Metal versus plastic for pancreatic pseudocyst drainage: clinical outcomes and success.
Endoscopic transmural drainage of pancreatic pseudocysts (PPs) by using double-pigtail (DP) plastic stents requires placement of multiple stents and can be restricted by inadequate drainage and leakage risk. Recently, the use of fully covered self-expanding metal stents (FCSEMSs) has been reported as an alternative to DP plastic stents. To evaluate the clinical outcomes, success rate, and adverse events of EUS-guided drainage of PPs with DP plastic stents and FCSEMSs. Retrospective cohort study. Two tertiary-care academic medical centers. This study involved 230 patients (mean age, 52.6 years) with PPs who underwent EUS-guided transmural drainage including 118 that were drained by using DP plastic stents and 112 by using FCSEMSs. A transgastric approach was used in 210 patients (91%), and transduodenal drainage was performed in 20 patients (9%). Stent deployment under EUS guidance. Technical success, early adverse events, stent occlusion requiring reintervention, and long-term success. At 12-month follow-up after the initial procedure, complete resolution of PPs by using DP plastic stents was lower compared with those that underwent drainage with FCSEMSs (89% vs 98%; P = .01). Procedural adverse events were noted in 31% in the DP plastic stent group and 16% in the FCSEMS group (P = .006). On multivariable analysis, patients with plastic stents were 2.9 times more likely to experience adverse events (odds ratio 2.9; 95% confidence interval, 1.4-6.3). Retrospective study. In patients with PPs, EUS-guided drainage by using FCSEMSs improves clinical outcomes and lowers adverse event rates compared with those drained with DP plastic stents.


Development of an Orofacial Esthetic Scale in prosthodontic patients.
Despite the interest and need to assess orofacial esthetics in prosthodontic patients, few self-reporting instruments are available to measure this construct, and none describe how prosthodontic patients perceive the appearance of their face, mouth, teeth, and dentures. The development of the Orofacial Esthetic Scale (OES) is reported in this article, in particular its conceptual framework, how questionnaire items were generated, and the scale's measurement model. After test conceptualization, the authors solicited esthetic concerns from 17 prosthodontic patients by asking them to evaluate their own photographs. A focus group of 8 dental professionals reduced the initial number of concerns/items and decided on an item response format. Pilot testing in 9 subjects generated the final instrument, the OES. Exploratory factor analysis was performed to investigate OES dimensionality and item analysis to investigate item difficulty and discrimination in 119 subjects. Prosthodontic patients generated an initial 28 esthetic concerns. These items were reduced to 8 preliminary representative items that were subsequently confirmed during pilot testing. Analysis supported 8 items assessing appearance: face, profile, mouth, tooth alignment, tooth shape, tooth color, gums, and overall impression, measured on an 11-point numeric rating scale (0 = very dissatisfied, 10 = very satisfied). Exploratory factor analysis found only 1 factor and high positive loadings for all items (.73 to .94) on the first factor, supporting the unidimensionality of the OES. The OES, developed especially for prosthodontic patients, is a brief questionnaire that assesses orofacial esthetic impacts.


NO to drought-multifunctional role of nitric oxide in plant drought: Do we have all the answers?
Nitric oxide (NO) is a versatile gaseous signaling molecule with increasing significance in plant research due to its association with various stress responses. Although, improved drought tolerance by NO is associated greatly with its ability to reduce stomatal opening and oxidative stress, it can immensely influence other physiological processes such as photosynthesis, proline accumulation and seed germination under water deficit. NO as a free radical can directly alter proteins, enzyme activities, gene transcription, and post-translational modifications that benefit functional recovery from drought. The present drought-mitigating strategies have focused on exogenous application of NO donors for exploring the associated physiological and molecular events, transgenic and mutant studies, but are inadequate. Considering the biphasic effects of NO, a cautious deployment is necessary along with a systematic approach for deciphering positively regulated responses to avoid any cytotoxic effects. Identification of NO target molecules and in-depth analysis of its effects under realistic field drought conditions should be an upmost priority. This detailed synthesis on the role of NO offers new insights on its functions, signaling, regulation, interactions and co-existence with different drought-related events providing future directions for exploiting this molecule towards improving drought tolerance in crop plants.


Evaluating the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in severely ill adults with COVID-19: A structured summary of a study protocol for a randomized controlled trial.
The aim of this study is to evaluate the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in hospitalized adults with severe SARS-CoV-2 infection. This is a prospective, single-center, phase 2, randomized, controlled trial that is blinded to participants and clinical outcome assessor. Eligible participants include adults (≥ 18 years) with evidence of SARS-CoV-2 infection by PCR test of nasopharyngeal or oropharyngeal swab within 14 days of randomization, evidence of infiltrates on chest radiography, peripheral capillary oxygen saturation (SpO2) ≤ 94% on room air, and/or need for supplemental oxygen, non-invasive mechanical ventilation, or invasive mechanical ventilation, who are willing and able to provide written informed consent prior to performing study procedures or who have a legally authorized representative available to do so. Exclusion criteria include participation in another clinical trial of anti-viral agent(s)* for coronavirus disease-2019 (COVID-19), receipt of any anti-viral agent(s)* with possible activity against SARS-CoV-2 <24 hours prior to plasma infusion, mechanical ventilation (including extracorporeal membrane oxygenation [ECMO]) for ≥ 5 days, severe multi-organ failure, history of allergic reactions to transfused blood products per NHSN/CDC criteria, known IgA deficiency, and pregnancy. Included participants will be hospitalized at the time of randomization and plasma infusion. *Use of remdesivir as treatment for COVID-19 is permitted. The study will be undertaken at Columbia University Irving Medical Center in New York, USA. The investigational treatment is anti-SARS-CoV-2 human convalescent plasma. To procure the investigational treatment, volunteers who recovered from COVID-19 will undergo testing to confirm the presence of anti-SARS-CoV-2 antibody to the spike trimer at a 1:400 dilution. Donors will also be screened for transfusion-transmitted infections (e.g. HIV, HBV, HCV, WNV, HTLV-I/II, T. cruzi, ZIKV). If donors have experienced COVID-19 symptoms within 28 days, they will be screened with a nasopharyngeal swab to confirm they are SARS-CoV-2 PCR-negative. Plasma will be collected using standard apheresis technology by the New York Blood Center. Study participants will be randomized in a 2:1 ratio to receive one unit (200 - 250 mL) of anti-SARS-CoV-2 plasma versus one unit (200 - 250 mL) of the earliest available control plasma. The control plasma cannot be tested for presence of anti-SARS-CoV-2 antibody prior to the transfusion, but will be tested for anti- SARS-CoV-2 antibody after the transfusion to allow for a retrospective per-protocol analysis. The primary endpoint is time to clinical improvement. This is defined as time from randomization to either discharge from the hospital or improvement by one point on the following seven-point ordinal scale, whichever occurs first. 1. Not hospitalized with resumption of normal activities 2. Not hospitalized, but unable to resume normal activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, requiring high-flow oxygen therapy or non-invasive mechanical ventilation 6. Hospitalized, requiring ECMO, invasive mechanical ventilation, or both 7. Death This scale, designed to assess clinical status over time, was based on that recommended by the World Health Organization for use in determining efficacy end-points in clinical trials in hospitalized patients with COVID-19. A recent clinical trial evaluating the efficacy and safety of lopinavir- ritonavir for patients hospitalized with severe COVID-19 used a similar ordinal scale, as have recent clinical trials of novel therapeutics for severe influenza, including a post-hoc analysis of a trial evaluating immune plasma. The primary safety endpoints are cumulative incidence of grade 3 and 4 adverse events and cumulative incidence of serious adverse events during the study period. Study participants will be randomized in a 2:1 ratio to receive anti-SARS-CoV-2 plasma versus control plasma using a web-based randomization platform. Treatment assignments will be generated using randomly permuted blocks of different sizes to minimize imbalance while also minimizing predictability. The study participants and the clinicians who will evaluate post-treatment outcomes will be blinded to group assignment. The blood bank and the clinical research team will not be blinded to group assignment. We plan to enroll 129 participants, with 86 in the anti-SARS-CoV-2 arm, and 43 in the control arm. Among the participants, we expect ~70% or n = 72 will achieve clinical improvement. This will yield an 80% power for a one-sided Wald test at 0.15 level of significance under the proportional hazards model with a hazard ratio of 1.5. Protocol AAAS9924, Version 17APR2020, 4/17/2020 Start of recruitment: April 20, 2020 Recruitment is ongoing. ClinicalTrials.gov: NCT04359810 Date of trial registration: April 24, 2020 Retrospectively registered FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


A pilot assessment tool of the need for oral health care and cost prediction in institutionalized elderly people.
To assess the dental treatment backlog and associated costs among institutionalized elderly people using a novel composite index, called the oral health index. Despite numerous reports about oral health of old individuals, there is still lack of a systematic and practical method to estimate their treatment need covering all relevant aspects of oral health. In addition, little has been published on associated treatment costs and prediction of such costs. An observational study was performed on 143 dentate institutionalized elderly people, whereby several clinical parameters were registered. The collected data were included in the oral health index representing the need for oral health care. This covered the number of caries lesions, number of residual roots, periodontal health condition, plaque score and denture condition with a final score of 0-9. To investigate the validity of the index, the treatment costs were estimated using the measured clinical parameters and later compared with the actual expenditure of the patients for the following 2 years. The average score of the index was 4.6 (SD 1.4) with 65.1% of the individuals having a score between 3 and 6 and 27.3% having a score of 6 and more, exhibiting medium and high need for oral health care, respectively. Only 30% of the patients underwent all the indicated treatments. The major reason of non-completion of the treatment was patient's refusal. From the fully treated group, 61.5% of the subjects actually spent within the predicted range while 38.5% of them spent more than estimated. The underestimation was related to yearly calculus removals leading to repeated calculation of the same costs and newly emerging dental problems (33% developed new caries and 20% was confronted with tooth fracture within the 2-year period). The novel index can be helpful to determine oral treatment needs and associated costs. Further research is needed to extend the clinical applicability of the index.


Simulation of a metallic SNOM tip illuminated by a parabolic mirror.
We investigate numerically a Scanning Near field Optical Microscope (SNOM) that uses a Parabolic Mirror (PM) to focus a radially polarized beam on a metallic tip. In order to overcome problems--like overestimated near fields or resonances--that arise when only considering finite tips, we have introduced a semi-infinite continuation of the tip, which incorporates the analytic solution of surface waves. For a realistic modeling the right description of the incident field is essential and we have complied with this requirement by a Bessel expansion of the focal fields, which is also applicable to an aplanatic objective. The established numerical model is used for an extensive study of model parameters like tip geometry, illumination directions and tip materials (Ag, Au, Al and Cu). Compared with a simplified inverted microscope configuration, the PM setup shows an increased field enhancement (factor of 2-2.5), which can be ascribed to the efficient coupling of the exciting field to tip surface plasmons.


Diversity patterns of ground beetles and understory vegetation in mature, secondary, and plantation forest regions of temperate northern China.
Plantation and secondary forests form increasingly important components of the global forest cover, but our current knowledge about their potential contribution to biodiversity conservation is limited. We surveyed understory plant and carabid species assemblages at three distinct regions in temperate northeastern China, dominated by mature forest (Changbaishan Nature Reserve, sampled in 2011 and 2012), secondary forest (Dongling Mountain, sampled in 2011 and 2012), and forest plantation habitats (Bashang Plateau, sampled in 2006 and 2007), respectively. The α-diversity of both taxonomic groups was highest in plantation forests of the Bashang Plateau. Beetle α-diversity was lowest, but plant and beetle species turnover peaked in the secondary forests of Dongling Mountain, while habitats in the Changbaishan Nature Reserve showed the lowest turnover rates for both taxa. Changbaishan Nature Reserve harbored the highest proportion of forest specialists. Our results suggest that in temperate regions of northern China, the protected larch plantation forest established over extensive areas might play a considerable role in maintaining a high biodiversity in relation to understory herbaceous plant species and carabid assemblages, which can be seen as indicators of forest disturbance. The high proportion of phytophagous carabids and the rarity of forest specialists reflect the relatively homogenous, immature status of the forest ecosystems on the Bashang Plateau. China's last remaining large old-growth forests like the ones on Changbaishan represent stable, mature ecosystems which require particular conservation attention.


3D measurement and simulation of surface acoustic wave driven fluid motion: a comparison.
The characterisation of the fluid motion induced by the acoustic streaming effect is of paramount interest for novel microfluidic devices based on surface acoustic waves (SAWs), e.g. for a detailed description of the achievable mixing efficiency and thus the design of such devices. Here, we present for the first time a quantitative 3D comparison between experimental measurements and numerical simulations of the acoustic streaming induced fluid flow inside a microchannel originating from a SAW. On the one hand, we performed fully three-dimensional velocity measurements using the astigmatism particle tracking velocimetry. On the other hand, we derived a novel streaming force approach solving the damped wave equation, which allows fast and easy 3D simulations of the acoustic streaming induced fluid flow. Furthermore, measurements of the SAW amplitude profile inside the fluid filled microchannel were performed. Based on these results, we obtained a very good agreement between the velocity measurements and the simulations of the fluid flow demonstrating the importance of comprising the actual shape of the SAW amplitude profile for quantitatively reliable simulations. It is shown that the novel streaming force approach is a valid approximation for the simulation of the acoustic streaming induced fluid flow, allowing a rapid and simple estimation of the flow field of SAW based microfluidic devices.


Adaptive downregulation of pheomelanin-related Slc7a11 gene expression by environmentally induced oxidative stress.
Pheomelanin is a sulphur-containing yellow-to-reddish pigment whose synthesis consumes the main intracellular antioxidant (glutathione; GSH) and its precursor cysteine. Cysteine used for pheomelanogenesis cannot be used for antioxidant protection. We tested whether the expression of Slc7a11, the gene regulating the transport of cysteine to melanocytes for pheomelanogenesis, is environmentally influenced when cysteine/GSH are most required for antioxidant protection. We found that zebra finches Taeniopygia guttata developing pheomelanin-pigmented feathers during a 12-day exposure to the pro-oxidant diquat dibromide downregulated the expression of Slc7a11 in feather melanocytes, but not the expression of other genes that affect pheomelanogenesis by mechanisms different from cysteine transport such as MC1R and Slc45a2. Accordingly, diquat-treated birds did not suffer increased oxidative stress. This indicates that some animals have evolved an adaptive epigenetic lability that avoids damage derived from pheomelanogenesis. This mechanism should be explored in human Slc7a11 to help combat some cancer types related to cysteine consumption.


Lumbar Juxtafacet Cysts.
To evaluate the factors affecting the clinical and radiological findings of juxtafacet cyst patients. Between January 2011 and December 2018, eight patients diagnosed with juxtafacet cyst were reviewed, retrospectively. Patient demographics; signs and symptoms; and neurological examination, radiological, and surgical findings were noted. The mean age was 54 years (range, 34â€"69 years) with five (62.5%) females and three (37.5%) males. There were nine juxtafacet cysts in eight patients. Five cysts (55.5%) were located at the L3â€"L4 level, two cysts (22.2%) at the L4â€"L5 level, and two cysts (22.2%) at the L5â€"S1 level. In all patients with L3â€"L4 cysts, the intercrest line was intersecting the spinal column at L4 vertebral body level. The most frequent symptoms were back pain and radiculopathy. Magnetic resonance imaging and computerized tomography revealed degenerative facet arthropathy in six patients (75%). Three patients (37.5%) had a medical history of trauma. One patient (12.5%) was treated conservatively. Seven patients (87.5%) were advised to undergo surgical treatment. Degeneration and instability are the main causes of juxtafacet cysts. They are mainly seen at the L4â€"L5 level due to higher movement capacity of this level. But, if the intercrest line intersects the spinal column at higher levels, degeneration and instability risks move to upper levels, and juxtafacet cysts may occur at the L3â€"L4 or upper levels.


Dysphagia in inflammatory myopathy: clinical characteristics, treatment strategies, and outcome in 62 patients.
To assess the clinical characteristics, treatment, and outcome of patients with inflammatory myopathy-associated dysphagia. We retrospectively reviewed the medical records of all patients with inflammatory myopathy-associated dysphagia seen at the Mayo Clinic in Rochester, Minn, between January 1, 1997, and December 31, 2001. A total of 783 patients were diagnosed as having inflammatory myopathy during the 5-year study period. Of these, 62 patients (41 women and 21 men; mean age, 68.6 years) had inflammatory myopathy-associated dysphagia: 26 with inclusion body myositis (IBM), 18 with dermatomyositis, 9 with polymyositis, and 9 with overlap syndrome. Dysphagia was a presenting symptom in 13 patients (21%), with the highest incidence in the IBM group. Videofluoroscopic examinations revealed pharyngeal pooling and impaired oropharyngeal and cricopharyngeal function. The benefits of swallowing compensation techniques and exercises were difficult to establish. Interventional procedures were performed in 24 patients (39%) and most frequently (62%) in patients with IBM, with cricopharyngeal myotomy being most beneficial. Patients with IBM had the least symptomatic improvement. Overall, 11 patients died during the median follow-up of 38 months, with respiratory failure due to aspiration pneumonia as the most common cause. Mortality was high in patients who required percutaneous endoscopic gastrostomy (7/11, 64%), and 1- year mortality was highest (31%) in those with dermatomyositis. Dysphagia is a serious and at times presenting problem in patients with inflammatory myopathy. It occurs most frequently and appears to be most refractory in patients with IBM. The mortality rate was high in patients who required percutaneous endoscopic gastrostomy, and the 1-year mortality rate was the highest in patients with dermatomyositis.


Unified functional network and nonlinear time series analysis for complex systems science: The pyunicorn package.
We introduce the pyunicorn (Pythonic unified complex network and recurrence analysis toolbox) open source software package for applying and combining modern methods of data analysis and modeling from complex network theory and nonlinear time series analysis. pyunicorn is a fully object-oriented and easily parallelizable package written in the language Python. It allows for the construction of functional networks such as climate networks in climatology or functional brain networks in neuroscience representing the structure of statistical interrelationships in large data sets of time series and, subsequently, investigating this structure using advanced methods of complex network theory such as measures and models for spatial networks, networks of interacting networks, node-weighted statistics, or network surrogates. Additionally, pyunicorn provides insights into the nonlinear dynamics of complex systems as recorded in uni- and multivariate time series from a non-traditional perspective by means of recurrence quantification analysis, recurrence networks, visibility graphs, and construction of surrogate time series. The range of possible applications of the library is outlined, drawing on several examples mainly from the field of climatology.


High Rates of Exclusive Breastfeeding in Both Arms of a Peer Counseling Study Promoting EBF Among HIV-Infected Kenyan Women.
Exclusive breastfeeding (EBF) is recommended for 6 months after delivery as the optimal infant feeding method and is especially important for prevention of mother-to-child HIV transmission (PMTCT). However, EBF promotion efforts among HIV-infected mothers in sub-Saharan Africa have achieved mixed success and require context-specific interventions. HIV-positive, pregnant women from six clinics in Nairobi were enrolled into a clinic-level, before-after counseling intervention study. All women received standard perinatal and HIV care. Women in the intervention arm were offered three counseling sessions that promoted EBF, described its benefits, and explained breastfeeding techniques. Mother-infant pairs were followed until 14 weeks postpartum, with infant HIV testing at 6 weeks. EBF prevalence at 14 weeks postpartum was compared between study arms using log-binomial regression. Proportions of 6-week HIV-free survival and 14-week infant survival were assessed using Cox regression. Risk estimates were adjusted for clinic, relationship status, and antiretroviral therapy. Between 2009 and 2013, 833 women were enrolled of whom 94% planned to practice EBF for 6 months and 95% were taking therapeutic or prophylactic antiretrovirals. Median age was 27 years; median CD4 count was 403 cells/μL. EBF prevalence at 14 weeks postpartum was 86% in the control and 81% in the intervention group (p = 0.19). No differences were observed between groups for 6-week HIV-free survival and 14-week infant survival. Women who received breastfeeding counseling were not more likely to breastfeed exclusively, in part due to high overall EBF prevalence in this study population. The high EBF prevalence is an important finding, given recent efforts to promote EBF in Kenya.


Effect of vaginal pH on efficacy of the controlled-release dinoprostone vaginal insert for cervical ripening/labor induction.
To evaluate whether vaginal pH alters the efficacy of the controlled-release dinoprostone vaginal insert (Cervidil) for cervical ripening/labor induction. Thirty-four women with an unfavorable cervix undergoing labor induction were enrolled in this prospective, double-blind investigation. Vaginal pH and Bishop score assessments were made by an independent examiner. All women received preinduction with the dinoprostone vaginal insert 10 mg intravaginally for 12 h. Twelve hours later, oxytocin induction initiated according to the standardized protocol and outcome data were collected. Mean (+/- SD) initial vaginal pH was 4.9 +/- 0.5 for the study cohort. No significant differences were noted between women with a high vaginal pH (> 4.5, n = 18) and those with a low vaginal pH (< or = 4.5, n = 16) with respect to maternal age, parity, gestational age, or initial Bishop score. Similarly, Bishop score change over the preinduction interval (3.2 vs. 3.3), time to active labor (28.6 vs. 24.6 h) and time to delivery (33.7 vs. 31.4 h) were not significantly different between the low and the high pH groups, respectively. Linear regression analysis revealed no significant association between vaginal pH and Bishop score change during the preinduction interval, time to active labor, time to complete dilatation, or time to delivery. Vaginal pH does not appear to influence the efficacy of the controlled-released dinoprostone vaginal insert for cervical ripening/labor induction.


Headache in epilepsy: A prospective observational study.
To assess the frequency and characteristics of interictal and postictal headaches (using International Classification of Headache Disorders, 3rd edition criteria) in a population of patients with epilepsy admitted to the Mayo Clinic Rochester epilepsy monitoring unit and assess their localizing value. This was a cross-sectional study. Participants were voluntarily recruited upon admission to the epilepsy monitoring unit. Two separate questionnaires were then administered. The first was to assess the presence and character of headaches experienced in the past 12 months. The second was to assess characteristics of postictal headaches experienced during their admission including localization. One-hundred and twenty subjects (77%) met inclusion criteria and completed the initial questionnaire. Mean age was 38.1 years (range 18-82), and 67 (55.8%) were female. Interictal headaches were reported in 97 of 120 (81%) subjects, and these met ICHD3 criteria for migraine in 48 (50%). Postictal headaches were reported by 75 of 120 (63%) subjects on the initial admission questionnaire, representing migraine in 38 (51%). Thirty-nine (32%) subjects completed the secondary questionnaire related to postictal headaches experienced during admission, of which nine (23%) met criteria for migraine. There was no seizure lateralizing or localizing value noted based on postictal headache localization. Migraine was frequent in this cohort and appears to be the dominant interictal and postictal headache type in patients with epilepsy. In this study, the first to assess incident postictal headache in the setting of an ictal EEG, headache localization was of no seizure localizing value. Few patients were being actively treated; suggesting headache management is often overlooked in the epilepsy population.


Clinical Context Generation for Imaging: A Design Thinking-based Analysis of a Pilot Project.
Design Thinking is a method for the practical, creative resolution of problems using the strategies used during the process of designing. It is increasingly being used in Medical enterprise to develop a solution-based approach to identify ambiguous problems and create alternative paths to the solution. We faced several challenges in the development of a clinical context generation tool and in this article, we retrospectively assess the usefulness of a Design Thinking approach had it been applied to a project related to Medical Imaging-related clinical context generation.


A MultiCenter Analysis of Factors Associated with Hearing Outcome for 2,735 Adults with Cochlear Implants.
While the majority of cochlear implant recipients benefit from the device, it remains difficult to estimate the degree of benefit for a specific patient prior to implantation. Using data from 2,735 cochlear-implant recipients from across three clinics, the largest retrospective study of cochlear-implant outcomes to date, we investigate the association between 21 preoperative factors and speech recognition approximately one year after implantation and explore the consistency of their effects across the three constituent datasets. We provide evidence of 17 statistically significant associations, in either univariate or multivariate analysis, including confirmation of associations for several predictive factors, which have only been examined in prior smaller studies. Despite the large sample size, a multivariate analysis shows that the variance explained by our models remains modest across the datasets (R2=0.12-0.21). Finally, we report a novel statistical interaction indicating that the duration of deafness in the implanted ear has a stronger impact on hearing outcome when considered relative to a candidate's age. Our multicenter study highlights several real-world complexities that impact the clinical translation of predictive factors for cochlear implantation outcome. We suggest several directions to overcome these challenges and further improve our ability to model patient outcomes with increased accuracy.


Interpersonal competence configurations, attachment to community, and residential aspirations of rural adolescents.
Adolescents who grow-up in rural areas often experience a tension between their attachment to the rural lifestyle afforded by their home community and a competing desire to gain educational, social, and occupational experiences that are only available in metropolitan areas. While these diverging pressures are well-documented, there is little information about linkages between rural high school students' views of their communities, their postsecondary aspirations, and their school adjustment. To address this issue, this study examined perceptions of community and residential aspirations in an ethnically diverse sample of 8,754 rural adolescents (51.5% female) in relationship to their competence and risk status in high school. Participants were from 73 rural high schools across 34 states. In addition, ratings on participants' school adjustment were provided by teachers (n = 667). High competence students (i.e., those in configurations of high positive and low negative teacher-rated characteristics) expressed positive perceptions of their rural lifestyle and many, particularly girls, indicated an interest in staying in or returning to their home community. Low competence youth (i.e., those in configurations of low positive and high negative teacher-rated characteristics) appeared to be less connected to their community and were more likely to express their intent to leave and not return. These results appear to qualify current concerns about "rural brain drain" and also suggest that the lack of attachment to the community may be a compounding risk factor for rural adolescents who have significant school adjustment problems.


A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator.
In an attempt to create an animal model of tissue-specific mitochondrial disease, we generated 'knockout' mice deficient in the heart/muscle isoform of the adenine nucleotide translocator (Ant1). Histological and ultrastructural examination of skeletal muscle from Ant1 null mutants revealed ragged-red muscle fibers and a dramatic proliferation of mitochondria, while examination of the heart revealed cardiac hypertrophy with mitochondrial proliferation. Mitochondria isolated from mutant skeletal muscle exhibited a severe defect in coupled respiration. Ant1 mutant adults also had a resting serum lactate level fourfold higher than that of controls, indicative of metabolic acidosis. Significantly, mutant adults manifested severe exercise intolerance. Therefore, Ant1 mutant mice have the biochemical, histological, metabolic and physiological characteristics of mitochondrial myopathy and cardiomyopathy.


In vivo effect of chronic hypoxia on the neurochemical profile of the developing rat hippocampus.
The cognitive deficits observed in children with cyanotic congenital heart disease suggest involvement of the developing hippocampus. Chronic postnatal hypoxia present during infancy in these children may play a role in these impairments. To understand the biochemical mechanisms of hippocampal injury in chronic hypoxia, a neurochemical profile consisting of 15 metabolite concentrations and 2 metabolite ratios in the hippocampus was evaluated in a rat model of chronic postnatal hypoxia using in vivo 1H NMR spectroscopy at 9.4 T. Chronic hypoxia was induced by continuously exposing rats (n = 23) to 10% O2 from postnatal day (P) 3 to P28. Fifteen metabolites were quantified from a volume of 9-11 microl centered on the left hippocampus on P14, P21, and P28 and were compared with normoxic controls (n = 14). The developmental trajectory of neurochemicals in chronic hypoxia was similar to that seen in normoxia. However, chronic hypoxia had an effect on the concentrations of the following neurochemicals: aspartate, creatine, phosphocreatine, GABA, glutamate, glutamine, glutathione, myoinositol, N-acetylaspartate (NAA), phosphorylethanolamine, and phosphocreatine/creatine (PCr/Cr) and glutamate/glutamine (Glu/Gln) ratios (P < 0.001 each, except glutamate, P = 0.04). The increased PCr/Cr ratio is consistent with decreased brain energy consumption. Given the well-established link between excitatory neurotransmission and brain energy metabolism, we postulate that elevated glutamate, Glu/Gln ratio, and GABA indicate suppressed excitatory neurotransmission in an energy-limited environment. Decreased NAA and phosphorylethanolamine suggest reduced neuronal integrity and phospholipid metabolism. The altered hippocampal neurochemistry during its development may underlie some of the cognitive deficits present in human infants at risk of chronic hypoxia.


Metatranscriptomics and Amplicon Sequencing Reveal Mutualisms in Seagrass Microbiomes.
Terrestrial plants benefit from many well-understood mutualistic relationships with root- and leaf-associated microbiomes, but relatively little is known about these relationships for seagrass and other aquatic plants. We used 16S rRNA gene amplicon sequencing and metatranscriptomics to assess potential mutualisms between microorganisms and the seagrasses Zostera marina and Zostera japonica collected from mixed beds in Netarts Bay, OR, United States. The phylogenetic composition of leaf-, root-, and water column-associated bacterial communities were strikingly different, but these communities were not significantly different between plant species. Many taxa present on leaves were related to organisms capable of consuming the common plant metabolic waste product methanol, and of producing agarases, which can limit the growth of epiphytic algae. Taxa present on roots were related to organisms capable of oxidizing toxic sulfur compounds and of fixing nitrogen. Metatranscriptomic sequencing identified expression of genes involved in all of these microbial metabolic processes at levels greater than typical water column bacterioplankton, and also identified expression of genes involved in denitrification and in bacterial synthesis of the plant growth hormone indole-3-acetate. These results provide the first evidence using metatranscriptomics that seagrass microbiomes carry out a broad range of functions that may benefit their hosts, and imply that microbe-plant mutualisms support the health and growth of aquatic plants.


A highly efficient short hairpin RNA potently down-regulates CCR5 expression in systemic lymphoid organs in the hu-BLT mouse model.
Inhibiting the expression of the HIV-1 coreceptor CCR5 holds great promise for controlling HIV-1 infection in patients. Here we report stable knockdown of human CCR5 by a short hairpin RNA (shRNA) in a humanized bone marrow/liver/thymus (BLT) mouse model. We delivered a potent shRNA against CCR5 into human fetal liver-derived CD34(+) hematopoietic progenitor/stem cells (HPSCs) by lentiviral vector transduction. We transplanted vector-transduced HPSCs solidified with Matrigel and a thymus segment under the mouse kidney capsule. Vector-transduced autologous CD34(+) cells were subsequently injected in the irradiated mouse, intended to create systemic reconstitution. CCR5 expression was down-regulated in human T cells and monocytes/macrophages in systemic lymphoid tissues, including gut-associated lymphoid tissue, the major site of HIV-1 replication. The shRNA-mediated CCR5 knockdown had no apparent adverse effects on T-cell development as assessed by polyclonal T-cell receptor Vbeta family development and naive/memory T-cell differentiation. CCR5 knockdown in the secondary transplanted mice suggested the potential of long-term hematopoietic reconstitution by the shRNA-transduced HPSCs. CCR5 tropic HIV-1 infection was effectively inhibited in mouse-derived human splenocytes ex vivo. These results demonstrate that lentiviral vector delivery of shRNA into human HPSCs could stably down-regulate CCR5 in systemic lymphoid organs in vivo.


Sample collection for laboratory-based study of the nasal airway and sinuses: a research compendium.
Collection of biologic samples from the nasal cavity and paranasal sinuses is of critical importance to the study of infectious or inflammatory conditions that affect both upper and lower airways. Numerous techniques for the study of ex-vivo samples exist, with specific applications, strengths, and weaknesses associated with each of them. In this compendium we summarize the available methods for collection of primary human samples and incorporate expert discussion of the pros, cons, and applications associated with each technique. An expert panel containing members of the American Rhinologic Society's Research and Grants Committee compiled this educational reference. Rationale for use and the potential advantages and disadvantages are discussed. Research protocols and key references are enumerated. Sampling of the nasal cavity and paranasal sinuses can be achieved through a number of methods. Nonspecific sinonasal secretions may be collected via forced exhalation, nasal lavage, and nasal spray aspiration. Targeted collection of sinonasal secretions may be achieved via endoscopic placement of absorbent matrices. Nasal cytology or collection of superficial epithelium may be completed via brushing or scraping of endonasal structures. Collection of mucosal biopsies may be completed via sinonasal explant or full-thickness biopsy. Multiple sampling techniques are available to collect biologic samples from the sinonasal cavity. These techniques differ in their ease of application, reproducibility, sample yield, and utility for different sinonasal pathologies or research goals. An appreciation of the benefits and drawbacks of each approach will allow investigators to select the techniques most appropriate for achieving research objectives.


30 to 50 ns liquid-crystal optical switches.
The optical switching time of twisted-nematic liquid-crystal cells using the liquid crystals, 5CB (C(5)H(11)-Ph-Ph-CN), 5OCB(C(5)H(11)-O-Ph-Ph-CN) and PCH5 (C(5)H(11)-Cy-Ph-CN) have been characterized as a function of temperature, bias voltage and switching voltage, V. The transition time from 90% to 10% transmission scales as V(-1.9) and is limited to 30 to 50 ns by the liquid-crystal breakdown electric field, ~100 V μm(-1). The time from the initial switching voltage step to 90% transmission, delay time, decreases with increasing bias and switching voltage. For 5CB and 5OCB the delay time approaches a constant value at higher electric fields, >10 V μm(-1). Both the transition and delay times decrease with increasing temperature. The minimum transition time at temperatures a few degrees below the nematic-isotropic temperature are 32, 32, and 44 ns and delay times are 44, 25 and 8 ns for 5CB, 5OCB, and PCH5 respectively.


Applicability of citronella oil (Cymbopogon winteratus) for the prevention of mosquito-borne diseases in the rural area of Tikapur, far-western Nepal.
Mosquito-borne diseases are a serious global problem, particularly in tropical and sub-tropical countries such as Nepal. Citronella oil is a natural mosquito repellent as well as a local fragrance in Nepal, which is accessible at very low cost because citronella plants are widely cultivated in rural areas of the Terai belt in Nepal. This study was conducted using a real-life randomized controlled pilot trial to confirm the effectiveness and applicability of locally-produced citronella oil as a mosquito repellent for the prevention of mosquito-borne diseases in Nepal. A repellency activity test was performed with 100% citronella oil (Cymbopogon winteratus) from April to May 2013 in the Tikapur Municipality of the Kailali district, Nepal. The test was divided into two trials: an indoor exposure (IE) test (N=101) and an outdoor exposure (OE) test (N=140) from 5.00 pm to 7.00 pm. Each trial contained an experimental citronella oil-applied group and a non-applied (control) group. The outcome measures were the protective effect of citronella oil against mosquitoes, the number of mosquito bites, the repellency percentage, the smell satisfaction and the irritation level. Experimental group had a significant protective effect against mosquito bites in IE (96.5%, n=57) and OE (95.7%, n=70) tests compared to the control group in IE (29.5%, n=44) and OE (28.6%, n=70) tests (experimental vs control groups, p<0.001). The repellency percentage for the OE test was 96.7%. In the smell satisfaction test (n=127), most of the participants responded with high satisfaction: 'good' (67.7%), 'very good' (16.5%), 'bad' (13.4%) and 'very bad' (2.4%). IE and OE tests showed similar satisfaction levels in each category. In the irritation level test (n=127), 87.4% and 12.6% responded with no irritation and slight irritation, respectively. There were no reports of moderate or severe irritation. The topical application of citronella oil can be employed as an easily-available, affordable and effective alternative mosquito repellent to prevent mosquito-borne diseases in rural areas such as Tikapur, Nepal.


Therapeutic efficacy of the somatostatin analog SMS 201-995 (octreotide) in acromegaly. Effects of dose and frequency and long-term safety.
To determine the efficacy of stepwise incremental doses, to compare twice- with thrice-daily administration of the same total daily dosage of the long-acting somatostatin analog SMS 201-995 (octreotide, Sandoz Australia, Sydney, Australia), and to evaluate the risk for cholelithiasis after long-term therapy for acromegaly. Nonrandomized, controlled trial. Tertiary care center at a medical research institute. Sequential sample of 19 patients with active acromegaly. Twenty-five age-matched normal subjects were also studied to establish the normal range for growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Eight patients (group 1) were treated with 100, 250, and 500 micrograms twice daily of octreotide, then switched to 333 micrograms three times daily, whereas 11 patients (group 2) were treated with 100, 200, 300, and 500 micrograms three times daily. Each treatment stage lasted 6 to 12 weeks. Octreotide, 100 micrograms administered twice or thrice daily, significantly reduced mean 12-hour and nadir GH (P less than 0.01), IGF-1 (P less than 0.05), and hand volume (P less than 0.05). Dose increment to 500 micrograms in both groups did not further reduce mean 12-hour GH, nadir GH, or hand volume. Switching from 500 micrograms twice daily to 333 micrograms thrice daily resulted in significant (P less than 0.05) reduction of mean 12-hour GH, IGF-1, and hand volume. Normalization of mean 12-hour GH and IGF-1 occurred in 8 of 19 patients; 7 of the 8 patients had pretherapy mean 12-hour GH below 20 mIU/L. The pretherapy mean blood glucose was a significant negative predictor (r = -0.89) of the change in mean blood glucose during therapy. Gallstones were present in 9 of 18 patients after therapy. Thrice-daily was more effective than twice-daily administration of octreotide, and dose increments above 100 micrograms thrice daily did not confer additional benefit. Biochemical remission was achieved in 40% of patients and was dependent on the GH concentration at initiation of treatment. Cholelithiasis is a risk of octreotide therapy. Octreotide is effective and can be considered as a first-line therapy in patients with acromegaly with mean pretherapy GH concentrations below 20 mIU/L. In patients with mean GH over 20 mIU/L, octreotide may be used as an adjuvant to surgery or radiotherapy.


Modafinil for excessive daytime sleepiness in myotonic dystrophy type 1--the patients' perspective.
Excessive daytime sleepiness (EDS), of very similar pattern to that seen in narcolepsy syndrome, is extremely common in myotonic dystrophy type 1 (DM1). In a significant minority it has a profound disabling effect on employment, social functioning and activities of daily living. Limited published studies have shown inconsistent results from use of the psychostimulant drug modafinil. A recent European Medicines Agency (EMA) review concluded that on current evidence regarding safety and efficacy, modafinil's use should be restricted to the treatment of narcolepsy. In other conditions (although DM1 was not specifically considered) it was concluded that there was insufficient evidence of benefit to outweigh potentially serious side-effects, including severe skin reactions and cardiac arrhythmia. Clinicians with extensive experience in the management of DM1 have found modafinil to be extremely effective in appropriately selected patients with a very low incidence of serious side-effects. Given the recent EMA review, patients have expressed concern about the potential restriction of the use of modafinil in DM1. This brief review is an audit of the experience of a large group of patients and their clinicians concerning EDS and DM1 and concludes that despite the limited literature there is strong evidence to support the use of modafinil in carefully selected patients.


Community-based intervention packages for reducing maternal and neonatal morbidity and mortality and improving neonatal outcomes.
While maternal, infant and under-five child mortality rates in developing countries have declined significantly in the past two to three decades, newborn mortality rates have reduced much more slowly. While it is recognised that almost half of the newborn deaths can be prevented by scaling up evidence-based available interventions such as tetanus toxoid immunisation to mothers; clean and skilled care at delivery; newborn resuscitation; exclusive breastfeeding; clean umbilical cord care; management of infections in newborns, many require facility based and outreach services. It has also been stated that a significant proportion of these mortalities and morbidities could also be potentially addressed by developing community-based packages interventions which should also be supplemented by developing and strengthening linkages with the local health systems. Some of the recent community-based studies of interventions targeting women of reproductive age have shown variable impacts on maternal outcomes and hence it is uncertain if these strategies have consistent benefit across the continuum of maternal and newborn care. To assess the effectiveness of community-based intervention packages in reducing maternal and neonatal morbidity and mortality; and improving neonatal outcomes. We searched The Cochrane Pregnancy and Childbirth Group's Trials Register (January 2010), World Bank's JOLIS (12 January 2010), BLDS at IDS and IDEAS database of unpublished working papers (12 January 2010), Google and Google Scholar (12 January 2010). All prospective randomised and quasi-experimental trials evaluating the effectiveness of community-based intervention packages in reducing maternal and neonatal mortality and morbidities; and improving neonatal outcomes. Two review authors independently assessed trial quality and extracted the data. The review included 18 cluster-randomised/quasi-randomised trials, covering a wide range of interventional packages, including two subsets from one trial. We incorporated data from these trials using generic inverse variance method in which logarithms of risk ratio estimates were used along with the standard error of the logarithms of risk ratio estimates. Our review did not show any reduction in maternal mortality (risk ratio (RR) 0.77; 95% confidence interval (CI) 0.59 to 1.02, random-effects (10 studies, n = 144,956), I² 39%, P value 0.10. However, significant reduction was observed in maternal morbidity (RR 0.75; 95% CI 0.61 to 0.92, random-effects (four studies, n = 138,290), I² 28%; neonatal mortality (RR 0.76; 95% CI 0.68 to 0.84, random-effects (12 studies, n = 136,425), I² 69%, P value < 0.001), stillbirths (RR 0.84; 95% CI 0.74 to 0.97, random-effects (11studies, n = 113,821), I² 66%, P value 0.001) and perinatal mortality (RR 0.80; 95% CI 0.71 to 0.91, random-effects (10 studies, n = 110,291), I² 82%, P value < 0.001) as a consequence of implementation of community-based interventional care packages. It also increased the referrals to health facility for pregnancy related complication by 40% (RR 1.40; 95% CI 1.19 to 1.65, fixed-effect (two studies, n = 22,800), I² 0%, P value 0.76), and improved the rates of early breastfeeding by 94% (RR 1.94; 95% CI 1.56 to 2.42, random-effects (six studies, n = 20,627), I² 97%, P value < 0.001). We assessed our primary outcomes for publication bias, but observed no such asymmetry on the funnel plot. Our review offers encouraging evidence of the value of integrating maternal and newborn care in community settings through a range of interventions which can be packaged effectively for delivery through a range of community health workers and health promotion groups. While the importance of skilled delivery and facility-based services for maternal and newborn care cannot be denied, there is sufficient evidence to scale up community-based care through packages which can be delivered by a range of community-based workers.


Methylation of the retinoblastoma tumor suppressor by SMYD2.
The retinoblastoma tumor suppressor (RB) is a central cell cycle regulator and tumor suppressor. RB cellular functions are known to be regulated by a diversity of post-translational modifications such as phosphorylation and acetylation, raising the possibility that RB may also be methylated in cells. Here we demonstrate that RB can be methylated by SMYD2 at lysine 860, a highly conserved and novel site of modification. This methylation event occurs in vitro and in cells, and it is regulated during cell cycle progression, cellular differentiation, and in response to DNA damage. Furthermore, we show that RB monomethylation at lysine 860 provides a direct binding site for the methyl-binding domain of the transcriptional repressor L3MBTL1. These results support the idea that a code of post-translational modifications exists for RB and helps guide its functions in mammalian cells.


Mapping for maternal and newborn health: the distributions of women of childbearing age, pregnancies and births.
The health and survival of women and their new-born babies in low income countries has been a key priority in public health since the 1990s. However, basic planning data, such as numbers of pregnancies and births, remain difficult to obtain and information is also lacking on geographic access to key services, such as facilities with skilled health workers. For maternal and newborn health and survival, planning for safer births and healthier newborns could be improved by more accurate estimations of the distributions of women of childbearing age. Moreover, subnational estimates of projected future numbers of pregnancies are needed for more effective strategies on human resources and infrastructure, while there is a need to link information on pregnancies to better information on health facilities in districts and regions so that coverage of services can be assessed. This paper outlines demographic mapping methods based on freely available data for the production of high resolution datasets depicting estimates of numbers of people, women of childbearing age, live births and pregnancies, and distribution of comprehensive EmONC facilities in four large high burden countries: Afghanistan, Bangladesh, Ethiopia and Tanzania. Satellite derived maps of settlements and land cover were constructed and used to redistribute areal census counts to produce detailed maps of the distributions of women of childbearing age. Household survey data, UN statistics and other sources on growth rates, age specific fertility rates, live births, stillbirths and abortions were then integrated to convert the population distribution datasets to gridded estimates of births and pregnancies. These estimates, which can be produced for current, past or future years based on standard demographic projections, can provide the basis for strategic intelligence, planning services, and provide denominators for subnational indicators to track progress. The datasets produced are part of national midwifery workforce assessments conducted in collaboration with the respective Ministries of Health and the United Nations Population Fund (UNFPA) to identify disparities between population needs, health infrastructure and workforce supply. The datasets are available to the respective Ministries as part of the UNFPA programme to inform midwifery workforce planning and also publicly available through the WorldPop population mapping project.


Comparative Analgesic Efficacy of Oxycodone/Acetaminophen vs Codeine/Acetaminophen for Short-Term Pain Management Following ED Discharge.
To test the hypothesis that oxycodone/acetaminophen provides analgesia superior to codeine/acetaminophen following emergency department (ED) discharge. Prospective, randomized, double-blind, trial. Adult inner city ED. ED patients with acute extremity pain who were discharged home. Patients randomized to oxycodone/acetaminophen (5 mg/325 mg) or codeine/acetaminophen (30 mg/300 mg). The primary outcome, obtained via telephone one day after ED discharge, was the between-group difference in improvement in numerical rating scale (NRS) pain scores over a 2-hour period following the most recent ingestion of study drug. Secondary outcomes included proportion of patients with >50% pain reduction, side-effect profile, and patient satisfaction. Two hundred and forty patients were enrolled. Mean baseline NRS scores were 7.9 in both groups. Mean decrease over 2 hours was 4.5 NRS units in the oxycodone/acetaminophen group vs 4.2 NRS units in the codeine/acetaminophen group, for a clinically and statistically nonsignificant difference of 0.2 NRS units (95% CI -0.4-0.9 NRS units). Similarly, 66% vs 61% achieved >50% pain relief for a nonsignificant difference of 5% (95% CI -8% to 17%). Side-effect profile and patient satisfaction were similar. Our hypothesis that oxycodone/acetaminophen provides analgesia superior to codeine/acetaminophen was rejected. Although pain within each group was reduced by more than half, the between-group difference was not significant. Pending independent validation, these unexpected findings suggest that codeine/acetaminophen, a Schedule III agent, may be a clinically reasonable outpatient opioid alternative to oxycodone/acetaminophen, a more tightly restricted Schedule II agent thought to be more prone to misuse.


A method for automatically extracting infectious disease-related primers and probes from the literature.
Primer and probe sequences are the main components of nucleic acid-based detection systems. Biologists use primers and probes for different tasks, some related to the diagnosis and prescription of infectious diseases. The biological literature is the main information source for empirically validated primer and probe sequences. Therefore, it is becoming increasingly important for researchers to navigate this important information. In this paper, we present a four-phase method for extracting and annotating primer/probe sequences from the literature. These phases are: (1) convert each document into a tree of paper sections, (2) detect the candidate sequences using a set of finite state machine-based recognizers, (3) refine problem sequences using a rule-based expert system, and (4) annotate the extracted sequences with their related organism/gene information. We tested our approach using a test set composed of 297 manuscripts. The extracted sequences and their organism/gene annotations were manually evaluated by a panel of molecular biologists. The results of the evaluation show that our approach is suitable for automatically extracting DNA sequences, achieving precision/recall rates of 97.98% and 95.77%, respectively. In addition, 76.66% of the detected sequences were correctly annotated with their organism name. The system also provided correct gene-related information for 46.18% of the sequences assigned a correct organism name. We believe that the proposed method can facilitate routine tasks for biomedical researchers using molecular methods to diagnose and prescribe different infectious diseases. In addition, the proposed method can be expanded to detect and extract other biological sequences from the literature. The extracted information can also be used to readily update available primer/probe databases or to create new databases from scratch.


Differential Risk for Homelessness Among US Male and Female Veterans With a Positive Screen for Military Sexual Trauma.
Military sexual trauma (MST) is associated with adverse physical and mental health outcomes following military separation. Recent research suggests that MST may be a determinant in several factors associated with postdeployment homelessness. To evaluate MST as an independent risk factor for homelessness and to determine whether risk varies by sex. A retrospective cohort study of US veterans who used Veterans Health Administration (VHA) services between fiscal years 2004 and 2013 was conducted using administrative data from the Department of Defense and VHA. Included in the study were 601 892 US veterans deployed in Iraq or Afghanistan who separated from the military between fiscal years 2001 and 2011 and subsequently used VHA services. Positive response to screen for MST administered in VHA facilities. Administrative evidence of homelessness within 30 days, 1 year, and 5 years following the first VHA encounter after last deployment. The mean (SD) age of the 601 892 participants was 38.9 (9.4) years, 527 874 (87.7%) were male, 310 854 (51.6%) were white, and 382 361 (63.5%) were enlisted in the Army. Among veterans with a positive screen for MST, rates of homelessness were 1.6% within 30 days, 4.4% within 1 year, and 9.6% within 5 years, more than double the rates of veterans with a negative MST screen (0.7%, 1.8%, and 4.3%, respectively). A positive screen for MST was significantly and independently associated with postdeployment homelessness. In regression models adjusted for demographic and military service characteristics, odds of experiencing homelessness were higher among those who screened positive for MST compared with those who screened negative (30-day: adjusted odds ratio [AOR], 1.89; 95% CI, 1.58-2.24; 1-year: AOR, 2.27; 95% CI, 2.04-2.53; and 5-year: AOR, 2.63; 95% CI, 2.36-2.93). Military sexual trauma screen status remained independently associated with homelessness after adjusting for co-occurring mental health and substance abuse diagnoses in follow-up regression models (30-day: AOR, 1.62; 95% CI, 1.36-1.93; 1-year: AOR, 1.49; 95% CI, 1.33-1.66; and 5-year: AOR, 1.39; 95% CI, 1.24-1.55). In the fully adjusted models, the interaction between MST status and sex was significant in the 30-day and 1-year cohorts (30-day: AOR, 1.54; 95% CI, 1.18-2.02; and 1-year: AOR, 1.46; 95% CI, 1.23-1.74), denoting higher risk for homelessness among males with a positive screen for MST. A positive screen for MST was independently associated with postdeployment homelessness, with male veterans at greater risk than female veterans. These results underscore the importance of the MST screen as a clinically important marker of reintegration outcomes among veterans. These findings demonstrate significant long-term negative effects and inform our understanding of the public health implications of sexual abuse and harassment.


Complete-proteome mapping of human influenza A adaptive mutations: implications for human transmissibility of zoonotic strains.
There is widespread concern that H5N1 avian influenza A viruses will emerge as a pandemic threat, if they become capable of human-to-human (H2H) transmission. Avian strains lack this capability, which suggests that it requires important adaptive mutations. We performed a large-scale comparative analysis of proteins from avian and human strains, to produce a catalogue of mutations associated with H2H transmissibility, and to detect their presence in avian isolates. We constructed a dataset of influenza A protein sequences from 92,343 public database records. Human and avian sequence subsets were compared, using a method based on mutual information, to identify characteristic sites where human isolates present conserved mutations. The resulting catalogue comprises 68 characteristic sites in eight internal proteins. Subtype variability prevented the identification of adaptive mutations in the hemagglutinin and neuraminidase proteins. The high number of sites in the ribonucleoprotein complex suggests interdependence between mutations in multiple proteins. Characteristic sites are often clustered within known functional regions, suggesting their functional roles in cellular processes. By isolating and concatenating characteristic site residues, we defined adaptation signatures, which summarize the adaptive potential of specific isolates. Most adaptive mutations emerged within three decades after the 1918 pandemic, and have remained remarkably stable thereafter. Two lineages with stable internal protein constellations have circulated among humans without reassorting. On the contrary, H5N1 avian and swine viruses reassort frequently, causing both gains and losses of adaptive mutations. Human host adaptation appears to be complex and systemic, involving nearly all influenza proteins. Adaptation signatures suggest that the ability of H5N1 strains to infect humans is related to the presence of an unusually high number of adaptive mutations. However, these mutations appear unstable, suggesting low pandemic potential of H5N1 in its current form. In addition, adaptation signatures indicate that pandemic H1N1/09 strain possesses multiple human-transmissibility mutations, though not an unusually high number with respect to swine strains that infected humans in the past. Adaptation signatures provide a novel tool for identifying zoonotic strains with the potential to infect humans.


Speckle Tracking Echocardiography: New Ways of Translational Approaches in Preeclampsia to Detect Cardiovascular Dysfunction.
Several studies have shown that women with a preeclamptic pregnancy exhibit an increased risk of cardiovascular disease. However, the underlying molecular mechanisms are unknown. Animal models are essential to investigate the causes of this increased risk and have the ability to assess possible preventive and therapeutic interventions. Using the latest technologies such as speckle tracking echocardiography (STE), it is feasible to map subclinical changes in cardiac diastolic and systolic function as well as structural changes of the maternal heart. The aim of this work is to compare cardiovascular changes in an established transgenic rat model with preeclampsia-like pregnancies with findings from human preeclamptic pregnancies by STE. The same algorithms were used to evaluate and compare the changes in echoes of human and rodents. Parameters of functionality such as global longitudinal strain (animal -23.54 ± 1.82% vs. -13.79 ± 0.57%, human -20.60 ± 0.47% vs. -15.45 ± 1.55%) as well as indications of morphological changes such as relative wall thickness (animal 0.20 ± 0.01 vs. 0.25 ± 0.01, human 0.34 ± 0.01 vs. 0.40 ± 0.02) are significantly altered in both species after preeclamptic pregnancies. Thus, the described rat model simulates the human situation quite well and is a valuable tool for future investigations regarding cardiovascular changes. STE is a unique technique that can be applied in animal models and humans with a high potential to uncover cardiovascular maladaptation and subtle pathologies.


Collagen copolymer toric posterior chamber phakic intraocular lenses to correct high myopic astigmatism.
To assess the safety, efficacy, stability, and predictability after implantation of a toric intraocular copolymer (Collamer) lens (pIOL) to correct high myopic astigmatism. Fernández-Vega Ophthalmological Institute, Oviedo, Spain. This study evaluated eyes that had implantation of a toric pIOL. Outcome measures were the uncorrected (UDVA) and corrected (CDVA) distance visual acuities (Snellen decimal), refraction, and postoperative complications. The study included 15 eyes of 12 patients (9 women). Preoperatively, the mean manifest spherical refraction was -1.98 diopters (D) +/- 1.32 (SD) (range -0.50 to -5.50 D) and the mean refractive cylinder, -4.85 +/- 0.83 D (range -6.50 to -4.00 D). At 12 months, the mean refractive cylinder was -0.55 +/- 0.52 D (range -1.50 to 0.00 D), with 93.3% of eyes having less than 1.00 D of cylinder. The mean spherical equivalent was -0.31 +/- 0.42 (range -1.00 to 0.75 D), with more than 70% of eyes within +/-0.50 D of the target. For the astigmatic components, 93.3% of eyes were within +/-1.00 D of J0 (r(2) = 0.98) and all eyes were within +/-1.00 D of J45 (r(2) = 0.98). The mean UDVA was 0.70 +/- 0.20 and the mean CDVA, 0.83 +/- 0.12. The overall efficacy index was 0.90. Postoperatively, all eyes had unchanged CDVA or gained 1 or more lines. The refractive outcomes and improvement in UDVA and CDVA were rapidly achieved and remained fairly consistent throughout the follow-up period, supporting the use of toric pIOLs in eyes with high astigmatism. No author has a financial or proprietary interest in any material or method mentioned.


Examining the adverse effects of limb position on pattern recognition based myoelectric control.
Pattern recognition of myoelectric signals for the control of prosthetic devices has been widely reported and debated. A large portion of the literature focuses on offline classification accuracy of pre-recorded signals. Historically, however, there has been a semantic gap between research findings and a clinically viable implementation. Recently, renewed focus on prosthetics research has pushed the field to provide more clinically relevant outcomes. One way to work towards this goal is to examine the differences between research and clinical results. The constrained nature in which offline training and test data is often collected compared to the dynamic nature of prosthetic use is just one example. In this work, we demonstrate that variations in limb position after training can have a substantial impact on the robustness of myoelectric pattern recognition.


Highly accelerated intracranial time-of-flight magnetic resonance angiography using wave-encoding.
To develop an accelerated 3D intracranial time-of-flight (TOF) magnetic resonance angiography (MRA) sequence with wave-encoding (referred to as 3D wave-TOF) and to evaluate two variants: wave-controlled aliasing in parallel imaging (CAIPI) and compressed-sensing wave (CS-wave). A wave-TOF sequence was implemented on a 3 T clinical scanner. Wave-encoded and Cartesian k-space datasets from six healthy volunteers were retrospectively and prospectively undersampled with 2D-CAIPI sampling and variable-density Poisson disk sampling. 2D-CAIPI, wave-CAIPI, standard CS, and CS-wave schemes were compared at various acceleration factors. Flow-related artifacts in wave-TOF were investigated, and a set of practicable wave parameters was developed. Quantitative analysis of wave-TOF and traditional Cartesian TOF MRA was performed by comparing the contrast-to-background ratio between the vessel and background tissue in source images, and the structural similarity index measure (SSIM) between the maximum intensity projection images from accelerated acquisitions and their respective fully sampled references. Flow-related artifacts caused by the wave-encoding gradients in wave-TOF were eliminated by properly chosen parameters. Images from wave-CAIPI and CS-wave acquisitions had a higher SNR and better-preserved contrast than traditional parallel imaging (PI) and CS methods. Maximum intensity projection images from wave-CAIPI and CS-wave acquisitions had a cleaner background, with vessels that were better depicted. Quantitative analyses indicated that wave-CAIPI had the highest contrast-to-background ratio, SSIM, and vessel-masked SSIM among the sampling schemes studied, followed by the CS-wave acquisition. 3D wave-TOF improves the capability of accelerated MRA and provides better image quality at higher acceleration factors compared to traditional PI- or CS-accelerated TOF, suggesting the potential use of wave-TOF in cerebrovascular disease.


Microalgal bioengineering for sustainable energy development: Recent transgenesis and metabolic engineering strategies.
Exploring the efficiency of algae to produce remarkable products can be directly benefitted by studying its mechanism at systems level. Recent advents in biotechnology like flux balance analysis (FBA), genomics and in silico proteomics minimize the wet lab exertion. It is understood that FBA predicts the metabolic products, metabolic pathways and alternative pathway to maximize the desired product, and these are key components for microalgae bio-engineering. This review encompasses recent transgenesis techniques and metabolic engineering strategies applied to different microalgae for improving different traits. Further it also throws light on RNAi and riboswitch engineering based methods which may be advantageous for high throughput microalgal research. A valid and optimally designed microalga can be developed where every engineering strategies meet each other successfully and will definitely fulfill the market needs. It is also to be noted that Omics (viz. genetic and metabolic manipulation with bioinformatics) should be integrated to develop a strain which could prove to be a futuristic solution for sustainable development for energy.


CD15+/CD16low human granulocytes from terminal cancer patients: granulocytic myeloid-derived suppressor cells that have suppressive function.
Myeloid-derived suppressor cells (MDSCs) are a subpopulation of myeloid cells with immunosuppressive function whose numbers are increased in conditions such as chronic infection, trauma, and cancer. Unlike murine MDSCs defined as CD11b(+)/Gr-1(+), there are no specific markers for human MDSCs. The goal of this study was to delineate a specific human MDSCs subpopulation in granulocytes from terminal cancer patients and investigate its clinical implications. Here, we show that the CD15(+)/CD16(low) subset was increased in terminal cancer patients compared with healthy donors (P = 0.009). Phorbol 12-myristate 13-acetate-activated granulocytes (CD16(low)/CD66b(++)/CD15(+)) that have a phenotype similar to MDSCs from cancer patients, effectively suppressed both proliferation and cytotoxicity of normal T cells. Among cancer patients, T-cell proliferation was highly suppressed by granulocytes isolated from terminal cancer patients with a high proportion of CD15(+)/CD16(low) cells. Patients with low peripheral blood levels of CD15(+)/CD16(low) cells had significantly longer survival than those with high levels (P = 0.0011). Patients with higher levels of CD15(+)/CD16(low) also tended to have poor performance status (P = 0.05). These data suggest that CD15(+)/CD16(low) granulocytes found in terminal cancer patients may play a role in the progression of cancer by inhibiting tumor immunity.


A case study of the New York City 2012-2013 influenza season with daily geocoded Twitter data from temporal and spatiotemporal perspectives.
Twitter has shown some usefulness in predicting influenza cases on a weekly basis in multiple countries and on different geographic scales. Recently, Broniatowski and colleagues suggested Twitter's relevance at the city-level for New York City. Here, we look to dive deeper into the case of New York City by analyzing daily Twitter data from temporal and spatiotemporal perspectives. Also, through manual coding of all tweets, we look to gain qualitative insights that can help direct future automated searches. The intent of the study was first to validate the temporal predictive strength of daily Twitter data for influenza-like illness emergency department (ILI-ED) visits during the New York City 2012-2013 influenza season against other available and established datasets (Google search query, or GSQ), and second, to examine the spatial distribution and the spread of geocoded tweets as proxies for potential cases. From the Twitter Streaming API, 2972 tweets were collected in the New York City region matching the keywords "flu", "influenza", "gripe", and "high fever". The tweets were categorized according to the scheme developed by Lamb et al. A new fourth category was added as an evaluator guess for the probability of the subject(s) being sick to account for strength of confidence in the validity of the statement. Temporal correlations were made for tweets against daily ILI-ED visits and daily GSQ volume. The best models were used for linear regression for forecasting ILI visits. A weighted, retrospective Poisson model with SaTScan software (n=1484), and vector map were used for spatiotemporal analysis. Infection-related tweets (R=.763) correlated better than GSQ time series (R=.683) for the same keywords and had a lower mean average percent error (8.4 vs 11.8) for ILI-ED visit prediction in January, the most volatile month of flu. SaTScan identified primary outbreak cluster of high-probability infection tweets with a 2.74 relative risk ratio compared to medium-probability infection tweets at P=.001 in Northern Brooklyn, in a radius that includes Barclay's Center and the Atlantic Avenue Terminal. While others have looked at weekly regional tweets, this study is the first to stress test Twitter for daily city-level data for New York City. Extraction of personal testimonies of infection-related tweets suggests Twitter's strength both qualitatively and quantitatively for ILI-ED prediction compared to alternative daily datasets mixed with awareness-based data such as GSQ. Additionally, granular Twitter data provide important spatiotemporal insights. A tweet vector-map may be useful for visualization of city-level spread when local gold standard data are otherwise unavailable.


The central domain of the matrix protein of HIV-1: influence on protein structure and virus infectivity.
The central region of the matrix protein p17 of HIV-1 is known to be essential during virus assembly. We substituted alanines for amino acid triplets in this region of p17 (amino acid residues 47 to 55: NPG LLE TSE). Introduction of the respective mutations into the gag-coding sequence of HI-proviruses and subsequent transfection into Cos-7 cells led to particle production and release. Exchange of LLE resulted in the production of non-infectious particles. These residues may be important for correct folding and assembly of the processed matrix protein and the production of infectious HIV. In vitro studies of wild-type and mutated matrix proteins using spectroscopic methods (NMR, fluorescence, CD) yielded detailed data about structure and stability. Two-dimensional NMR spectroscopy showed that wild-type and mutant proteins (p17-NPG and p17-TSE) are well folded. Besides structural changes at the mutated site, chemical shift changes indicate small but significant long range structural rearrangements. The stability against chemically and thermally induced unfolding of the mutants p17-NPG and p17-TSE was slightly decreased, while that of p17-LLE was drastically diminished. The alterations have only a local effect on protein folding for the mutants p17-NPG and p17-TSE, and the globular tertiary structure remains nearly unchanged. For p17-LLE, however, the substitutions seem to trigger significant changes in structural elements.


Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma.
Asthma is considered a Th2 cell–associated disorder. Despite this, both the Th1 cell–associated cytokine IFN-γ and airway neutrophilia have been implicated in severe asthma. To investigate the relative contributions of different immune system components to the pathogenesis of asthma, we previously developed a model that exhibits several features of severe asthma in humans, including airway neutrophilia and increased lung IFN-γ. In the present studies, we tested the hypothesis that IFN-γ regulates mast cell function in our model of chronic asthma. Engraftment of mast cell–deficient KitW(-sh/W-sh) mice, which develop markedly attenuated features of disease, with wild-type mast cells restored disease pathology in this model of chronic asthma. However, disease pathology was not fully restored by engraftment with either IFN-γ receptor 1–null (Ifngr1–/–) or Fcε receptor 1γ–null (Fcer1g–/–) mast cells. Additional analysis, including gene array studies, showed that mast cell expression of IFN-γR contributed to the development of many FcεRIγ-dependent and some FcεRIγ-independent features of disease in our model, including airway hyperresponsiveness, neutrophilic and eosinophilic inflammation, airway remodeling, and lung expression of several cytokines, chemokines, and markers of an alternatively activated macrophage response. These findings identify a previously unsuspected IFN-γ/mast cell axis in the pathology of chronic allergic inflammation of the airways in mice.


Newly Eligible Enrollees In Medicaid Spend Less And Use Less Care Than Those Previously Eligible.
Understanding the health care spending and utilization of various types of Medicaid enrollees is important for assessing the budgetary implications of both expansion and contraction in Medicaid enrollment. Despite the intense debate surrounding the Affordable Care Act (ACA), however, little information is available on the spending and utilization patterns of the nonelderly adult enrollees who became newly eligible for Medicaid under the ACA. Using data for 2012-14 from the Medical Expenditure Panel Survey, we compared health care spending and utilization of newly eligible Medicaid enrollees with those of nondisabled adults who were previously eligible and enrolled. We found that average monthly expenditures for newly eligible enrollees were $180-21 percent less than the $228 average for previously eligible enrollees. Utilization differences between these groups likely contributed to this differential.


Structured override reasons for drug-drug interaction alerts in electronic health records.
The study sought to determine availability and use of structured override reasons for drug-drug interaction (DDI) alerts in electronic health records. We collected data on DDI alerts and override reasons from 10 clinical sites across the United States using a variety of electronic health records. We used a multistage iterative card sort method to categorize the override reasons from all sites and identified best practices. Our methodology established 177 unique override reasons across the 10 sites. The number of coded override reasons at each site ranged from 3 to 100. Many sites offered override reasons not relevant to DDIs. Twelve categories of override reasons were identified. Three categories accounted for 78% of all overrides: "will monitor or take precautions," "not clinically significant," and "benefit outweighs risk." We found wide variability in override reasons between sites and many opportunities to improve alerts. Some override reasons were irrelevant to DDIs. Many override reasons attested to a future action (eg, decreasing a dose or ordering monitoring tests), which requires an additional step after the alert is overridden, unless the alert is made actionable. Some override reasons deferred to another party, although override reasons often are not visible to other users. Many override reasons stated that the alert was inaccurate, suggesting that specificity of alerts could be improved. Organizations should improve the options available to providers who choose to override DDI alerts. DDI alerting systems should be actionable and alerts should be tailored to the patient and drug pairs.


Comparison of Radical Scavenging Activity, Cytotoxic Effects and Apoptosis Induction in Human Melanoma Cells by Taiwanese Propolis from Different Sources.
Propolis is a sticky substance that is collected from plants by honeybees. We previously demonstrated that propolins A, B, C, D, E and F, isolated from Taiwanese propolis (TP), could effectively induce human melanoma cell apoptosis and were strong antioxidant agents. In this study, we evaluated TP for free radical scavenging activity by DPPH (1,2-diphenyl-2-picrylhydrazyl). The phenolic concentrations were quantified by the Folin-Ciocalteu method. The apoptosis trigger activity in human melanoma cells was evaluated. TP contained a higher level of phenolic compounds and showed strong capability to scavenge free radicals. Additionally, TP1g, TP3, TP4 and TP7 exhibited a cytotoxic effect on human melanoma cells, with an IC(50) of approximately 2.3, 2.0, 3.3 and 3.3 μg/ml, respectively. Flow cytometric analysis for DNA fragmentation indicated that TP1g, TP2, TP3 and TP7 could induce apoptosis in human melanoma cells and there is a marked loss of cells from the G2/M phase of the cell cycle. To address the mechanism of the apoptosis effect of TP, we evaluated its effects on induction of apoptosis-related proteins in human melanoma cells. The levels of procaspase-3 and PARP [poly(ADP-ribose) polymerase] were markedly decreased. Furthermore, propolins A, B, C, D, E and F in TP were determined using HPLC. The results indicate that TP is a rich source of these compounds. The findings suggest that TP induces apoptosis in human melanoma cells due to its high level of propolins.


The relationship between substance use and exit security on psychiatric wards.
In this paper we report on the rates of drug/alcohol use on acute psychiatric wards in relation to levels and intensity of exit security measures. Many inpatient wards have become permanently locked, with staff concerned about the risk of patients leaving the ward and harming themselves or others, and of people bringing illicit substances into the therapeutic environment. In 2004/2005, a cross sectional survey on 136 acute psychiatric wards across three areas of England was undertaken. A comprehensive range of data including door locking and drug/alcohol use were collected over 6 months on each ward. In 2006, supplementary data on door locking and exit security were collected. Door locking, additional exit security measures and substance misuse rates of the 136 wards were analysed and the associations between these were investigated. No consistent relationships were found with exit security features, intensity of drug/alcohol monitoring procedures, or the locking of the ward door. There were indications that use of breath testing for alcohol might reduce usage and that the use of 'sniffer' dogs was associated with greater alcohol use. Greater exit security or locking of the ward door had no influence on rates of use of alcohol or illicit drugs by inpatients and thus cannot form part of any strategy to control substance use by inpatients. There are some grounds to believe that a greater use of screening might help reduce the frequency of alcohol/substance use on wards and may lead to a reduction in verbal abuse.


Adult age differences in the use of prosody for syntactic parsing and recall of spoken sentences.
In this experiment, young and elderly adults listened to and recalled sentences that were varied in speech rate through computer-controlled time compression. Half of the sentences at each speech rate were presented with a normal prosodic pattern that reinforced the lexically defined syntactic structure of the sentences, and half were presented with a prosodic contour that conflicted with that structure. Both young and elderly subjects showed better recall for slower speech rates and when prosody was consistent with syntactic structure, but these effects were larger for elderly subjects. When syntax and prosody were placed in conflict, elderly subjects were more likely than the young to reconstruct the lexical content of the presented sentences to produce responses with a syntactic structure consistent with the prosody marking. Although elderly adults may be disadvantaged by rapid speech input rates, we show that they rely on normal prosody to aid syntactic parsing as a step toward language comprehension.


'PrP systemic deposition disease': clinical and pathological characteristics of novel familial prion disease with 2-bp deletion in codon 178.
A novel TYPE of prion disease associated mainly with autonomic-sensory polyneuropathy was reported by us previously. Here the autopsy pathology for patient 1 (the sister) and the clinical characteristics of her younger brother (patient 2) are newly reported. Polymerase chain reaction based restriction fragment length polymorphism analysis of the prion protein gene (PRNP) was performed on both patients and their father (normal control). Polymerase chain reaction based restriction fragment length polymorphism analysis revealed a 2-bp deletion (CT) in codon 178 that causes an additional variable 25 amino acids at the C terminal, from the mutation site to the premature stop codon at codon 203, in both patients 1 and 2 but not in their father. The autopsy of patient 1 showed remarkable prion protein (PrP) deposits in the sympathetic ganglion and peripheral nerves, correlated to her severe autonomic sensory failure. PrP deposits were also found in the central nervous system and peripheral organs such as the heart, lung, stomach, jejunum, ileum, colon, urinary bladder and adrenal gland. The symptoms and biopsy findings of patient 2 were nearly the same as those reported previously for patient 1. His cognitive function was well preserved, but autonomic functions were severely impaired. His biopsied samples showed PrP deposits in the sural nerve and nerve plexuses of the stomach and colon. The present unique 2-bp deletion (CT) in codon 178 induced a 'PrP systemic deposition disease' such as pan-autonomic failure, sensory neuropathy and mild cognitive impairment with a specific pathology.


Program Implementation Approaches to Build and Sustain Health Care Coordination for Type 2 Diabetes.
As more people enter the U.S. health care system under the Affordable Care Act (ACA), it is increasingly critical to deliver coordinated, high-quality health care. The ACA supports implementation and sustainability of efficient health care models, given expected limits in available resources. This article highlights implementation strategies to build and sustain care coordination, particularly ones consistent with and reinforced by the ACA. It focuses on disease self-management programs to improve the health of patients with type 2 diabetes, exemplified by grantees of the Alliance to Reduce Disparities in Diabetes. We conducted interviews with grantee program representatives throughout their 5-year programs and conducted a qualitative framework analysis of data to identify key themes related to care coordination. The most promising care coordination strategies that grantee programs described included establishing clinic-community collaborations, embedding community health workers within care management teams, and sharing electronic data. Establishing provider buy-in was crucial for these strategies to be effective. This article adds new insights into strategies promoting effective care coordination. The strategies that grantees implemented throughout the program align with ACA requirements, underscoring their relevance to the changing U.S. health care environment and the likelihood of further support for program sustainability.


Postpartum Cardiomyopathy and Considerations for Breastfeeding.
Postpartum cardiomyopathy (PPCM) is a rare condition that develops near the end of pregnancy or in the months after giving birth, manifesting as heart failure secondary to left ventricular systolic dysfunction. Clinical progression varies considerably, with both end-stage heart failure occurring within days and spontaneous recovery seen. Treatment pathways for heart failure are well established, but the evidence about the safety of medicines passed to infants during breastfeeding is scarce and mainly poor; this often leads to an incorrect decision that a mother should not breastfeed. Given its benefits to both mother and infant, breastfeeding should not routinely be ruled out if the mother is taking heart failure medication but the consequences for the infant need to be considered. An informed risk assessment to minimise potential harm to the infant can be carried out using the evidence that is available along with a consideration of drug properties, adverse effects, paediatric use and pharmacokinetics. In most cases, risks can be managed and infants can be monitored for potential problems. Breastfeeding can be encouraged in women with cardiac dysfunction with PPCM although treatment for the mother takes priority with breastfeeding compatibility being the secondary consideration. International research is continuing to establish efficacy and safety of pharmacotherapy in PPCM.


Efficacy and tolerability of folate-aminopterin therapy in a rat focal model of multiple sclerosis.
Activated macrophages in the experimental model of multiple sclerosis (MS) express folate receptor-β (FR-β), representing a promising target for the treatment of MS. Here, we both evaluated the efficacy of a novel folate-aminopterin construct (EC2319) in a rat focal model of multiple sclerosis (MS) and investigated the utility of 68Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate (68Ga-FOL) for assessing inflammatory lesions. In addition, we investigated whether FR-β is expressed in the brain of patients with MS. Focal delayed-type hypersensitivity experimental autoimmune encephalomyelitis (fDTH-EAE) was induced in 40 Lewis rats; 20 healthy Lewis rats were used as controls. Rats were divided into six groups according to the duration of disease (control, acute, or chronic) and intervention (vehicle versus EC2319). 68Ga-FOL analyses, histology, and immunofluorescence of the brain were performed to evaluate the efficacy of subcutaneously administered EC2319 on lesion development. Immunofluorescence was used to assess FR-β expression in postmortem brain samples from 5 patients with MS and 5 healthy controls. Immunofluorescence and histological analyses revealed significant reductions in FR-β expression (P < 0.05) and lesion size (P < 0.01), as well as improved inducible nitric oxide synthase/mannose receptor C type 1 ratios (P < 0.01) in macrophages and microglia during the chronic but not acute phase of fDTH-EAE in EC2319-treated rats. The uptake of IV-injected 68Ga-FOL in the brain was low and did not differ between the groups, but the in vitro binding of 68Ga-FOL was significantly lower in EC2319-treated rats (P < 0.01). FR-β positivity was observed in chronically active lesions and in normal-appearing white matter in MS brain samples. EC2319 was well tolerated and attenuated inflammation and lesion development in a rat model of a chronic progressive form of MS. Human MS patients have FR-β-positive cells in chronically active plaques, which suggests that these results may have translational relevance.


Ultraslow optical waveguiding in an atomic Bose-Einstein condensate.
We investigate waveguiding of ultraslow light pulses in an atomic Bose-Einstein condensate. We show that under the conditions of off-resonant electromagnetically induced transparency, waveguiding with a few ultraslow modes can be realized. The number of modes that can be supported by the condensate can be controlled by means of experimentally accessible parameters. Propagation constants and the mode conditions are determined analytically using a Wentzel-Kramers-Brillouin analysis. Mode profiles are found numerically.


Pharmacologically Aware Phage Therapy: Pharmacodynamic and Pharmacokinetic Obstacles to Phage Antibacterial Action in Animal and Human Bodies.
The use of viruses infecting bacteria (bacteriophages or phages) to treat bacterial infections has been ongoing clinically for approximately 100 years. Despite that long history, the growing international crisis of resistance to standard antibiotics, abundant anecdotal evidence of efficacy, and one successful modern clinical trial of efficacy, this phage therapy is not yet a mainstream approach in medicine. One explanation for why phage therapy has not been subject to more widespread implementation is that phage therapy research, both preclinical and clinical, can be insufficiently pharmacologically aware. Consequently, here we consider the pharmacological obstacles to phage therapy effectiveness, with phages in phage therapy explicitly being considered to serve as drug equivalents. The study of pharmacology has traditionally been differentiated into pharmacokinetic and pharmacodynamic aspects. We therefore separately consider the difficulties that phages as virions can have in traveling through body compartments toward reaching their target bacteria (pharmacokinetics) and the difficulties that phages can have in exerting antibacterial activity once they have reached those bacteria (pharmacodynamics). The latter difficulties, at least in part, are functions of phage host range and bacterial resistance to phages. Given the apparently low toxicity of phages and the minimal side effects of phage therapy as practiced, phage therapy should be successful so long as phages can reach the targeted bacteria in sufficiently high numbers, adsorb, and then kill those bacteria. Greater awareness of what obstacles to this success generally or specifically can exist, as documented in this review, should aid in the further development of phage therapy toward wider use.


Recurrent EWSR1-CREB3L1 gene fusions in sclerosing epithelioid fibrosarcoma.
Sclerosing epithelioid fibrosarcoma (SEF) and low-grade fibromyxoid sarcoma (LGFMS) are 2 distinct types of sarcoma, with a subset of cases showing overlapping morphologic and immunohistochemical features. LGFMS is characterized by expression of the MUC4 protein, and about 90% of cases display a distinctive FUS-CREB3L2 gene fusion. In addition, SEF is often MUC4 positive, but is genetically less well studied. Fluorescence in situ hybridization (FISH) studies have shown involvement of the FUS gene in the majority of so-called hybrid LGFMS/SEF and in 10% to 25% of sarcomas with pure SEF morphology. In this study, we investigated a series of 10 primary tumors showing pure SEF morphology, 4 cases of LGFMS that at local or distant relapse showed predominant SEF morphology, and 1 primary hybrid LGFMS/SEF. All but 1 case showed diffuse expression for MUC4. Using FISH, reverse transcription polymerase chain reaction, and/or mRNA sequencing in selected cases, we found recurrent EWSR1-CREB3L1 fusion transcripts by reverse transcription polymerase chain reaction in 3/10 pure SEF cases and splits and deletions of the EWSR1 and/or CREB3L1 genes by FISH in 6 additional cases. All 5 cases of LGFMS with progression to SEF morphology or hybrid features had FUS-CREB3L2 fusion transcripts. Our results indicate that EWSR1 and CREB3L1 rearrangements are predominant over FUS and CREB3L2 rearrangements in pure SEF, highlighting that SEF and LGFMS are different tumor types, with different impacts on patient outcome.