Current progress in the production of recombinant human fibrinogen in the milk of transgenic animals.
The mammary gland of transgenic animals has several advantages for production of heterologous proteins including a high cell density that results in high concentrations of secreted protein. While the mammary gland appears to be able to secrete fully assembled recombinant human fibrinogen (rhfib) at 0.1 to 5 g/l levels, some unassembled rhfib chains are also secreted. Presently, the relationship between unassembled rhfib and the coordinated translation of each nascent rhfib polypeptide in the mammary epithelia is unknown. The secretion of fully and partially assembled rhfib is widely variable among mammalian cell lines and where previously no cell line has been shown to secrete beta chain alone. We have observed that mammary epithelia can secrete B beta chain into milk as well as immature forms of other recombinant proteins, suggesting it likely uses a different secretory pathway than does the liver. This difference in secretory behavior is possibly due to the natural design of milk, where the precise regulation of post translational modifications and intracellular pools of nascent polypeptides needed to achieve fibrinogen assembly may be less important to fulfill the nutritional function of most milk proteins.


Climate change, migration and health systems resilience: Need for interdisciplinary research.
Climate change is one of today's major challenges, and among the causes of population movement and international migration. Climate migrants impact health systems and how their ability to respond and adapt to their needs and patterns. To date, the resilience of health systems in the context of climate change has barely been explored. The purpose of this article is to show the importance of studying the relationship between climate change, migration, and the resilience of health systems from an interdisciplinary perspective. Resilience is an old concept, notably in the field of psychology, and is increasingly applied to the study of health systems. Yet, no research has analysed the resilience of health systems in the context of climate change. While universal health coverage is a major international goal, little research to date focused on the existing links between climate, migration, health systems and resilience. We propose an interdisciplinary approach relying on the concept of health system resilience to study adaptive and transformative strategies to articulate climate change, migration and health systems.


Evaluating patient-reported outcome measures (PROMs) for bladder cancer: a systematic review using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist.
Patient-reported outcome measures (PROMs) are important tools used to understand patient-focused outcomes from care. Various PROMs have been developed for patients with bladder cancer (BC), although the disease's heterogeneity makes selection difficult. Accurate measurement of health-related quality of life (HRQL) can only be achieved if the PROM chosen is 'fit for purpose' (i.e. psychometrically sound). Systematic reviews of psychometric properties are useful for selecting the best PROM for a specific purpose. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) developed a checklist to improve the selection of health measurement instruments as part of a review process. Our aims were to undertake a systematic review, using the COSMIN criteria, to assess the quality of studies that report the psychometric properties of PROMs used with people with BC and determine the psychometric quality of these PROMs. An electronic search of seven databases including PubMed, MEDLINE and EMBASE (PROSPERO reference CRD42016051974) was undertaken to identify English language publications, published between January 1990 and September 2017 that evaluated psychometric properties of PROMs used in BC research. Two researchers independently screened abstracts and selected full-text papers. Studies were rated on methodological quality using the COSMIN checklist. Overall, 4663 records were screened and 23 studies, reporting outcomes in 3568 patients, were evaluated using the COSMIN checklist. Most PROMs had limited information reported about their psychometric properties. Studies reporting on the Bladder Cancer Index (BCI) and Functional Assessment of Cancer Therapy Vanderbilt Cystectomy Index (FACT-VCI) provided the most detail and these PROMs could be evaluated on the most COSMIN properties. Based on the available evidence, no existing PROM stands out as the most appropriate to measure HRQL in BC populations. This is due to two factors; (i) the heterogeneity of BC and its treatments (ii) no PROM was evaluated on all COSMIN measurement properties due to a lack of validation studies. We suggest future evaluation of generic, cancer generic and BC-specific PROMs to better understand their application with BC populations and propose strategies to help clinicians and researchers.


Quantifying muscle fatigue during walking in people with multiple sclerosis.
This study aimed to examine muscle fatigue in lower leg muscles in of people with multiple sclerosis and healthy controls, and whether muscle fatigue coincided with potential changes in gait. In this case-control study, people with multiple sclerosis (n = 8; 3male; mean age (SD) = 49.7 (9.6) yr) and age-matched healthy controls (n = 10; 4male; mean age (SD) = 47.4 (8.7) yr) walked on a treadmill for 12-min at self-paced speed. Muscle fatigue was indirectly quantified by a decrease in median frequency and increase in root mean square of surface electromyographic recordings of lower leg muscles. Walking speed, ankle push-off power and net ankle work were calculated from marker positions and force plate data using inverse dynamic calculations. People with multiple sclerosis showed larger decreases in median frequency of soleus (most affected leg: p = 0.003; least affected leg: p = 0.009) and larger increases in root mean square of soleus (most and least affected leg: p = 0.037), gastrocnemius medialis (most affected leg: p = 0.003; least affected leg: p = 0.005) and lateralis (most and least affected leg: p < 0.001) compared to controls. Walking speed (p = 0.001), ankle push-off power (most affected leg: p = 0.018; least affected leg: p = 0.001) and net work around the ankle (most affected leg: p = 0.046; least affected leg: p = 0.001) were lower in people with multiple sclerosis compared to controls, but increased in both groups. The results yield preliminary evidence that soleus muscles of people with multiple sclerosis fatigue during prolonged walking. Changes in electromyography of gastrocnemius muscles could however be related to muscle fatigue, changes in gait or a combination.


The cytoarchitecture of the nucleus angularis of the barn owl (Tyto alba).
The cochlear nucleus angularis (NA) of the barn owl (Tyto alba) was analyzed using Golgi, Nissl, and tract tracing techniques. NA forms a column of cells in the dorsolateral brainstem that partly overlaps with, and is rostral and lateral to, the cochlear nucleus magnocellularis (NM). Highest best frequencies are mapped in lateral NA (NAl), intermediate in medial NA (NAm), and lowest in the foot region (NAf). Cell density followed the tonotopic axis and decreased with decreasing best frequency. NA contained four major cell classes: planar, radiate, vertical, and stubby. Planar and radiate classes were further subdivided into bipolar and multipolar types according to their number of primary dendrites. Planar neurons were confined to an isofrequency band, whereas radiate neurons had dendrites that could extend across an isofrequency band. Vertical cells had long dendrites oriented perpendicularly to isofrequency bands. Stubby cells were the most numerous and were confined to an isofrequency band because of their short dendrites. Neurons in each of these four classes projected to the inferior colliculus and dorsal nucleus of the lateral lemniscus.


Bird population trends are linearly affected by climate change along species thermal ranges.
Beyond the effects of temperature increase on local population trends and on species distribution shifts, how populations of a given species are affected by climate change along a species range is still unclear. We tested whether and how species responses to climate change are related to the populations locations within the species thermal range. We compared the average 20 year growth rates of 62 terrestrial breeding birds in three European countries along the latitudinal gradient of the species ranges. After controlling for factors already reported to affect bird population trends (habitat specialization, migration distance and body mass), we found that populations breeding close to the species thermal maximum have lower growth rates than those in other parts of the thermal range, while those breeding close to the species thermal minimum have higher growth rates. These results were maintained even after having controlled for the effect of latitude per se. Therefore, the results cannot solely be explained by latitudinal clines linked to the geographical structure in local spring warming. Indeed, we found that populations are not just responding to changes in temperature at the hottest and coolest parts of the species range, but that they show a linear graded response across their European thermal range. We thus provide insights into how populations respond to climate changes. We suggest that projections of future species distributions, and also management options and conservation assessments, cannot be based on the assumption of a uniform response to climate change across a species range or at range edges only.


Emergence of recombinant forms of HIV: dynamics and scaling.
The ability to accelerate the accumulation of favorable combinations of mutations renders recombination a potent force underlying the emergence of forms of HIV that escape multi-drug therapy and specific host immune responses. We present a mathematical model that describes the dynamics of the emergence of recombinant forms of HIV following infection with diverse viral genomes. Mimicking recent in vitro experiments, we consider target cells simultaneously exposed to two distinct, homozygous viral populations and construct dynamical equations that predict the time evolution of populations of uninfected, singly infected, and doubly infected cells, and homozygous, heterozygous, and recombinant viruses. Model predictions capture several recent experimental observations quantitatively and provide insights into the role of recombination in HIV dynamics. From analyses of data from single-round infection experiments with our description of the probability with which recombination accumulates distinct mutations present on the two genomic strands in a virion, we estimate that approximately 8 recombinational strand transfer events occur on average (95% confidence interval: 6-10) during reverse transcription of HIV in T cells. Model predictions of virus and cell dynamics describe the time evolution and the relative prevalence of various infected cell subpopulations following the onset of infection observed experimentally. Remarkably, model predictions are in quantitative agreement with the experimental scaling relationship that the percentage of cells infected with recombinant genomes is proportional to the percentage of cells coinfected with the two genomes employed at the onset of infection. Our model thus presents an accurate description of the influence of recombination on HIV dynamics in vitro. When distinctions between different viral genomes are ignored, our model reduces to the standard model of viral dynamics, which successfully predicts viral load changes in HIV patients undergoing therapy. Our model may thus serve as a useful framework to predict the emergence of multi-drug-resistant forms of HIV in infected individuals.


Systematic Review and Meta-Analysis of Community- and Choice-Based Health State Utility Values for Lung Cancer.
Using appropriate health state utility values (HSUVs) is critical for economic evaluation of new lung cancer interventions, such as low-dose computed tomography screening and immunotherapy. Therefore, we provide a systematic review and meta-analysis of community- and choice-based HSUVs for lung cancer. On 6 March 2017, we conducted a systematic search of the following databases: Embase, Ovid MEDLINE, Web of Science, Cochrane CENTRAL, Google Scholar, and the School of Health and Related Research Health Utility Database. The search was updated on 17 April 2019. Studies reporting mean or median lung cancer-specific HSUVs including a measure of variance were included and assessed for relevance and validity. Studies with high relevance (i.e. community- and choice-based) were further analysed. Mean HSUVs were pooled using random-effects models for all stages, stages I-II, and stages III-IV. For studies with a control group, we calculated the disutility due to lung cancer. A sensitivity analysis included only the methodologically most comparable studies (i.e. using the EQ-5D instrument and matching tariff). Subgroup analyses were conducted by time to death, histology, sex, age, treatment modality, treatment line, and progression status. We identified and analysed 27 studies of high relevance. The pooled HSUV was 0.68 (95% confidence interval [CI] 0.61-0.75) for all stages, 0.78 (95% CI 0.70-0.86) for stages I-II, and 0.69 (95% CI 0.65-0.73) for stages III-IV (p = 0.02 vs. stage I-II). Heterogeneity was present in each pooled analysis (p < 0.01; I2 = 92-99%). Disutility due to lung cancer ranged from 0.11 (95% CI 0.05-0.17) to 0.27 (95% CI 0.18-0.36). In the sensitivity analysis with the methodologically most comparable studies, stage-specific HSUVs varied by country. Such studies were only identified for Canada, China, Spain, the UK, the USA, Denmark, Germany, and Thailand. In the subgroup analysis by time to death, HSUVs for metastatic non-small-cell lung cancer ranged from 0.83 (95% CI 0.82-0.85) at ≥ 360 days from death to 0.56 (95% CI 0.46-0.66) at < 30 days from death. Among patients with metastatic non-small-cell lung cancer, HSUVs were lower for those receiving third- or fourth-line treatment and for those with progressed disease. Results of subgroup analyses by histology, sex, age, and treatment modality were ambiguous. The presented evidence supports the use of stage- and country-specific HSUVs. However, such HSUVs are unavailable for most countries. Therefore, our pooled HSUVs may provide the best available stage-specific HSUVs for most countries. For metastatic non-small-cell lung cancer, adjusting for the decreased HSUVs in the last year of life may be considered, as may further stratification of HSUVs by treatment line or progression status. If required, HSUVs for other health states may be identified using our comprehensive breakdown of study characteristics.


Outcomes in patients with acute coronary syndrome in a referral hospital in sub-Saharan Africa.
Coronary artery disease and its acute presentation are being increasingly recognised and treated in sub-Saharan Africa. It is just over a decade since the introduction of interventional cardiology for coronary artery disease in Kenya. Local and regional data, and indeed data from sub-Saharan Africa on long-term outcomes of acute coronary syndromes (ACS) are lacking. A retrospective review of all ACS admissions to the Aga Khan University Hospital, Nairobi (AKUHN) between January 2012 and December 2013 was carried out to obtain data on patient characteristics, treatment and in-patient outcomes. Patient interviews and a review of clinic records were conducted to determine long-term mortality rates and major adverse cardiovascular events. A total of 230 patients were included in the analysis; 101 had a diagnosis of ST-segment myocardial infarction (STEMI), 93 suffered a non-ST-segment myocardial infarction (NSTEMI), and 36 had unstable angina (UA). The mean age was 60.5 years with 81.7% being male. Delayed presentation (more than six hours after symptom onset) was common, accounting for 66.1% of patients. Coronary angiography was performed in 85.2% of the patients. In-hospital mortality rate was 7.8% [14.9% for STEMI and 2.3% for non-ST-segment ACS (NSTE-ACS, consisting of NSTEMI and UA)], and the mortality rates at 30 days and one year were 7.8 and 13.9%, respectively. Heart failure occurred in 40.4% of STEMI and 16.3% of NSTE-ACS patients. Re-admission rate due to recurrent myocardial infarction, stroke or bleeding at one year was 6.6%. In our series, the in-hospital, 30-day and one-year mortality rates following ACS remain high, particularly for STEMI patients. Delayed presentation to hospital following symptom onset is a major concern.


Impaired judgments of sadness but not happiness following bilateral amygdala damage.
Although the amygdala's role in processing facial expressions of fear has been well established, its role in the processing of other emotions is unclear. In particular, evidence for the amygdala's involvement in processing expressions of happiness and sadness remains controversial. To clarify this issue, we constructed a series of morphed stimuli whose emotional expression varied gradually from very faint to more pronounced. Five morphs each of sadness and happiness, as well as neutral faces, were shown to 27 subjects with unilateral amygdala damage and 5 with complete bilateral amygdala damage, whose data were compared to those from 12 brain damaged and 26 normal controls. Subjects were asked to rate the intensity and to label the stimuli. Subjects with unilateral amygdala damage performed very comparably to controls. By contrast, subjects with bilateral amygdala damage showed a specific impairment in rating sad faces, but performed normally in rating happy faces. Furthermore, subjects with right unilateral amygdala damage performed somewhat worse than subjects with left unilateral amygdala damage. The findings suggest that the amygdala's role in processing of emotional facial expressions encompasses multiple negatively valenced emotions, including fear and sadness.


Technological devices in peripheral percutaneous interventions.
New innovations and novel approaches to peripheral arterial occlusive disease have brought enormous benefits to the vascular patient. Diseases that were once manageable only by surgical intervention are now easily and successfully treated by minimally invasive procedures. While the early days of percutaneous intervention were filled with inventions of new devices, today the focus centers on using modern technology and manufacturing to further improve upon these devices. Advances in guidewires and catheters have allowed us to visualize and treat lesions in nearly any vessel, and technology is guiding us towards specialized applications for specific lesions in specific vessels. However, one of the big hurdles remaining in treating arterial occlusive diseases is the rate of restenosis and the need for reinterventions. The location and architecture of these vessels make them uniquely difficult to treat, and call for new technology to address these challenges. Current developments of drug-eluting and bioabsorbable stents are at the forefront of new advancements specifically directed at improving current patency and restenosis rates; perhaps the next step in percutaneous intervention will rely on nanotechnology and the molecular surface engineering that may achieve a new era of devices that are able to target specific cell ligands or proteins to prevent the inflammatory and proliferative response from vessels. The present review will focus on the current literature regarding technological devices in peripheral percutaneous interventions and clinical applications. Future advancements in materials engineering and biotechnology will continue to improve the current standard of percutaneous intervention for peripheral arterial occlusive diseases.


Impact of catheter-induced iatrogenic coronary artery dissection with or without postprocedural flow impairment: A report from a Japanese multicenter percutaneous coronary intervention registry.
Despite the ever-increasing complexity of percutaneous coronary intervention (PCI), the incidence, predictors, and in-hospital outcomes of catheter-induced coronary artery dissection (CICAD) is not well defined. In addition, there are little data on whether persistent coronary flow impairment after CICAD will affect clinical outcomes. We evaluated 17,225 patients from 15 participating hospitals within the Japanese PCI registry from January 2008 to March 2016. Associations between CICAD and in-hospital adverse cardiovascular events were evaluated using multivariate logistic regression. Outcomes of patients with CICAD with or without postprocedural flow impairment (TIMI flow ≤ 2 or 3, respectively) were analyzed. The population was predominantly male (79.4%; mean age, 68.2 ± 11.0 years); 35.6% underwent PCI for complex lesions (eg. chronic total occlusion or a bifurcation lesion.). CICAD occurred in 185 (1.1%), and its incidence gradually decreased (p < 0.001 for trend); postprocedural flow impairment was observed in 43 (23.2%). Female sex, complex PCI, and target lesion in proximal vessel were independent predictors (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.53-3.10; OR, 2.19; 95% CI, 1.58-3.04; and OR, 1.55; 95% CI, 1.06-2.28, respectively). CICAD was associated with an increased risk of in-hospital adverse events (composite of new-onset cardiogenic shock and new-onset heart failure) regardless of postprocedural flow impairment (OR, 10.9; 95% CI, 5.30-22.6 and OR, 2.27; 95% CI, 1.20-4.27, respectively for flow-impaired and flow-recovered CICAD). In conclusion, CICAD occurred in roughly 1% of PCI cases; female sex, complex PCI, and proximal lesion were its independent risk factors. CICAD was associated with adverse in-hospital cardiovascular events regardless of final flow status. Our data implied that the appropriate selection of PCI was necessary for women with complex lesions.


Long- and short-term complications of episiotomy.
Although extensively applied in obstetrics practice to facilitate delivery by increasing the vaginal birth conduit, most episiotomy studies are in the context of short- or medium-term outcomes, and the number of studies investigating the long-term effects is insufficient. Episiotomy is often considered associated with urinary and/or anal incontinence and dyspareunia; however, there is no concrete evidence for this issue. Current meta-analyses and reviews that assessed the studies available in the literature revealed that episiotomy does not decrease the rates of urinary incontinence, perineal pain, and sexual dysfunction and that routine episiotomy does not prevent pelvic floor damage; thus, the recommended use of mediolateral episiotomy is restricted, rather than routine. According to the limited number of studies on sexual function, there seems to be a linear relationship between the degree of perineal laceration and postpartum dyspareunia. It is still not clear whether episiotomy has any impact on pelvic floor relaxation, pelvic organ prolapse, and sexual dysfunction in the long term.


Multidimensional analysis of an evolving lineage.
To identify the forces directing organismal evolution, a general analytical system is developed to synthesize structuralist and Darwinian traditions in an explicitly historical framework. Morphological features of lungless salamanders are examined to identify hierarchical systems of developmental and functional constraint on evolution and their interactions with processes at the genic and populational levels. Characteristic patterns of change occur repeatedly in the evolutionary history of this group.


Neonatal hypoglycemic brain - injury a common cause of infantile onset remote symptomatic epilepsy.
To study the etiology of remote symptomatic epilepsy with onset in the first 3 years of life. Patients with neonatal hypoglycemic brain injury (NHBI), were further studied for risk factors and clinical features. The study was conducted at a tertiary pediatric neurology service between May-August 2004. Consecutive patients were recruited prospectively. The probable etiological diagnoses were based primarily on cranial imaging. Two radiologists, blinded to the etiological diagnosis, reviewed the cranial imaging and suggested the likely etiology based on published imaging criteria. There were three categories i.e, (i) perinatal encephaloclastic conditions (PEC) e.g., hypoxic ischemic encephalopathy (HIE) etc, (ii) developmental (DV) e.g., tuberous sclerosis, etc and (iii) postnatal (PN) e.g., trauma, etc. Three risk factors (birth weight, type of delivery, feeding difficulty) were compared between NHBI and developmental etiology (DV) groups. Neurological findings were compared between the NHBI vs the other perinatal groups. Seizure details were studied only in the NHBI group. 63 boys and 37 girls were recruited. Mean age of seizure onset was 13.9 months. PEC were seen in 50 patients, DV in 28 patients and PN in 5. NHBI was seen in 23 patients and was the most frequent cause of epilepsy. Low birth weight (LBW), neonatal feeding difficulties and cesarean delivery were significant risk factors for NHBI vis a vis the DV group. Microcephaly, autism, visual impairment and apraxia of hand use were common while spasticity or dystronia were rare in NHBI. Spasms were the commonest seizure type. Neonatal hypoglycemia is the most common etiology of remote symptomatic infantile onset epilepsy. LBW, poor neonatal feeding and cesarean delivery are significant clinical correlates.


Can clinical factors estimate insulin resistance in type 1 diabetes?
An insulin resistance syndrome (IRS) score was developed based on clinical risk factors in adults with childhood-onset type 1 diabetes in the Epidemiology of Diabetes Complications (EDC) Study and was validated using euglycemic-hyperinsulinemic clamp studies. Hypertension, waist-to-hip ratio (WHR), triglyceride and HDL cholesterol levels, family history of type 2 diabetes, and glycemic control were risk factors used to define the score. A score of 1 (lowest likelihood IRS) to 3 (highest likelihood IRS) was assigned for each risk factor. Eligible subjects (n = 24) were recruited from the EDC cohort based on tertile of IRS score. Subjects received an overnight insulin infusion to normalize glucose levels, then underwent a 3-h euglycemic-hyperinsulinemic (60 mU x m(-2) x min(-1)) clamp. Glucose disposal rate (GDR) was determined during the last 30 min of the clamp. The GDR differed significantly by IRS group (9.65 +/- 2.99, 8.02 +/- 1.39, and 5.68 +/- 2.16 mg x kg(-1) x min(-1), P < 0.01). The GDR was inversely correlated with the IRS score (r = -0.64, P < 0.01). Using linear regression, the combination of risk factors that yielded the highest adjusted r2 value (0.57, P < 0.001) were WHR, hypertension, and HbA1. This study found that clinical risk factors can be used to identify subjects with type 1 diabetes who are insulin resistant, and it provides validation of a score based on clinical factors to determine the extent of insulin resistance in type 1 diabetes. This score will be applied to the entire EDC population in future studies to determine the effect of insulin resistance on complications.


Validation of the MD Anderson Symptom Inventory-Head-and-Neck-Filipino (MDASI-HN-F): clinical utility of symptom screening among patients with head-and-neck cancer.
Symptom burden and quality of life (QOL) are of particular importance in head-and-neck cancer treatment. The MD Anderson Symptom Inventory-Head-and-Neck (MDASI-HN) is a simple symptom assessment tool practicable for patient follow-up, but a validated Filipino translation was previously unavailable. The objectives of this study were to develop a valid Filipino translation of the MDASI-HN, to test the sensitivity of the validated MDASI core-F, and to report the prevalence and pattern of head-and-neck symptoms in our cohort. An MDASI-HN-Filipino (MDASI-HN-F) version was developed and examined for convergent validity, internal consistency, test-retest reliability, known-group validity and sensitivity to change. Eligible participants were aged 18-80 years, with histopathologically-proven head-and-neck (except thyroid) cancer, able to understand and read English and Filipino, and without cognitive impairment or other conditions precluding self-administration of the questionnaire. Participants (n=100) were aged 18-76 years; the majority were aged <60, male, married, had college schooling, or were from a Tagalog-speaking region. The validity of the MDASI HN-F was demonstrated in all parameters. Age or educational attainment did not affect convergent validity or test-retest reliability. At baseline, 48% had multiple moderate/severe symptoms and 38% had at least one severe symptom. The MDASI-HN-F is valid, reliable and sensitive. The sensitivity of the MDASI core-F is demonstrated, and its validity and reliability reaffirmed. Moderate and severe head-and-neck symptoms are prevalent in early-stage and advanced-stage head-and-neck cancers, reflecting the utility of symptom screening for improvement of symptom management, QOL and compliance to treatment.


Probing the evolution, ecology and physiology of marine protists using transcriptomics.
Protists, which are single-celled eukaryotes, critically influence the ecology and chemistry of marine ecosystems, but genome-based studies of these organisms have lagged behind those of other microorganisms. However, recent transcriptomic studies of cultured species, complemented by meta-omics analyses of natural communities, have increased the amount of genetic information available for poorly represented branches on the tree of eukaryotic life. This information is providing insights into the adaptations and interactions between protists and other microorganisms and macroorganisms, but many of the genes sequenced show no similarity to sequences currently available in public databases. A better understanding of these newly discovered genes will lead to a deeper appreciation of the functional diversity and metabolic processes in the ocean. In this Review, we summarize recent developments in our understanding of the ecology, physiology and evolution of protists, derived from transcriptomic studies of cultured strains and natural communities, and discuss how these novel large-scale genetic datasets will be used in the future.


PICO Linguist and BabelMeSH: development and partial evaluation of evidence-based multilanguage search tools for MEDLINE/PubMed.
PICO Linguist and BabelMeSH are multilanguage search tools intended for users whose native language is not English. A database of medical terms was created using concept identification equivalents of English terms to other languages. The primary sources of vocabularies were UMLS, MeSH, WHO EMRO and UMLF. The search interface changes according to the language selected which allows search terms to be entered in the native language. The user can limit the search output according to the language of publication but citations retrieved are in English only. Links may be provided to journals if published online. Evaluation of the French and Spanish versions using journal key words and a list of common diseases showed 77.5% and 86.5% accuracy respectively. User feedback was positive. PICO Linguist and BabelMeSH could be useful and convenient tools in finding current evidence sources in the medical literature especially for non-English medical terms that may be difficult to express in English.


Distal border fragments of the equine navicular bone: association between magnetic resonance imaging characteristics and clinical lameness.
Distal border fragments of the navicular bone are increasingly being detected due to the improved capabilities of magnetic resonance imaging (MRI), but their clinical significance remains unclear. The purpose of this retrospective study was to describe the location, size, and frequency of fragments in a cohort of horses presented for MRI of the foot and to compare MRI findings with severity of lameness. Archived MRI studies and medical records were searched from March 2006 to June 2008. Horses were included if a distal border fragment of the navicular bone was visible in MRI scans. Confidence interval comparisons and linear regression analyses were used to test hypotheses that fragments were associated with lameness and lameness severity was positively correlated with fragment volume and biaxial location. A total of 453 horses (874 limbs) were included. Fragments were identified in 60 horses (13.25%) and 90 limbs (10.3%). Fifty percent of the horses had unilateral fragments and 50% had bilateral fragments. Fragments were located at the lateral (62.2%), medial (8.89%), or medial and lateral (28.9%) angles of the distal border of the navicular bone. There was no increased probability of being categorized as lame if a fragment was present. There was no significant difference in fragment volume across lameness severity categorizations. Confidence intervals indicated a slightly increased probability of being classified as lame if both medial and lateral fragments were present. Findings indicated that distal border fragments of the navicular bone in equine MRI studies are unlikely to be related to existing lameness.


Kinematic, kinetic and electromyographic adaptation to speed and resistance in double poling cross country skiing.
This study incorporated variations in speed and the horizontal resistance acting upon elite female skiers during double poling (DP) on a treadmill and specifically analyzed biomechanical adaptations to these variations. Whole body kinematics and pole force data were recorded and used to calculate the moment of force acting on the shoulder and elbow joints. Data were obtained with a 3D optoelectronic system using reflective markers at given anatomical landmarks. Forces along the long axis of the right pole were measured with a piezoelectric force transducer. Surface electrodes were used to record EMG activity in the rectus femoris, rectus abdominis, latissimus dorsi and triceps brachii muscles. In a first set of recordings, the participants double poled with zero elevation at five different speeds from 8 to 17 km h(-1). In a second set of recordings, horizontal resistance was added by weights (0.4-1.9 kg) attached to a pulley system pulling the skier posteriorly during DP at 14 km h(-1). Results showed increasing relative duration of the thrust phase with increasing resistance, but not with speed. Significant kinematic differences occurred with increase in both speed and resistance. The mean (±SD) horizontal force components ranged between 1.7 (±1.3) and 2.8 (±1.1) percent (%) bodyweight (BW) in the speed adaptation and 3.1 (±0.6) and 4.0 (±1.3) % BW in the adaptation to horizontal resistance. Peak muscle activity showed a central to peripheral (proximo-distal) activation sequence. The temporal cycle phase pattern in the adaptation to speed and horizontal resistance differed.


Haemodynamic studies during the management of severe tetanus.
Detailed invasive haemodynamic studies were performed in 27 of 32 patients with severe tetanus. Nineteen had severe uncomplicated tetanus and eight had associated major complications, chiefly infection and pulmonary complications. The results were compared with those obtained from 15 healthy male volunteers who served as controls. There were two deaths in 32 patients (mortality 6.25 per cent). Severe tetanus without major complications was characterized by a high output hyperkinetic circulatory state with tachycardia (heart rate 131 (19.2) beats/minute), increased stroke volume index (43.1 (10.7) ml/m2), increased cardiac index (5.48 (0.94) l/min/m2) and a normal left ventricular stroke work index (60.5 (15.9) g/m/m2). Volume loading demonstrated a significant haemodynamic response and increased vascular capacitance. Even so the maximum percent rise from baseline values of these indices after volume load was significantly higher in controls (p < 0.001). Autonomic cardiovascular disturbances affected both sympathetic and parasympathetic activity. Hypertension and tachycardia alternating with hypotension and bradycardia were related to sudden fluctuations in systemic vascular resistance. Our studies suggested some degree of myocardial dysfunction in patients with severe uncomplicated tetanus. The haemodynamics of severe tetanus were masked and altered by complicating infection, pneumonia, and atelectasis.


Breastfeeding and the prevalence of allergic diseases in schoolchildren: Does reverse causation matter?
Infants at higher risk of allergic diseases might be breastfed for longer periods compared with infants at lower risk in the hope that breastfeeding might reduce the risk of atopic disorders. Therefore, this intention could manifest as an apparent allergy-promoting effect of breastfeeding or reverse causation. To analyze the effect of breast feeding on the prevalence of allergic diseases at school age, a large questionnaire survey was administered to the parents of schoolchildren aged 7-15 yrs. 13,215 parents responded (response rate, 90.1%). Prevalence rates of allergic diseases were compared according to the type of feeding in infancy (either complete breastfeeding, mixed feeding or complete artificial feeding). In both univariate and multivariate analysis, compared with those with complete artificial feeding, those with mixed and complete breastfeeding showed a significantly lower prevalence of bronchial asthma (BA) (p = 0.01 and 0.003, respectively). On the other hand, in univariate analysis, the prevalence of atopic dermatitis (AD) and food allergy (FA) were significantly higher in those with complete breastfeeding (p = 0.04 and 0.01, respectively). There was a significantly higher proportion of complete breastfeeding among those with greater risk of allergic diseases (presence of family history, either eczema or wheeze within 6 months after birth, or FA in infancy). Therefore, our multivariate analysis included these risks as confounding factors, and we found that the promoting effects of breastfeeding on AD and FA disappeared. In conclusion, our data clearly showed the inhibitory effect of breastfeeding on the prevalence of BA at school age. The apparent promoting effect of breastfeeding on the prevalence of AD and FA is most likely because of reverse causation.


Coffee consumption and incident dementia.
Coffee consumption has been frequently reported for its protective association with incident dementia. However, this association has mostly been reported in studies with short follow-up periods, and it remains unclear to what extent reverse causality influences this association. Studying the long-term effect of coffee consumption on dementia with stratified follow-up time may help resolve this issue. In the population-based Rotterdam Study, coffee consumption was assessed in 1989-1991 (N = 5,408), and reassessed in 1997-1999 (N = 4,368). Follow-up for dementia was complete until 2011. We investigated the association of coffee consumption and incident dementia for the two examination rounds separately using flexible parametric survival models. We studied the entire follow-up period as well as stratified follow-up time at 4 years. For both examination rounds, we did not find an association between coffee consumption and dementia over the entire follow-up. In contrast, for both examination rounds, a protective association was observed only in the follow-up stratum of 0-4 years. Our data suggest that coffee consumption is not associated with incident dementia during long-term. The protective association observed in the short-term might be driven by reverse causality.


Competition of hydrogen bonds and halogen bonds in complexes of hypohalous acids with nitrogenated bases.
A theoretical study of the complexes formed by hypohalous acids (HOX, X = F, Cl, Br, I, and At) with three nitrogenated bases (NH 3, N 2, and NCH) has been carried out by means of ab initio methods, up to MP2/aug-cc-pVTZ computational method. In general, two minima complexes are found, one with an OH...N hydrogen bond and the other one with a X...N halogen bond. While the first one is more stable for the smallest halogen derivatives, the two complexes present similar stabilities for the iodine case and the halogen-bonded structure is the most stable one for the hypoastatous acid complexes.


Expression-Based Cell Lineage Analysis in Drosophila Through a Course-Based Research Experience for Early Undergraduates.
A variety of genetic techniques have been devised to determine cell lineage relationships during tissue development. Some of these systems monitor cell lineages spatially and/or temporally without regard to gene expression by the cells, whereas others correlate gene expression with the lineage under study. The GAL4 Technique for Real-time and Clonal Expression (G-TRACE) system allows for rapid, fluorescent protein-based visualization of both current and past GAL4 expression patterns and is therefore amenable to genome-wide expression-based lineage screens. Here we describe the results from such a screen, performed by undergraduate students of the University of California, Los Angeles (UCLA) Undergraduate Research Consortium for Functional Genomics (URCFG) and high school summer scholars as part of a discovery-based education program. The results of the screen, which reveal novel expression-based lineage patterns within the brain, the imaginal disc epithelia, and the hematopoietic lymph gland, have been compiled into the G-TRACE Expression Database (GED), an online resource for use by the Drosophila research community. The impact of this discovery-based research experience on student learning gains was assessed independently and shown to be greater than that of similar programs conducted elsewhere. Furthermore, students participating in the URCFG showed considerably higher STEM retention rates than UCLA STEM students that did not participate in the URCFG, as well as STEM students nationwide.


Noninvasive imaging and analysis of skin lesions for early detection of cutaneous malignant melanoma.
Knowledge of the depth of invasion and three-dimensional (3D) characteristics of skin lesions is crucial to the early diagnosis and prognosis of malignant melanoma. These parameters are currently available only after biopsy. A clinical prototype of an optical imaging instrument, called a nevoscope, has been developed to noninvasively image skin lesions. The nevoscope provides multiple views of a transilluminated skin lesion. These views provide a three-dimensional perception of the lesion. In addition, image-analysis techniques are applied to these images to quantify various diagnostic parameters, such as 3D geometric features and surface texture and pigmentation characteristics. Clinical trials are under way to evaluate the utility of the nevoscope as a diagnostic tool for early detection of melanoma. The construction of the clinical prototype and the integrated clinical imaging environment are described. The development of iterative reconstruction techniques suitable for nevoscopy data is also described. Experimental reconstructions of a physical tissue-like phantom and an in-vivo lesion are presented. The phantom is recovered effectively. Thus, nevoscopy is of potential diagnostic value.


Chapter one: exposure measurements.
Determining human exposure to suspended particulate concentrations requires measurements that quantify different particle properties in microenvironments where people live, work, and play. Particle mass, size, and chemical composition are important exposure variables, and these are typically measured with time-integrated samples on filters that are later submitted to laboratory analyses. This requires substantial sample handling, quality assurance, and data reduction. Newer technologies are being developed that allow in-situ, time-resolved measurements for mass, carbon, sulfate, nitrate, particle size, and other variables. These are large measurement systems that are more suitable for fixed monitoring sites than for personal applications. Human exposure studies need to be designed to accomplish specific objectives rather than to serve too many purposes. Resources need to be divided among study design, field sampling, laboratory analysis, quality assurance, data management, and data analysis phases. Many exposure projects allocated too little to the non-measurement activities.


Point-of-care viral load monitoring: outcomes from a decentralized HIV programme in Malawi.
Routinely monitoring the HIV viral load (VL) of people living with HIV (PLHIV) on anti-retroviral therapy (ART) facilitates intensive adherence counselling and faster ART regimen switch when treatment failure is indicated. Yet standard VL-testing in centralized laboratories can be time-intensive and logistically difficult in low-resource settings. This paper evaluates the outcomes of the first four years of routine VL-monitoring using Point-of-Care technology, implemented by Médecins Sans Frontières (MSF) in rural clinics in Malawi. We conducted a retrospective cohort analysis of patients eligible for routine VL- testing between 2013 and 2017 in four decentralized ART-clinics and the district hospital in Chiradzulu, Malawi. We assessed VL-testing coverage and the treatment failure cascade (from suspected failure (first VL>1000 copies/mL) to VL suppression post regimen switch). We used descriptive statistics and multivariate logistic regression to assess factors associated with suspected failure. Among 21,400 eligible patients, VL-testing coverage was 85% and VL suppression was found in 89% of those tested. In the decentralized clinics, 88% of test results were reviewed on the same day as blood collection, whereas in the district hospital the median turnaround-time for results was 85 days. Among first-line ART patients with suspected failure (N = 1544), 30% suppressed (VL<1000 copies/mL), 35% were treatment failures (confirmed by subsequent VL-testing) and 35% had incomplete VL follow-up. Among treatment failures, 80% (N = 540) were switched to a second-line regimen, with a higher switching rate in the decentralized clinics than in the district hospital (86% vs. 67%, p < 0.01) and a shorter median time-to-switch (6.8 months vs. 9.7 months, p < 0.01). Similarly, the post-switch VL-testing rate was markedly higher in the decentralized clinics (61% vs. 26%, p < 0.01). Overall, 79% of patients with a post-switch VL-test were suppressed. Viral load testing at the point-of-care in Chiradzulu, Malawi achieved high coverage and good drug regimen switch rates among those identified as treatment failures. In decentralized clinics, same-day test results and shorter time-to-switch illustrated the game-changing potential of POC-based VL-testing. Nevertheless, gaps were identified along all steps of the failure cascade. Regular staff training, continuous monitoring and creating demand are essential to the success of routine VL-testing.


PERSISTENCE OF SPATIAL VARIANCE AND SPATIAL PATTERN IN THE ABUNDANCE OF A SUBMERGED PLANT.
Organisms usually benefit from heterogeneous conditions, but, by doing so, may reduce the degree of heterogeneity. The question therefore arises how heterogeneity is maintained. We investigated within-year spatiotemporal patterns in a monospecific stand of a submerged plant (fennel pondweed, Potamogeton pectinatus), with the novelty that we distinguished between different forms of heterogeneity: spatial variance (the frequency distribution of densities) and spatial pattern (the spatial distribution of densities). We repeatedly measured plant biomass that was affected by swan predation, winter mortality, and summer regrowth. Spatial variance was enhanced mostly by swan foraging, despite the fact that swans appear to exploit patches to the same threshold level. Spatial pattern, which had vanished after swan foraging, reestablished due to spatial pattern in winter mortality and was further enhanced by plant regrowth. We found that variance and pattern each have their own temporal dynamics and are maintained by different biological processes. We therefore advocate that it is pivotal to distinguish between variance and pattern in the study of spatial heterogeneity.


Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy.
Recently, de novo SCN8A missense mutations have been identified as a rare dominant cause of epileptic encephalopathies (EIEE13). Functional studies on the first described case demonstrated gain-of-function effects of the mutation. We describe a novel de novo mutation of SCN8A in a patient with epileptic encephalopathy, and functional characterization of the mutant protein. Whole exome sequencing was used to discover the variant. We generated a mutant cDNA, transfected HEK293 cells, and performed Western blotting to assess protein stability. To study channel functional properties, patch-clamp experiments were carried out in transfected neuronal ND7/23 cells. The proband exhibited seizure onset at 6 months of age, diffuse brain atrophy, and more profound developmental impairment than the original case. The mutation p.Arg233Gly in the voltage sensing transmembrane segment D1S4 was present in the proband and absent in both parents. This mutation results in a temperature-sensitive reduction in protein expression as well as reduced sodium current amplitude and density and a relative increased response to a slow ramp stimulus, though this did not result in an absolute increased current at physiological temperatures. The new de novo SCN8A mutation is clearly deleterious, resulting in an unstable protein with reduced channel activity. This differs from the gain-of-function attributes of the first SCN8A mutation in epileptic encephalopathy, pointing to heterogeneity of mechanisms. Since Nav1.6 is expressed in both excitatory and inhibitory neurons, a differential effect of a loss-of-function of Nav1.6 Arg223Gly on inhibitory interneurons may underlie the epilepsy phenotype in this patient.


Intermittently administered human parathyroid hormone(1-34) treatment increases intracortical bone turnover and porosity without reducing bone strength in the humerus of ovariectomized cynomolgus monkeys.
Cortical porosity in patients with hyperparathyroidism has raised the concern that intermittent parathyroid hormone (PTH) given to treat osteoporotic patients may weaken cortical bone by increasing its porosity. We hypothesized that treatment of ovariectomized (OVX) cynomolgus monkeys for up to 18 months with recombinant human PTH(1-34) [hPTH(1-34)] LY333334 would significantly increase porosity in the midshaft of the humerus but would not have a significant effect on the strength or stiffness of the humerus. We also hypothesized that withdrawal of PTH for 6 months after a 12-month treatment period would return porosity to control OVX values. OVX female cynomolgus monkeys were given once daily subcutaneous (sc) injections of recombinant hPTH(1-34) LY333334 at 1.0 microg/kg (PTH1), 5.0 microg/kg (PTH5), or 0.1 ml/kg per day of phosphate-buffered saline (OVX). Sham OVX animals (sham) were also given vehicle. After 12 months, PTH treatment was withdrawn from half of the monkeys in each treatment group (PTH1-W and PTH5-W), and they were treated for the remaining 6 months with vehicle. Double calcein labels were given before death at 18 months. After death, static and dynamic histomorphometric measurements were made intracortically and on periosteal and endocortical surfaces of sections from the middiaphysis of the left humerus. Bone mechanical properties were measured in the right humeral middiaphysis. PTH dose dependently increased intracortical porosity. However, the increased porosity did not have a significant detrimental effect on the mechanical properties of the bone. Most porosity was concentrated near the endocortical surface where its mechanical effect is small. In PTH5 monkeys, cortical area (Ct.Ar) and cortical thickness (Ct.Th) increased because of a significantly increased endocortical mineralizing surface. After withdrawal of treatment, porosity in PTH1-W animals declined to sham values, but porosity in PTH5-W animals remained significantly elevated compared with OVX and sham. We conclude that intermittently administered PTH(1-34) increases intracortical porosity in a dose-dependent manner but does not reduce the strength or stiffness of cortical bone.


An analysis of the use of hyperoxia for measuring venous cerebral blood volume: comparison of the existing method with a new analysis approach.
Hyperoxia is known to cause an increase in the blood oxygenation level dependent (BOLD) signal that is primarily localised to the venous vasculature. This contrast mechanism has been proposed as a way to measure venous cerebral blood volume (CBVv) without the need for more invasive contrast media. In the existing method the analysis modelled the data as a dynamic contrast agent experiment, with the assumption that the BOLD signal of tissue was dominated by intravascular signal. The effects on the accuracy of the method due to extravascular BOLD signal changes, as well as signal modulation by intersubject differences in baseline physiology, such as haematocrit and oxygen extraction fraction, have so far been unexplored. In this study the effect of extravascular signal and intersubject physiological variability was investigated by simulating the hyperoxia CBVv experiment using a detailed BOLD signal model. This analysis revealed substantial uncertainty in the measurement of CBVv using the existing analysis based on dynamic contrast agent experiments. Instead, the modelling showed a simple and direct relationship between the BOLD signal change and CBVv, and an alternative analysis method with much reduced uncertainty was proposed based on this finding. Both methods were tested experimentally, with the new method producing results that are consistent with the limited literature in this area.


Are Early Seizures Predictive of Epilepsy after a Stroke? Results of a Population-Based Study.
In addition to determining the cumulative incidence and risk factors for early seizures (ES), late seizures (LS) and post stroke epilepsy (PSE), we aimed at checking if ES represented a risk factor for epilepsy and if early treatment after ES prevented the occurrence of subsequent seizures. This study was part of a 2-year prospective community-based registry of all cerebrovascular events in the district of Udine (153,312 inhabitants), North-Eastern Italy, between April 1, 2007 and March 31, 2009. People with transient ischemic attacks (TIAs) were excluded from this study. In all, 782 cases of stroke (79.28% ischemic, 14.83% hemorrhagic, 3.20% subarachnoid hemorrhage and 2.69% undetermined) were identified. The incidence of ES, LS and PSE was 5.10, 3.14 and 2.22%, respectively. Intracerebral hemorrhage, subarachnoid hemorrhage, stroke of undetermined origin and hyponatremia, represented risk factors for ES (p < 0.05). Among ischemic strokes, ES risk factors were hyponatremia (p = 0.024) and hemorrhagic transformation (p = 0.046). LS risk factors were younger age (p = 0.004) and cortical location of stroke (p = 0.004). Within ischemic strokes, LS risk factors were younger age (p = 0.020) and cortical location (p < 0.0001). Within intracerebral hemorrhages, the only risk factor for LS was the presence of a previous ES (p = 0.017). PSE risk factors were the same as for LS. All acute conditions related to the occurrence of stroke are implicated in the pathogenesis of ES, which becomes a risk factor for LS only in the setting of intracerebral hemorrhages. Therefore, early antiepileptic treatment is needed only in this situation.


Sources of variation in consumer-diet delta 15N enrichment: a meta-analysis.
Measurements of delta15N of consumers are usually higher than those of their diet. This general pattern is widely used to make inferences about trophic relationships in ecological studies, although the underlying mechanisms causing the pattern are poorly understood. However, there can be substantial variation in consumer-diet delta15N enrichment within this general pattern. We conducted an extensive literature review, which yielded 134 estimates from controlled studies of consumer-diet delta15N enrichment, to test the significance of several potential sources of variation by means of meta-analyses. We found patterns related to processes of nitrogen assimilation and excretion. There was a significant effect of the main biochemical form of nitrogenous waste: ammonotelic organisms show lower delta15N enrichment than ureotelic or uricotelic organisms. There were no significant differences between animals feeding on plant food, animal food, or manufactured mixtures, but detritivores yielded significantly lower estimates of enrichment. delta15N enrichment was found to increase significantly with the C:N ratio of the diet, suggesting that a nitrogen-poor diet can have an effect similar to that already documented for fasting organisms. There were also differences among taxonomic classes: molluscs and crustaceans generally yielded lower delta15N enrichment. The lower delta 15N enrichment might be related to the fact that molluscs and crustaceans excrete mainly ammonia, or to the fact that many were detritivores. Organisms inhabiting marine environments yielded significantly lower estimates of delta15N enrichment than organisms inhabiting terrestrial or freshwater environments, a pattern that was influenced by the number of marine, ammonotelic, crustaceans and molluscs. Overall, our analyses point to several important sources of variation in delta15N enrichment and suggest that the most important of them are the main biochemical form of nitrogen excretion and nutritional status. The variance of estimates of delta15N enrichment, as well as the fact that enrichment may be different in certain groups of organisms should be taken into account in statistical approaches for studying diet and trophic relationships.


Geographic Representativeness of a Web-Based Smoking Cessation Intervention: Reach Equity Analysis.
Cigarette smoking is the leading cause of preventable death and disease in the United States. Smoking prevalence is higher in rural areas than in metropolitan areas, due partly to differences in access to cessation treatment. With internet use at 89% of all US adults, digital approaches could increase use of cessation treatment and reduce smoking. We investigated the extent to which smokers from rural areas use a digital cessation resource. We compared the geographic distribution of registered users of a free Web-based smoking cessation program with the geographic distribution of US smokers. We mapped user-provided ZIP codes to Rural-Urban Continuum Codes. A total of 59,050 of 118,574 users (49.80%) provided valid ZIP codes from 2013 to 2017. We used US National Survey of Drug Use and Health data from 2013 to 2017 to compare the geographic distribution of our sample of Web-based cessation users with the geographic distribution of US smokers. Reach ratios and 95% confidence intervals quantified the extent to which rural smokers' representation in the sample was proportionate to their representation in the national smoking population. Reach ratios less than 1 indicate underrepresentation. Smokers from rural areas were significantly underrepresented in 2013 (reach ratio 0.89, 95% CI 0.87-0.91) and 2014 (reach ratio 0.89, 95% CI 0.86-0.92), proportionally represented in 2015 (reach ratio 1.08, 95% CI 1.02-1.14) and 2016 (reach ratio 1.03, 95% CI 0.94-1.14), and proportionally overrepresented in 2017 (reach ratio 1.16, 95% CI 1.12-1.21). Smokers from Large Metro areas were proportionally represented in 2013 and 2014 but underrepresented in 2015 (reach ratio 0.97, 95% CI 0.94-1.00), 2016 (reach ratio 0.89, 95% CI 0.85-0.94), and 2017 (reach ratio 0.89, 95% CI 0.86-0.91). Results suggest that smokers from rural areas are more than proportionally reached by a long-standing digital cessation intervention. The underrepresentation of smokers from Large Metro areas warrants further study.


Transdisciplinary synthesis for ecosystem science, policy and management: The Australian experience.
Mitigating the environmental effects of global population growth, climatic change and increasing socio-ecological complexity is a daunting challenge. To tackle this requires synthesis: the integration of disparate information to generate novel insights from heterogeneous, complex situations where there are diverse perspectives. Since 1995, a structured approach to inter-, multi- and trans-disciplinary(1) collaboration around big science questions has been supported through synthesis centres around the world. These centres are finding an expanding role due to ever-accumulating data and the need for more and better opportunities to develop transdisciplinary and holistic approaches to solve real-world problems. The Australian Centre for Ecological Analysis and Synthesis (ACEAS <http://www.aceas.org.au>) has been the pioneering ecosystem science synthesis centre in the Southern Hemisphere. Such centres provide analysis and synthesis opportunities for time-pressed scientists, policy-makers and managers. They provide the scientific and organisational environs for virtual and face-to-face engagement, impetus for integration, data and methodological support, and innovative ways to deliver synthesis products. We detail the contribution, role and value of synthesis using ACEAS to exemplify the capacity for synthesis centres to facilitate trans-organisational, transdisciplinary synthesis. We compare ACEAS to other international synthesis centres, and describe how it facilitated project teams and its objective of linking natural resource science to policy to management. Scientists and managers were brought together to actively collaborate in multi-institutional, cross-sectoral and transdisciplinary research on contemporary ecological problems. The teams analysed, integrated and synthesised existing data to co-develop solution-oriented publications and management recommendations that might otherwise not have been produced. We identify key outcomes of some ACEAS working groups which used synthesis to tackle important ecosystem challenges. We also examine the barriers and enablers to synthesis, so that risks can be minimised and successful outcomes maximised. We argue that synthesis centres have a crucial role in developing, communicating and using synthetic transdisciplinary research.


Independent component analysis as a tool to eliminate artifacts in EEG: a quantitative study.
Independent component analysis (ICA) is a novel technique that calculates independent components from mixed signals. A hypothetical clinical application is to remove artifacts in EEG. The goal of this study was to apply ICA to standard EEG recordings to eliminate well-known artifacts, thus quantifying its efficacy in an objective way. Eighty samples of recordings with spikes and evident artifacts of electrocardiogram (EKG), eye movements, 50-Hz interference, muscle, or electrode artifact were studied. ICA components were calculated using the Joint Approximate Diagonalization of Eigen-matrices (JADE) algorithm. The signal was reconstructed excluding those components related to the artifacts. A normalized correlation coefficient was used as a measure of the changes caused by the suppression of these components. ICA produced an evident clearing-up of signals in all the samples. The morphology and the topography of the spike were very similar before and after the removal of the artifacts. The correlation coefficient showed that the rest of the signal did not change significantly. Two examiners independently looked at the samples to identify the changes in the morphology and location of the discharge and the artifacts. In conclusion, ICA proved to be a useful tool to clean artifacts in short EEG samples, without having the disadvantages associated with the digital filters. The distortion of the interictal activity measured by correlation analysis was minimal.


Community- versus healthcare-acquired bloodstream infections at Groote Schuur Hospital, Cape Town, South Africa.
Bloodstream infections (BSIs) cause considerable morbidity and mortality. The epidemiology of bacterial infections differs in community and hospital settings. Regular surveillance and reporting of pathogens and antimicrobial susceptibility can assist in appropriate management of BSIs. To describe the distribution of organisms and of antibiotic susceptibility among isolates from blood cultures at a tertiary academic hospital during a 1-year period, stratifying by place of infection acquisition. This was a retrospective descriptive study of bloodstream isolates from cultures from adults (>13 years of age) routinely submitted between 1 October 2011 and 30 September 2012 to the clinical laboratory at Groote Schuur Hospital, Cape Town, South Africa. Community-acquired infections were compared with healthcare-acquired infections, defined as infections developing at least 48 hours after admission or within 3 months of admission to a healthcare facility. Frequencies and proportions of infecting organisms are presented, along with susceptibility results for selected pathogens. The hospital-acquired isolates were stratified by ward (emergency, general medical or general surgical ward or intensive care unit (ICU)) to determine organism frequency and susceptibility patterns by hospital ward. Among adults, 740 non-duplicate pathogens were isolated from BSIs. Nearly three-quarters of infections were healthcare acquired. Enterobacteriaceae and non-fermentative Gram-negative bacilli were predominant among healthcare-acquired pathogens (39.2% and 28.5%, respectively), while Enterobacteriaceae and Gram-positive organisms were the most common among community-acquired pathogens (39.2% and 54.3%, respectively). The majority of community-acquired Enterobacteriaceae were highly susceptible to antibiotics (gentamicin 95.6%, ceftriaxone 96.1% and ciprofloxacin 92.2%), whereas 64.6% of healthcare-associated isolates were susceptible to gentamicin, 58.5% to ceftriaxone and 70% to ciprofloxacin. All community-acquired Staphylococcus aureus isolates v. 52.4% of healthcare-acquired isolates were susceptible to cloxacillin. The susceptibility of healthcare-acquired Pseudomonas aeruginosa and Acinetobacter baumanii complex isolates was <80% to all antibiotics with the exception of colistin. Klebsiella spp., S. aureus and Escherichia coli were the commonest causes of healthcare-acquired infections in all areas outside of the ICUs, whereas Acinetobacter was common in the ICUs and rare in all other areas. The distinction between community- and healthcare-acquired infections is critical in antibiotic selection because narrow-spectrum agents can be utilised for community-acquired infections. The considerable antibiotic resistance of healthcare-acquired pathogens highlights the importance of infection prevention and control. This type of surveillance could be incorporated into routine laboratory practice.


Serum From Melioidosis Survivors Diminished Intracellular Burkholderia pseudomallei Growth in Macrophages: A Brief Research Report.
Melioidosis is a neglected tropical disease with high mortality rate. It is caused by the Gram-negative, CDC category B select agent Burkholderia pseudomallei (B. ps) that is intrinsically resistant to first-line antibiotics. An antibody-based vaccine is likely to be the most effective control measure. Previous studies have demonstrated significant mechanistic roles of antibodies in protection against death in animal models, but data from human melioidosis is scarce. Herein, we used in-vitro antibody-dependent cellular phagocytosis and growth inhibition assays to assess the mechanism of protective antibodies in patients with acute melioidosis. We found that serum from patients who survived the disease enable more live B. ps to be engulfed by THP-1 derived macrophages (median 1.7 × 103 CFU/ml, IQR 1.1 × 103-2.5 × 103 CFU/ml) than serum from patients who did not survive (median 1.2 × 103 CFU/ml, IQR 0.7 × 103-1.8 × 103, p = 0.02). In addition, the intracellular growth rate of B. ps pre-opsonized with serum from survivors (median 7.89, IQR 5.58-10.85) was diminished when compared with those with serum from non-survivors (median 10.88, IQR 5.42-14.88, p = 0.04). However, the difference of intracellular bacterial growth rate failed to reach statistical significance when using purified IgG antibodies (p = 0.09). These results provide new insights into a mechanistic role of serum in protection against death in human melioidosis for antibody-based vaccine development.


Extensive chordate and annelid macrosynteny reveals ancestral homeobox gene organization.
Genes with the homeobox motif are crucial in developmental biology and widely implicated in the evolution of development. The Antennapedia (ANTP)-class is one of the two major classes of animal homeobox genes, and includes the Hox genes, renowned for their role in patterning the anterior-posterior axis of animals. The origin and evolution of the ANTP-class genes are a matter of some debate. A principal guiding hypothesis has been the existence of an ancient gene Mega-cluster deep in animal ancestry. This hypothesis was largely established from linkage data from chordates, and the Mega-cluster hypothesis remains to be seriously tested in protostomes. We have thus mapped ANTP-class homeobox genes to the chromosome level in a lophotrochozoan protostome. Our comparison of gene organization in Platynereis dumerilii and chordates indicates that the Mega-cluster, if it did exist, had already been broken up onto four chromosomes by the time of the protostome-deuterostome ancestor (PDA). These results not only elucidate an aspect of the genome organization of the PDA but also reveal high levels of macrosynteny between P. dumerilii and chordates. This implies a very low rate of interchromosomal genome rearrangement in the lineages leading to P. dumerilii and the chordate ancestor since the time of the PDA.


Species and gene divergence in Littorina snails detected by array comparative genomic hybridization.
Array comparative genomic hybridization (aCGH) is commonly used to screen different types of genetic variation in humans and model species. Here, we performed aCGH using an oligonucleotide gene-expression array for a non-model species, the intertidal snail Littorina saxatilis. First, we tested what types of genetic variation can be detected by this method using direct re-sequencing and comparison to the Littorina genome draft. Secondly, we performed a genome-wide comparison of four closely related Littorina species: L. fabalis, L. compressa, L. arcana and L. saxatilis and of populations of L. saxatilis found in Spain, Britain and Sweden. Finally, we tested whether we could identify genetic variation underlying "Crab" and "Wave" ecotypes of L. saxatilis. We could reliably detect copy number variations, deletions and high sequence divergence (i.e. above 3%), but not single nucleotide polymorphisms. The overall hybridization pattern and number of significantly diverged genes were in close agreement with earlier phylogenetic reconstructions based on single genes. The trichotomy of L. arcana, L. compressa and L. saxatilis could not be resolved and we argue that these divergence events have occurred recently and very close in time. We found evidence for high levels of segmental duplication in the Littorina genome (10% of the transcripts represented on the array and up to 23% of the analyzed genomic fragments); duplicated genes and regions were mostly the same in all analyzed species. Finally, this method discriminated geographically distant populations of L. saxatilis, but we did not detect any significant genome divergence associated with ecotypes of L. saxatilis. The present study provides new information on the sensitivity and the potential use of oligonucleotide arrays for genotyping of non-model organisms. Applying this method to Littorina species yields insights into genome evolution following the recent species radiation and supports earlier single-gene based phylogenies. Genetic differentiation of L. saxatilis ecotypes was not detected in this study, despite pronounced innate phenotypic differences. The reason may be that these differences are due to single-nucleotide polymorphisms.


Change practice now! Using atraumatic needles to prevent post lumbar puncture headache.
Lumbar puncture (LP) is a key diagnostic procedure in medicine. Post lumbar puncture headache (PLPHA) is a well recognized complication of LP. Evidence suggests that using atraumatic needles for diagnostic LP (ATNLP) reduces risk of PLPHA. However, clinicians in Europe and the USA routinely use traumatic needles for diagnostic LP (TNLP). The occurrence of PLPHA following ATNLP and TNLP was compared in a clinical setting. Further, a survey was performed exploring use of ATNLP amongst UK neurologists. Service development study. Patients were followed up 2 and 7 days after LP using blinded telephone assessment. A questionnaire was developed to assess use of ATNLP amongst UK neurologists. Frequency, onset, duration and severity of PLPHA were recorded as were use of analgesia, general practitioner consultations, hospital readmissions, days off work due to PLPHA and cost. Neurologists were asked about their familiarity with, and use of, ATNLP. One hundred and nine participants attending the Royal London Hospital were included, and 74 attendees of the Association of British Neurologists 2012 conference completed an on-site questionnaire. ATNLP reduced the rate of PLPHA (27.1% vs. 60.4%; P < 0.01). In those participants who developed PLPHA symptoms were short lived (mean 50 h vs. 94 h, P = 0.02) and less severe after ATNLP. Use of ATNLP led to significant cost savings. Only one in five UK neurologists regularly use ATNLP stating lack of training and availability of atraumatic needles as main reasons. ATNLP significantly reduces the risk of PLPHA. Training is required 3 to facilitate a change from TNLP to ATNLP amongst clinicians.


Feasibility of a randomized controlled trial to assess treatment of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection in Saudi Arabia: a survey of physicians.
The Middle East Respiratory Syndrome coronavirus (MERS-CoV) is an emerging respiratory pathogen with a high mortality rate and no specific treatments available to date. The purpose of this study was to determine the feasibility of conducting a randomized controlled trial (RCT) of convalescent plasma therapy for MERS-CoV-infected patients by using MERS-CoV-specific convalescent plasma obtained from previously recovered patients. A survey was adapted from validated questionnaire originally aimed to measure network capacities and capabilities within the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC). The questionnaire was modified for this study to include 26 items that were divided into three main domains of interest: (1) the ability to care for critically ill MERS-CoV patients; (2) laboratory capacity to diagnose MERS-CoV and blood bank ability to prepare convalescent plasma; and (3), research capacity to conduct randomized controlled trials. The questionnaire was emailed to physicians. Of 582 physicians who were invited to the survey, 327 responded (56.2 %). The professional focus of the majority of respondents was critical care (106/249 (43 %)), pediatrics (59/249, (24 %)) or internal medicine (52/249 (21 %)) but none was blood banking. Nearly all respondents (251/263 (95 %)) reported to have access to ICU facilities within their institutions. Most respondents (219/270 (81 %)) reported that intensivists were the most physician group responsible for treatment decisions about critically ill SARI patients. While 125/165 respondents (76 %) reported that they conduct research in ICUs, and 80/161 (49.7 %) had been involved in the conduct of RCTs, including using a placebo comparison (60/161 (37 %)), only 49/226 (21 %) of respondents regularly participated in research networks. Our survey indicated that in the Kingdom of Saudi Arabia (KSA), ICUs are the most likely clinical locations for conducting a clinical trial of convalescent plasma therapy for MERS-CoV, and that most ICUs have experience with such research designs.


A trans-diagnostic perspective on obsessive-compulsive disorder.
Progress in understanding the underlying neurobiology of obsessive-compulsive disorder (OCD) has stalled in part because of the considerable problem of heterogeneity within this diagnostic category, and homogeneity across other putatively discrete, diagnostic categories. As psychiatry begins to recognize the shortcomings of a purely symptom-based psychiatric nosology, new data-driven approaches have begun to be utilized with the goal of solving these problems: specifically, identifying trans-diagnostic aspects of clinical phenomenology based on their association with neurobiological processes. In this review, we describe key methodological approaches to understanding OCD from this perspective and highlight the candidate traits that have already been identified as a result of these early endeavours. We discuss how important inferences can be made from pre-existing case-control studies as well as showcasing newer methods that rely on large general population datasets to refine and validate psychiatric phenotypes. As exemplars, we take 'compulsivity' and 'anxiety', putatively trans-diagnostic symptom dimensions that are linked to well-defined neurobiological mechanisms, goal-directed learning and error-related negativity, respectively. We argue that the identification of biologically valid, more homogeneous, dimensions such as these provides renewed optimism for identifying reliable genetic contributions to OCD and other disorders, improving animal models and critically, provides a path towards a future of more targeted psychiatric treatments.


Colposcopic evaluation of cervix with persistent inflammatory Pap smear: A prospective analytical study.
Inflammatory Pap smear is the most common report received by a gynecologist. The cervical screening algorithm for benign cellular changes on the Pap smear recommends treatment of infection if indicated and a repeat Pap smear in 4 to 6 months time. If the inflammatory changes still persist, subject the patient to colposcopy. However, in practice, this is not followed, especially in developing countries like ours where proper screening protocols are not available. Hence, a good number of patients in the premalignant stage are being missed. This study was undertaken to evaluate patients with persistent inflammatory Pap smears without atypia using colposcopy. A prospective analytical study of 150 gynecologial patients with persistent inflammatory Pap smear between 2006 and 2008 in an out-patient setting. All of them were subjected to colposcopy and biopsy from the abnormal areas. The incidence of cervical intraepithelial neoplasia (CIN)/invasive carcinoma was calculated by proportions/percentages. The incidence of invasive carcinoma was <1%. But, the incidence of pre-malignant lesions (CIN) was high (20.9%). CIN 2/3 and carcinoma in situ were present in 6.9% of the cases. Patients with persistent inflammatory Pap smears can harbour a high proportion of CIN and hence these patients will need further evaluation.


Yeast biomass production: a new approach in glucose-limited feeding strategy.
The aim of this work was to implement experimentally a simple glucose-limited feeding strategy for yeast biomass production in a bubble column reactor based on a spreadsheet simulator suitable for industrial application. In biomass production process using Saccharomyces cerevisiae strains, one of the constraints is the strong tendency of these species to metabolize sugars anaerobically due to catabolite repression, leading to low values of biomass yield on substrate. The usual strategy to control this metabolic tendency is the use of a fed-batch process in which where the sugar source is fed incrementally and total sugar concentration in broth is maintained below a determined value. The simulator presented in this work was developed to control molasses feeding on the basis of a simple theoretical model in which has taken into account the nutritional growth needs of yeast cell and two input data: the theoretical specific growth rate and initial cell biomass. In experimental assay, a commercial baker's yeast strain and molasses as sugar source were used. Experimental results showed an overall biomass yield on substrate of 0.33, a biomass increase of 6.4 fold and a specific growth rate of 0.165 h(-1) in contrast to the predicted value of 0.180 h-1 in the second stage simulation.


Pediatric palliative care and inpatient hospital costs: a longitudinal cohort study.
Pediatric palliative care (PPC) improves the quality of life for children with life-limiting conditions, but the cost of care associated with PPC has not been quantified. This study examined the association between inpatient cost and receipt of PPC among high-cost inpatients. The 10% most costly inpatients treated at a children's hospital in 2010 were studied, and factors associated with receipt of PPC were determined. Among patients dying during 2010, we compared 2010 inpatient costs between PPC recipients and nonrecipients. Inpatient costs during the 2-year follow up period between PPC recipients and nonrecipients were also compared. Patients were analyzed in 2 groups: those who died and those who survived the 2-year follow-up. Of 902 patients, 86 (10%) received PPC. Technology dependence, older age, multiple chronic conditions, PICU admission, and death in 2010 were independently associated with receipt of PPC. PPC recipients had increased inpatient costs compared with nonrecipients during 2010. Among patients who died during the 2-year follow-up, PPC recipients had significantly lower inpatient costs. Among survivors, PPC recipients had greater inpatient costs. When controlling for patient complexity, differences in inpatient costs were not significant. The relationship of PPC to inpatient costs is complex. PPC seems to lower costs among patients approaching death. Patients selectively referred to PPC who survive most often do so with chronic serious illnesses that predispose them to remain lifelong high-resource utilizers.


Classification of transient behaviours in a time-dependent toggle switch model.
Waddington's epigenetic landscape is an intuitive metaphor for the developmental and evolutionary potential of biological regulatory processes. It emphasises time-dependence and transient behaviour. Nowadays, we can derive this landscape by modelling a specific regulatory network as a dynamical system and calculating its so-called potential surface. In this sense, potential surfaces are the mathematical equivalent of the Waddingtonian landscape metaphor. In order to fully capture the time-dependent (non-autonomous) transient behaviour of biological processes, we must be able to characterise potential landscapes and how they change over time. However, currently available mathematical tools focus on the asymptotic (steady-state) behaviour of autonomous dynamical systems, which restricts how biological systems are studied. We present a pragmatic first step towards a methodology for dealing with transient behaviours in non-autonomous systems. We propose a classification scheme for different kinds of such dynamics based on the simulation of a simple genetic toggle-switch model with time-variable parameters. For this low-dimensional system, we can calculate and explicitly visualise numerical approximations to the potential landscape. Focussing on transient dynamics in non-autonomous systems reveals a range of interesting and biologically relevant behaviours that would be missed in steady-state analyses of autonomous systems. Our simulation-based approach allows us to identify four qualitatively different kinds of dynamics: transitions, pursuits, and two kinds of captures. We describe these in detail, and illustrate the usefulness of our classification scheme by providing a number of examples that demonstrate how it can be employed to gain specific mechanistic insights into the dynamics of gene regulation. The practical aim of our proposed classification scheme is to make the analysis of explicitly time-dependent transient behaviour tractable, and to encourage the wider use of non-autonomous models in systems biology. Our method is applicable to a large class of biological processes.


Narrative competence among hearing-impaired and normal-hearing children: analytical cross-sectional study.
oral narrative is a means of language development assessment. However, standardized data for deaf patients are scarce. The aim here was to compare the use of narrative competence between hearing-impaired and normal-hearing children. analytical cross-sectional study at the Department of Speech-Language and Hearing Sciences, Universidade Federal de São Paulo. twenty-one moderately to profoundly bilaterally hearing-impaired children (cases) and 21 normal-hearing children without language abnormalities (controls), matched according to sex, age, schooling level and school type, were studied. A board showing pictures in a temporally logical sequence was presented to each child, to elicit a narrative, and the child's performance relating to narrative structure and cohesion was measured. The frequencies of variables, their associations (Mann-Whitney test) and their 95% confidence intervals was analyzed. the deaf subjects showed poorer performance regarding narrative structure, use of connectives, cohesion measurements and general punctuation (P < 0.05). There were no differences in the number of propositions elaborated or in referent specification between the two groups. The deaf children produced a higher proportion of orientation-related propositions (P = 0.001) and lower proportions of propositions relating to complicating actions (P = 0.015) and character reactions (P = 0.005). hearing-impaired children have abnormalities in different aspects of language, involving form, content and use, in relation to their normal-hearing peers. Narrative competence was also associated with the children's ages and the school type.


Mechanistic analysis of aliphatic β-lactones in Vibrio harveyi reveals a quorum sensing independent mode of action.
N-Acylhomoserine lactones are autoinducers of quorum sensing (QS) in Gram-negative bacteria. We exploit here the role of structurally related β-lactones in the inhibition of Vibrio harveyi bioluminescence and identify a derivative with nanomolar potency. Surprisingly, QS was not affected and combined proteomic/biochemical studies revealed insights into the cellular mode of action.


A study on expertise of agents and its effects on cooperative Q-learning.
Cooperation in learning (CL) can be realized in a multiagent system, if agents are capable of learning from both their own experiments and other agents' knowledge and expertise. Extra resources are exploited into higher efficiency and faster learning in CL as compared to that of individual learning (IL). In the real world, however, implementation of CL is not a straightforward task, in part due to possible differences in area of expertise (AOE). In this paper, reinforcement-learning homogenous agents are considered in an environment with multiple goals or tasks. As a result, they become expert in different domains with different amounts of expertness. Each agent uses a one-step Q-learning algorithm and is capable of exchanging its Q-table with those of its teammates. Two crucial questions are addressed in this paper: "How the AOE of an agent can be extracted?" and "How agents can improve their performance in CL by knowing their AOEs?" An algorithm is developed to extract the AOE based on state transitions as a gold standard from a behavioral point of view. Moreover, it is discussed that the AOE can be implicitly obtained through agents' expertness in the state level. Three new methods for CL through the combination of Q-tables are developed and examined for overall performance after CL. The performances of developed methods are compared with that of IL, strategy sharing (SS), and weighted SS (WSS). Obtained results show the superior performance of AOE-based methods as compared to that of existing CL methods, which do not use the notion of AOE. These results are very encouraging in support of the idea that "cooperation based on the AOE" performs better than the general CL methods.


The cotton rat (Sigmodon hispidus) is a permissive small animal model of human metapneumovirus infection, pathogenesis, and protective immunity.
Human metapneumovirus (hMPV) is a newly described paramyxovirus that is an important cause of acute respiratory tract disease. We undertook to develop a small animal model of hMPV infection, pathogenesis, and protection. Hamsters, guinea pigs, cotton rats, and nine inbred strains of mice were inoculated intranasally with hMPV. The animals were sacrificed, and nasal and lung tissue virus yields were determined by plaque titration. None of the animals exhibited respiratory symptoms. The quantity of virus present in the nasal tissue ranged from 4.6 x 10(2) PFU/gram tissue (C3H mice) to greater than 10(5) PFU/gram (hamster). The amount of virus in the lungs was considerably less than in nasal tissue in each species tested, ranging from undetectable (<5 PFU/g; guinea pigs) to 1.8 x 10(5) PFU/gram (cotton rat). The peak virus titer in cotton rat lungs occurred on day 4 postinfection. hMPV-infected cotton rat lungs examined on day 4 postinfection exhibited histopathological changes consisting of peribronchial inflammatory infiltrates. Immunohistochemical staining detected virus only at the luminal surfaces of respiratory epithelial cells throughout the respiratory tract. hMPV-infected cotton rats mounted virus-neutralizing antibody responses and were partially protected against virus shedding and lung pathology on subsequent rechallenge with hMPV. Viral antigen was undetectable in the lungs on challenge of previously infected animals. This study demonstrates that the cotton rat is a permissive small animal model of hMPV infection that exhibits lung histopathology associated with infection and that primary infection protected animals against subsequent infection. This model will allow further in vivo studies of hMPV pathogenesis and evaluation of vaccine candidates.


Acetyl-L-carnitine for dementia.
Dementia is a common mental health problem affecting 5% of those over 65. Various pathological processes are linked to memory impairment in dementia, particularly those affecting the cholinergic neurotransmitter system. Acetyl-l-carnitine (ALC) is derived from carnitine and is described as having several properties which may be beneficial in dementia. This includes activity at cholinergic neurons, membrane stabilization and enhancing mitochondrial function. Work on the effects of ALC has been ongoing since the 1980s yet the efficacy of ALC in cognitive decline remains unclear. Early studies suggested a beneficial effect of ALC on cognition and behaviour in aging subjects. However, later, larger studies have not supported these findings. Some of the difficulties lie in the early and later studies differing widely in methodology and assessment tools used, and are therefore difficult to compare. ALC is not currently in routine clinical use. The objective of this review is to establish whether Acetyl-l-carnitine is clinically effective in the treatment of people with dementia. The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 8 January 2003 using the terms acetyl-l-carnitine, l-carnitine acetyl ester, acetylcarnitine. All double-blind, randomized, trials involving people with dementia in which treatment with ALC was compared with a placebo group Data were extracted by a reviewer (SH) and entered into Revman 4.1 software. Where possible intention-to-treat data were used, but most of the analyses were of completers (people who completed the study). There are 11 included trials, all of which had restricted the participants to people with Alzheimer's disease. All trials assessed the cognitive effects of ALC and in addition six considered severity of dementia, six considered functional ability and six considered clinical global impression. There were statistically significant treatment effects in favour of ALC at 12 and 24 weeks for the numbers showing improvement as determined by Clinical Global Impression, [OR 2.33, 95% CI 1.25 to 4.35, P<0.01] and [OR 3.91, 95% CI 1.32 to 11.54, P=0.01] but not as determined by the CIGIC at 52 weeks. There was no evidence of benefit for ALC in the areas of cognition, severity of dementia, functional ability or Clinical Global Impression as a continuous measure. Various adverse events were reported, but from the meta-analyses there were no statistically significant differences between treated and placebo groups. There is evidence for benefit of ALC on clinical global impression, but there was no evidence using objective assessments in any other area of outcome. Given the large number of comparisons made, the statistically significant result may be due to chance. At present there is no evidence to recommend its routine use in clinical practice. Although the intention of the review was to access ALC for the treatment of all dementias, the included trials had confined themselves to participants with Alzheimer's disease. Individual patient data may add to the findings, as would trials including other types of dementia and other outcomes (e.g. mood and caregiver quality of life). However, the evidence does not suggest that ALC is likely to prove an important therapeutic agent. More work on the pharmacokinetics of ALC in humans is also required.


One-way transmission through the subwavelength slit in nonsymmetric metallic gratings.
An approach for obtaining one-way transmission in the beaming regime is suggested that is based on the directional radiation of surface plasmons in nonsymmetric metallic gratings with a single slit. In contrast to the various nonsymmetric one-way diffraction gratings that have recently been proposed, the possibility of obtaining of narrow beams is demonstrated. Strong directional selectivity can appear a wide range of the observation angles, while the angle of incidence is retained.


On the accuracy of explicitly correlated coupled-cluster interaction energies--have orbital results been beaten yet?
The basis set convergence of weak interaction energies for dimers of noble gases helium through krypton is studied for six variants of the explicitly correlated, frozen geminal coupled-cluster singles, doubles, and noniterative triples [CCSD(T)-F12] approach: the CCSD(T)-F12a, CCSD(T)-F12b, and CCSD(T)(F12*) methods with scaled and unscaled triples. These dimers were chosen because CCSD(T) complete-basis-set (CBS) limit benchmarks are available for them to a particularly high precision. The dependence of interaction energies on the auxiliary basis sets has been investigated and it was found that the default resolution-of-identity sets cc-pVXZ/JKFIT are far from adequate in this case. Overall, employing the explicitly correlated approach clearly speeds up the basis set convergence of CCSD(T) interaction energies, however, quite surprisingly, the improvement is not as large as the one achieved by a simple addition of bond functions to the orbital basis set. Bond functions substantially improve the CCSD(T)-F12 interaction energies as well. For small and moderate bases with bond functions, the accuracy delivered by the CCSD(T)-F12 approach cannot be matched by conventional CCSD(T). However, the latter method in the largest available bases still delivers the CBS limit to a better precision than CCSD(T)-F12 in the largest bases available for that approach. Our calculations suggest that the primary reason for the limited accuracy of the large-basis CCSD(T)-F12 treatment are the approximations made at the CCSD-F12 level and the non-explicitly correlated treatment of triples. In contrast, the explicitly correlated second-order Mo̸ller-Plesset perturbation theory (MP2-F12) approach is able to pinpoint the complete-basis-set limit MP2 interaction energies of rare gas dimers to a better precision than conventional MP2. Finally, we report and analyze an unexpected failure of the CCSD(T)-F12 method to deliver the core-core and core-valence correlation corrections to interaction energies consistently and accurately.


Treatment outcomes of patients on second-line antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis.
A growing proportion of patients on antiretroviral therapy in resource-limited settings have switched to second-line regimens. We carried out a systematic review in order to summarize reported rates and reasons for virological failure among people on second-line therapy in resource-limited settings. Two reviewers independently searched four databases and three conference websites. Full text articles were screened and data extracted using a standardized data extraction form. We retrieved 5812 citations, of which 19 studies reporting second-line failure rates in 2035 patients across low-income and middle-income countries were eligible for inclusion. The cumulative pooled proportion of adult patients failing virologically was 21.8, 23.1, 26.7 and 38.0% at 6, 12, 24 and 36 months, respectively. Most studies did not report adequate information to allow discrimination between drug resistance and poor adherence as reasons for virological failure, but for those that did poor adherence appeared to be the main driver of virological failure. Mortality on second-line was low across all time points. Rates of virological failure on second-line therapy are high in resource-limited settings and associated with duration of exposure to previous drug regimens and poor adherence. The main concern appears to be poor adherence, rather than drug resistance, from the limited number of studies accessing both factors. Access to treatment options beyond second-line remains limited and, therefore, a cause for a concern for those patients in whom drug resistance is the identified cause of virological failure.