Phasic dopamine release in the nucleus accumbens in response to pro-social 50 kHz ultrasonic vocalizations in rats.
Rats emit ultrasonic vocalizations (USVs) that are thought to serve as situation-dependent affective signals and accomplish important communicative functions. In appetitive situations, rats produce 50 kHz USVs, whereas 22 kHz USVs occur in aversive situations. Reception of 50 kHz USVs induces social approach behavior, while 22 kHz USVs lead to freezing behavior. These opposite behavioral responses are paralleled by distinct brain activation patterns, with 50 kHz USVs, but not 22 kHz USVs, activating neurons in the nucleus accumbens (NAcc). The NAcc mediates appetitive behavior and is critically modulated by dopaminergic afferents that are known to encode the value of reward. Therefore, we hypothesized that 50 kHz USVs, but not 22 kHz USVs, elicit NAcc dopamine release. While recording dopamine signaling with fast-scan cyclic voltammetry, freely moving rats were exposed to playback of four acoustic stimuli via an ultrasonic speaker in random order: (1) 50 kHz USVs, (2) 22 kHz USVs, (3) time- and amplitude-matched white noise, and (4) background noise. Only presentation of 50 kHz USVs induced phasic dopamine release and elicited approach behavior toward the speaker. Both of these effects, neurochemical and behavioral, were most pronounced during initial playback, but then declined rapidly with subsequent presentations, indicating a close temporal relationship between the two measures. Moreover, the magnitudes of these effects during initial playback were significantly correlated. Collectively, our findings show that NAcc dopamine release encodes pro-social 50 kHz USVs, but not alarming 22 kHz USVs. Thus, our results support the hypothesis that these call types are processed in distinct neuroanatomical regions and establish a functional link between pro-social communicative signals and reward-related neurotransmission.


Diffusion in crowded biological environments: applications of Brownian dynamics.
Biochemical reactions in living systems occur in complex, heterogeneous media with total concentrations of macromolecules in the range of 50 - 400 mgml. Molecular species occupy a significant fraction of the immersing medium, up to 40% of volume. Such complex and volume-occupied environments are generally termed 'crowded' and/or 'confined'. In crowded conditions non-specific interactions between macromolecules may hinder diffusion - a major process determining metabolism, transport, and signaling. Also, the crowded media can alter, both qualitatively and quantitatively, the reactions in vivo in comparison with their in vitro counterparts. This review focuses on recent developments in particle-based Brownian dynamics algorithms, their applications to model diffusive transport in crowded systems, and their abilities to reproduce and predict the behavior of macromolecules under in vivo conditions.


Modelling oral malodour from a tongue biofilm.
A new model about the genesis of malodour emanating from the tongue is introduced. A new approach uses mathematical formulae to combine existing empirical knowledge and bring it into context. The resulting description of halitosis includes the three-dimensional structure of the tongue dorsum surface as the substratum, and the transfer of oxygen and metabolites based on a four-dimensional partial differential equation solved by finite element analysis. The transport mechanisms of diffusion, flow, volatilization and chemical reaction are considered. The model predicts the majority of volatiles emanating from the back of the tongue at the end of a swallowing cycle, which correlates with empirical findings. Because the model is conceptual it allows greater freedom and precision than in vivo experimentation.


The ISWI and CHD1 chromatin remodelling activities influence ADH2 expression and chromatin organization.
Nucleosome remodelling complexes play a key role in gene activation in response to environmental changes by driving promoter chromatin to reach an accessible configuration. They also mediate genome-wide chromatin organization, although their role in processes other than activation-related chromatin remodelling are poorly understood. The Saccharomyces cerevisiae ADH2 gene represents an excellent model for understanding the role of chromatin structure and remodelling in gene regulation. Following glucose depletion, highly positioned promoter nucleosomes are destabilized leading to strictly regulated kinetics of transcriptional activation. Nevertheless, no chromatin remodelling activities responsible for establishing or remodelling ADH2 chromatin structure have been identified to date. Here we show that the absence of the Isw1 and Chd1 ATP-dependent chromatin remodelling activities delays the maximal expression of ADH2 without impairing the chromatin remodelling that occurs upon activation. Instead, a destabilized chromatin structure on the ADH2 coding and termination region is observed in the absence of Isw1 or Chd1 in repressing conditions. The specific Isw1 complex involved in this nucleosome repositioning is Isw1b because the deletion of Ioc2 and Ioc4, but not of Ioc3, causes the same phenotype as the deletion of Isw1. Moreover, the lack of Chd1 combined with the absence of Isw1 and Isw2 impairs nucleosome spacing along the ADH2 gene, and genome-wide in S. cerevisiae. Thus, the ISWI and Chd1 remodelling factors are not only involved in transcription-related chromatin remodelling, but also are required to maintain a specific chromatin configuration across the yeast genome.


An analysis of missed cases with surgical emergencies admitted in non-surgical departments. Case series and а review of the literature.
The delayed diagnosis in emergency surgery can be associated with significant morbidity and mortality and often lead to litigations. The aim of the present work is to analyse the outcome in cases with non-trauma surgical emergencies wrongly admitted in non-surgical departments. A retrospective trial in two independent University hospitals was conducted. The first group encompassed the patients worked-up in the Surgical unit of Emergency department (2014-2018). The second one included all cases visited Emergency department (2018). Only cases with acute abdomen and delayed diagnosis and operation were included. The analysis included the proportion of the delayed diagnosis, time between admission and operation, intraoperative diagnosis, complications and mortality rate. In the first group there were 30 194 visits in the surgical unit with 15 836 hospitalizations (52.4%). Twenty patients of the last (0.13%) were admitted in the Clinic of Infectious disease and subsequently operated. The mean delay between hospitalization and operation was 3 days (1-10). Seventeen patients (85%) were operated with mortality of 10%. In the second group, there were a total of 22 760 visits with 11 562 discharged cases. Of the last, 1.7% (n=192) were re-admitted in a surgical ward, 25 of which underwent urgent surgery (0.2%). The missed surgical cases represent only a small proportion of the patients in emergency department. The causes for wrong initial admissions in our series were misinterpretation of the symptoms, insufficient clinical examination and underuse of US and CT. The careful clinical assessment, point-of care US and CT may decrease the rate of the delayed diagnosis.


Rotigotine transdermal system as add-on to oral dopamine agonist in advanced Parkinson's disease: an open-label study.
Achieving optimal symptom control with minimal side effects is a major goal in clinical practice. Dual-agent dopamine receptor agonist (DA) therapy in Parkinson's disease (PD) may represent a promising approach to treatment, as the combination of different pharmacokinetic/pharmacological profiles may result in a lesser need for high dosages and, accordingly, may be well tolerated. The objective of the current study was to investigate safety and efficacy of rotigotine transdermal system as add-on to oral DA in patients with advanced PD inadequately controlled with levodopa and low-dose oral DA. PD0015 was an open-label, multinational study in patients with advanced-PD and sleep disturbance or early-morning motor impairment. Patients were titrated to optimal dose rotigotine (≤8 mg/24 h) over 1-4 weeks and maintained for 4-7 weeks (8-week treatment). Dosage of levodopa and oral DA (pramipexole ≤1.5 mg/day, ropinirole ≤6.0 mg/day) was stable. Primary variable was Clinical Global Impressions (CGI) item 4: side effects, assessing safety. Other variables included adverse events (AEs), Patient Global Impressions of Change (PGIC), Unified Parkinson's Disease Rating Scale (UPDRS) II and III, Parkinson's Disease Sleep Scale (PDSS-2), Pittsburgh Sleep Quality Index (PSQI), and "off" time. Of 90 patients who received rotigotine, 79 (88%) completed the study; 5 (6%) withdrew due to AEs. Most (83/89; 93%) had a CGI-4 score <3 indicating that rotigotine add-on therapy did not interfere with functioning; 6 (7%) experienced drug-related AEs that interfered with functioning (score ≥3). AEs occurring in ≥5% were application site pruritus (13%), dizziness (10%), orthostatic hypotension (10%), nausea (8%), dyskinesia (8%), and nasopharyngitis (6%). Numerical improvements in motor function (UPDRS III), activities of daily living (UPDRS II), sleep disturbances (PDSS-2, PSQI), and reduction in "off" time were observed. The majority (71/88; 81%) improved on PGIC. Addition of rotigotine transdermal system to low-dose oral DA in patients with advanced-PD was feasible and may be associated with clinical benefit. ClinicalTrials.gov identifier NCT01723904 . Trial registration date: November 6, 2012.


Future trends in the treatment of rheumatoid arthritis: cytokine targets.
Recently, anti-inflammatory cytokines and cytokine-blocking agents such as monoclonal antibodies, soluble receptors and receptor antagonists have been explored as therapeutic agents for patients with rheumatoid arthritis. The anti-inflammatory cytokines interleukin 10 (IL-10), which reverses the cartilage degradation induced by antigen-stimulated mononuclear cells, and IL-4, which reduces prostaglandin production by synoviocytes, are currently being tested for their clinical efficacy. Trials with the tumour necrosis factor alpha blocking agents infliximab (monoclonal antibody) and etanercept (the fusion protein of soluble tumour necrosis factor receptors linked to human immunoglobulin) have produced improvements in clinical and laboratory measures of inflammation with mild side-effects. Trials of IL-1 blockade with recombinant human IL-1 receptor antagonist produced significant improvement of clinical parameters with mild side-effects. Blockade of IL-6, the cytokine that induces biosynthesis of acute-phase proteins, has been attempted with i.v. injections of anti-IL-6 monoclonal antibodies with improvement in clinical variables as well as reduced acute-phase proteins.


Combined use of hyperthermia and radiation therapy for treating locally advanced cervical carcinoma.
Hyperthermia is a type of cancer treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells. It was introduced into clinical oncology practice several decades ago. Positive clinical results, mostly obtained in single institutions, resulted in clinical implementation albeit in a limited number of cancer centres worldwide. Because large scale randomised clinical trials (RCTs) are lacking, firm conclusions cannot be drawn regarding its definitive role as an adjunct to radiotherapy in the treatment of locally advanced cervical carcinoma (LACC). To assess whether adding hyperthermia to standard radiotherapy for LACC has an impact on (1) local tumour control, (2) survival and (3) treatment related morbidity. The electronic databases of the Cochrane Central Register of Controlled Trials (CENTRAL), (Issue 1, 2009) and Cochrane Gynaecological Cancer Groups Specialised Register, MEDLINE, EMBASE, online databases for trial registration, handsearching of journals and conference abstracts, reviews, reference lists, and contacts with experts were used to identify potentially eligible trials, published and unpublished until January 2009. RCTs comparing radiotherapy alone (RT) versus combined hyperthermia and radiotherapy (RHT) in patients with LACC. Between 1987 and 2009 the results of six RCTs were published, these were used for the current analysis. 74% of patients had FIGO stage IIIB LACC. Treatment outcome was significantly better for patients receiving the combined treatment (Figures 1 to 3). The pooled data analysis yielded a significantly higher complete response rate (relative risk (RR) 0.56; 95% confidence interval (CI) 0.39 to 0.79; p < 0.001), a significantly reduced local recurrence rate at 3 years (hazard ratio (HR) 0.48; 95% CI 0.37 to 0.63; p < 0.001) and a significanly better overall survival (OS) at three years following the combined treatment with RHT(HR 0.67; 95% CI 0.45 to 0.99; p = 0.05). No significant difference was observed in treatment related acute (RR 0.99; 95% CI 0.30 to 3.31; p = 0.99) or late grade 3 to 4 toxicity (RR 1.01; CI 95% 0.44 to 2.30; p = 0.96) between both treatments. The limited number of patients available for analysis, methodological flaws and a significant over-representation of patients with FIGO stage IIIB prohibit drawing definite conclusions regarding the impact of adding hyperthermia to standard radiotherapy. However, available data do suggest that the addition of hyperthermia improves local tumour control and overall survival in patients with locally advanced cervical carcinoma without affecting treatment related grade 3 to 4 acute or late toxicity.


Integrated survival analysis using an event-time approach in a Bayesian framework.
Event-time or continuous-time statistical approaches have been applied throughout the biostatistical literature and have led to numerous scientific advances. However, these techniques have traditionally relied on knowing failure times. This has limited application of these analyses, particularly, within the ecological field where fates of marked animals may be unknown. To address these limitations, we developed an integrated approach within a Bayesian framework to estimate hazard rates in the face of unknown fates. We combine failure/survival times from individuals whose fates are known and times of which are interval-censored with information from those whose fates are unknown, and model the process of detecting animals with unknown fates. This provides the foundation for our integrated model and permits necessary parameter estimation. We provide the Bayesian model, its derivation, and use simulation techniques to investigate the properties and performance of our approach under several scenarios. Lastly, we apply our estimation technique using a piece-wise constant hazard function to investigate the effects of year, age, chick size and sex, sex of the tending adult, and nesting habitat on mortality hazard rates of the endangered mountain plover (Charadrius montanus) chicks. Traditional models were inappropriate for this analysis because fates of some individual chicks were unknown due to failed radio transmitters. Simulations revealed biases of posterior mean estimates were minimal (≤ 4.95%), and posterior distributions behaved as expected with RMSE of the estimates decreasing as sample sizes, detection probability, and survival increased. We determined mortality hazard rates for plover chicks were highest at <5 days old and were lower for chicks with larger birth weights and/or whose nest was within agricultural habitats. Based on its performance, our approach greatly expands the range of problems for which event-time analyses can be used by eliminating the need for having completely known fate data.


Evidence of expanded host range and mammalian-associated genetic changes in a duck H9N2 influenza virus following adaptation in quail and chickens.
H9N2 avian influenza viruses continue to circulate worldwide; in Asia, H9N2 viruses have caused disease outbreaks and established lineages in land-based poultry. Some H9N2 strains are considered potentially pandemic because they have infected humans causing mild respiratory disease. In addition, some of these H9N2 strains replicate efficiently in mice without prior adaptation suggesting that H9N2 strains are expanding their host range. In order to understand the molecular basis of the interspecies transmission of H9N2 viruses, we adapted in the laboratory a wildtype duck H9N2 virus, influenza A/duck/Hong Kong/702/79 (WT702) virus, in quail and chickens through serial lung passages. We carried out comparative analysis of the replication and transmission in quail and chickens of WT702 and the viruses obtained after 23 serial passages in quail (QA23) followed by 10 serial passages in chickens (QA23CkA10). Although the WT702 virus can replicate and transmit in quail, it replicates poorly and does not transmit in chickens. In contrast, the QA23CkA10 virus was very efficient at replicating and transmitting in quail and chickens. Nucleotide sequence analysis of the QA23 and QA23CkA10 viruses compared to the WT702 virus indicated several nucleotide substitutions resulting in amino acid changes within the surface and internal proteins. In addition, a 21-amino acid deletion was found in the stalk of the NA protein of the QA23 virus and was maintained without further modification in the QA23CkA10 adapted virus. More importantly, both the QA23 and the QA23CkA10 viruses, unlike the WT702 virus, were able to readily infect mice, produce a large-plaque phenotype, showed faster replication kinetics in tissue culture, and resulted in the quick selection of the K627 amino acid mammalian-associated signature in PB2. These results are in agreement with the notion that adaptation of H9 viruses to land-based birds can lead to strains with expanded host range.


MEG correlates of learning novel objects properties in children.
Learning the functional properties of objects is a core mechanism in the development of conceptual, cognitive and linguistic knowledge in children. The cerebral processes underlying these learning mechanisms remain unclear in adults and unexplored in children. Here, we investigated the neurophysiological patterns underpinning the learning of functions for novel objects in 10-year-old healthy children. Event-related fields (ERFs) were recorded using magnetoencephalography (MEG) during a picture-definition task. Two MEG sessions were administered, separated by a behavioral verbal learning session during which children learned short definitions about the "magical" function of 50 unknown non-objects. Additionally, 50 familiar real objects and 50 other unknown non-objects for which no functions were taught were presented at both MEG sessions. Children learned at least 75% of the 50 proposed definitions in less than one hour, illustrating children's powerful ability to rapidly map new functional meanings to novel objects. Pre- and post-learning ERFs differences were analyzed first in sensor then in source space. Results in sensor space disclosed a learning-dependent modulation of ERFs for newly learned non-objects, developing 500-800 msec after stimulus onset. Analyses in the source space windowed over this late temporal component of interest disclosed underlying activity in right parietal, bilateral orbito-frontal and right temporal regions. Altogether, our results suggest that learning-related evolution in late ERF components over those regions may support the challenging task of rapidly creating new semantic representations supporting the processing of the meaning and functions of novel objects in children.


Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension.
Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of primary pulmonary hypertension (PPH). Here we found that PA-SMCs from patients with PPH grow faster than PA-SMCs from controls when stimulated by serotonin or serum and that these effects are due to increased expression of the serotonin transporter (5-HTT), which mediates internalization of indoleamine. In the presence of 5-HTT inhibitors, the growth stimulatory effects of serum and serotonin were markedly reduced and the difference between growth of PA-SMCs from patients and controls was no longer observed. As compared with controls, the expression of 5-HTT was increased in cultured PA-SMCs as well as in platelets and lungs from patients with PPH where it predominated in the media of thickened pulmonary arteries and in onion-bulb lesions. The L-allelic variant of the 5HTT gene promoter, which is associated with 5-HTT overexpression and increased PA-SMC growth, was present in homozygous form in 65% of patients but in only 27% of controls. We conclude that 5-HTT activity plays a key role in the pathogenesis of PA-SMC proliferation in PPH and that a 5HTT polymorphism confers susceptibility to PPH.


Muscle synergies demonstrate only minimal changes after treatment in cerebral palsy.
Children with cerebral palsy (CP) have altered synergies compared to typically-developing peers, reflecting different neuromuscular control strategies used to move. While these children receive a variety of treatments to improve gait, whether synergies change after treatment, or are associated with treatment outcomes, remains unknown. We evaluated synergies for 147 children with CP before and after three common treatments: botulinum toxin type-A injection (n = 52), selective dorsal rhizotomy (n = 38), and multi-level orthopaedic surgery (n = 57). Changes in synergy complexity were measured by the number of synergies required to explain > 90% of the total variance in electromyography data and total variance accounted for by one synergy. Synergy weights and activations before and after treatment were compared using the cosine similarity relative to average synergies of 31 typically-developing (TD) peers. There were minimal changes in synergies after treatment despite changes in walking patterns. Number of synergies did not change significantly for any treatment group. Total variance accounted for by one synergy increased (i.e., moved further from TD peers) after botulinum toxin type-A injection (1.3%) and selective dorsal rhizotomy (1.9%), but the change was small. Synergy weights did not change for any treatment group (average 0.001 ± 0.10), but synergy activations after selective dorsal rhizotomy did change and were less similar to TD peers (- 0.03 ± 0.07). Only changes in synergy activations were associated with changes in gait kinematics or walking speed after treatment. Children with synergy activations more similar to TD peers after treatment had greater improvements in gait. While many of these children received significant surgical procedures and prolonged rehabilitation, the minimal changes in synergies after treatment highlight the challenges in altering neuromuscular control in CP. Development of treatment strategies that directly target impaired control or are optimized to an individual's unique control may be required to improve walking function.


[Replication of hepatitis C virus genome].
The studies on the mechanism of HCV replication proliferated after the development of cell culture based-subgenomic HCV replicon system and genome-length HCV RNA replication system. Furthermore, these RNA replication systems have been improved to be suitable systems for the screening of anti-HCV reagents by the introduction of reporter genes such as luciferase. Genetic analysis of HCV RNAs obtained in long-term cell culture of HCV replicon or genome-length HCV RNA-harboring cells revealed that genetic mutations in HCV RNAs accumulated in a time-dependent manner. The genetic diversity of HCVs was also enlarged in a time-dependent manner. The appearance of adaptive mutation in HCV replicon or genome-length HCV RNA is one of characteristic features of HCV RNA replication system. Although human hepatoma-derived HuH-7 cell line was mainly used for HCV RNA replication systems, a specific combination of adaptive mutations led to develop the HCV RNA replication systems using a new human hepatoma cell line other than HuH-7.


Screening for atrial fibrillation during influenza vaccinations by primary care nurses using a smartphone electrocardiograph (iECG): A feasibility study.
People with unknown atrial fibrillation (AF), who are often asymptomatic, have a substantially increased risk of stroke. Although recommended in European guidelines, AF screening is not routinely performed. Screening at the time of influenza vaccination presents an ideal opportunity to detect AF in large numbers in a primary care medical setting, with an existing annual recall system for patients aged ≥65 years. Cross-sectional pilot study of handheld smartphone electrocardiogram (iECG) screening to identify unknown AF. General practices in Sydney, Australia, were recruited during the influenza-vaccination period of April-June 2015. Practice nurses screened patients aged ≥65 years with a 30-second iECG, which has a validated algorithm for detecting AF in real time. In order to confirm the accuracy of the algorithm, two research cardiologists reviewed de-identified iECGs. In order to explore barriers and enablers, semi-structured interviews were conducted with selected nurses, practice managers and general practitioners. Five general practices were recruited, and 973/2476 (39%) patients attending influenza vaccination were screened. Screening took an average of 5 minutes (range 1.5-10 minutes); however, abnormal iECGs required additional time. Newly identified AF was found in 8/973 patients (0.8%). The sensitivity of the iECG automated algorithm was 95% (95% confidence interval: 83-99%) and the specificity was 99% (95% confidence interval: 98-100%). Screening by practice nurses was well accepted by practice staff. Key enablers were the confidence and competence of nurses and a 'designated champion' to lead screening at the practice. Barriers were practice specific, and mainly related to staff time and funding. Screening with iECG during influenza vaccination by primary care nurses is feasible and well accepted by practice staff. Addressing barriers is likely to increase uptake.


Pharmacoeconomic issues in the treatment of depression.
The goal of pharmacoeconomics is to define the cost and value of different treatment strategies. The cost-effectiveness analysis, one model used in the study of pharmacoeconomics, considers not only the cost of the drug itself, but also the labor costs associated with physician and pharmacy visits, and expenses for laboratory testing. Drugs that require more intensive medical surveillance, either for dose adjustments or overall management of treatment-related side effects, can escalate costs. In the case of antidepressant drugs, various cost-effectiveness analyses have shown that the total cost of disease management is similar for generic tricyclics and the more expensive selective serotonin reuptake inhibitors. This outcome is due to the higher labor costs associated with tricyclics that offset their acquisition cost advantage. The application of cost-effectiveness studies in formulary decision-making and clinical practice guidelines, will maximize the use of health care resources.


Outcomes and prognostic factors for pediatric cancer patients admitted to an intensive care unit in a university hospital.
The aim of this study was to investigate the factors predicting Pediatric Intensive Care Unit (PICU) mortality and the outcomes in cancer patients admitted to PICU. We conducted a retrospective study in 48 consecutive cancer patients admitted to the PICU between January 1, 2015 and January 1, 2018. A total of 48 patients (21 males and 27 females) were enrolled in this study. The median age was 77 (33,5-149) months. The median duration of PICU stay was 5 (2-9) days. Patients were classified according to their stage of disease. Ten (20.8%) patients were in the remission group, 9 (18.8%) patients were in the induction period and 29 (60.5%) patients were in the progressive diseasegruops. Thirtynine patients (81.2%) had hematological malignancies, 6 (12.5%) had extracranial solid tumors and 3 (6.3%) had intracranial solid tumors. Thirty-seven patients died and the mortality rate was found to be 77.1%. mortality rates were 11%, 88% and 93% for patients in remission,during induction period and in the progressive disease group, respectively (p < 0.01).The most frequent reasons of PICU admission were respiratory failure in 29 (60.4%), sepsis in 12 (25%), circulatory collaps in 2 (4.2%), and other reasons in 5 patients (10.4%). The median PRISM III among survivors was significantly lower than non-survivors (13.1 ± 6.4; vs. 20.7 ± 5.2; p < 0.001). At a cut-off value of 13, the sensitivity of the PRISM III was 94.4% and the specificity was 58.3% (AUC: 0.821). OSDwas present in 41 (85%) patients, 82% of them died (34/41). The presence of MOF, the use of mechanical ventilation and inotrop support were significantly related with mortality. Univariate logistic regression analysis showed that male gender [odds ratio (OR)=5.588, P= 0.041, 95% confidence interval (95%CI) 1.070-29.191], presence of organ system dysfunction[OR=12.143, P= 0.008, 95%CI 1.947- 75.736], need for mechanical ventilation[OR=34.000, P= 0.001, 95%CI 5.272-219.262], IS [OR=8.5, P= 0.001, 95%CI 1.318-54.817]were the predictors ofhigh mortality in pediatric cancer patients. PRISM III score ≥ 13 was a predictive criteria of PICU mortality. We conclude that the key to improving survival rates is to pick up on this group of patients as soon as possible.We, believe that cancer patients could be saved by earlier evaluation and intervention by the PICU team when they have a less severe disease.


Plasmids of Shigella flexneri serotype 1c strain Y394 provide advantages to bacteria in the host.
Shigella flexneri has an extremely complex genome with a significant number of virulence traits acquired by mobile genetic elements including bacteriophages and plasmids. S. flexneri serotype 1c is an emerging etiological agent of bacillary dysentery in developing countries. In this study, the complete nucleotide sequence of two plasmids of S. flexneri serotype 1c strain Y394 was determined and analysed. The plasmid pINV-Y394 is an invasive or virulence plasmid of size 221,293 bp composed of a large number of insertion sequences (IS), virulence genes, regulatory and maintenance genes. Three hundred and twenty-eight open reading frames (ORFs) were identified in pINV-Y394, of which about a half (159 ORFs) were identified as IS elements. Ninety-seven ORFs were related to characterized genes (majority of which are associated with virulence and their regulons), and 72 ORFs were uncharacterized or hypothetical genes. The second plasmid pNV-Y394 is of size 10,866 bp and encodes genes conferring resistance against multiple antibiotics of clinical importance. The multidrug resistance gene cassette consists of tetracycline resistance gene tetA, streptomycin resistance gene strA-strB and sulfonamide-resistant dihydropteroate synthase gene sul2. These two plasmids together play a key role in the fitness of Y394 in the host environment. The findings from this study indicate that the pathogenic S. flexneri is a highly niche adaptive pathogen which is able to co-evolve with its host and respond to the selection pressure in its environment.


Effect of surround propinquity on the open-loop accommodative response.
The effect of knowledge of surround propinquity, ie, awareness of proximity of the adjacent surroundings, on the open-loop accommodative response (AR) was determined by comparing measurements of accommodation obtained in total darkness in two different-sized rooms. The AR was measured in two laboratories, one 2.5-m square and the other 6.75 x 2.75 m. Steady-state accommodation was assessed on two occasions in each room using an infrared optometer. On the first occasion, the subjects (n = 10) were fully aware of the laboratory dimensions and topography. For the second trial, they were blind-folded before entering the laboratory and hence were unaware of the experimental location. When subjects were unaware of the laboratory dimensions, no significant difference existed between the recorded values of AR. However, when subjects were initially able to observe the size of the room, the AR in darkness was significantly higher in the smaller laboratory. This suggests that proximally induced accommodation, initiated by prior knowledge of the dimensions of the laboratory, was responsible for this increase in AR. Furthermore, it is proposed that complex interactions exist between proximal, tonic, and other nonoptical accommodative stimuli such that it may be impossible to isolate an individual, nonoptical accommodative component.


Safety and effectiveness of nurse telephone consultation in out of hours primary care: randomised controlled trial. The South Wiltshire Out of Hours Project (SWOOP) Group.
To determine the safety and effectiveness of nurse telephone consultation in out of hours primary care by investigating adverse events and the management of calls. Block randomised controlled trial over a year of 156 matched pairs of days and weekends in 26 blocks. One of each matched pair was randomised to receive the intervention. One 55 member general practice cooperative serving 97 000 registered patients in Wiltshire. All patients contacting the out of hours service or about whom contact was made during specified times over the trial year. A nurse telephone consultation service integrated within a general practice cooperative. The out of hours period was 615 pm to 1115 pm from Monday to Friday, 1100 am to 1115 pm on Saturday, and 800 am to 1115 pm on Sunday. Experienced and specially trained nurses received, assessed, and managed calls from patients or their carers. Management options included telephone advice; referral to the general practitioner on duty (for telephone advice, an appointment at a primary care centre, or a home visit); referral to the emergency service or advice to attend accident and emergency. Calls were managed with the help of decision support software. Deaths within seven days of a contact with the out of hours service; emergency hospital admissions within 24 hours and within three days of contact; attendance at accident and emergency within three days of a contact; number and management of calls in each arm of the trial. 14 492 calls were received during the specified times in the trial year (7308 in the control arm and 7184 in the intervention arm) concerning 10 134 patients (10.4% of the registered population). There were no substantial differences in the age and sex of patients in the intervention and control groups, though male patients were underrepresented overall. Reasons for calling the service were consistent with previous studies. Nurses managed 49.8% of calls during intervention periods without referral to a general practitioner. A 69% reduction in telephone advice from a general practitioner, together with a 38% reduction in patient attendance at primary care centres and a 23% reduction in home visits was observed during intervention periods. Statistical equivalence was observed in the number of deaths within seven days, in the number of emergency hospital admissions, and in the number of attendances at accident and emergency departments. Conclusions Nurse telephone consultation produced substantial changes in call management, reducing overall workload of general practitioners by 50% while allowing callers faster access to health information and advice. It was not associated with an increase in the number of adverse events. This model of out of hours primary care is safe and effective.


Tensile bond strength of metal bracket bonding to glazed ceramic surfaces with different surface conditionings.
The objective of this study was to compare the tensile bond strength of metal brackets bonding to glazed ceramic surfaces using three various surface treatments. Forty two glazed ceramic disks were assigned to three groups. In the first and second groups the specimens were etched with 9.5% hydrofluoric acid (HFA). Subsequently in first group, ceramic primer and adhesive were applied, but in second group a bonding agent alone was used. In third group, specimens were treated with 35% phosphoric acid followed by ceramic primer and adhesive application. Brackets were bonded with light cure composites. The specimens were stored in distilled water in the room temperature for 24 hours and thermocycled 500 times between 5°C and 55°C. The universal testing machine was used to test the tensile bond strength and the adhesive remenant index scores between three groups was evaluated. The data were subjected to one-way ANOVA, Tukey and Kruskal-Wallis tests respectively. The tensile bond strength was 3.69±0.52 MPa forfirst group, 2.69±0.91 MPa for second group and 3.60±0.41 MPa for third group. Group II specimens showed tensile strength values significantly different from other groups (P<0.01). In spite of limitations in laboratory studies it may be concluded that in application of Scotch bond multipurpose plus adhesive, phosphoric acid can be used instead of HFA for bonding brackets to the glazed ceramic restorations with enough tensile bond strength.


Aetiology of skeletal muscle 'cramps' during exercise: a novel hypothesis.
The aetiology of exercise-associated muscle cramps (EAMC), defined as 'painful, spasmodic, involuntary contractions of skeletal muscle during or immediately after physical exercise', has not been well investigated and is therefore not well understood. This review focuses on the physiological basis for skeletal muscle relaxation, a historical perspective and analysis of the commonly postulated causes of EAMC, and known facts about EAMC from recent clinical studies. Historically, the causes of EAMC have been proposed as (1) inherited abnormalities of substrate metabolism ('metabolic theory') (2) abnormalities of fluid balance ('dehydration theory'), (3) abnormalities of serum electrolyte concentrations ('electrolyte theory') and (4) extreme environmental conditions of heat or cold ('environmental theory'). Detailed analyses of the available scientific literature including data from recent studies do not support these hypothesis for the causes of EAMC. In a recent study, electromyographic (EMG) data obtained from runners during EAMC revealed that baseline activity is increased (between spasms of cramping) and that a reduction in the baseline EMG activity correlates well with clinical recovery. Furthermore, during acute EAMC the EMG activity is high, and passive stretching is effective in reducing EMG activity. This relieves the cramp probably by invoking the inverse stretch reflex. In two animal studies, abnormal reflex activity of the muscle spindle (increased activity) and the Golgi tendon organ (decreased activity) has been observed in fatigued muscle. We hypothesize that EAMC is caused by sustained abnormal spinal reflex activity which appears to be secondary to muscle fatigue. Local muscle fatigue is therefore responsible for increased muscle spindle afferent and decreased Golgi tendon organ afferent activity. Muscles which cross two joints can more easily be placed in shortened positions during exercise and would therefore decrease the Golgi tendon organ afferent activity. In addition, sustained abnormal reflex activity would explain increased baseline EMG activity between acute bouts of cramping. Finally, passive stretching invokes afferent activity from the Golgi tendon organ, thereby relieving the cramp and decreasing EMG activity.


The influence of distance on ambulatory care use, death, and readmission following a myocardial infarction.
To examine whether patients admitted for treatment of a myocardial infarction (MI) who live farther from their source of care are less likely to be followed in an outpatient clinic, and whether patients who receive follow-up care are less likely to die or to have a subsequent acute care admission. Department of Veterans Affairs (VA) databases to identify a national sample of 4,637 MI patients discharged in 1992, their use of care, and vital status within the subsequent year. Sociodemographics, comorbid diagnoses, invasive cardiac procedures, hospital teaching status, and distance to patients' admitting hospital were determined. Using these longitudinal data, we examined the relationship between patient characteristics, distance to care, and use of outpatient care after discharge. We then examined the relationship between the use of ambulatory care and subsequent death and readmission. Patients living more than 20 miles from their admitting hospital were less likely to use ambulatory services. Patients receiving ambulatory care were 79 percent as likely to die within the year as those without any follow-up care (95% C.I. = 0.66, 0.94). Patients living more than 20 miles from their admitting hospital were more likely to die independent of their likelihood of receiving VA outpatient follow-up. Among patients who did not die in the subsequent year, those receiving ambulatory care were 33 percent more likely to be readmitted to a VA hospital with a cardiac diagnosis (95% C.I. = 1.12, 1.57). Distance may pose a barrier to outpatient follow-up for some VA patients after a MI. It also may limit patients' ability to access medical care quickly in the event of a recurrent acute event. Ambulatory care after discharge may be an important factor determining survival for patients with cardiac disease.


Bias detection and correction in RNA-Sequencing data.
High throughput sequencing technology provides us unprecedented opportunities to study transcriptome dynamics. Compared to microarray-based gene expression profiling, RNA-Seq has many advantages, such as high resolution, low background, and ability to identify novel transcripts. Moreover, for genes with multiple isoforms, expression of each isoform may be estimated from RNA-Seq data. Despite these advantages, recent work revealed that base level read counts from RNA-Seq data may not be randomly distributed and can be affected by local nucleotide composition. It was not clear though how the base level read count bias may affect gene level expression estimates. In this paper, by using five published RNA-Seq data sets from different biological sources and with different data preprocessing schemes, we showed that commonly used estimates of gene expression levels from RNA-Seq data, such as reads per kilobase of gene length per million reads (RPKM), are biased in terms of gene length, GC content and dinucleotide frequencies. We directly examined the biases at the gene-level, and proposed a simple generalized-additive-model based approach to correct different sources of biases simultaneously. Compared to previously proposed base level correction methods, our method reduces bias in gene-level expression estimates more effectively. Our method identifies and corrects different sources of biases in gene-level expression measures from RNA-Seq data, and provides more accurate estimates of gene expression levels from RNA-Seq. This method should prove useful in meta-analysis of gene expression levels using different platforms or experimental protocols.


The significance of "nonsignificance" in randomized controlled studies: a discussion inspired by a double-blinded study on St. John's wort (Hypericum perforatum L.) for premenstrual symptoms.
This study aimed to investigate the efficacy of St. John's wort extract (SJW) as a treatment for premenstrual symptoms. The study was a randomized, double-blinded, placebo-controlled trial, with two parallel treatment groups. After a no-treatment baseline cycle, volunteers were randomized to either SJW or placebo for a further two menstrual cycles. A postal trial conducted from The University of Reading, Berkshire, England. One hundred and sixty-nine (169) normally menstruating women who experienced recurrent premenstrual symptoms were recruited onto the study. One hundred and twenty-five (125) completed the protocol and were included in the analysis. Six hundred milligrams (600) mg of SJW (standardized to contain 1800 microg of hypericin) or placebo (containing lactose and cellulose). A menstrual diary was used to assess changes in premenstrual symptoms. The anxiety-related subgroup of symptoms of this instrument was used as the primary outcome measure. After averaging the effects of treatment over both treatment cycles it was found that there was a trend for SJW to be superior to placebo. However, this finding was not statistically significant. The possibility that this nonsignificant finding resulted from insufficient statistical power in the study, rather than a lack of efficacy of SJW, is discussed. Following this discussion the recommendation is made that, in future, similar studies should be powered to detect a minimum clinically relevant difference between treatments.


Enzymatic properties of purified murine fatty acid transport protein 4 and analysis of acyl-CoA synthetase activities in tissues from FATP4 null mice.
Fatty acid transport protein 4 (FATP4) is an integral membrane protein expressed in the plasma and internal membranes of the small intestine and adipocyte as well as in the brain, kidney, liver, skin, and heart. FATP4 has been hypothesized to be bifunctional, exhibiting both fatty acid transport and acyl-CoA synthetase activities that work in concert to mediate fatty acid influx across biological membranes. To determine whether FATP4 is an acyl-CoA synthetase, the murine protein was engineered to contain a C-terminal FLAG epitope tag, expressed in COS1 cells via adenovirus-mediated infection and purified to near homogeneity using alpha-FLAG affinity chromatography. Kinetic analysis of the enzyme was carried out for long chain (palmitic acid, C16:0) and very long chain (lignoceric acid, C24:0) fatty acids as well as for ATP and CoA. FATP4 exhibited substrate specificity for C16:0 and C24:0 fatty acids with a V(max)/K(m) (C16:0)/V(max)/K(m) (C24:0) of 1.5. Like purified FATP1, FATP4 was insensitive to inhibition by triacsin C but was sensitive to feedback inhibition by acyl-CoA. Although purified FATP4 exhibited high levels of palmitoyl-CoA and lignoceroyl-CoA synthetase activity, extracts from the skin and intestine of FATP4 null mice exhibited reduced esterification for C24:0, but not C16:0 or C18:1, suggesting that in vivo, defects in very long chain fatty acid uptake may underlie the skin disorder phenotype of null mice.


Changes in brain activity in response to problem solving during the abstinence from online game play.
Several studies have suggested that addictive disorders including substance abuse and pathologic gambling might be associated with dysfunction on working memory and prefrontal activity. We hypothesized that excessive online game playing is associated with deficits in prefrontal cortex function and that recovery from excessive online game playing might improve prefrontal cortical activation in response to working memory stimulation. Thirteen adolescents with excessive online game playing (AEOP) and ten healthy adolescents (HC) agreed to participate in this study. The severity of online game play and playing time were evaluated for a baseline measurement and again following four weeks of treatment. Brain activation in response to working memory tasks (simple and complex calculations) at baseline and subsequent measurements was assessed using BOLD functional magnetic resonance imaging (fMRI). Compared to the HC subjects, the AEOP participants exhibited significantly greater activity in the right middle occipital gyrus, left cerebellum posterior lobe, left premotor cortex and left middle temporal gyrus in response to working memory tasks during baseline measurements. After four weeks of treatment, the AEOP subjects showed increased activity within the right dorsolateral prefrontal cortex and left occipital fusiform gyrus. After four weeks of treatment, changes in the severity of online game playing were negatively correlated with changes in the mean β value of the right dorsolateral prefrontal cortex in response to complex stimulation. We suggest that the effects of online game addiction on working memory may be similar to those observed in patients with substance dependence.


Modulation of nociceptive and acoustic startle responses to an unpredictable threat in men and women.
The present study examined whether a moderately aversive abdominal threat would lead to greater enhancement in affect- and pain-related defensive responding as indexed by the acoustic startle reflex (ASR) and nociceptive flexion reflex (NFR) in women compared to men. We also predicted sex differences in threat-related autonomic arousal measured by skin conductance responses (SCRs) to acoustic startle and noxious sural nerve stimulation. Unpredictable threat was manipulated by alternating 30-second safe ("no abdominal stimulation will be given") and threat ("abdominal stimulation may occur at anytime") periods. The experiment consisted of 2 blocks, each containing 4 safe and 4 threat periods in which the ASR or NFR was randomly probed 9-21 seconds following period onset. Unpredictable abdominal threat potentiated both ASR and NFR responses compared to periods signaling safety. SCRs to acoustic startle probes and noxious sural nerve stimulation were also significantly elevated during the threat vs safe periods. No sex differences in ASR or startle-evoked SCRs emerged. However, nociceptive responding was moderated by sex; females showed significant increases in NFR magnitudes across both safe and threat periods compared to males. Females also showed greater threat-potentiated SCRs to sural nerve stimulation than males. Our findings indicate that both affect- and pain-related defense and arousal systems are strongly influenced by threat of an aversive, unpredictable event, a situation associated with anticipatory anxiety. Females, compared to males, showed greater nociceptive responding and pain modulation when exposed to an unpredictable threatening context, whereas affect-driven ASR responses showed no such sex differentiation.


AAPM medical physics practice guideline 13.a: HDR brachytherapy, part A.
The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education, and professional practice of medical physics. The AAPM has more than 8000 members and is the principal organization of medical physicists in the United States. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines (MPPGs) will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner. Each medical physics practice guideline represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiology requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guidelines and technical standards by those entities not providing these services is not authorized. The following terms are used in the AAPM practice guidelines: (1) Must and must not: Used to indicate that adherence to the recommendation is considered necessary to conform to this practice guideline. (2) Should and should not: Used to indicate a prudent practice to which exceptions may occasionally be made in appropriate circumstances. Approved by AAPM's Executive Committee April 28, 2022.


A research agenda for humanitarian health ethics.
This paper maps key research questions for humanitarian health ethics: the ethical dimensions of healthcare provision and public health activities during international responses to situations of humanitarian crisis. Development of this research agenda was initiated at the Humanitarian Health Ethics Forum (HHE Forum) convened in Hamilton, Canada in November 2012. The HHE Forum identified priority avenues for advancing policy and practice for ethics in humanitarian health action. The main topic areas examined were: experiences and perceptions of humanitarian health ethics; training and professional development initiatives for humanitarian health ethics; ethics support for humanitarian health workers; impact of policies and project structures on humanitarian health ethics; and theoretical frameworks and ethics lenses. Key research questions for each topic area are presented, as well as proposed strategies for advancing this research agenda. Pursuing the research agenda will help strengthen the ethical foundations of humanitarian health action.


Reliability of urinary 6-sulfatoxymelatonin as a biomarker in breast cancer.
The objective of this study is to evaluate the effect of cryopreservation at different storage temperatures on urinary 6-sulfatoxymelatonin (aMT6s) concentration. Overnight urine from 28 postmenopausal women participating in the ORDET cohort study was filtered and separated into 6 mL aliquots. Urine samples were stored at -80 degrees C and at -30 degrees C for an average of 14 years. Urinary aMT6s concentration was assessed using a competitive immunoassay. Mean aMT6s values of samples stored at -30 degrees C were systematically lower than those of samples stored at -80 degrees C (10.7 ng/mL versus 15.8 ng/mL, p<0.001). Bland Altman plots showed disagreement between determinations at different storage temperatures at the highest levels of the metabolite concentration. The degree of agreement evaluated in terms of intraclass correlation coefficient was 0.68 (95% CI 0.41-0.84, p<0.0001). Pearson's correlation coefficient between aMT6s values of the two differently stored samples was 0.93 (p<0.001), while the Kendal tau coefficient for rank distribution was 0.73 (p<0.001). Our data suggest that storage temperatures might affect degradation of aMT6s during storage. However, individual characterization by melatonin levels does not seem to be affected by cryopreservation conditions.


Intraoperative mass spectrometry mapping of an onco-metabolite to guide brain tumor surgery.
For many intraoperative decisions surgeons depend on frozen section pathology, a technique developed over 150 y ago. Technical innovations that permit rapid molecular characterization of tissue samples at the time of surgery are needed. Here, using desorption electrospray ionization (DESI) MS, we rapidly detect the tumor metabolite 2-hydroxyglutarate (2-HG) from tissue sections of surgically resected gliomas, under ambient conditions and without complex or time-consuming preparation. With DESI MS, we identify isocitrate dehydrogenase 1-mutant tumors with both high sensitivity and specificity within minutes, immediately providing critical diagnostic, prognostic, and predictive information. Imaging tissue sections with DESI MS shows that the 2-HG signal overlaps with areas of tumor and that 2-HG levels correlate with tumor content, thereby indicating tumor margins. Mapping the 2-HG signal onto 3D MRI reconstructions of tumors allows the integration of molecular and radiologic information for enhanced clinical decision making. We also validate the methodology and its deployment in the operating room: We have installed a mass spectrometer in our Advanced Multimodality Image Guided Operating (AMIGO) suite and demonstrate the molecular analysis of surgical tissue during brain surgery. This work indicates that metabolite-imaging MS could transform many aspects of surgical care.


Modeling the cost of eradicating livestock-associated methicillin-resistant staphylococcus aureus in countries with a high proportion of positive herds.
Due to an increased incidence of human infections, livestock-associated methicillin-resistant Staphylococcus Aureus (LA-MRSA) in pigs and its spread into the human population has been a major public and political issue in Denmark. Similar concerns are also being raised about LA-MRSA in other Western European countries. At a time when the proportion of LA-MRSA-positive pig farms was low, Norway adopted a 'trace and destroy' strategy aimed at keeping LA-MRSA out of the pig population. However, to date, no country with a high proportion of LA-MRSA-positive pig herds has chosen to use an eradication strategy. This study analyses the cost and complexities of conducting an LA-MRSA eradication program in a situation where a large proportion of herds are positive. The total cost of the eradication program was estimated based on the following components: 1) planning, 2) monitoring and testing, 3) cleaning and disinfection, 4) production gains and losses, 5) net reduction in breeding exports, and 6) loss of genetic progress, including the costs of a mitigating caesarean section strategy in breeding herds. Costs were related to the depopulation of 1 million sows, to gilt supply (as this was an important limiting factor during an eradication program in Denmark), and to aggregated losses linked to a temporary halt on breeding progress. Using conservative assumptions, the total eradication costs were estimated at €1.8 billion, broken down into: planning costs (3%), monitoring and testing (6%), cleaning and disinfection (19%), production gains and losses (33%), net loss from breeding exports (19%) and loss of genetic progress (20%). The long-term effects of an LA-MRSA eradication program for Danish pig production were uncertain and were therefore not taken into account in the analysis.


Augmentation treatment in major depressive disorder: focus on aripiprazole.
Major depressive disorder (MDD) is a disabling psychiatric condition for which effective treatment remains an outstanding need. Antidepressants are currently the mainstay of treatment for depression; however, almost two-thirds of patients will fail to achieve remission with initial treatment. As a result, a range of augmentation and combination strategies have been used in order to improve outcomes for patients. Despite the popularity of these approaches, limited data from double-blind, randomized, placebo-controlled studies are available to allow clinicians to determine which are the most effective augmentation options or which patients are most likely to respond to which options. Recently, evidence has shown that adjunctive therapy with atypical antipsychotics has the potential for beneficial antidepressant effects in the absence of psychotic symptoms. In particular, aripiprazole has shown efficacy as an augmentation option with standard antidepressant therapy in two, large, randomized, double-blind studies. Based on these efficacy and safety data, aripiprazole was recently approved by the FDA as adjunctive therapy for MDD. The availability of this new treatment option should allow more patients with MDD to achieve remission and, ultimately, long-term, successful outcomes.


Hypoxia in the Baltic Sea: biogeochemical cycles, benthic fauna, and management.
Hypoxia has occurred intermittently over the Holocene in the Baltic Sea, but the recent expansion from less than 10 000 km(2) before 1950 to >60 000 km(2) since 2000 is mainly caused by enhanced nutrient inputs from land and atmosphere. With worsening hypoxia, the role of sediments changes from nitrogen removal to nitrogen release as ammonium. At present, denitrification in the water column and sediments is equally important. Phosphorus is currently buried in sediments mainly in organic form, with an additional contribution of reduced Fe-phosphate minerals in the deep anoxic basins. Upon the transition to oxic conditions, a significant proportion of the organic phosphorus will be remineralized, with the phosphorus then being bound to iron oxides. This iron-oxide bound phosphorus is readily released to the water column upon the onset of hypoxia again. Important ecosystems services carried out by the benthic fauna, including biogeochemical feedback-loops and biomass production, are also lost with hypoxia. The results provide quantitative knowledge of nutrient release and recycling processes under various environmental conditions in support of decision support tools underlying the Baltic Sea Action Plan.


Exposures at day labor corners: using existing georeferenced data to describe features of urban environments.
Latino day laborers are male immigrants from mainly Mexico and Central America who congregate at corners, that is, informal hiring sites, to solicit short-term employment. Studies describing the occupational environment of Latino day laborers traditionally measure jobsite exposures, not corner exposures. We sought to elucidate exposures at corners by describing their demographic, socioeconomic, occupational, business, built, and physical environmental characteristics and by comparing corner characteristics with other locations in a large urban county in Texas. We used multiple publicly available data sets from the U.S. Census, local tax authority, Google's Nearby Places Application Programming Interface, and Environmental Protection Agency at fine spatial scale to measure 34 characteristics of corners with matched comparison locations. Corners were located close to highways, high-traffic intersections, hardware and moving stores, and gas stations. Corners were in neighborhoods with large foreign-born and Latino populations, high rates of limited English proficiency, and high construction-sector employment. Publicly available data sources describe demographic, socioeconomic, occupational, business, built, and physical environment characteristics of urban environments at fine spatial scale. Using these data, we identified unique corner-based exposures experienced by day laborers. Future research is needed to understand how corner environments may influence health for this uniquely vulnerable population.


Evaluating genetic differentiation of Anopheles arabiensis in relation to larval habitats in Kenya.
Anopheles arabiensis, an important vector of malaria in sub-Saharan Africa shows great versatility in utilizing a broad range of larval habitats. Most studies on the population genetic structure of this species have focused on adult mosquitoes collected mainly indoors and have found populations within relatively short distances to be panmictic. Various authors suggested that the incipient speciation between the chromosomal forms of Anopheles gambiae s.s. in West Africa involved adaptation to different habitats of larvae. To investigate if similar process occurs in An. arabiensis, we analyzed samples from four different larval habitats alongside a sample of adult mosquitoes collected indoors at eight microsatellite loci. We tested the hypothesis that An. arabiensis is subdivided into populations that are adapted to exploit different larval habitats. Overall, the level of genetic differentiation among the larval subpopulations was low with the mean pairwise Fst estimate based on information from all the loci being 0.0232 (P=0.1691) although differentiation was only significant for comparisons between certain larval samples and the adult samples. In addition, there was strong evidence against subdivision among larvae when multilocus simultaneous assignment tests were used. These results do not provide sufficient support for the hypothesis that An. arabiensis is subdivided into subpopulations that specialize to exploit different larval habitats.


Human-specific CpG "beacons" identify loci associated with human-specific traits and disease.
Regulatory change has long been hypothesized to drive the delineation of the human phenotype from other closely related primates. Here we provide evidence that CpG dinucleotides play a special role in this process. CpGs enable epigenome variability via DNA methylation, and this epigenetic mark functions as a regulatory mechanism. Therefore, species-specific CpGs may influence species-specific regulation. We report non-polymorphic species-specific CpG dinucleotides (termed "CpG beacons") as a distinct genomic feature associated with CpG island (CGI) evolution, human traits and disease. Using an inter-primate comparison, we identified 21 extreme CpG beacon clusters (≥ 20/kb peaks, empirical p < 1.0 × 10(-3)) in humans, which include associations with four monogenic developmental and neurological disease related genes (Benjamini-Hochberg corrected p = 6.03 × 10(-3)). We also demonstrate that beacon-mediated CpG density gain in CGIs correlates with reduced methylation in these species in orthologous CGIs over time, via human, chimpanzee and macaque MeDIP-seq. Therefore mapping into both the genomic and epigenomic space the identified CpG beacon clusters define points of intersection where a substantial two-way interaction between genetic sequence and epigenetic state has occurred. Taken together, our data support a model for CpG beacons to contribute to CGI evolution from genesis to tissue-specific to constitutively active CGIs.


Cathodoluminescent spectroscopic imaging of surface plasmon polaritons in a 1-dimensional plasmonic crystal.
Angle-resolved measurements on a cathodoluminescence (CL) detection system equipped with a 200 keV transmission electron microscope were performed on a 1-dimensional silver grating. The dispersion curves of surface plasmon polaritons (SPPs) on the grating were derived from the angle-resolved CL spectra, and patterns of SPP standing waves at the plasmonic band edge were directly observed.


Community-Based Study Recruitment of American Indian Cigarette Smokers and Electronic Cigarette Users.
Data on the effectiveness of strategies for the recruitment of American Indians (AIs) into research is needed. This study describes and compares methods for identifying and recruiting AI tobacco users into a pilot study. Community-based strategies were used to recruit smokers (n = 35), e-cigarette users (n = 28), and dual users (n = 32) of AI descent. Recruitment was considered proactive if study staff contacted the individual at a pow wow, health fair, or vape shop and participation on-site or reactive if the individual contacted the study staff and participation occurred later. Screened, eligible, participated and costs and time spent were compared with Chi square tests. To understand AI descent, the relationship between number of AI grandparents and AI blood quantum was examined. Number of participants screened via the proactive strategy was similar to the reactive strategy (n = 84 vs. n = 82; p-value = 0.8766). A significantly greater proportion of individuals screened via the proactive than the reactive strategy were eligible (77 vs. 50%; p-value = 0.0002) and participated (75 vs. 39%; p-value = < 0.0001). Per participant cost and time estimated for the proactive strategy was $89 and 87 min compared to $79 and 56 min for the reactive strategy. Proportion at least half AI blood quantum was 32, 33, and 70% among those with 2, 3, and 4 AI grandparents, respectively (p = 0.0017). Proactive strategies resulted in two-thirds of the sample, but required more resources than reactive strategies. Overall, we found both strategies were feasible and resulted in the ability to reach sample goals. Lastly, number of AI biological grandparents may be a good, non-invasive indicator of AI blood quantum.


Habit Reversal Therapy in Obsessive Compulsive Related Disorders: A Systematic Review of the Evidence and CONSORT Evaluation of Randomized Controlled Trials.
Background: Habit Reversal Therapy (HRT) has long been used in the treatment of Tourette Syndrome and Tic Disorders. It has more recently been used to treat Trichotillomania and skin picking behaviors, both considered as Obsessive Compulsive Related Disorders (OCRD). Objectives: This literature review sought to establish and quality assess the existing randomized controlled trial evidence supporting the use of HRT in the DSM-5 family of OCRDs. Search Methods: EMBASE, PsycINFO, PubMed, and Cochrane databases were searched for key terms relating to each OCRD (as classified in the DSM-5), and HRT. Selection Criteria: Titles and abstracts were screened, and any literature matching pre-specified criteria were then selected to be reviewed further. Of these, 8 Randomized Controlled Trials (RCT) relating to Trichotillomania, and 2 RCTs relating to Excoriation Disorder, were extracted and reviewed against the 2010 Consolidating Standards of Reporting Trials (CONSORT) statement. Results: The review identified 10 RCTs of HRT, but these were limited to patients with a primary diagnosis of Trichotillomania or "excoriation behavior," only. There were some reports of the use of HRT in Tourette Syndrome or Tic Disorder with secondary OCD, but the OCD symptoms were not reliably reported on. Conclusion: There is a gap in the current literature regarding the use of HRT in the DSM-5 OCRDs. In those RCTs that have been reported, the quality of study methodology was questionable as evaluated by CONSORT criteria. The implications of these findings are discussed, and suggestions are made for future research.


Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia.
Magnesium (Mg(2+)) is an essential ion for cell growth, neuroplasticity and muscle contraction. Blood Mg(2+) levels <0.7 mmol/L may cause a heterogeneous clinical phenotype, including muscle cramps and epilepsy and disturbances in K(+) and Ca(2+) homeostasis. Over the last decade, the genetic origin of several familial forms of hypomagnesaemia has been found. In 2000, mutations in FXYD2, encoding the γ-subunit of the Na(+)-K(+)-ATPase, were identified to cause isolated dominant hypomagnesaemia (IDH) in a large Dutch family suffering from hypomagnesaemia, hypocalciuria and chondrocalcinosis. However, no additional patients have been identified since then. Here, two families with hypomagnesaemia and hypocalciuria were screened for mutations in the FXYD2 gene. Moreover, the patients were clinically and genetically characterized. We report a p.Gly41Arg FXYD2 mutation in two families with hypomagnesaemia and hypocalciuria. Interestingly, this is the same mutation as was described in the original study. As in the initial family, several patients suffered from muscle cramps, chondrocalcinosis and epilepsy. Haplotype analysis revealed an overlapping haplotype in all families, suggesting a founder effect. The recurrent p.Gly41Arg FXYD2 mutation in two new families with IDH confirms that FXYD2 mutation causes hypomagnesaemia. Until now, no other FXYD2 mutations have been reported which could indicate that other FXYD2 mutations will not cause hypomagnesaemia or are embryonically lethal.


Membrane protein megahertz crystallography at the European XFEL.
The world's first superconducting megahertz repetition rate hard X-ray free-electron laser (XFEL), the European XFEL, began operation in 2017, featuring a unique pulse train structure with 886 ns between pulses. With its rapid pulse rate, the European XFEL may alleviate some of the increasing demand for XFEL beamtime, particularly for membrane protein serial femtosecond crystallography (SFX), leveraging orders-of-magnitude faster data collection. Here, we report the first membrane protein megahertz SFX experiment, where we determined a 2.9 Å-resolution SFX structure of the large membrane protein complex, Photosystem I, a > 1 MDa complex containing 36 protein subunits and 381 cofactors. We address challenges to megahertz SFX for membrane protein complexes, including growth of large quantities of crystals and the large molecular and unit cell size that influence data collection and analysis. The results imply that megahertz crystallography could have an important impact on structure determination of large protein complexes with XFELs.


Uvulopalatopharyngoplasty May Reduce the Incidence of Dementia Caused by Obstructive Sleep Apnea: National Insurance Service Survey 2007-2014.
Numerous studies have found that obstructive sleep apnea (OSA) causes or exacerbates dementia, including Alzheimer disease and vascular dementia. However, the evidence is often conflicting. Moreover, no study has investigated the effect of surgical treatment for OSA on dementia. This retrospective cohort study analyzed data from the Korea National Health Insurance Corporation. A total of 125,417 participants (age 40 years or older) with a new diagnosis of OSA between 2007 and 2014 were included. The participants were classified into two groups: those who underwent uvulopalatopharyngoplasty (UPPP group, n = 12,664) and those who underwent no surgical treatment (no surgery group, n = 112,753). Propensity score matching by age and sex was used to select the control group of 627,085 participants. Mean follow-up duration was 4.6 ± 2.3 years. The primary endpoint was newly diagnosed Alzheimer dementia, vascular dementia, or other types of dementia. Compared with the control group, the hazard ratio (HR) and 95% confidence interval of dementia was calculated for patients with OSA. In the no-surgery group, the incidence of Alzheimer disease (HR 1.30 [1.22-1.38]), vascular dementia (HR 1.20 [1.05-1.36]), and other types of dementia (HR 1.35 [1.20-1.54]) was significantly higher than those among the control group. In the UPPP group, the incidence of Alzheimer disease (HR 1.08 [0.80-1.45]), vascular dementia (HR 0.58 [0.30-1.12]), and other types of dementia (HR 1.00 [0.57-1.77]) was similar to control levels. Uvulopalatopharyngoplasty may have a preventive effect on dementia in patients with OSA.


A fast and accurate computational method for the linear-combination-based isotropic periodic sum.
An isotropic periodic sum (IPS) is a powerful technique to reasonably calculate intermolecular interactions for wide range of molecular systems under periodic boundary conditions. A linear-combination-based IPS (LIPS) has been developed to attain computational accuracy close to an exact lattice sum, such as the Ewald sum. The algorithm of the original LIPS method has a high computational cost because it needs long-range interaction calculations in real space. This becomes a performance bottleneck for long-time molecular simulations. In this work, the combination of an LIPS and fast Fourier transform (FFT) was developed, and evaluated on homogeneous and heterogeneous molecular systems. This combinational approach of LIPS/FFT attained computational efficiency close to that of a smooth particle mesh Ewald while maintaining the same high accuracy as the original LIPS. We concluded that LIPS/FFT has great potential to extend the capability of IPS techniques for the fast and accurate computation of many types of molecular systems.


[Basic sanitary conditions in Iporanga, São Paulo State, Brazil].
To assess the pollution of water bodies by domestic sewage and to evaluate the basic sanitation conditions of residences and the knowledge of the local population concerning intestinal parasitic diseases and the hazards they present to public health. Thirteen water samples were collected from each of four sites in different water bodies of the Bairro da Serra region, in Iporanga, São Paulo State. Rates of total and fecal coliforms were measured and median values were presented so as to show domestic sewage contamination in the area. Questionnaires were administered to 50% of local households in order to obtain information on water supply and disposal of domestic sewage and solid waste, and to evaluate knowledge of the transmission, health hazards, and prevention of intestinal parasitic diseases among the local population. The Betari river showed microbiological indexes indicative of pollution by domestic sewage. Higher levels were verified both upstream and downstream from the Bairro da Serra. Median values were even higher in two of the river's tributary streams, indicating strong pollution by domestic sewage and lack of conformity with current legislation. In 91% of the households investigated, sewage disposal was done by means of septic tanks, most of which were rudimentary and contributed to the contamination of the environment. The knowledge of 62% of interviewed subjects concerning the transmission of helminthic diseases was considered as poor. Our results indicate a risk of proliferation of intestinal parasitoses and of other water-transmitted diseases, an issue which is aggravated by increases in population caused by the region's vocation for ecotourism.


Orbital Pseudotumor as a Rare Extrahepatic Manifestation of Hepatitis C Infection.
Hepatitis C is frequently accompanied by immune-related extrahepatic manifestations affecting the skin, kidneys, central and peripheral nervous system and exocrine glands. We present the case of a 40-year-old man with left-sided ptosis, exophthalmos and headache. MRI demonstrated left-sided orbital pseudotumor with lacrimal and retro-orbital contrast enhancement extending to the cavernous sinus and the vestibulocochlear nerve. Immunological tests of serum and cerebrospinal fluid identified hepatitis C virus (HCV) as a potential causative agent but did not indicate any additional infectious, malignant or immunological disorder. Hepatological evaluation revealed no signs of advanced liver disease. After initial spontaneous improvement, the patient subsequently developed vestibulocochlear failure with gait disorder, tinnitus and transient left-parietal sensory loss. Lacrimal biopsy demonstrated lymphocytic infiltrate, prompting steroid treatment. After initial improvement, steroids could not be tapered below 40 mg daily for several months due to recurrent symptoms. Twelve months after the initial presentation, the patient's chronic HCV infection was successfully treated with sofosbuvir, simeprevir and ribavirin and he remains now free of symptoms without steroids. In patients with chronic hepatitis C, lymphocytic infiltrate of the salivary and lacrimal glands is a frequent phenomenon. However, the extent of the lymphocytic infiltrate beyond the lacrimal gland to the tip of the orbit, cavernous sinus and vestibulocochlear nerve as in our patient is highly unusual. For all symptomatic extrahepatic manifestations of hepatitis C infection, treatment of HCV as the underlying immune stimulus is recommended, and it helped to control the symptoms in our patient. In addition, long-term follow-up for recurrent lymphocyte infiltrate and development of lymphoma is warranted.


Effects of Rosa canina fruit extract on neutrophil respiratory burst.
Respiratory burst leads polymorphonuclear neutrophils (PMN) to produce reactive oxygen species (ROS) such as superoxide anions (O(2)(o-)), hypochlorous acid (HOCl) and hydrogen peroxide (H(2)O(2)) which may possess deleterious effects for the organism. Rosa canina fruits are well known to contain a large amount of vitamin C which is antioxidant. This study was focused on the polyphenolics contained in rose hips to evaluate their antioxidative properties. We prepared a rose hip extract deprived of vitamin C. The extract contained mainly phenolics such as proanthocyanidins and flavonoids. We investigated its effects directly against (O(2)(o-)), HOCl and H(2)O(2) and investigated its effects on isolated PMN. For that, in vitro inflammatory conditions were reproduced by stimulating PMN with stimuli having different transductional pathways, in order to determine a possible mechanism of action. The results showed that the extract can inhibit ROS tested in acellular and cellular systems. The IC(50) obtained were 5.73 mg/L, 1.33 mg/L and 2.34 mg/L respectively for (O(2)(o-)), HOCl and H(2)O(2) in acellular experiments. For cellular experiments, the IC(50) were quite similar. Thus, the extract did not present an effect on PMN metabolism. Therefore, the antioxidative effects of Rosa canina are due not only to vitamin C but also to polyphenolics.


Using natural language processing to enable in-depth analysis of clinical messages posted to an Internet mailing list: a feasibility study.
An Internet mailing list may be characterized as a virtual community of practice that serves as an information hub with easy access to expert advice and opportunities for social networking. We are interested in mining messages posted to a list for dental practitioners to identify clinical topics. Once we understand the topical domain, we can study dentists' real information needs and the nature of their shared expertise, and can avoid delivering useless content at the point of care in future informatics applications. However, a necessary first step involves developing procedures to identify messages that are worth studying given our resources for planned, labor-intensive research. The primary objective of this study was to develop a workflow for finding a manageable number of clinically relevant messages from a much larger corpus of messages posted to an Internet mailing list, and to demonstrate the potential usefulness of our procedures for investigators by retrieving a set of messages tailored to the research question of a qualitative research team. We mined 14,576 messages posted to an Internet mailing list from April 2008 to May 2009. The list has about 450 subscribers, mostly dentists from North America interested in clinical practice. After extensive preprocessing, we used the Natural Language Toolkit to identify clinical phrases and keywords in the messages. Two academic dentists classified collocated phrases in an iterative, consensus-based process to describe the topics discussed by dental practitioners who subscribe to the list. We then consulted with qualitative researchers regarding their research question to develop a plan for targeted retrieval. We used selected phrases and keywords as search strings to identify clinically relevant messages and delivered the messages in a reusable database. About half of the subscribers (245/450, 54.4%) posted messages. Natural language processing (NLP) yielded 279,193 clinically relevant tokens or processed words (19% of all tokens). Of these, 2.02% (5634 unique tokens) represent the vocabulary for dental practitioners. Based on pointwise mutual information score and clinical relevance, 325 collocated phrases (eg, fistula filled obturation and herpes zoster) with 108 keywords (eg, mercury) were classified into 13 broad categories with subcategories. In the demonstration, we identified 305 relevant messages (2.1% of all messages) over 10 selected categories with instances of collocated phrases, and 299 messages (2.1%) with instances of phrases or keywords for the category systemic disease. A workflow with a sequence of machine-based steps and human classification of NLP-discovered phrases can support researchers who need to identify relevant messages in a much larger corpus. Discovered phrases and keywords are useful search strings to aid targeted retrieval. We demonstrate the potential value of our procedures for qualitative researchers by retrieving a manageable set of messages concerning systemic and oral disease.


Prospective Intention-Based Lifestyle Contracts: mHealth Technology and Responsibility in Healthcare.
As the rising costs of lifestyle-related diseases place increasing strain on public healthcare systems, the individual's role in disease may be proposed as a healthcare rationing criterion. Literature thus far has largely focused on retrospective responsibility in healthcare. The concept of prospective responsibility, in the form of a lifestyle contract, warrants further investigation. The responsibilisation in healthcare debate also needs to take into account innovative developments in mobile health technology, such as wearable biometric devices and mobile apps, which may change how we hold others accountable for their lifestyles. Little is known about public attitudes towards lifestyle contracts and the use of mobile health technology to hold people responsible in the context of healthcare. This paper has two components. Firstly, it details empirical findings from a survey of 81 members of the United Kingdom general public on public attitudes towards individual responsibility and rationing healthcare, prospective and retrospective responsibility, and the acceptability of lifestyle contracts in the context of mobile health technology. Secondly, we draw on the empirical findings and propose a model of prospective intention-based lifestyle contracts, which is both more aligned with public intuitions and less ethically objectionable than more traditional, retrospective models of responsibility in healthcare.


Towards a "free radical theory of graying": melanocyte apoptosis in the aging human hair follicle is an indicator of oxidative stress induced tissue damage.
Oxidative stress is generated by a multitude of environmental and endogenous challenges such as radiation, inflammation, or psychoemotional stress. It also speeds the aging process. Graying is a prominent but little understood feature of aging. Intriguingly, the continuous melanin synthesis in the growing (anagen) hair follicle generates high oxidative stress. We therefore hypothesize that hair bulb melanocytes are especially susceptible to free radical-induced aging. To test this hypothesis, we subjected human scalp skin anagen hair follicles from graying individuals to macroscopic and immunohistomorphometric analysis and organ culture. We found evidence of melanocyte apoptosis and increased oxidative stress in the pigmentary unit of graying hair follicles. The "common" deletion, a marker mitochondrial DNA-deletion for accumulating oxidative stress damage, occurred most prominently in graying hair follicles. Cultured unpigmented hair follicles grew better than pigmented follicles of the same donors. Finally, cultured pigmented hair follicles exposed to exogenous oxidative stress (hydroquinone) showed increased melanocyte apoptosis in the hair bulb. We conclude that oxidative stress is high in hair follicle melanocytes and leads to their selective premature aging and apoptosis. The graying hair follicle, therefore, offers a unique model system to study oxidative stress and aging and to test antiaging therapeutics in their ability to slow down or even stop this process.


Protocol adherence and the ability to achieve target haemoglobin levels in haemodialysis patients.
Anemia management remains complicated in patients with endstage renal disease on hemodialysis. We wished to evaluate the effect of protocol adherence to EPO and intravenous iron dosing on achieving the desired range of hemoglobin levels. A cohort of hemodialysis patients was studied to evaluate the rate of adherence to EPO and iron dosing protocols over a 5 month period. A database was completed to evaluate all known comorbidities, demographic factors, and facility issues that might affect hemoglobin levels. A logistic regression model was employed to evaluate the effect of adherence to the anemia protocols on the probability of achieving a hemoglobin level below, within or above the targeted range of 11-12.5 g/dl. Among 2114 patients, we found that adherence to both the EPO and iron dosing protocol resulted in the greatest probability of achieving the target hemoglobin range (56 +/- 5% in anemia protocol adherent patients versus 42 +/- 7% in non adherent patients). This was predominantly due to a lowered risk of having above target hemoglobin levels rather than below. The use of the anemia protocols was associated with lower rates of hospitalization (9 +/- 0.7 visits/100 months in adherent group vs 15 +/- 2 in non adherent group) and lower utilization of both EPO and intravenous iron. Furthermore, patients in the adherent groups had less variability of their hemoglobin levels month by month, at least as judged by standard deviation. Adherence to anemia protocols, as practiced in the dialysis units included in this cohort, may improve hemodialysis patients' ability to achieve target hemoglobin levels, and by avoiding above target hemoglobin values, lower drug utilization and reduce variability of hemoglobin levels.


The Effect of Walnut Oil Consumption on Blood Sugar in Patients With Diabetes Mellitus Type 2.
Prevalence of diabetes mellitus type 2 (DM) is increasing globally. Considering the potential role of poly-unsaturated fatty acids in prevention of DM type 2 and lipid profiles improvement, some studies have been carried out on walnut. However, there are no studies on control of blood sugar in DM type 2 patients using walnut. The current study aimed to evaluate the effect of walnut oil on blood sugar in DM type 2 patients. This randomized control clinical trial was performed on 100 patients with DM type 2. For the experiment group (n = 50), walnut oil (15 g/day for three months) was added to their diet, while the control group (n = 50) did not undergo any interventions. Before initiation of the experiment and after the experiment, the systolic and diastolic blood pressure (SBP and DBP) levels, fasting blood sugar (FBS) and HbA1c were measured. The two groups were not significantly different for SBP, DBP, body weight, and Body Mass Index. HbA1c level decreased significantly in the experiment group by 7.86% ± 21.97 (P = 0.005) from 7.00 ± 1.08 before the intervention to 6.37 ± 1.29 after the intervention. Also, FBS level decreased significantly by 8.24% ± 16.77 (P = 0.001); from 158.37 ± 48.16 before the intervention to 137.91 ± 23.24 after the intervention in the experimental group. These changes in the control group were not significant. Consumption of walnut oil (15 g/day for three months) was shown to improve blood glucose level but, no changes were noted for bodyweight and blood pressure in type two diabetic patients.


Development of weight and age-based dosing of daily primaquine for radical cure of vivax malaria.
In many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients of all ages. However, for many anti-malarial drugs, including primaquine, there is evidence that children have lower exposures than adults for the same weight-adjusted dose. The aim of the study was to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax. The recommended adult target dose of 0.5 mg/kg/day (30 mg in a 60 kg patient) is highly efficacious against tropical P. vivax and was assumed to produce optimal drug exposure. Primaquine doses were calculated using allometric scaling to derive a weight-based primaquine regimen over a weight range from 5 to 100 kg. Growth curves were constructed from an anthropometric database of 53,467 individuals from the Greater Mekong Subregion (GMS) to define weight-for-age relationships. The median age associated with each weight was used to derive an age-based dosing regimen from the weight-based regimen. The proposed weight-based regimen has 5 dosing bands: (i) 5-7 kg, 5 mg, resulting in 0.71-1.0 mg/kg/day; (ii) 8-16 kg, 7.5 mg, 0.47-0.94 mg/kg/day; (iii) 17-40 kg, 15 mg, 0.38-0.88 mg/kg/day; (iv) 41-80 kg, 30 mg, 0.37-0.73 mg/kg/day; and (v) 81-100 kg, 45 mg, 0.45-0.56 mg/kg/day. The corresponding age-based regimen had 4 dosing bands: 6-11 months, 5 mg, 0.43-1.0 mg/kg/day; (ii) 1-5 years, 7.5 mg, 0.35-1.25 mg/kg/day; (iii) 6-14 years, 15 mg, 0.30-1.36 mg/kg/day; and (iv) ≥ 15 years, 30 mg, 0.35-1.07 mg/kg/day. The proposed weight-based regimen showed less variability around the primaquine dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands for both regimens. The age-based regimen might not be applicable to regions outside the GMS, which must be based on local anthropometric data. Pharmacokinetic data in small children are needed urgently to inform the proposed regimens.


Therapeutic Potential and Immunomodulatory Role of Coenzyme Q10 and Its Analogues in Systemic Autoimmune Diseases.
Coenzyme Q10 (CoQ10) is a mitochondrial electron carrier and a powerful lipophilic antioxidant located in membranes and plasma lipoproteins. CoQ10 is endogenously synthesized and obtained from the diet, which has raised interest in its therapeutic potential against pathologies related to mitochondrial dysfunction and enhanced oxidative stress. Novel formulations of solubilized CoQ10 and the stabilization of reduced CoQ10 (ubiquinol) have improved its bioavailability and efficacy. Synthetic analogues with increased solubility, such as idebenone, or accumulated selectively in mitochondria, such as MitoQ, have also demonstrated promising properties. CoQ10 has shown beneficial effects in autoimmune diseases. Leukocytes from antiphospholipid syndrome (APS) patients exhibit an oxidative perturbation closely related to the prothrombotic status. In vivo ubiquinol supplementation in APS modulated the overexpression of inflammatory and thrombotic risk-markers. Mitochondrial abnormalities also contribute to immune dysregulation and organ damage in systemic lupus erythematosus (SLE). Idebenone and MitoQ improved clinical and immunological features of lupus-like disease in mice. Clinical trials and experimental models have further demonstrated a therapeutic role for CoQ10 in Rheumatoid Arthritis, multiple sclerosis and type 1 diabetes. This review summarizes the effects of CoQ10 and its analogs in modulating processes involved in autoimmune disorders, highlighting the potential of these therapeutic approaches for patients with immune-mediated diseases.


Brushing force of manual and sonic toothbrushes affects dental hard tissue abrasion.
This study aimed to determine the brushing forces applied during in vivo toothbrushing with manual and sonic toothbrushes and to analyse the effect of these brushing forces on abrasion of sound and eroded enamel and dentin in vitro. Brushing forces of a manual and two sonic toothbrushes (low and high frequency mode) were measured in 27 adults before and after instruction of the respective brushing technique and statistically analysed by repeated measures analysis of variance (ANOVA). In the in vitro experiment, sound and eroded enamel and dentin specimens (each subgroup n = 12) were brushed in an automatic brushing machine with the respective brushing forces using a fluoridated toothpaste slurry. Abrasion was determined by profilometry and statistically analysed by one-way ANOVA. Average brushing force of the manual toothbrush (1.6 ± 0.3 N) was significantly higher than for the sonic toothbrushes (0.9 ± 0.2 N), which were not significantly different from each other. Brushing force prior and after instruction of the brushing technique was not significantly different. The manual toothbrush caused highest abrasion of sound and eroded dentin, but lowest on sound enamel. No significant differences were detected on eroded enamel. Brushing forces of manual and sonic toothbrushes are different and affect their abrasive capacity. Patients with severe tooth wear and exposed and/or eroded dentin surfaces should use sonic toothbrushes to reduce abrasion, while patients without tooth wear or with erosive lesions confining only to enamel do not benefit from sonic toothbrushes with regard to abrasion.


Mechanism for the Substitution of an Aqua Ligand of UO2(OH2)5(2+) by Chloride.
Geometry and energy of the reactant (UO2(OH2)5·Cl(+)), the transition state (UO2(OH2)5···Cl(+) (‡)), and the product (UO2Cl(OH2)4·OH2(+)) of the title reaction have been computed with complete active space SCF (geometries and vibrational frequencies) and multiconfiguration quasi-degenerate second-order perturbation theory (total energies). Hydration was treated using the polarizable continuum model. The two investigated active spaces, (12/11) and (12/12), produce the same results. In contrast to the water exchange reaction on UO2(OH2)5(2+), which proceeds via the associative (A) mechanism (which is a two step reaction involving an intermediate with an increased coordination number, UO2(OH2)6(2+)), water substitution by chloride follows the associative interchange (Ia) mechanism (which does not proceed via any intermediate). In this case, structure and imaginary mode of the transition state are not straightforward criteria for the attribution of the substitution mechanism, since they are both typical for the A pathway. The Ia mechanism was derived from the computed intrinsic reaction coordinate, which showed that no intermediate (for example UO2Cl(OH2)5(+)) exists as a local minimum on the potential energy surface. The activation free enthalpy is 31 kJ mol(-1). As for the water exchange reaction, the dissociative mechanism is unlikely to operate because of its higher free activation enthalpy (by ≈25 kJ mol(-1)).


SEQMINER: An R-Package to Facilitate the Functional Interpretation of Sequence-Based Associations.
Next-generation sequencing has enabled the study of a comprehensive catalogue of genetic variants for their impact on various complex diseases. Numerous consortia studies of complex traits have publically released their summary association statistics, which have become an invaluable resource for learning the underlying biology, understanding the genetic architecture, and guiding clinical translations. There is great interest in the field in developing novel statistical methods for analyzing and interpreting results from these genotype-phenotype association studies. One popular platform for method development and data analysis is R. In order to enable these analyses in R, it is necessary to develop packages that can efficiently query files of summary association statistics, explore the linkage disequilibrium structure between variants, and integrate various bioinformatics databases. The complexity and scale of sequence datasets and databases pose significant computational challenges for method developers. To address these challenges and facilitate method development, we developed the R package SEQMINER for annotating and querying files of sequence variants (e.g., VCF/BCF files) and summary association statistics (e.g., METAL/RAREMETAL files), and for integrating bioinformatics databases. SEQMINER provides an infrastructure where novel methods can be distributed and applied to analyzing sequence datasets in practice. We illustrate the performance of SEQMINER using datasets from the 1000 Genomes Project. We show that SEQMINER is highly efficient and easy to use. It will greatly accelerate the process of applying statistical innovations to analyze and interpret sequence-based associations. The R package, its source code and documentations are available from http://cran.r-project.org/web/packages/seqminer and http://seqminer.genomic.codes/.