg/dl). Skeletal complications occurred in 15.8% and lymphoma in 1.4% of recipients. Complete long-term rehabilitation was achieved in all but two of the surviving patients. These data support the short- and long-term effectiveness of triple-drug therapy. This regimen reduces the incidence of rejection, infection, and lymphoma, as well as the degree of renal failure. However, the incidence of posttransplant coronary artery disease has not been reduced, and graft atherosclerosis represents the major cause of late graft failure and death.


Generation of genic diversity among Streptococcus pneumoniae strains via horizontal gene transfer during a chronic polyclonal pediatric infection.
Although there is tremendous interest in understanding the evolutionary roles of horizontal gene transfer (HGT) processes that occur during chronic polyclonal infections, to date there have been few studies that directly address this topic. We have characterized multiple HGT events that most likely occurred during polyclonal infection among nasopharyngeal strains of Streptococcus pneumoniae recovered from a child suffering from chronic upper respiratory and middle-ear infections. Whole genome sequencing and comparative genomics were performed on six isolates collected during symptomatic episodes over a period of seven months. From these comparisons we determined that five of the isolates were genetically highly similar and likely represented a dominant lineage. We analyzed all genic and allelic differences among all six isolates and found that all differences tended to occur within contiguous genomic blocks, suggestive of strain evolution by homologous recombination. From these analyses we identified three strains (two of which were recovered on two different occasions) that appear to have been derived sequentially, one from the next, each by multiple recombination events. We also identified a fourth strain that contains many of the genomic segments that differentiate the three highly related strains from one another, and have hypothesized that this fourth strain may have served as a donor multiple times in the evolution of the dominant strain line. The variations among the parent, daughter, and grand-daughter recombinant strains collectively cover greater than seven percent of the genome and are grouped into 23 chromosomal clusters. While capturing in vivo HGT, these data support the distributed genome hypothesis and suggest that a single competence event in pneumococci can result in the replacement of DNA at multiple non-adjacent loci.


Associations between sleep health and grey matter volume in the UK Biobank cohort (n = 33 356).
As suggested by previous research, sleep health is assumed to be a key determinant of future morbidity and mortality. In line with this, recent studies have found that poor sleep is associated with impaired cognitive function. However, to date, little is known about brain structural abnormalities underlying this association. Although recent findings link sleep health deficits to specific alterations in grey matter volume, evidence remains inconsistent and reliant on small sample sizes. Addressing this problem, the current preregistered study investigated associations between sleep health and grey matter volume (139 imaging-derived phenotypes) in the UK Biobank cohort (33 356 participants). Drawing on a large sample size and consistent data acquisition, sleep duration, insomnia symptoms, daytime sleepiness, chronotype, sleep medication and sleep apnoea were examined. Our main analyses revealed that long sleep duration was systematically associated with larger grey matter volume of basal ganglia substructures. Insomnia symptoms, sleep medication and sleep apnoea were not associated with any of the 139 imaging-derived phenotypes. Short sleep duration, daytime sleepiness as well as late and early chronotype were associated with solitary imaging-derived phenotypes (no recognizable pattern, small effect sizes). To our knowledge, this is the largest study to test associations between sleep health and grey matter volume. Clinical implications of the association between long sleep duration and larger grey matter volume of basal ganglia are discussed. Insomnia symptoms as operationalized in the UK Biobank do not translate into grey matter volume findings.


Psychological approach to successful ageing predicts future quality of life in older adults.
Public policies aim to promote well-being, and ultimately the quality of later life. Positive perspectives of ageing are underpinned by a range of appraoches to successful ageing. This study aimed to investigate whether baseline biological, psychological and social aproaches to successful ageing predicted future QoL. Postal follow-up in 2007/8 of a national random sample of 999 people aged 65 and over in 1999/2000. Of 496 valid addresses of survivors at follow-up, the follow-up response rate was 58% (287). Measures of the different concepts of successful ageing were constructed using baseline indicators. They were assessed for their ability to independently predict quality of life at follow-up. Few respondents achieved all good scores within each of the approaches to successful ageing. Each approach was associated with follow-up QoL when their scores were analysed continuously. The biomedical (health) approach failed to achieve significance when the traditional dichotomous cut-off point for successfully aged (full health), or not (less than full health), was used. In multiple regression analyses of the relative predictive ability of each approach, only the psychological approach (perceived self-efficacy and optimism) retained significance. Only the psychological approach to successful ageing independently predicted QoL at follow-up. Successful ageing is not only about the maintenance of health, but about maximising one's psychological resources, namely self-efficacy and resilience. Increasing use of preventive care, better medical management of morbidity, and changing lifestyles in older people may have beneficial effects on health and longevity, but may not improve their QoL. Adding years to life and life to years may require two distinct and different approaches, one physical and the other psychological. Follow-up health status, number of supporters and social activities, and self-rated active ageing also significantly predicted QoL at follow-up. The longitudinal sample bias towards healthy survivors is likely to underestimate these results.


WHAT IS A "NEIGHBORHOOD"? DEFINITION IN STUDIES ABOUT DEPRESSIVE SYMPTOMS IN OLDER PERSONS.
The almost irrefutable hypothesis that place matters continues to grow in popularity. Epidemiological and public health researchers are studying social and physical environment's effect on individual health outcomes. Advances in the field are hindered by the lack of consistency in measuring and labeling social contexts. Greater definitional precision is required. In order to give an example of this, "neighborhood" studies between 2000 and 2012 dealing with depression symptomatology in older adults were identified with an exhaustive search. Only those where the terms neighborhood, and mental health, or mental well-being, or CES-D appear were included for the initial review. After additionally selecting for age and the presence of the Center for Epidemiologic Studies Depression (CES-D) measure, from an initial 98 articles, we end up with 11 articles. We focus on how neighborhoods are defined and briefly highlight findings on CES-D. For the most part, the definition of neighborhood is limited, frequently justified, and typically hidden in the methodological details and closing arguments of an article. In general, articles evade the discussion of polygon appropriateness with relation to the term neighborhood. Our review suggests that a good starting point for advancing this field of inquiry would be to increase the definitional precision of the term neighborhood and to offer an upfront disclosure with more appropriate terminology. Doing so may lead place-effect investigations in population aging and frailty down a more productive road.


Statistical lessons learned for designing cluster randomized pragmatic clinical trials from the NIH Health Care Systems Collaboratory Biostatistics and Design Core.
Pragmatic clinical trials embedded within health care systems provide an important opportunity to evaluate new interventions and treatments. Networks have recently been developed to support practical and efficient studies. Pragmatic trials will lead to improvements in how we deliver health care and promise to more rapidly translate research findings into practice. The National Institutes of Health (NIH) Health Care Systems Collaboratory was formed to conduct pragmatic clinical trials and to cultivate collaboration across research areas and disciplines to develop best practices for future studies. Through a two-stage grant process including a pilot phase (UH2) and a main trial phase (UH3), investigators across the Collaboratory had the opportunity to work together to improve all aspects of these trials before they were launched and to address new issues that arose during implementation. Seven Cores were created to address the various considerations, including Electronic Health Records; Phenotypes, Data Standards, and Data Quality; Biostatistics and Design Core; Patient-Reported Outcomes; Health Care Systems Interactions; Regulatory/Ethics; and Stakeholder Engagement. The goal of this article is to summarize the Biostatistics and Design Core's lessons learned during the initial pilot phase with seven pragmatic clinical trials conducted between 2012 and 2014. Methodological issues arose from the five cluster-randomized trials, also called group-randomized trials, including consideration of crossover and stepped wedge designs. We outlined general themes and challenges and proposed solutions from the pilot phase including topics such as study design, unit of randomization, sample size, and statistical analysis. Our findings are applicable to other pragmatic clinical trials conducted within health care systems. Pragmatic clinical trials using the UH2/UH3 funding mechanism provide an opportunity to ensure that all relevant design issues have been fully considered in order to reliably and efficiently evaluate new interventions and treatments. The integrity and generalizability of trial results can only be ensured if rigorous designs and appropriate analysis choices are an essential part of their research protocols.


Cerebrovascular response to hypoxia in young vs aged rats.
Cerebrovascular responses of young and aged rats were tested to graded levels of hypoxia using a modification of the Levine ischemic-hypoxic rat model in which one carotid artery was ligated. Rats were anesthetized with 70% N2O, 30% O2 and cortical and subcortical cerebral blood flow (CBF) were measured with radioactive microspheres. CBF and cerebral cortical oxygen consumption (CMRO2) were measured under control conditions and during hypoxia with arterial oxygen content maintained at approximately 9, 5 and 3 ml . dl-1. CBF responses in cortical and subcortical tissues were similar between young and aged under control conditions and during moderate hypoxia (CaO2 = 9 ml . dl-1). Maximum cerebrovascular responses to severe hypoxia were greater in young than in aged rats and these trends were significant in both ligated and unligated cortical tissue (p less than 0.05). CMRO2 was maintained at control levels during moderate hypoxia but decreased significantly more in aged than in young rats when CaO2 was decreased to 3 ml . dl-1. These results suggest that baseline CBF and the sensitivity of cerebrovascular receptors to moderate hypoxia are similar in young vs aged rats but that maximum reactivity severe hypoxia is attenuated in aged subjects. CBF measured after one minute of hypoxia, before the induction of brain tissue acidosis, produced no significant change in the CBF response to hypoxia or in the difference between young and aged rats. Brain tissue pH changes do not appear to be the major factor for mediating CBF increases during hypoxia in young or aged rats, although it may interact with other mediators of the response.


Cell-resolved blood flow simulations of saccular aneurysms: effects of pulsatility and aspect ratio.
We study the effect of pulsatile flow on the transport of red blood cells (RBCs) and platelets into aneurysm geometries with varying dome-to-neck aspect ratios (AR). We use a validated two-dimensional lattice Boltzmann model for blood plasma with a discrete element method for both RBCs and platelets coupled by the immersed boundary method. Flow velocities and vessel diameters were matched with measurements of cerebral perforating arteries and flow was driven by a synthetic heartbeat curve typical for such vessel sizes. We observe a flow regime change as the aspect ratio increases from a momentum-driven regime in the small aspect ratio to a shear-driven regime in the larger aspect ratios. In the small aspect ratio case, we see the development of a re-circulation zone that exhibits a layering of high (greater than or equal to 7 s) and low (less than 7 s) residence cells. In the shear-driven regime, we see high and low residence cells well mixed, with an increasing population of cells that are trapped inside the aneurysm as the aspect ratio increases. In all cases, we observe aneurysms that are platelet-rich and red blood cell-poor when compared with their respective parental vessel populations. Pulsatility also plays a role in the small aspect ratio as we observe a smaller population of older trapped cells along the aneurysm wall in the pulsatile case when compared with a steady flow case. Pulsatility does not have a significant effect in shear-driven regime aspect ratios.