Radiomics in precision medicine for lung cancer.
With the improvement of external radiotherapy delivery accuracy, such as intensity-modulated and stereotactic body radiation therapy, radiation oncology has recently entered in the era of precision medicine. Despite these precise irradiation modalities, lung cancers remain one of the most aggressive human cancers worldwide, possibly because of diverse genotypic alterations that drive and maintain lung tumorigenesis. It has been long recognized that imaging could aid in the diagnosis, tumor delineation, and monitoring of lung cancer. Moreover, accumulating evidence suggests that imaging information could be further used to tailor treatment type and intensity, as well as predict treatment outcomes in radiotherapy. However, these imaging tasks have been carried out either qualitatively or using simplistic metrics that doesn't take advantage of the full scale of imaging knowledge. Radiomics, which is a recent field of research that aims to provide a more quantitative representation of imaging information relating tumor phenotypes to clinical and genotypic endpoints by embedding extracted image features into predictive mathematical models. These predictive models can be a key component in the clinician decision making and treatment personalization. This review provides an overview of the radiomics application and its methodology for radiation oncology studies in lung cancer.


Role of Ca(2+) in injury-induced changes in sodium current in rat skeletal muscle.
Characteristics of voltage-dependent sodium current recorded from adult rat muscle fibers in loose patch mode were rapidly altered following nearby impalement with a microelectrode. Hyperpolarized shifts in the voltage dependence of activation and fast inactivation occurred within minutes. In addition, the amplitude of the maximal sodium current decreased within 30 min of impalement. Impalement triggered a sustained elevation of intracellular Ca(2+). However, buffering Ca(2+) by loading fibers with AM-BAPTA did not affect the hyperpolarized shifts in activation and inactivation, although it did prevent the reduction in current amplitude. Surprisingly, the rise in intracellular Ca(2+) occurred even in the absence of extracellular Ca(2+). This result indicated that the injury-induced Ca(2+) increase came from an intracellular source, but it was not blocked by an inhibitor of release from the sarcoplasmic reticulum, which suggested involvement of mitochondria. Ca(2+) release from mitochondria triggered by carbonyl cyanide 3-chlorophenylhydrazone was sufficient to cause a reduction in sodium current amplitude but had little effect of the voltage dependence of activation and fast inactivation. Our data suggest the effects of muscle injury can be separated into a Ca(2+)-dependent reduction in amplitude and a largely Ca(2+)-independent shift in activation and fast inactivation. Together, the impalement-induced changes in sodium current reduce the number of sodium channels available to open at the resting potential and may limit further depolarization and thus promote survival of muscle fibers following injury.


The involvement of upstream stimulatory factor 1 in Dutch patients with familial combined hyperlipidemia.
Recently, the upstream stimulatory factor 1 gene (USF1) was proposed as a candidate gene for familial combined hyperlipidemia (FCH). In this study, we examined the previously identified risk haplotype of USF1 with respect to FCH and its related phenotypes in 36 Dutch FCH families. The diagnosis of FCH was based on both the traditional diagnostic criteria and a nomogram. The two polymorphisms, USF1s1 and USF1s2, were in complete linkage disequilibrium. No association was found for the individual single nucleotide polymorphisms (SNPs) with FCH defined by the nomogram (USF1s1, P = 0.53; USF1s2, P = 0.53), whereas suggestive associations were found when using the traditional diagnostic criteria for FCH (USF1s1, P = 0.08; USF1s2, P = 0.07). USF1 was associated with total cholesterol (USF1s1, P = 0.05; USF1s2, P = 0.04) and apolipoprotein B (USF1s1, P = 0.06; USF1s2, P = 0.04). Small dense LDL showed a suggestive association (USF1s1, P = 0.10; USF1s2, P = 0.09). The results from the haplotype analyses supported the results obtained for the individual SNPs. In conclusion, the previously identified risk haplotype of USF1 showed a suggestive association with FCH and contributed to the related lipid traits in our Dutch FCH families.


Altitude training causes haematological fluctuations with relevance for the Athlete Biological Passport.
The impact of altitude training on haematological parameters and the Athlete Biological Passport (ABP) was evaluated in international-level elite athletes. One group of swimmers lived high and trained high (LHTH, n = 10) for three to four weeks at 2130 m or higher whereas a control group (n = 10) completed a three-week training camp at sea-level. Haematological parameters were determined weekly three times before and four times after the training camps. ABP thresholds for haemoglobin concentration ([Hb]), reticulocyte percentage (RET%), OFF score and the abnormal blood profile score (ABPS) were calculated using the Bayesian model. After altitude training, six swimmers exceeded the 99% ABP thresholds: two swimmers exceeded the OFF score thresholds at day +7; one swimmer exceeded the OFF score threshold at day +28; one swimmer exceeded the threshold for RET% at day +14; and one swimmer surpassed the ABPS threshold at day +14. In the control group, no values exceeded the individual ABP reference range. In conclusion, LHTH induces haematological changes in Olympic-level elite athletes which can exceed the individually generated references in the ABP. Training at altitude should be considered a confounding factor for ABP interpretation for up to four weeks after altitude exposure but does not consistently cause abnormal values in the ABP.


The importance of regional models in assessing canine cancer incidences in Switzerland.
Fitting canine cancer incidences through a conventional regression model assumes constant statistical relationships across the study area in estimating the model coefficients. However, it is often more realistic to consider that these relationships may vary over space. Such a condition, known as spatial non-stationarity, implies that the model coefficients need to be estimated locally. In these kinds of local models, the geographic scale, or spatial extent, employed for coefficient estimation may also have a pervasive influence. This is because important variations in the local model coefficients across geographic scales may impact the understanding of local relationships. In this study, we fitted canine cancer incidences across Swiss municipal units through multiple regional models. We computed diagnostic summaries across the different regional models, and contrasted them with the diagnostics of the conventional regression model, using value-by-alpha maps and scalograms. The results of this comparative assessment enabled us to identify variations in the goodness-of-fit and coefficient estimates. We detected spatially non-stationary relationships, in particular, for the variables related to biological risk factors. These variations in the model coefficients were more important at small geographic scales, making a case for the need to model canine cancer incidences locally in contrast to more conventional global approaches. However, we contend that prior to undertaking local modeling efforts, a deeper understanding of the effects of geographic scale is needed to better characterize and identify local model relationships.


Community perceptions of the socio-economic structural context influencing HIV and TB risk, prevention and treatment in a high prevalence area in the era of antiretroviral therapy.
Following calls for targeted HIV prevention interventions in so-called "hotspots", we explored subjective perceptions of community members in places considered to be high HIV and tuberculosis (TB) transmission areas and those with low prevalence. Although more people now have access to antiretroviral therapy (ART), some areas are still experiencing high HIV transmission rates, presenting a barrier to the elimination of HIV. A rapid qualitative assessment approach was used to access a sample of 230 people who contributed narratives of their experiences and perceptions of transmission, treatment and prevention of HIV and TB in their communities. Theoretical propositions case study strategy was used to inform and guide the thematic analysis of the data with Research Department of Epidemiology & Public Health, University College London, London, UK. Our results support the concept of linking perceived control to health through the identification of structural factors that increase communities' sense of agency. People in these communities did not feel they had the efficacy to effect change in their milieu. The few socio-economic opportunities promote social mobility in search of better prospects which may have a negative impact on community cohesion and prevention strategies. Communities were more concerned with improving their immediate social and economic situations and prioritised this above the prevention messages. Therefore approaches that focus on changing the structural and environmental barriers to prevention may increase people's perceived control. Multifaceted strategies that address the identified constructs of perceived control may influence the social change necessary to make structural interventions successful.


Clinical review: Prothrombin complex concentrates--evaluation of safety and thrombogenicity.
Prothrombin complex concentrates (PCCs) are used mainly for emergency reversal of vitamin K antagonist therapy. Historically, the major drawback with PCCs has been the risk of thrombotic complications. The aims of the present review are to examine thrombotic complications reported with PCCs, and to compare the safety of PCCs with human fresh frozen plasma. The risk of thrombotic complications may be increased by underlying disease, high or frequent PCC dosing, and poorly balanced PCC constituents. The causes of PCC thrombogenicity remain uncertain but accumulating evidence indicates the importance of factor II (prothrombin). With the inclusion of coagulation inhibitors and other manufacturing improvements, today's PCCs may be considered safer than earlier products. PCCs may be considered preferable to fresh frozen plasma for emergency anticoagulant reversal, and this is reflected in the latest British and American guidelines. Care should be taken to avoid excessive substitution with prothrombin, however, and accurate monitoring of patients' coagulation status may allow thrombotic risk to be reduced. The risk of a thrombotic complication due to treatment with PCCs should be weighed against the need for rapid and effective correction of coagulopathy.


Melasma: update on management.
Melasma is a common, acquired, chronic cutaneous pigment disorder that is often difficult to treat and has a high recurrence rate. The goal of a melasma treatment regimen is to decrease pigment production and increase elimination. Topical tyrosinase inhibitors block melanin synthesis and thereby reduce pigment production. Peels and laserand light-based devices increase melanin elimination. A multimodality treatment approach targeting both pigment production and elimination is necessary to achieve equilibrium and disease remission. Maintenance treatments are often necessary due to the high recurrence rate. Strict photoprotection is critical to prevent melanogenesis and rebound. Targeting the vasculature via pulsed dye laser or tranexamic acid is another approach to treatment.


The role of acidity in solid tumour growth and invasion.
Acidic pH is a common characteristic of human tumours. It has a significant impact on tumour progression and response to therapies. In this paper, we develop a simple model of three-dimensional tumour growth to examine the role of acidosis in the interaction between normal and tumour cell populations. Both vascular and avascular tumour dynamics are investigated, and a number of different behaviours are observed. Whilst an avascular tumour always proceeds to a benign steady state, a vascular tumour may display either benign or invasive dynamics, depending on the value of a critical parameter. Analysis of the model allows us to assess novel therapies directed towards changing the level of acidity within the tumour.


Diagnostic Accuracy of Platelet/Lymphocyte Ratio for Screening Complex Coronary Lesion in Different Age Group of Patients with Acute Coronary Syndrome.
with the increasing number of patients with acute coronary syndrome (ACS) with complex coronary lesion and the increasing needs of coronary artery bypass grafting (CABG) procedures, there is an increasing need for a tool to perform early stratification in high-risk patients, which can be used in daily clinical practice, even at first-line health care facilities setting in Indonesia. It is expected that early stratification of high-risk patients can reduce morbidity and mortality rate in patients with ACS. This study aimed to identify diagnostic accuracy of platelet/lymphocyte ratio (PLR) and the optimum cut-off point of PLR as a screening tool for identifying a complex coronary lesion in patients ≤45 and >45 years old. this was a retrospective cross-sectional study, conducted at the ICCU of Cipto Mangunkusumo Hospital. Data was obtained from medical records of adult patients with ACS who underwent coronary angiography between January 2012 - July 2015. The inclusion criteria were adult ACS patients (aged ≥18 years old), diagnosed with ACS and underwent coronary angiography during hospitalization. Diagnostic accuracy was determined by calculating sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR-). The cut-off point was determined using ROC curve. the proportion of ACS patients with complex coronary lesion in our study was 47.2%. The optimum cut-off point in patients aged ≤45 years was 111.06 with sensitivity, specificity, LR+ and LR of 91.3%, 91.9%, 11.27 and 0.09, respectively. The optimum cut-off points in patients aged >45 years was 104.78 with sensitivity, specificity, LR+ and LR of 91.7%, 58.6%, 2.21 and 0.14, respectively. the optimum cut-off point for PLR in patients aged ≤ 45 years is 111.06 and for patients with age >45 years is 104.78 with diagnostic accuracy, represented by AUC of 93.9% (p<0.001) and 77.3% (p<0.001), respectively for both age groups.


Efficacy of a new navigable percutaneous disc decompression device (L'DISQ) in patients with herniated nucleus pulposus related to radicular pain.
An institutional, prospective clinical data analysis. To evaluate the safety and efficacy of a new navigable percutaneous disc decompression device (L'DISQ) in patients with lumbar disc herniation with radicular pain. We performed disc decompressions using L'DISQ on 27 patients with persistent disabling back and leg pain for 1 month or longer (average 6.48 months) due to a herniated lumbar intervertebral disc. Baseline data were prospectively gathered before the index procedure and at 1, 4, 12, and 24 weeks post-procedure. Data included pain intensity (visual analog scale [VAS]), measure of disability (Oswestry Disability Index [ODI] and Rolando-Morris Questionnaire [RM]), health-related quality of life (Bodily Pain Scale of Short Form-36 version 2 [SF-36 BP]), and passive straight leg raising test (SLR). The VAS fell from 7.08±1.22 to 1.84±0.99 scores at 24 weeks post-procedure. At 24 weeks, the ODI had fallen from 41.88±10.61 to 16.66±8.55% and the RM from 11.52±3.91 to 2.68±1.97 points. The SF-36 BP dropped significant improvement from 32.89±5.83 to 49.57±4.96 scales. In the SLR test, the angular change of 24 weeks showed considerable improvement from 60.20±20.02 to 83.00±14.29 degrees. No major complication occurred, although two cases developed a disc reherniation 1 month post-procedure. The L'DISQ device is specifically designed to remove herniated disc using a wand that can be navigated into a disc protrusion or extrusion. Following decompression, we measured clinically significant pain improvement and decreased disability for patients with both radicular and axial pain caused by protruded and extruded discs.


Effects of multisensory yoga on behavior in a male child with Apert and Asperger syndrome.
This case focused on a 7-year-old boy with Apert and Asperger's syndrome who attended 8, 45 min multisensory yoga sessions, twice a week, during 4-week camp. Results from the pre- and post-tests on Treatment and Research Institute for Autism Social Skills Assessment showed improvements in the total score changes from 19 to 7 for disruptive behaviors. Sparks Target Behavior Checklist scores changed from eight to one showing progression in ability to stay on task. Yoga Pose Rating Scale displayed the transformation in total scores from 80 = emerging to 115 = consistency in pose performance. The field notes revealed the positive development in expressive emotions, social engagement, and decline in looking around. Outside class parent and school behavioral specialist reported the improved ability to self-regulate stress using lion's breath and super brain. These findings indicate an improvement in behaviors that influenced the physical performance, emotional expression, and social interaction after yoga training for this child.


An objective measurement of urinary continence recovery with pelvic floor physiotherapy following robotic assisted radical prostatectomy.
To assess the impact of structured pelvic floor physiotherapy including repeated standardized measurements in regaining urinary continence in those men who have undergone a robotic-assisted laparoscopic radical prostatectomy (RALP). A retrospective database was created on men who had undergone a RALP while under the care of two senior urological surgeons between January 2013 and July 2016 and then took part in a formal pelvic floor rehabilitation program were included in the study. Men were initially seen pre-operatively and then after removal of their indwelling catheter commenced their structured continence program. They were instructed to record their pad weights commencing at week four post-RALP. For each subsequent week, an average of the 24-hour urine leakage was recorded and compared to their first recorded week (baseline) to assess improvement of urinary continence over time. Forty-five men with a median age of 63.7 years were followed up for a mean of 11.3 weeks post-operatively. The mean daily urine leakage during the first recorded week was 408.0 mL. This decreased to 205.8 and 110.1 mL at 2 and 3 months post-RALP (P<0.05). This equated to a significant 57.1% (95% CI, 52.9% to 61.3%) and 75.6% (95% CI, 72.3% to 78.8%) improvement in urinary leakage at the same respective time points. There is considerable improvement of urinary leakage following RALP in the short-term in men who participated in a structured, physiotherapist-led pelvic floor re-training program.


Age of language learning shapes brain structure: a cortical thickness study of bilingual and monolingual individuals.
We examined the effects of learning a second language (L2) on brain structure. Cortical thickness was measured in the MRI datasets of 22 monolinguals and 66 bilinguals. Some bilingual subjects had learned both languages simultaneously (0-3 years) while some had learned their L2 after achieving proficiency in their first language during either early (4-7 years) or late childhood (8-13 years). Later acquisition of L2 was associated with significantly thicker cortex in the left inferior frontal gyrus (IFG) and thinner cortex in the right IFG. These effects were seen in the group comparisons of monolinguals, simultaneous bilinguals and early and late bilinguals. Within the bilingual group, significant correlations between age of acquisition of L2 and cortical thickness were seen in the same regions: cortical thickness correlated with age of acquisition positively in the left IFG and negatively in the right IFG. Interestingly, the monolinguals and simultaneous bilinguals did not differ in cortical thickness in any region. Our results show that learning a second language after gaining proficiency in the first language modifies brain structure in an age-dependent manner whereas simultaneous acquisition of two languages has no additional effect on brain development.


Effects of Calcium, Vitamin D, and Hormone Therapy on Cardiovascular Disease Risk Factors in the Women's Health Initiative: A Randomized Controlled Trial.
To analyze the treatment effect of calcium+vitamin D supplementation, hormone therapy, both, and neither on cardiovascular disease risk factors. We conducted a prospective, randomized, double-blind, placebo-controlled trial among Women's Health Initiative (WHI) participants. The predefined primary outcome was low-density lipoprotein cholesterol (LDL-C). Between September 1993 and October 1998, a total of 68,132 women aged 50-79 years were recruited and randomized to the WHI-Dietary Modification (n=48,835) and WHI-Hormone Therapy trials (n=27,347). Subsequently, 36,282 women from WHI-Hormone Therapy (16,089) and WHI-Dietary Modification (n=25,210) trials were randomized in the WHI-Calcium+Vitamin D trial to 1,000 mg elemental calcium carbonate plus 400 international units vitamin D3 daily or placebo. Our study group included 1,521 women who participated in both the hormone therapy and calcium+vitamin D trials and were in the 6% subsample of trial participants with blood sample collections at baseline and years 1, 3, and 6. The average treatment effect with 95% confidence interval, for LDL-C, compared with placebo, was -1.6, (95% confidence interval [CI] -5.5 to 2.2) mg/dL for calcium+vitamin D alone, -9.0 (95% CI -13.0 to -5.1) mg/dL for hormone therapy alone, and -13.8 (95% CI -17.8 to -9.8) mg/dL for the combination. There was no evidence of a synergistic effect of calcium+vitamin D+hormone therapy on LDL-C (P value for interaction=.26) except in those with low total intakes of vitamin D, for whom there was a significant synergistic effect on LDL (P value for interaction=.03). Reductions in LDL-C were greater among women randomized to both calcium+vitamin D and hormone therapy than for those randomized to either intervention alone or to placebo. The treatment effect observed in the calcium+vitamin D+hormone therapy combination group may be additive rather than synergistic. For clinicians and patients deciding to begin calcium+vitamin D supplementation, current use of hormone therapy should not influence that decision. ClinicalTrials.gov, https://clinicaltrials.gov, NCT00000611.


Effect of dextran on cerebral function and blood after cardiac arrest. An experimental study on the dog.
EEG activity and regional cerebral blood flow were monitored during 5 hour survival following cardiac arrest in 32 pentobarbital anesthetized mongrel dogs. The animals were mechanically ventilated and blood gases were maintained at physiologic levels. Regional cerebral blood flow and cardiac output were measured using 15 mu microspheres. EEG was recorded from 6 epidural electrodes using bipolar techniques. The animals were divided into 3 groups. The animals in Group I had an arrest of 8-11 minutes and those in Group II and III had an arrest of 12-16 minutes. Group II animals received no treatment. Group III animals were given 1 g/kg of dextran 40 at a concentration of 10% in normal saline following the arrest and maintained with 10 mg/kg/min during the 5 hours of recovery. In Groups I and III there was shorter duration of a flat EEG and 5 hours after the arrest the EEG activity was closer to normal than in Group II. After 5 hours the EEG scores of Group III were significantly greater than Group II (p less than 0.03). The cortical grey matter and hippocampus had the greatest reduction of blood flow following cardiac arrest. The mean cortical grey matter blood flow in Group II was less than in Groups I and III at 3 hours. After 5 hours the grey matter blood flow was greater in Group III than in Group II (p less than 0.09). The findings of this study are consistent with the hypothesis that after cardiac arrest perfusion abnormalities persist or develop after return of blood pressure and that these can be corrected or prevented with improved functional survival by treatment with dextran 40 after the arrest.


Impact and acceptability of HIV self-testing for trans men and trans women: A mixed-methods subgroup analysis of the SELPHI randomised controlled trial and process evaluation in England and Wales.
Globally, trans people are disproportionately affected by HIV, but research on strategies to increase testing are limited. SELPHI is a randomised-controlled-trial (RCT) of 10,135 cis men, trans men, and trans women reporting lifetime anal intercourse with male partners (cis or trans), evaluating whether the offer of free HIV self-testing (HIVST) increases diagnosis. This subgroup analysis from the SELPHI RCT aims to describe key HIVST outcomes and HIVST acceptability for trans people. SELPHI recruited using social networking and trans focused social media. Participants were randomised 60/40 to baseline HIVST (Biosure™) (BT) vs no baseline HIVST (nBT); and at 3-months (if completed the survey and reported recent CAI) 50/50 to 3-monthly HIVST (RT) vs no repeat HIVST (nRT). Outcomes were self-reported through online surveys. We conducted a qualitative study of semi-structured peer-led participant interviews (n = 20) exploring HIVST motivations and experiences. These were analysed using a framework approach. SELPHI recruited and randomised 118 trans men and trans women (94 trans men, 24 trans women), of whom 20 (16 trans men, 4 trans women) underwent the second randomisation. Median age at baseline was 29 (IQR: 22, 37), 79% were white, 79% were UK born, 37% had degree level education, and 31% had never tested for HIV. 62% (n = 59) of trans men completed the 3-month survey, but survey completion by trans women in nBT was too low (1/11) for randomised comparison. In trans men HIV testing uptake by 3 months was significantly higher in BT (95% 36/38) vs nBT (29%, 6/21) (RR=3.32 (1.68, 6.55) p<0.001). Trans people randomised to RT reported 3 times higher rate of HIV testing compared to nRT during the two-year follow-up (IRR 3.66 (1.86, 8.01) p<0.0001). STI testing frequency (mean number of tests during each 13 week period/ 2-year follow-up) was not significantly different across interventions: RT (0.03) and nRT (0.01) (IRR=1.86 95%CI; 0.77, 5.15; p = 0.15). Social harms were rare. Acceptability was very high in BT: 97% (38/39) found instructions easy to understand, 97% (37/38) found the HIVST simple to use and 100% (39/39) reported good overall experience. In interviews, reported HIVST benefits included increased autonomy, privacy, convenience and avoidance of health care providers perceived to be discriminatory and services that increased dysphoria. Minor lancet and test processing issues were reported. HIVST significantly increased testing uptake and frequency in trans men and trans people overall, although recruitment and retention of trans women was low. HIVST acceptability was high and indicates easy access to this novel technology may increase HIV testing access for this key population.


Sexual differences in the auditory system of the tree frog Eleutherodactylus coqui.
Acoustic playback experiments with calling males in their natural habitat and two-choice orientation experiments with females indicate that males and females of the neotropical tree frog Elutherodactylus coqui respond to different notes in the two-note call of the male. This functional dichotomy of the two notes in the male's call reflects a difference in the distribution of the best excitatory frequencies of primary auditory neurons for the males and females. To the best of our knowledge, Eleutherodactylus is the first known example of a vertebrate in which the peripheral auditory sensitivity shows a sexual difference.


Evaluation and management of hypertension in the elderly.
Treatment of hypertension in the elderly is a challenge. Elevated blood pressure (> 140/80 mmHg) in the elderly (60+ years) can be either systolic, diastolic or combination of both. Arterial stiffness, intimal hyperplasia and non-compliance of the vascular tree have been underlying factors. Prevalence of hypertension increases with advancing age and varies with the population under study; therefore screening this population should not only be limited to those at risk. Presentation is often due to complications such as stroke, cardiovascular events, and erectile dysfunction or due to presentation of an unrelated disorder The presence of co-morbidity, drug interaction and their side effects should be considered in the management of hypertension in the elderly. With the advent of several classes of antihypertensives, there is no shortage of drug options for treatment of hypertension in the elderly, but a careful and individualized approach is needed.


CT and MR of lymphomatoid granulomatosis of the CNS: report of four cases and review of the literature.
Lymphomatoid granulomatosis is an uncommon disease characterized by a perivascular pleomorphic cellular infiltration and necrosis. CNS involvement occurs in 20% of the cases. CT findings have been described in five of the previously reported cases of CNS lymphomatoid granulomatosis, and include unifocal, multifocal, and diffuse contrast-enhancing supratentorial lesions. We reviewed the CT scans of three patients and the MR image of a fourth patient with histologically confirmed CNS lymphomatoid granulomatosis. The lesions were in the posterior fossa in three of the four cases. Hemorrhage, which was present in three of the four cases, was detected by imaging studies in two and at autopsy in the third. Systemic involvement was present at autopsy in three cases and was clinically suspected in the fourth. A diagnosis of CNS lymphomatoid granulomatosis should be considered when hemorrhagic or posterior fossa lesions occur in patients with constitutional symptoms.


Wide-Angle Viewing System versus Conventional Indirect Ophthalmoscopy for Scleral Buckling.
Wide-angle viewing systems (WAVSs) were originally established for pars plana vitrectomy. However, their application to scleral buckling surgery was recently reported. In this study, we compared the outcomes of scleral buckling using a noncontact WAVS with that of scleral buckling using conventional indirect ophthalmoscopy for rhegmatogenous retinal detachment. The clinical records of 39 eyes (39 patients) with rhegmatogenous retinal detachment primarily treated between November 2012 and June 2014 at the Vitreo-Retina Surgical Division Clinic at the Department of Ophthalmology, Keio University Hospital were retrospectively reviewed. Scleral bucking was performed using WAVS with surgical placement of an endoilluminator in 16 eyes and indirect ophthalmoscopy in 23 eyes. The patients in these groups were consecutive over different intervals. The preoperative demographics, success rate of retinal reattachment, intraoperative findings, and postoperative complications were evaluated. There were no significant differences in pre- or postoperative conditions between groups, and similar surgical outcomes were achieved with the WAVS and conventional procedures. However, compared with the conventional procedure, the WAVS procedure resulted in fewer intraoperative corneal epithelial disorders (p = 0.049) and decreased the surgical duration of segmental buckling (p = 0.02); therefore, it may be suggested as an effective alternative procedure.


A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.
Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease. Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism. 5, 10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine. Reduced MTHFR activity with a thermolabile enzyme has been reported in patients with coronary and peripheral artery disease. We have identified a common mutation in MTHFR which alters a highly-conserved amino acid; the substitution occurs at a frequency of approximately 38% of unselected chromosomes. The mutation in the heterozygous or homozygous state correlates with reduced enzyme activity and increased thermolability in lymphocyte extracts; in vitro expression of a mutagenized cDNA containing the mutation confirms its effect on thermolability of MTHFR. Finally, individuals homozygous for the mutation have significantly elevated plasma homocysteine levels. This mutation in MTHFR may represent an important genetic risk factor in vascular disease.


Vascular complication in live related renal transplant: An experience of 1945 cases.
Among the surgical complications in renal transplantation, the vascular complications are probably most dreaded, dramatic, and likely to cause sudden loss of renal allograft. We present our experience and analysis of the outcome of such complications in a series of 1945 live related renal transplants. One thousand nine hundred and forty five consecutive live related renal transplants were evaluated retrospectively for vascular complications. Complications were recorded and analyzed for frequency, time of presentation, clinical presentation, and their management. The age of patients ranged from 6 to 56 years (mean = 42). Vascular complications were found in 25 patients (1.29%). Most common among these was transplant renal artery stenosis found in 11 (0.58%), followed by transplant reznal artery thrombosis in 9 (0.46%), renal vein thrombosis in 3 (0.15%), and aneurysm formation at arterial anastmosis in 2 (0.10%) patient. The time of presentation also varied amongst complications. All cases of arterial thrombosis had sudden onset anuria with minimal or no abdominal discomfort, while venous thrombosis presented as severe oliguria associated with intense graft site pain and tenderness. Management of cases with vascular thrombosis was done by immediate surgical exploration. Two patients of renal artery stenosis were managed with angioplasty and stent placement. Major vascular complications are relatively uncommon after renal transplantation but still constitute an important cause of graft loss in early postoperative period. Aneurysm and vessel thrombosis usually require graft nephrectomy. Transplant renal artery stenosis is amenable to correction by endovascular techniques.


Dynamic lightpath provisioning with signal quality guarantees in survivable translucent optical networks.
This paper studies the problem of signal-quality-guaranteed lightpath provisioning in survivable translucent optical networks under dynamic traffic. A new protection scheme, called regeneration-segment protection (RSP), is proposed. Provisioning approaches with shared path protection and shared RSP are presented. Two main signal quality constraints are integrated with the provisioning problem. Different regenerator placement strategies for working path and protection path are employed. Joint path selection method is used to select the "optimal" working-protection pair. With the above considerations, survivable lightpath provisioning with signal-quality-guarantees is achieved in a cost-effective manner. Results show that in a moderate-size network, RSP has less blocking probability than path protection when the network load is low or modest. Besides, RSP obtains better performance in terms of recovery time than path protection in all network scenarios.


Effectiveness and safety of a second and third biological agent after failing etanercept in juvenile idiopathic arthritis: results from the Dutch National ABC Register.
To evaluate the effectiveness and safety of switching to a second or third biological agent in juvenile idiopathic arthritis (JIA) after etanercept failure. The Arthritis and Biologicals in Children Register aims to include all Dutch JIA patients who have used biological agents. Data on the disease course were used to estimate drug survival with Kaplan-Meier and calculate adverse event (AE) rates. Of 307 biologically naive JIA patients who started etanercept, 80 (26%) switched to a second and 22 (7%) to a third biological agent. During 1030 patient-years of follow-up after the introduction of etanercept, 49 switches to adalimumab, 28 infliximab, 17 anakinra, four abatacept and four trial drugs were evaluated. 84% (95% CI 80% to 88%) of patients who started etanercept as a first biological agent were, after 12 months, still on the drug, compared with 47% (95% CI 35% to 60%) who started a second and 51% (95% CI 26% to 76%) who started a third biological agent. Patients who switched because of primary ineffectiveness continued the second agent less often (32%, 95% CI 12% to 53%). After etanercept failure, drug continuation of adalimumab was similar to infliximab for patients with non-systemic JIA; anakinra was superior to a second TNF-blocker for systemic JIA. AE rates within first 12 months after initiation were comparable for each course and each biological agent. Switching to another biological agent is common, especially for systemic JIA patients. A second (and third) agent was less effective than the first. The choice of second biological agent by the physician mainly depends on availability and JIA category.


Face and Content Validity of a Probe Tube Placement Training Simulator.
Probe tube placement is an important skill audiologists must learn to make real-ear measurements in an audiology clinic. With current evidence-based guidelines recommending insertion of the probe tube within 5 mm of the tympanic membrane (TM) for proper acoustical measurements, students must be well trained to ensure they are capable to perform this placement in clinical practice. This is not always the case as it has been found that real-ear measurements are not performed in a clinic as often as required. To address this, a simulator consisting of a 3D-printed ear model and an optical tracking system was developed to provide a training system for students to practice probe tube placement and to provide a method to evaluate competency before starting clinical practicum placements. Two simulators were developed, an adult model and a pediatric model. To assess the face and content validity of the two probe tube placement simulators (adult and pediatric) and define barriers and facilitators to implementing this system into an educational setting. Participants followed the setup and operating instructions designed to guide them through each functionality of the simulator. A questionnaire was used to assess face and content validity, applicability to an educational setting, and to determine perceived barriers and facilitators to using the probe tube simulators for training purposes. Five additional probe tube placements with each simulator were performed in which distance-to-TM was recorded. Twelve participants with significant probe tube placement experience. Participants rated each question in the questionnaire from 0% to 100% depending on their level of agreement. Averages and standard deviations (SDs) were compiled and presented for each section (face validity, content validity, and applicability to an educational setting). Final facilitators and barriers for the simulator were compiled and the top answers of each are presented. The five quantitative probe tube placement measurements for each participant were averaged, SDs were calculated, and contacts with the TM while placing the probe tube were recorded. The average face validity score over all questions for the adult model was 65% (SD = 18.2) whereas the pediatric model received a score of 64% (16.4). The overall content validity average score was 78.7% (17) and applicability to an educational setting had an average score of 80% (5.33). The average distance-to-TM across all trials and participants was 3.74 mm (1.82) for the adult model and 2.77 mm (0.94) for the pediatric model with only one participant exceeding the recommended maximum of 5 mm. Listed shortcomings of the current simulator included realism of the 3D-printed ear, ease of insertion of an otoscope tip into the ear, ability to visualize the ear canal "landmarks" and the TM, and foam tip insertion experience. Results were generally very positive for the simulator, and future iterations will look to improve the flexibility and texture of the ear, as well as the otoscopic view of the ear canal and TM.


Effects of fatiguing isometric and isokinetic ankle exercises on postural control while standing on firm and compliant surfaces.
Fatiguing exercises used across studies to induce alterations in postural control are diverse and may explain the different findings reported. This study aimed to compare the effects of two types of fatiguing plantarflexion exercises on postural control on a firm and a compliant surface. Ten healthy young men (29 ± 4 years) were asked to stand as steadily as possible for 30 s, blindfolded with feet together, on a firm and a compliant surface before and immediately after an isometric and an isokinetic fatiguing exercise. Maximal force reduction due to fatigue was found significant but similar between exercises. No significant difference was found between the fatiguing exercises on all Center of Pressure (CoP) parameters. Both fatiguing exercises induced increases in CoP excursion area, CoP variability and CoP velocity in both planes (antero-posterior, mediolateral) on the compliant surface. On the firm surface, both fatiguing exercises only induced increases in CoP variability and CoP velocity in the fatigued plane (antero-posterior). Isometric and isokinetic fatiguing exercises, when producing a similar level of force reduction, induce similar decreases in postural control. The effects of fatigue on postural control in healthy young men are more pronounced when standing on a compliant surface, i.e. when proprioceptive information at the ankle is altered.


Distribution of tyrosinated and nontyrosinated alpha-tubulin during mitosis.
The C-terminus of alpha-tubulin undergoes a reversible posttranslational tyrosination/detyrosination. The distributions of the tyrosinated (Tyr) and nontyrosinated (Glu) species during mitosis of cultured cells have been investigated by immunofluorescence using antibodies directed against the C-terminus of either Tyr or Glu tubulin. The distribution of Tyr tubulin differed from that of Glu tubulin at each stage of mitosis; in general, the distribution of Tyr tubulin was similar to that of total tubulin, whereas Glu tubulin had a more restricted distribution. The Glu species was found in half-spindle fibers but was not detected in astral fibers at any stage and was seen in the interzone only during telophase. These results were confirmed by a direct comparison of the distributions of Tyr and Glu tubulin in cells double-labeled with the two antibodies. Evidence for the occurrence of Tyr and Glu tubulin in each class of half-spindle fibers (kinetochore and polar) was obtained from the staining patterns of the two antibodies in cold-treated cells. Immunoblots of extracts prepared from synchronous mitotic cells showed that Glu tubulin was a minor species of the total tubulin in the spindle; no changes in the amount of either Tyr or Glu tubulin were detected at any stage of mitosis. These results show that Tyr tubulin is the major species in the mitotic spindle and is found in all classes of spindle fibers, whereas Glu tubulin is present in small amounts and shows a more restricted distribution. The presence of two biochemically distinct forms of alpha-tubulin in the spindle may be important for spindle function.


Vagus nerve stimulation for partial and generalized epilepsy from infancy to adolescence.
Vagus nerve stimulation (VNS) is approved by the FDA for the treatment of partial epilepsy in patients older than 12 years. Authors of the current study performed a large retrospective analysis and comparison of VNS outcomes in children with an age ≥ and < 12 years, including those with partial and generalized epilepsy. A retrospective review of the records of pediatric patients (age < 18 years) who had undergone primary VNS system implantation between 2001 and 2010 by a single pediatric neurosurgeon was undertaken. Considered data included demographics, epilepsy type (partial vs generalized), seizure frequency, seizure duration, postictal period duration, and antiepileptic medication use. One hundred forty-six patients (49% female) were followed up for a mean of 41 months after VNS implantation. Thirty-two percent of patients had partial epilepsy and 68% had generalized epilepsy. After VNS system implantation, seizure frequency was reduced in 91% of patients, seizure duration in 50%, postictal period in 49%, and antiepileptic medication use in 75%. There was no significant difference in age, sex, or duration of follow-up according to epilepsy type. Neither was there any significant difference in seizure frequency reduction, seizure duration, postictal period, medication use, overall clinical improvement, or improvement in quality of life based on an age ≥ or < 12 years or epilepsy type. Vagus nerve stimulation reduced both seizure frequency and antiepileptic medication use in the majority of pediatric patients regardless of sex, age cohort, or epilepsy type. Vagus nerve stimulation also reduced seizure duration and postictal period in approximately half of the pediatric patients. Contrary to expectation, children with partial epilepsy do not benefit from VNS at higher rates than those with generalized epilepsy.


Capillary electrophoresis evidence for the stereoselective metabolism of itraconazole in man.
Itraconazole (ITC) is a hydrophobic antimycotic drug with three chiral centers that is used clinically as a stereoisomeric mixture. A chiral capillary electrophoretic method for the separation of ITC stereoisomers and those of its main metabolite hydroxyitraconazole (HITC) was developed to determine the stereoselective nature of the ITC to HITC biotransformation. The method is based on the formation of inclusion complexes of the target analytes with the negatively charged sulfated beta-cyclodextrin in the presence of moderate concentrations of methanol in a low-pH phosphate buffer. The addition of polyethylene glycol 4000 was found to be critical in obtaining baseline resolution of eight peaks, two from ITC, four from HITC, and two from R051012 (internal standard), in under 20 min. Application of the developed procedure to serum samples from patients being treated with ITC showed clearly the presence of a stereoselective component in the metabolism of this antimycotic drug. This could be shown from in vitro incubations with single enzyme Supersomes to be in part due to the stereoselective formation of HITC by the human CYP3A4 enzyme. For one patient, monitoring of the ITC and HITC concentrations and peak ratios over a 103 day period of treatment with ITC showed a strong dependency of the chiral ITC ratio to the concentration of ITC, while the dominant enantiomeric ratio of HITC was largely independent of the total HITC concentration.


Risk of upper gastrointestinal complications associated with cyclooxygenase-2 selective and nonselective nonsteroidal antiinflammatory drugs.
To estimate the risk of upper gastrointestinal complications associated with use of cyclooxygenase-2 (COX-2) selective (celecoxib and rofecoxib) and individual nonselective nonsteroidal antiinflammatory drugs (NSAIDs) compared with nonuse of these drugs. Nested case-control study. Administrative health care databases of Saskatchewan, Canada. Among a population of men and women aged 20-89 years who were covered by public health insurance with prescription drug benefits between November 15, 1999, and December 31, 2001, 726 case patients with first hospitalization for upper gastrointestinal complications (with validation of cases through review of hospital medical records) were confirmed from 1,054,532 person-years of follow-up, and 20,002 control patients were randomly selected from all eligible controls, frequency matched to cases on their index date (+/- 3 mo). Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between upper gastrointestinal complications and use of NSAIDs. Current rofecoxib and naproxen users had the highest risk for upper gastrointestinal complications with adjusted ORs of 3.6 (95% CI 2.2-5.7) and 3.4 (95% CI 1.8-6.7), respectively. No association was found between the risk of upper gastrointestinal complications and use of celecoxib (OR 1.1, 95% CI 0.7-1.8) or the use of diclofenac plus misoprostol (OR 0.7, 95% CI 0.3-1.8). A dose-response relationship was observed for rofecoxib and naproxen with ORs for high dose of 5.2 (95% CI 2.5-10.6) and 5.1 (95% CI 2.1-12.3), respectively. Short-term users of celecoxib and naproxen had a higher risk than long-term users, whereas among users of rofecoxib the risk was higher among long-term than short-term users. These findings support the variability of individual NSAIDs in the elevated risk of upper gastrointestinal complications. Our results suggest that the risk for rofecoxib is similar to that for naproxen. Celecoxib users appear to have a similar risk for upper gastrointestinal complications as nonusers; however, the risk may be increased at the start of treatment with celecoxib.


Incidence of preventable postoperative readmissions following pancreaticoduodenectomy: implications for patient education.
To determine readmission rates post-pancreaticoduodenectomy (PD), readmission reasons following PD, and patients' postoperative education prior to discharge. Retrospective, descriptive study of established medical records of patients who have undergone PD from 2006-2008. PD cohort from a pancreatic cancer program. 62 patients aged 18 years or older, diagnosed with pancreatic cancer, who had PD. Data abstracted from inpatient and outpatient electronic records as per study protocol and entered into Excel® spreadsheet for analysis. Incidences of and reasons for readmissions post the PD procedure. Discharge education given to patients prior to discharge. Patients were discharged at mean postoperative day 11.3. Readmission rate was 28%. Reasons for readmission were dehydration or malnutrition (n = 10, 16%) and surgical site infection (n = 7, 11%); 10% of patients (n = 6) had documented difficulties with dehydration, malnutrition, and failure to thrive noted at follow-up. PD discharge teaching was documented in a mandatory discharge form. No standard curriculum was used. Patients undergoing PD experience an increase in self-care demand postdischarge. Poor discharge education can lead to high rates of readmission, specifically for dehydration and malnutrition, mandating an assessment of patient education prior to discharge. Close attention must be given to the needs of patients with pancreatic cancer postdischarge. Trying to identify the areas of educational deficit at patient readmission could help nurses identify what they can do to minimize preventable complications. Educational focus for patients undergoing PD should be on prevention of dehydration, malnutrition, and surgical site infections.


Multiple courses of antenatal corticosteroids for preterm birth study: outcomes in children at 5 years of age (MACS-5).
A single course of antenatal corticosteroid therapy is recommended for pregnant women at risk of preterm birth between 24 and 33 weeks' gestational age. However, 50% of women remain pregnant 7 to 14 days later, leading to the question of whether additional courses should be given to women remaining at risk for preterm birth. The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study (MACS) was an international randomized clinical trial that compared multiple courses of antenatal corticosteroids with a single course in women at risk of preterm birth. To determine the effects of single vs multiple courses of antenatal corticosteroid therapy on death or neurodevelopmental disability (neuromotor, neurosensory, or neurocognitive/neurobehavioral function) at 5 years of age in children whose mothers participated in MACS. Our secondary aims were to determine the effect on height, weight, head circumference, blood pressure, intelligence, and specific cognitive (visual, spatial, and language) skills. Cohort follow-up study of children seen between June 2006 and May 2012 at 55 centers. In total, 1724 women (2141 children) were eligible for the study, of whom 1728 children (80.7% of the 2141 eligible children) participated and 1719 children contributed to the primary outcome. Single and multiple courses of antenatal corticosteroid therapy. The primary outcome was death or survival with a neurodevelopmental disability in 1 of the following domains: neuromotor (nonambulatory cerebral palsy), neurosensory (blindness, deafness, or need for visual/hearing aids), or neurocognitive/neurobehavioral function (abnormal attention, memory, or behavior). There was no significant difference between the groups in the risk of death or neurodevelopmental disability: 217 of 871 children (24.9%) in the multiple-courses group vs 210 of 848 children (24.8%) in the single-course group (odds ratio, 1.02 [95% CI, 0.81 to 1.29]; P = .84). Multiple courses, compared with a single course, of antenatal corticosteroid therapy did not increase or decrease the risk of death or disability at 5 years of age. Because of a lack of strong conclusive evidence of short-term or long-term benefits, it remains our opinion that multiple courses not be recommended in women with ongoing risk of preterm birth. clinicaltrials.gov Identifier: NCT00187382.


Corticospinal facilitation during first and third person imagery.
Motor imagery can be defined as the covert rehearsal of movement. Previous research with transcranial magnetic stimulation (TMS) has demonstrated that motor imagery increases the corticospinal excitability of the primary motor cortex in the area corresponding to the representation of the muscle involved in the imagined movement. This research, however, has been limited to imagery of oneself in motion. We extend the TMS research by contrasting first person imagery and third person imagery of index finger abduction-adduction movements. Motor evoked potentials were recorded from first dorsal interosseous (FDI) and abductor digiti minimi (ADM) during single pulse TMS. Participants performed first and third person motor imagery, visual imagery, and static imagery. Visual imagery involved non biological motion while static imagery involved a first person perspective of the unmoving hand. Relative to static imagery, excitability during imagined movement increased in FDI but not ADM. The facilitation in first person imagery adds to previous findings. A greater facilitation of MEPs recorded from FDI was found in third person imagery where the action was clearly attributable to another person. We interpret this novel result in the context of observed action and imagined observation of self action, and attribute the result to activation of mirror systems for matching the imagined action with an inner visuo-motor template.


Sustained effects of atmospheric [CO2] and nitrogen availability on forest soil CO2 efflux.
Soil CO2 efflux (Fsoil ) is the largest source of carbon from forests and reflects primary productivity as well as how carbon is allocated within forest ecosystems. Through early stages of stand development, both elevated [CO2] and availability of soil nitrogen (N; sum of mineralization, deposition, and fixation) have been shown to increase gross primary productivity, but the long-term effects of these factors on Fsoil are less clear. Expanding on previous studies at the Duke Free-Air CO2 Enrichment (FACE) site, we quantified the effects of elevated [CO2] and N fertilization on Fsoil using daily measurements from automated chambers over 10 years. Consistent with previous results, compared to ambient unfertilized plots, annual Fsoil increased under elevated [CO2] (ca. 17%) and decreased with N (ca. 21%). N fertilization under elevated [CO2] reduced Fsoil to values similar to untreated plots. Over the study period, base respiration rates increased with leaf productivity, but declined after productivity saturated. Despite treatment-induced differences in aboveground biomass, soil temperature and water content were similar among treatments. Interannually, low soil water content decreased annual Fsoil from potential values - estimated based on temperature alone assuming nonlimiting soil water content - by ca. 0.7% per 1.0% reduction in relative extractable water. This effect was only slightly ameliorated by elevated [CO2]. Variability in soil N availability among plots accounted for the spatial variability in Fsoil , showing a decrease of ca. 114 g C m(-2) yr(-1) per 1 g m(-2) increase in soil N availability, with consistently higher Fsoil in elevated [CO2] plots ca. 127 g C per 100 ppm [CO2] over the +200 ppm enrichment. Altogether, reflecting increased belowground carbon partitioning in response to greater plant nutritional needs, the effects of elevated [CO2] and N fertilization on Fsoil in this stand are sustained beyond the early stages of stand development and through stabilization of annual foliage production.


Zygosaccharomyces bailii and Z. rouxii induced ethanol formation in apple juice supplemented with different natural preservatives: A response surface methodology approach.
In this study, ethanol produced by osmophilic yeasts, Zygosaccharomyces bailii and Z. rouxii, in apple juice preserved with mint essential oil (MEO), carvacrol and natamycin instead of synthetic preservatives was modeled. Some processing parameters such as sodium benzoate (SB, 0-0.1%) used as a positive control, storage temperature (4-20 °C) and storage time (1-41 days) were selected in the study. Box-Behnken design in response surface methodology was used to evaluate the effects of processing parameters on ethanol levels of apple juice and three models were created for three preservatives for each yeast. Preservative type affected the ethanol formation in apple juice for both yeasts studied. Increase of preservative concentration decreased the ethanol formation during the storage period. The best effective preservative was determined as MEO and Z. bailii was found to be quite resistant yeast against to the preserving agents for three models as compared to Z. rouxii. Ethanol level increased with the increase of both storage temperature and time for both yeasts. The results showed that apple juice could be preserved by these three preservatives, but the MEO was the most effective agent for apple juice during the storage.


Dams in the Cadillac Desert: downstream effects in a geomorphic context.
This paper was motivated by the 25th anniversary of the publication of Marc Reisner's book, Cadillac Desert: The American West and its Disappearing Water. Dams are ubiquitous on rivers in the United States, and large dams and storage reservoirs are the hallmark of western U.S. riverscapes. The effects of dams on downstream river ecosystems have attracted much attention and are encapsulated in the serial discontinuity concept (SDC). In the SDC, dams create abrupt shifts in continua of downstream changes in physical and biotic properties. In this paper, we develop a framework for understanding how channel geometry and network structure influence how the physical components of habitat and the biota rebound from discontinuities set up by large dams. We apply this framework to data describing the flow regime, temperature, sediment flux, and fish community composition below Garrison Dam on the Missouri River, Glen Canyon Dam on the Colorado River, and Flaming Gorge Dam on the Green River. Sediment flux in dam tailwaters is under strong control by channel geometry. By contrast, dam-related changes in temperature and flow variation are not significantly modulated by channel geometry or tributary inputs if flow volumes are small (Missouri and Colorado River tributaries). Instead, small tributaries provide near-native conditions (flow and temperature variation) and, as such, provide key refuges for biota from novel habitats in mainstem rivers below large dams. Unregulated tributaries that are large relative to their respective mainstem (e.g., Yampa River) provide refuges as well as significant amelioration of flow and temperature effects from upstream dams. Finally, the proportion of native fish increases with distance from dam and exhibits sharp increases near tributary junctions. These results suggest that tributaries-even minor ones in terms of relative discharge-act as key refugia for native species in regulated river networks. Moreover, large, unregulated tributaries are key to restoring continuity in physical habitat and the biota in large regulated rivers.


Translation and measurement properties of the Swedish version of ACL-Return to Sports after Injury questionnaire.
Psychological factors may be a hindrance for returning to sport after an anterior cruciate ligament (ACL) reconstruction. The ACL-Return to Sport after Injury scale (ACL-RSI) measures athletes' emotions, confidence in performance, and risk appraisal in relation to return to sport. The aim of this study was to translate the ACL-RSI scale from English to Swedish and to examine some of the measurement properties of the Swedish version. The ACL-RSI was translated and culturally adapted. A professional expert group and five patients evaluated face validity. One hundred and eighty-two patients completed the translated ACL-RSI, a project-specific questionnaire, the Tampa Scale of Kinesiophobia (TSK), the Knee-Self-Efficacy Scale (K-SES), the Multidimensional Health Locus of Control (MHLC-C), the Knee injury and Osteoarthritis Outcome Score (KOOS), and the Anterior Cruciate Ligament-Quality of Life (ACL-QoL) questionnaires. Fifty-three patients answered the ACL-RSI twice to examine reproducibility. The ACL-RSI showed good face validity, internal consistency (Cronbach's alpha = 0.948), low floor and ceiling effects and high construct validity when evaluated against the TSK, K-SES, MHLC-C, KOOS, and ACL-QoL scales. The reproducibility was also high (intra-class correlation = 0.893). Therefore, the ACL-RSI can be used to evaluate psychological factors relevant to returning to sport after ACL reconstruction surgery.


Bioinformatics and multiepitope DNA immunization to design rational snake antivenom.
Snake venom is a potentially lethal and complex mixture of hundreds of functionally diverse proteins that are difficult to purify and hence difficult to characterize. These difficulties have inhibited the development of toxin-targeted therapy, and conventional antivenom is still generated from the sera of horses or sheep immunized with whole venom. Although life-saving, antivenoms contain an immunoglobulin pool of unknown antigen specificity and known redundancy, which necessitates the delivery of large volumes of heterologous immunoglobulin to the envenomed victim, thus increasing the risk of anaphylactoid and serum sickness adverse effects. Here we exploit recent molecular sequence analysis and DNA immunization tools to design more rational toxin-targeted antivenom. We developed a novel bioinformatic strategy that identified sequences encoding immunogenic and structurally significant epitopes from an expressed sequence tag database of a venom gland cDNA library of Echis ocellatus, the most medically important viper in Africa. Focusing upon snake venom metalloproteinases (SVMPs) that are responsible for the severe and frequently lethal hemorrhage in envenomed victims, we identified seven epitopes that we predicted would be represented in all isomers of this multimeric toxin and that we engineered into a single synthetic multiepitope DNA immunogen (epitope string). We compared the specificity and toxin-neutralizing efficacy of antiserum raised against the string to antisera raised against a single SVMP toxin (or domains) or antiserum raised by conventional (whole venom) immunization protocols. The SVMP string antiserum, as predicted in silico, contained antibody specificities to numerous SVMPs in E. ocellatus venom and venoms of several other African vipers. More significantly, the antiserum cross-specifically neutralized hemorrhage induced by E. ocellatus and Cerastes cerastes cerastes venoms. These data provide valuable sequence and structure/function information of viper venom hemorrhagins but, more importantly, a new opportunity to design toxin-specific antivenoms-the first major conceptual change in antivenom design after more than a century of production. Furthermore, this approach may be adapted to immunotherapy design in other cases where targets are numerous, diverse, and poorly characterized such as those generated by hypermutation or antigenic variation.


Parental and neonatal risk factors for atopy, airway hyper-responsiveness, and asthma.
Previous studies have not resolved the importance of several potential risk factors for the development of childhood atopy, airway hyperresponsiveness, and wheezing, which would allow the rational selection of interventions to reduce morbidity from asthma. Risk factors for these disorders were examined in a birth cohort of 1037 New Zealand children. Responses to questions on respiratory symptoms and measurements of lung function and airway responsiveness were obtained every two to three years throughout childhood and adolescence, with over 85% cohort retention at age 18 years. Atopy was determined by skin prick tests at age 13 years. Relations between parental and neonatal factors, the development of atopy, and features of asthma were determined by comparison of proportions and logistic regression. Male sex was a significant independent predictor for atopy, airway hyper-responsiveness, hay fever, and asthma. A positive family history, especially maternal, of asthma strongly predicted childhood atopy, airway hyperresponsiveness, asthma, and hay fever. Maternal smoking in the last trimester was correlated with the onset of childhood asthma by the age of 1 year. Birth in the winter season increased the risk of sensitisation to cats. Among those with a parental history of asthma or hay fever, birth in autumn and winter also increased the risk of sensitisation to house dust mites. The number of siblings, position in the family, socioeconomic status, and birth weight were not consistently predictive of any characteristic of asthma. Male sex, parental atopy, and maternal smoking during pregnancy are risk factors for asthma in young children. Children born in winter exhibit a greater prevalence of sensitisation to cats and house dust mites. These data suggest possible areas for intervention in children at risk because of parental atopy.


The purple line as a measure of labour progress: a longitudinal study.
Vaginal examination (VE) and assessment of the cervix is currently considered to be the gold standard for assessment of labour progress. It is however inherently imprecise with studies indicating an overall accuracy for determining the diameter of the cervix at between 48-56%. Furthermore, VEs can be unpleasant, intrusive and embarrassing for women, and are associated with the risk of introducing infection. In light of increasing concern world wide about the use of routine interventions in labour it may be time to consider alternative, less intrusive means of assessing progress in labour. The presence of a purple line during labour, seen to rise from the anal margin and extend between the buttocks as labour progresses has been reported. The study described in this paper aimed to assess in what percentage of women in labour a purple line was present, clear and measurable and to determine if any relationship existed between the length of the purple line and cervical dilatation and/or station of the fetal head. This longitudinal study observed 144 women either in spontaneous labour (n = 112) or for induction of labour (n = 32) from admission through to final VE. Women were examined in the lateral position and midwives recorded the presence or absence of the line throughout labour immediately before each VE. Where present, the length of the line was measured using a disposable tape measure. Within subjects correlation, chi-squared test for independence, and independent samples t-test were used to analyse the data. The purple line was seen at some point in labour for 109 women (76%). There was a medium positive correlation between length of the purple line and cervical dilatation (r = +0.36, n = 66, P = 0.0001) and station of the fetal head (r = +0.42, n = 56, P < 0.0001). The purple line does exist and there is a medium positive correlation between its length and both cervical dilatation and station of the fetal head. Where the line is present, it may provide a useful guide for clinicians of labour progress along side other measures. Further research is required to assess whether measurement of the line is acceptable to women in labour and also clinicians.


Spinal G-protein-gated potassium channels contribute in a dose-dependent manner to the analgesic effect of mu- and delta- but not kappa-opioids.
Opioids can evoke analgesia by inhibiting neuronal targets in either the brain or spinal cord, and multiple presynaptic and postsynaptic inhibitory mechanisms have been implicated. The relative significance of presynaptic and postsynaptic inhibition to opioid analgesia is essentially unknown, as are the identities and relevant locations of effectors mediating opioid actions. Here, we examined the distribution of G-protein-gated potassium (GIRK) channels in the mouse spinal cord and measured their contribution to the analgesia evoked by spinal administration of opioid receptor-selective agonists. We found that the GIRK channel subunits GIRK1 and GIRK2 were concentrated in the outer layer of the substantia gelatinosa of the dorsal horn. GIRK1 and GIRK2 were found almost exclusively in postsynaptic membranes of putative excitatory synapses, and a significant degree of overlap with the mu-opioid receptor was observed. Although most GIRK subunit labeling was perisynaptic or extrasynaptic, GIRK2 was found occasionally within the synaptic specialization. Genetic ablation or pharmacologic inhibition of spinal GIRK channels selectively blunted the analgesic effect of high but not lower doses of the mu-opioid receptor-selective agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin. Dose-dependent contributions of GIRK channels to the analgesic effects of the -opioid receptor-selective agonists Tyr-D-Ala-Phe-Glu-Val-Val-Gly amide and [D-Pen(2,5)]-enkephalin were also observed. In contrast, the analgesic effect of the agonist (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methanesulfonate hydrate was preserved despite the absence of GIRK channels. We conclude that the activation of postsynaptic GIRK1 and/or GIRK2-containing channels in the spinal cord dorsal horn represents a powerful, albeit relatively insensitive, means by which intrathecal mu- and -selective opioid agonists evoke analgesia.


HIV-1 protease inhibitors. A review for clinicians.
The clinical care of people infected with human immunodeficiency virus (HIV) has been substantially affected by the introduction of HIV-specific protease inhibitors (PIs). The 4 PIs available are saquinavir mesylate, ritonavir, indinavir sulfate, and nelfinavir mesylate. Comparison studies have not been reported; therefore, an assessment of the available data to aid clinicians and patients in choosing appropriate treatment will be presented. A systematic review of peer-reviewed publications, abstracts from national and international conferences, and product registration information through September 1996. Criteria used to select studies include their relevance to PIs, having been published in the English language, and pertinence for clinicians. Data quality and validity included the venue of the publication and relevance to clinical care. Oral adminstration of ritonavir, indinavir, or nelfinavir generates sustainable drug serum levels to effectively inhibit the protease enzyme; however, saquinavir may not generate sustained levels necessary to inhibit the protease enzyme. Patients treated with ritonavir, indinavir, or nelfinavir experience similar reductions in viral load and increases in CD4+ lymphocytes; smaller effects occur among those treated with saquinavir. Two randomized placebo-controlled studies conducted among patients with severe immune system suppression and substantial zidovudine treatment experience demonstrated reduced HIV disease progression and reduced mortality with PI treatment. Genotypic resistance to PIs occurs; the clinical relevance of resistance is unclear. The costs of these agents including required monitoring impose new and substantial costs. The PIs have emerged as critical drugs for people with HIV infection. Optimal use involves combination with reverse transcriptase inhibitors. Resistance develops to each agent, and cross-resistance is likely. These agents must be used at full doses with attention to ensuring patient compliance. The expense of these agents may be offset by forestalling disease progression and death and returning people to productive life. Selecting the initial PI must be individualized, and factors to consider include proven activity, possible toxicities, dosing regimens, drug interactions, and costs.


Are health problems systemic? Politics of access and choice under Beveridge and Bismarck systems.
Industrialised countries face similar challenges for improving the performance of their health system. Nevertheless, the nature and intensity of the reforms required are largely determined by each country's basic social security model. Most reforms in Beveridge-type systems have sought to increase choice and reduce waiting times while those in major Bismarck-type systems have focused on cost control by constraining the choice of providers. This paper looks at the main differences in performance of five countries and reviews their recent reform experience, focusing on three questions: Are there systematic differences in performance of Beveridge and Bismarck-type systems? What are the key parameters of healthcare system, which underlie these differences? Have recent reforms been effective? Our results do not suggest that one system-type performs consistently better than the other. In part, this may be explained by the heterogeneity in organisational design and governance both within and across these systems. Insufficient attention to those structural differences may explain the limited success of a number of recent reforms. Thus, while countries may share similar problems in terms of improving healthcare performance, adopting a 'copy-and-paste' approach to healthcare reform is likely to be ineffective.


Regeneration of rat corpora cavernosa tissue by transplantation of CD133+ cells derived from human bone marrow and placement of biodegradable gel sponge sheet.
The objective is to develop an easier technique for regenerating corpora cavernosa tissue through transplantation of human bone marrow-derived CD133 + cells into a rat corpora cavernosa defect model. We excised 2 mm × 2 mm squares of the right corpora cavernosa of twenty-three 8-week-old male nude rats. Alginate gel sponge sheets supplemented with 1 × 10 4 CD133 + cells were then placed over the excised area of nine rats. Functional and histological evaluations were carried out 8 weeks later. The mean intracavernous pressure/mean arterial pressure ratio for the nine rats (0.34258 ± 0.0831) was significantly higher than that for eight rats with only the excision (0.0580 ± 0.0831, P = 0.0238) and similar to that for five rats for which the penis was exposed, and there was no excision (0.37228 ± 0.1051, P = 0.8266). Immunohistochemical analysis revealed that the nine fully treated rats had venous sinus-like structures and quantitative reverse transcription polymerase chain reaction analysis of extracts from their alginate gel sponge sheets revealed that the amounts of mRNA encoding the nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) were significantly higher than those for rats treated with alginate gel sheets without cell supplementation (NGF: P = 0.0309; VEGF: P < 0.0001). These findings show that transplantation of CD133 + cells accelerates functional and histological recovery in the corpora cavernosa defect model.


Examining subjective sleep quality in adults with hoarding disorder.
Hoarding disorder (HD), characterized by difficulty parting with possessions and functionally impairing clutter, affects 2-6% of the population. Originally considered part of Obsessive-Compulsive Disorder (OCD), HD became a distinct diagnostic entity in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) in 2013. While sleep impacts OCD, little is known about sleep in HD. As HD patients often report poor sleep in clinical settings, understanding global subjective sleep quality and disturbances may lead to novel therapeutic targets. To address this gap, the authors used a sample of convenience: an existing data set designed to screen research study eligibility and explore the psychopathology and phenomenology of OCD and HD. The data set included information collected from individuals with HD (n = 38), OCD (n = 26), and healthy participants (n = 22) about insomnia, sleep quality, and mood using interviews and structured instruments including the Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), and Depression Anxiety Stress Scales (DASS). In this data set, HD and OCD groups reported significantly greater insomnia symptoms and poorer sleep quality compared with healthy controls while controlling for depression, age, and gender. A sizable minority of HD and OCD individuals met criteria for comorbid sleep disorders. OCD and HD groups differed in delayed sleep phase prevalence. To our knowledge, this is the first study examining subjective sleep quality and insomnia in HD as compared to healthy individuals and those with OCD, while controlling for relevant clinical characteristics. Given that there are evidence-based treatments for insomnia and other sleep disorders, our study raises the possibility that treatment interventions targeting sleep may improve HD outcomes.


Antibodies reactive to Plasmodium falciparum serine repeat antigen in children with Burkitt lymphoma from Ghana.
The role of protective immunity to Plasmodium falciparum (Pf) malaria in Burkitt lymphoma (BL) is unknown. We investigated the association between BL and antibodies reactive to SE36 antigen, a recombinant protein based on P. falciparum serine repeat antigen 5 gene, targeted by protective malaria immune responses. Cases were children (0-14 years) enrolled at the Korle-Bu Teaching Hospital, Accra, Ghana, during 1965-1994 with BL confirmed by histology or cytology (92% of cases). Controls were apparently healthy children enrolled contemporaneous to the cases from the nearest neighbor house to the case house and were age,- sex-frequency-matched to the cases. Anti-SE36 IgG antibodies were measured using enzyme-linked absorbent immunoassays (ELISAs). SE36 titers were estimated by extrapolating ELISA optical density readings to a standard fitting curve. Anti-SE36 titers were log-transformed for analysis. Odds ratios (ORs) and two-sided 95% confidence intervals (95% CIs) were estimated using unconditional logistic regression. The mean log endpoint dilution titers were 0.63 logs lower in cases than in controls (8.26 [SD 1.68] vs. 8.89 [SD 1.75], Student's t-test, p = 0.019). Lower titers were observed in cases than controls aged 0-4 years (p = 0.05) and in those aged 5-14 years (p = 0.06). Low and medium tertiles of anti-SE36 IgG antibodies were associated with increased OR for BL ([OR 1.67, 95% CI 1.21-2.31] and [OR 1.33, 95% CI 0.96-1.86], respectively, p(trend) = 0.002) in analyses adjusting for age, sex, calendar period and test plate. Our findings suggest that compared to similarly aged children enrolled from the same community, children with BL in Ghana have lower antibodies to SE36 antigen.


Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study.
To investigate the relation of diabetes to dementia, Alzheimer disease (AD), and vascular dementia (VaD), through analyses of incidence, mortality, and neuropathologic outcomes in a prospective population-based study of the oldest old. The Vantaa 85+ study included 553 residents living in the city of Vantaa, Finland, and aged ≥85 years on April 1, 1991. Survivors were reexamined in 1994, 1996, 1999, and 2001. Autopsies were performed in 291 persons who died during the follow-up (48% of total population). Diabetes was assessed according to self-report, medical record of physician-diagnosed diabetes, or use of antidiabetic medication. Macroscopic infarcts were identified from 1-cm coronal slices of cerebral hemispheres, 5-mm transverse brainstem slices, and sagittal cerebellum slices. Methenamine silver staining was used for β-amyloid, methenamine silver-Bodian staining for neurofibrillary tangles, and modified Bielschowsky method for neuritic plaques. Cox proportional hazards and multiple logistic regression models were used to analyze the association of diabetes with dementia and neuropathology, respectively. Diabetes at baseline doubled the incidence of dementia, AD, and VaD, and increased mortality. Individuals with diabetes were less likely to have β-amyloid (hazard ratio [HR] [95% confidence interval (CI)] was 0.48 [0.23-0.98]) and tangles (HR [95% CI] 0.72 [0.39-1.33]) but more likely to have cerebral infarcts (HR [95% CI] 1.88 [1.06-3.34]) after all adjustments. Elderly patients with diabetes develop more extensive vascular pathology, which alone or together with AD-type pathology (particularly in APOE ε4 carriers) results in increased dementia risk.


Is high-intensity exercise better than moderate-intensity exercise for weight loss?
This viewpoint debates the state-of-the-art research focusing on the optimal intensity of the exercise programs for inducing a sustained weight or fat-mass loss in overweight/obese people. In our demanding society, the most attractive messages in the popular press are those promising the best results in a short time. This might explain the emphasis given by media to those scientific articles that report the efficacy on weight loss of exercise programs by their shorter duration and higher intensity. However, in the literature on overweight or obese people, there is little conclusive evidence for more favorable effects with high-intensity training than with continuous moderate-intensity exercise on body weight or fat mass loss. Since both exercise protocols have been demonstrated as useful to reduce body weight, the decision on the intensity of exercise prescription should be individualized and based on outcomes different from fat or weight loss. In this regard, there are pro and contra arguments for the prescription of high-intensity aerobic exercise in obese people. Among the pro arguments, is the demonstration that, in several studies, high-intensity training appears to induce superior improvements in aerobic fitness. Among the contra arguments to prescribe high-intensity exercise is the demonstration that prescribing a higher-intensity exercise decreases adherence and results in the completion of less exercise. Thus, a successful exercise program should be proposed at a moderate intensity and a low perceived effort because obese subjects who have low self-efficacy, poor mood status, and are not familiar with high-intensity workouts could easily drop out.


Controversies in Allergy: Choosing a Biologic for Patients with Severe Asthma.
The availability of a range of new biological treatments targeting type-2 inflammation has provided new opportunities for patients with more severe asthma. Treatment has a bigger effect on exacerbations than day-to-day symptoms, and efficacy increases with increasing intensity of type-2 airway inflammation as reflected by the blood eosinophil count and fractional exhaled nitric oxide. The similarity of the clinical effects and target populations coupled with the absence of direct head-to-head comparative data makes it difficult to choose the right biologic for a given patient. In this review, we summarize the key efficacy data from phase 3 trials; discuss indirect comparisons; review clinical and laboratory variables that may be associated with a differential response to treatment; outline practical considerations that might be important to individual patients; and suggest an algorithm for choosing the most appropriate biologic to start with and the first choice to switch to.


Local pH and effective pKA of weak polyelectrolytes - insights from computer simulations.
In this work we study the titration behavior of weak polyelectrolytes by computer simulations. We analyze the local pH near the chains at various conditions and provide molecular-level insight which complements the recent experimental determination of this quantity. Next, we analyze the non-ideal titration behaviour of weak polyelectrolytes in solution, calculate the effective ionization constant and compare the simulation results with theoretical predictions. In contrast with the universal behaviour with respect to chain length, we find non-universality and deviations from theory with respect to polymer concentration and permittivity of the solvent. The latter we explain in terms of counterion condensation and ion correlation effects, which lead to reversal of the non-ideal titration behaviour at very low permittivities. We discuss the impact of these findings on the interpretation of experimental results.


Comparison of techniques for detecting antigens of Giardia lamblia and Cryptosporidium parvum in faeces.
To compare the use of commercial monoclonal antibody test systems--the Giardia CEL IF test and the Crypto CEL IF test--for the detection of Giardia lamblia and Cryptosporidium parvum antigens in faeces with conventional techniques. Sensitivity and specificity were evaluated using preparations of cysts of G lamblia and purified oocysts of C parvum. Evaluation of 59 random faecal samples passing through the Department of Clinical Parasitology, Hospital for Tropical Diseases, London, was carried out for both organisms. The fluorescence staining techniques proved more sensitive than other tests routinely used for diagnosis.


Development of a Bird Integrity Index: measuring avian response to disturbance in the Blue Mountains of Oregon, USA.
The Bird Integrity Index (BII) presented here uses bird assemblage information to assess human impacts to 28 stream reaches in the Blue Mountains of eastern Oregon. Eighty-one candidate metrics were extracted from bird survey data for testing. The metrics represented aspects of bird taxonomic richness, tolerance or intolerance to human disturbance, dietary preferences, foraging techniques, and nesting strategies that were expected to be positively or negatively affected by human activities in the region. To evaluate the responsiveness of each metric, it was plotted against an index of reach and watershed disturbance that included attributes of land use/land cover, road density, riparian cover, mining impacts, and percent area in clearcut and partial-cut logging. Nine of the 81 candidate bird metrics remained after eliminating unresponsive and highly correlated metrics. Individual metric scores ranged from 0 to 10, and BII scores varied between 0 and 100. BII scores varied from 78.6 for a minimally disturbed, reference stream reach to 30.4 for the most highly disturbed stream reach. The BII responded clearly to varying riparian conditions and to the cumulative effects of disturbances, such as logging, grazing, and mining, which are common in the mountains of eastern Oregon. This BII for eastern Oregon was compared to an earlier BII developed for the agricultural and urban disturbance regime of the Willamette Valley in western Oregon. The BII presented here was sensitive enough to distinguish differences in condition among stream riparian zones with disturbances that were not as obvious or irreversible as those in the agricultural/urban conditions of western Oregon.


MyoD expression in the forming somites is an early response to mesoderm induction in Xenopus embryos.
We describe the cloning, cDNA sequence and embryonic expression of a Xenopus homologue of MyoD, a mouse gene encoding a DNA-binding protein that can activate muscle gene expression in cultured cells. The predicted Xenopus MyoD protein sequence is remarkably similar to mouse MyoD. Zygotic expression of MyoD begins in early gastrulae, but there is a low level of unlocalized maternal message. Northern blot analysis of dissected embryos and in situ hybridization show that MyoD RNA is restricted to the gastrula mesoderm and to the somites of neurulae and tailbud embryos. The time and place of MyoD expression are consistent with a role for MyoD in the activation of other muscle genes in the somites of the frog embryo. However, MyoD is skeletal muscle-specific and is not expressed even in the early embryonic heart, which co-expresses cardiac and skeletal actin isoforms. Striated muscle genes can therefore be activated in some embryonic tissues in the absence of MyoD. The concentration of MyoD in the somites falls once they have formed, suggesting that MyoD may act there transiently to establish muscle gene expression. MyoD transcription is activated following mesoderm induction, and is the earliest muscle-specific response to mesoderm-inducing factors so far described.


Residential smoking therapy.
To evaluate a pilot 4-day residential smoking treatment program for smokers who had relapsed after participation in an outpatient smoking program. A single-arm clinical trial. Participants stayed in a supportive, smoke-free environment for 4 days during which they attended educational sessions on nutrition, exercise, and psychology. Nicotine withdrawal was treated with nicotine inhalers and patches. After discharge, participants attended monthly outpatient group sessions for 6 months. The Durham, NC Veterans Affairs Medical Center residential unit. Twenty-three medical outpatient smokers. Seven-day point prevalence smoking abstinence was determined by self-report of zero cigarettes smoked and verified by exhaled carbon monoxide <8 parts per million. Participants' mean age was 57.4 years; 100% were male; 61% were Caucasian; and 39% were African American. The mean score on the Fagerström Test for Nicotine Dependence was 7.1 (SD 2.3). Daily nicotine doses ranged from the nicotine inhaler alone to 56 mg of transdermal nicotine plus nicotine inhaler. Verified smoking abstinence on discharge (after 4 days) was 21/23 or 91.3% (95% confidence interval [95% CI], 73 to 100). At 6 months, the 7-day point abstinence rate was 6/23 or 26.1% (95% CI, 15 to 36). This pilot residential smoking treatment program was designed to assist smokers who relapsed after outpatient treatment. Four days of residential smoking therapy successfully relieved smoking withdrawal. At 6 months after discharge, participants maintained an abstinence rate comparable to other medical therapies for smoking.


Grafted polymer chains suppress nanoparticle diffusion in athermal polymer melts.
We measure the center-of-mass diffusion of poly(methyl methacrylate) (PMMA)-grafted nanoparticles (NPs) in unentangled to slightly entangled PMMA melts using Rutherford backscattering spectrometry. These grafted NPs diffuse ∼100 times slower than predicted by the Stokes-Einstein relation assuming a viscosity equal to bulk PMMA and a hydrodynamic NP size equal to the NP core diameter, 2Rcore = 4.3 nm. This slow NP diffusion is consistent with an increased effective NP size, 2Reff ≈ 20 nm, nominally independent of the range of grafting density and matrix molecular weights explored in this study. Comparing these experimental results to a modified Daoud-Cotton scaling estimate for the brush thickness as well as dynamic mean field simulations of polymer-grafted NPs in athermal polymer melts, we find that 2Reff is in quantitative agreement with the size of the NP core plus the extended grafted chains. Our results suggest that grafted polymer chains of moderate molecular weight and grafting density may alter the NP diffusion mechanism in polymer melts, primarily by increasing the NP effective size.


Variation in Anticonvulsant Selection and Electroencephalographic Monitoring Following Severe Traumatic Brain Injury in Children-Understanding Resource Availability in Sites Participating in a Comparative Effectiveness Study.
Early posttraumatic seizures may contribute to worsened outcomes after traumatic brain injury. Evidence to guide the evaluation and management of early posttraumatic seizures in children is limited. We undertook a survey of current practices of continuous electroencephalographic monitoring, seizure prophylaxis, and the management of early posttraumatic seizures to provide essential information for trial design and the development of posttraumatic seizure management pathways. Surveys were sent to site principal investigators at all 43 sites participating in the Approaches and Decisions in Acute Pediatric TBI trial at the time of the survey. Surveys consisted of 12 questions addressing strategies to 1) implement continuous electroencephalographic monitoring, 2) posttraumatic seizure prophylaxis, 3) treat acute posttraumatic seizures, 4) treat status epilepticus and refractory status epilepticus, and 5) monitor antiseizure drug levels. Institutions comprised a mixture of free-standing children's hospitals and university medical centers across the United States and Europe. Site principal investigators of the Approaches and Decisions in Acute Pediatric TBI trial. None. Continuous electroencephalographic monitoring was available in the PICU in the overwhelming majority of clinical sites (98%); however, the plans to operationalize such monitoring for children varied considerably. A similar majority of sites report that administration of prophylactic antiseizure medications is anticipated in children (93%); yet, a minority reports that a specified protocol for treatment of posttraumatic seizures is in place (43%). Reported medication choices varied substantially between sites, but the majority of sites reported pentobarbital for refractory status epilepticus (81%). The presence of treatment protocols for seizure prophylaxis, early posttraumatic seizures, posttraumatic status epilepticus, and refractory status epilepticus was associated with decreased reported medications (all p < 0.05). This study reports the current management practices for early posttraumatic seizures in select academic centers after pediatric severe traumatic brain injury. The substantial variation in continuous electroencephalographic monitoring implementation, choice of seizure prophylaxis medications, and management of early posttraumatic seizures across institutions was reported, signifying the areas of clinical uncertainty that will help provide focused design of clinical trials. Although sites with treatment protocols reported a decreased number of medications for the scenarios described, completion of the Approaches and Decisions in Acute Pediatric TBI trial will be able to determine if these protocols lead to decreased variability in medication administration in children at the clinical sites.


Transmission characteristics of MERS and SARS in the healthcare setting: a comparative study.
The Middle East respiratory syndrome (MERS) coronavirus has caused recurrent outbreaks in the Arabian Peninsula since 2012. Although MERS has low overall human-to-human transmission potential, there is occasional amplification in the healthcare setting, a pattern reminiscent of the dynamics of the severe acute respiratory syndrome (SARS) outbreaks in 2003. Here we provide a head-to-head comparison of exposure patterns and transmission dynamics of large hospital clusters of MERS and SARS, including the most recent South Korean outbreak of MERS in 2015. To assess the unexpected nature of the recent South Korean nosocomial outbreak of MERS and estimate the probability of future large hospital clusters, we compared exposure and transmission patterns for previously reported hospital clusters of MERS and SARS, based on individual-level data and transmission tree information. We carried out simulations of nosocomial outbreaks of MERS and SARS using branching process models rooted in transmission tree data, and inferred the probability and characteristics of large outbreaks. A significant fraction of MERS cases were linked to the healthcare setting, ranging from 43.5 % for the nosocomial outbreak in Jeddah, Saudi Arabia, in 2014 to 100 % for both the outbreak in Al-Hasa, Saudi Arabia, in 2013 and the outbreak in South Korea in 2015. Both MERS and SARS nosocomial outbreaks are characterized by early nosocomial super-spreading events, with the reproduction number dropping below 1 within three to five disease generations. There was a systematic difference in the exposure patterns of MERS and SARS: a majority of MERS cases occurred among patients who sought care in the same facilities as the index case, whereas there was a greater concentration of SARS cases among healthcare workers throughout the outbreak. Exposure patterns differed slightly by disease generation, however, especially for SARS. Moreover, the distributions of secondary cases per single primary case varied highly across individual hospital outbreaks (Kruskal-Wallis test; P < 0.0001), with significantly higher transmission heterogeneity in the distribution of secondary cases for MERS than SARS. Simulations indicate a 2-fold higher probability of occurrence of large outbreaks (>100 cases) for SARS than MERS (2 % versus 1 %); however, owing to higher transmission heterogeneity, the largest outbreaks of MERS are characterized by sharper incidence peaks. The probability of occurrence of MERS outbreaks larger than the South Korean cluster (n = 186) is of the order of 1 %. Our study suggests that the South Korean outbreak followed a similar progression to previously described hospital clusters involving coronaviruses, with early super-spreading events generating a disproportionately large number of secondary infections, and the transmission potential diminishing greatly in subsequent generations. Differences in relative exposure patterns and transmission heterogeneity of MERS and SARS could point to changes in hospital practices since 2003 or differences in transmission mechanisms of these coronaviruses.