Characterization of human immunodeficiency virus type 1 Vif particle incorporation.
The human immunodeficiency virus type 1 (HIV-1) Vif protein is necessary at the time of viral particle formation yet functionally manifests its effect after virions enter target cells. This suggests that Vif either acts on another viral protein or is itself incorporated into particles. In this study, we have examined the latter possibility. We confirm our previous observation that Vif is incorporated into human immunodeficiency virus type 1 virions at a ratio of approximately 1 molecule of Vif for every 75 to 220 molecules of p24, or 7 to 20 molecules per virion. Furthermore, we demonstrate that the relative concentration of Vif is much lower in particles than in infected cells, whereas the opposite is observed for the main virus components. The viral envelope, Nef, Vpr, Vpu, protease, reverse transcriptase, integrase, nucleocapsid, and p6gag proteins as well as the viral genomic RNA are dispensable for Vif packaging. Furthermore, mutating several highly conserved residues (H-108, C-114, C-133, L-145, and Q-146) or deleting the C-terminal 18 amino acids of Vif, either of which severely impairs Vif function, does not abolish its incorporation into virions. Finally, Vif can be packaged into murine leukemia virus particles. On the basis of these data, we conclude that the specificity of Vif incorporation into virions remains an open question.


The memorizing capacity of polymers.
Properties of one and the same polymer can vary greatly with the history of a sample, reflecting its memory of past events. I propose that this remarkable changeability of polymer properties can be related to the immense variability of non-equilibrium conformational states, providing polymers with capacities for responding and adapting to changes in environmental conditions and to external stimuli. By decoding the relations between properties and meta-stable conformational states, we may be able to accomplish polymer products with selectable unique properties. In support of this claim, I first present a few typical examples focusing on changes induced by varying drying, freezing, or crystallization procedures, relevant in many industrial processing strategies for polymeric systems. In these examples, deviations from equilibrium conformations are controlled by a preparation parameter and the annealing/aging time and temperature. Subsequently, I briefly discuss the possibilities for a quantitative description of chain conformations deviating from equilibrium, which allow establishing a link between changes on a molecular level and their macroscopic behavior. A comprehensive and systematic investigation of out-of-equilibrium polymer properties will widen the scope of polymer science and enlarge the range of applications of polymers based on their responsiveness and adaptability derived from their memorizing capacities.


View into the integrating sphere through the observation window.
The repartition of the single reflections in an integrating sphere is discussed using a model sphere where wall and screen are divided into twenty-six zones. The results lead to a simplified model with three zones and three partial luminous fluxes. In this simplified model sphere, the net hold is defined as that part of the volume of the sphere that is hidden by the screen when one looks into the sphere through the sphere window. The optimal place and the optimal size of the screen are determined with assumption of a constant net hold. Then the screen is mainly given by the ratio between the diameter of the net hold and the observation window. Further influences will only slightly affect place and size of the screen.


Genomic characterization of NDM-1 and 5, and OXA-181 carbapenemases in uropathogenic Escherichia coli isolates from Riyadh, Saudi Arabia.
Urinary tract infections (UTIs) associated with Escherichia coli are a growing threat with an increase in the prevalence of multidrug resistant (MDR) strains, particularly ß-lactamase producers, occurring globally. We investigated the presence of carbapenem-resistant uropathogenic E. coli clones in community-acquired UTIs in Riyadh, Kingdom of Saudi Arabia (KSA) to identify the virulence and resistance structures of the resistant clones and relate the isolates to those circulating globally. A combination of comparative genomics and phenotypic approaches were used to characterize ten MDR-uropathogenic Escherichia coli isolates recovered from UTI patients in Riyadh between November 2014 and January 2015. We report the presence of NDM-1 and 5, and OXA-181 in carbapenem-resistant UPEC strains from Riyadh, KSA. Single nucleotide polymorphism analyses demonstrated that these ten isolates fell into four phylogenetically distinct clades within the UPEC phylogeny. Comparative genomic analyses indicate that these diverse clones could be distinguished according to their multilocus sequencing type (MLST), serology, and virulence and antimicrobial gene architectures. These clones include the blaNDM-1 carrying isolates of the globally predominant MDR ST131 and ST69 types, previously identified as one of the most common UPEC strains in KSA. This is in addition to clones of ST23Cplx (ST410) and ST448Cplx (ST448) that have likely evolved from common intestinal strains, carrying copies of ß-lactamase genes including blaNDM-5, blaCTX-M-15, blaTEM-1, blaCMY-42, blaOXA-1 and blaOXA-181. These data have identified an emerging public health concern and highlight the need to use comprehensive approaches to detect the structure of MDR E. coli populations associated with community-acquired UTIs in KSA.


Nanoparticle ejection from Au induced by single Xe ion impacts
In situ transmission electron microscopy has been used to observe sputtered Au during Xe ion irradiation in transmission geometry. The sputtered Au was collected on an electron transparent carbon foil. Nanoparticles were observed on the collector foil after they were ejected by single ion impacts. The ejection is from the melt zone formed during the thermal spike phase of a displacement cascade produced near the surface by a single ion impact. Such single ion impacts are also capable of producing craters. Ejected nanoparticles can make a significant contribution to sputtering.


Improved algorithm for elemental analysis by laser-induced breakdown spectroscopy.
We propose a calibration-free algorithm for retrieval of elemental concentrations using laser-induced breakdown spectroscopy. This is a simple and improved version of other ratio-based algorithms as it needs only one trial parameter to estimate all other concentrations. The present algorithm has been used to estimate the composition of a brass sample, and the results agree within 1% with electron probe microanalyzer measurements.


Brain correlates of phonological recoding of visual symbols.
Learning to read involves setting up associations between meaningless visual inputs (V) and their phonological representations (P). Here, we recorded the brain signals (ERPs and fMRI) associated with phonological recoding (i.e., V-P conversion processes) in an artificial learning situation in which participants had to learn the associations between 24 unknown visual symbols (Japanese Katakana characters) and 24 arbitrary monosyllabic names. During the learning phase on Day 1, the strength of V-P associations was manipulated by varying the proportion of correct and erroneous associations displayed during a two-alternative forced choice task. Recording event related potentials (ERPs) during the learning phase allowed us to track changes in the processing of these visual symbols as a function of the strength of V-P associations. We found that, at the end of the learning phase, ERPs were linearly affected by the strength of V-P associations in a time-window starting around 200ms post-stimulus onset on right occipital sites and ending around 345ms on left occipital sites. On Day 2, participants had to perform a matching task during an fMRI session and the strength of these V-P associations was again used as a probe for identifying brain regions related to phonological recoding. Crucially, we found that the left fusiform gyrus was gradually affected by the strength of V-P associations suggesting that this region is involved in the brain network supporting phonological recoding processes.


Sublexical properties of spoken words modulate activity in Broca's area but not superior temporal cortex: implications for models of speech recognition.
Many models of spoken word recognition posit that the acoustic stream is parsed into phoneme level units, which in turn activate larger representations [McClelland, J. L., & Elman, J. L. The TRACE model of speech perception. Cognitive Psychology, 18, 1-86, 1986], whereas others suggest that larger units of analysis are activated without the need for segmental mediation [Greenberg, S. A multitier theoretical framework for understanding spoken language. In S. Greenberg & W. A. Ainsworth (Eds.), Listening to speech: An auditory perspective (pp. 411-433). Mahwah, NJ: Erlbaum, 2005; Klatt, D. H. Speech perception: A model of acoustic-phonetic analysis and lexical access. Journal of Phonetics, 7, 279-312, 1979; Massaro, D. W. Preperceptual images, processing time, and perceptual units in auditory perception. Psychological Review, 79, 124-145, 1972]. Identifying segmental effects in the brain's response to speech may speak to this question. For example, if such effects were localized to relatively early processing stages in auditory cortex, this would support a model of speech recognition in which segmental units are explicitly parsed out. In contrast, segmental processes that occur outside auditory cortex may indicate that alternative models should be considered. The current fMRI experiment manipulated the phonotactic frequency (PF) of words that were auditorily presented in short lists while participants performed a pseudoword detection task. PF is thought to modulate networks in which phoneme level units are represented. The present experiment identified activity in the left inferior frontal gyrus that was positively correlated with PF. No effects of PF were found in temporal lobe regions. We propose that the observed phonotactic effects during speech listening reflect the strength of the association between acoustic speech patterns and articulatory speech codes involving phoneme level units. On the basis of existing lesion evidence, we interpret the function of this auditory-motor association as playing a role primarily in production. These findings are consistent with the view that phoneme level units are not necessarily accessed during speech recognition.


Assessment of cognitive dysfunction in kidney disease.
Cognitive dysfunction includes reduced mental alertness, intellectual impairment, decreased attention and concentration, memory deficits and diminished perceptual-motor coordination. Chronic kidney disease (CKD) patients may suffer from cognitive impairment, which may decrease an individual's quality of life, increase resource utilization and result in suboptimal medical care. This study was carried out on 120 patients with different stages of CKD from our nephrology outpatient clinic divided into three groups: Group I: 50 CKD patients, stage 3 and stage 4; Group II: 50 end-stage renal disease patients on regular hemodialysis with K t/v >1.1; and Group III: 20 acute kidney injury patients, followed-up till their renal functions stabilized besides Group IV: 20 healthy subjects served as controls. All patients underwent laboratory investigations and psychometric tests, which include trial making test part B, digit span test, digit symbol test and mini-mental state examination. There was a significant difference of mean values of cognitive function tests in Groups I, II and III on comparing them with Group IV. Stage 3 CKD scored better than stage 4 CKD, which was worse than hemodialysis patients, and lastly acute kidney injury patients had mild cognitive impairment, which was restored after recovery. We found an association between hemoglobin and cognitive function tests score in the studied groups. The degree of cognitive impairment was associated with the severity of CKD, and dialysis improved cognitive performance.


Health effects of laser printer emissions: a controlled exposure study.
Ultrafine particles emitted from laser printers are suspected to elicit adverse health effects. We performed 75-minute exposures to emissions of laser printing devices (LPDs) in a standardized, randomized, cross-over manner in 23 healthy subjects, 14 mild, stable asthmatics, and 15 persons reporting symptoms associated with LPD emissions. Low-level exposures (LLE) ranged at the particle background (3000 cm-3 ) and high-level exposures (HLE) at 100 000 cm-3 . Examinations before and after exposures included spirometry, body plethysmography, transfer factors for CO and NO (TLCO, TLNO), bronchial and alveolar NO, cytokines in serum and nasal secretions (IL-1β, IL-5, IL-6, IL-8, GM-CSF, IFNγ, TNFα), serum ECP, and IgE. Across all participants, no statistically significant changes occurred for lung mechanics and NO. There was a decrease in volume-related TLNO that was more pronounced in HLE, but the difference to LLE was not significant. ECP and IgE increased in the same way after exposures. Nasal IL-6 showed a higher increase after LLE. There was no coherent pattern regarding the responses in the participant subgroups or single sets of variables. In conclusion, the experimental acute responses to short but very high-level LPD exposures were small and did not indicate clinically relevant effects compared to low particle number concentrations.


The evolution of cooperation on correlated payoff landscapes.
We study the evolution of cooperation in the prisoner's dilemma game on time-invariant heterogeneous payoff landscapes on regular and heterogeneous networks. Correlations in the landscape structure and their implications for the evolution of cooperation are investigated. On regular networks we find that negatively and neutrally correlated payoff landscapes strongly enhance cooperation, while positively correlated landscapes may suppress the evolution of cooperation. On heterogeneous networks, cooperation is facilitated if payoff stochasticity is positively correlated with network heterogeneity and may be suppressed otherwise.


Inflammation-related genetic variants predict toxicity following definitive radiotherapy for lung cancer.
Definitive radiotherapy improves locoregional control and survival in inoperable non-small cell lung cancer patients. However, radiation-induced toxicities (pneumonitis/esophagitis) are common dose-limiting inflammatory conditions. We therefore conducted a pathway-based analysis to identify inflammation-related single-nucleotide polymorphisms associated with radiation-induced pneumonitis or esophagitis. A total of 11,930 single-nucleotide polymorphisms were genotyped in 201 stage I-III non-small cell lung cancer patients treated with definitive radiotherapy. Validation was performed in an additional 220 non-small cell lung cancer cases. After validation, 19 single-nucleotide polymorphisms remained significant. A polygenic risk score was generated to summarize the effect from validated single-nucleotide polymorphisms. Significant improvements in discriminative ability were observed when the polygenic risk score was added into the clinical/epidemiological variable-based model. We then used 277 lymphoblastoid cell lines to assess radiation sensitivity and expression quantitative trait loci (eQTL) relationships of the identified single-nucleotide polymorphisms. Three genes (PRKCE, DDX58, and TNFSF7) were associated with radiation sensitivity. We concluded that inflammation-related genetic variants could contribute to the development of radiation-induced toxicities.


Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma.
Poroma is a benign skin tumor exhibiting terminal sweat gland duct differentiation. The present study aimed to explore the potential role of gene fusions in the tumorigenesis of poromas. RNA sequencing and reverse transcription PCR identified highly recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poromas (92/104 lesions, 88.5%) and their rare malignant counterpart, porocarcinomas (7/11 lesions, 63.6%). A WWTR1-NUTM1 fusion was identified in a single lesion of poroma. Fluorescent in-situ hybridization confirmed genomic rearrangements involving these genetic loci. Immunohistochemical staining could readily identify the YAP1 fusion products as nuclear expression of the N-terminal portion of YAP1 with a lack of the C-terminal portion. YAP1 and WWTR1, also known as YAP and TAZ, respectively, encode paralogous transcriptional activators of TEAD, which are negatively regulated by the Hippo signaling pathway. The YAP1 and WWTR1 fusions strongly transactivated a TEAD reporter and promoted anchorage-independent growth, confirming their tumorigenic roles. Our results demonstrate the frequent presence of transforming YAP1 fusions in poromas and porocarcinomas and suggest YAP1/TEAD-dependent transcription as a candidate therapeutic target against porocarcinoma.


Heterotopic ossification in wartime wounds.
Heterotopic ossification (HO) refers to the formation of mature lamellar bone in nonosseous tissue. In the setting of high-energy wartime extremity wounds, HO is expected to complicate up to 64% of patients, has a predilection for the residual limbs of amputees, and remains a significant source of disability. Although the inciting events and the definitive cell(s) of origin continue to remain elusive, animal models and human histology samples suggest that HO formation follows a predictable sequence of events culminating in endochondral ossification. Primary prophylaxis is not medically or logistically practical in most cases because patients have generally sustained massive wounds and are undergoing serial debridements during an intercontinental aeromedical evacuation. Surgical excision of symptomatic lesions is warranted only after an appropriate trial of conservative measures and is associated with low recurrence rates in appropriately selected patients. Future research regarding prognostication and defining the early molecular biology of ectopic bone may permit individualized prophylaxis and development of novel targeted therapies.


Host genetics role in the pathogenesis of periodontal disease and caries.
This study aimed to produce the latest summary of the evidence for association of host genetic variants contributing to both periodontal diseases and caries. Two systematic searches of the literature were conducted in Ovid Medline, Embase, LILACS and Cochrane Library for large candidate gene studies (CGS), systematic reviews and genome-wide association studies reporting data on host genetic variants and presence of periodontal disease and caries. A total of 124 studies were included in the review (59 for the periodontitis outcome and 65 for the caries outcome), from an initial search of 15,487 titles. Gene variants associated with periodontitis were categorized based on strength of evidence and then compared with gene variants associated with caries. Several gene variants showed moderate to strong evidence of association with periodontitis, although none of them had also been associated with the caries trait. Despite some potential aetiopathogenic similarities between periodontitis and caries, no genetic variants to date have clearly been associated with both diseases. Further studies or comparisons across studies with large sample size and clear phenotype definition could shed light into possible shared genetic risk factors for caries and periodontitis.


Mechanism for the degradation of erythromycin A and erythromycin A 2'-ethyl succinate in acidic aqueous solution.
A major drawback of the antibiotic erythromycin A is its extreme acid sensitivity, leading to rapid inactivation in the stomach. The accepted model for degradation in aqueous acidic solution has erythromycin A in equilibrium with erythromycin A enol ether and degrading to anhydroerythromycin A. We report a detailed kinetic study of the acidic degradation of erythromycin A and of erythromycin A 2'-ethyl succinate (the market-leading pediatric prodrug), investigating the reaction rates and degradation products via NMR. This reveals that the accepted mechanism is incorrect and that both the enol ether and the anhydride are in equilibrium with the parent erythromycin. By implication, both the anhydride and enol ether are antibacterially inactive reservoirs for the parent erythromycin. The actual degradation pathway is the slow loss of cladinose from erythromycin A (or erythromycin A 2'-ethyl succinate), which is reported here for the first time in a kinetic study. The kinetic analysis is based on global, nonlinear, simultaneous least-squares fitting of time course concentrations for all species across multiple datasets to integrated rate expressions, to provide robust estimates of the rate constants.


Directed evolution of a new catalytic site in 2-keto-3-deoxy-6-phosphogluconate aldolase from Escherichia coli.
Aldolases are carbon bond-forming enzymes that have long been identified as useful tools for the organic chemist. However, their utility is limited in part by their narrow substrate utilization. Site-directed mutagenesis of various enzymes to alter their specificity has been performed for many years, typically without the desired effect. More recently directed evolution has been employed to engineer new activities onto existing scaffoldings. This approach allows random mutation of the gene and then selects for fitness to purpose those proteins with the desired activity. To date such approaches have furnished novel activities through multiple mutations of residues involved in recognition; in no instance has a key catalytic residue been altered while activity is retained. We report a double mutant of E. coli 2-keto-3-deoxy-6-phosphogluconate aldolase with reduced but measurable enzyme activity and a synthetically useful substrate profile. The mutant was identified from directed-evolution experiments. Modification of substrate specificity is achieved by altering the position of the active site lysine from one beta strand to a neighboring strand rather than by modification of the substrate recognition site. The new enzyme is different to all other existing aldolases with respect to the location of its active site to secondary structure. The new enzyme still displays enantiofacial discrimination during aldol addition. We have determined the crystal structure of the wild-type enzyme (by multiple wavelength methods) to 2.17 A and the double mutant enzyme to 2.7 A resolution. These results suggest that the scope of directed evolution is substantially larger than previously envisioned in that it is possible to perturb the active site residues themselves as well as surrounding loops to alter specificity. The structure of the double mutant shows how catalytic competency is maintained despite spatial reorganization of the active site with respect to substrate.


Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study.
Now that more than two decades have passed since the first reports of intraductal papillary-mucinous neoplasms (IPMNs), it has become clear that IPMN consists of a spectrum of neoplasms with both morphological and immunohistochemical variations. At a meeting of international experts on pancreatic precursor lesions held in 2003, it was agreed that a consensus classification of IPMN subtypes should be established to enable a more detailed analysis of the clinicopathological significance of the variations. Based on our experience and on information from the literature, we selected representative histological examples of IPMNs and defined a consensus nomenclature and criteria for classifying variants as distinctive IPMN subtypes including gastric type, intestinal type, pancreatobiliary type, and oncocytic type. These definitions can be used for further analyses of the clinicopathological significance of the variations of IPMN.


Intralesional Vitamin D Injection May Be an Effective Treatment Option for Warts.
Plantar warts are typically resistant to treatment. In recent years, treatments have included administration of intralesional tuberculin; measles, mumps, rubella vaccine; and Candida albicans antigen immunotherapy. To the best of our knowledge, there are no reports of intralesional vitamin D administration for the treatment of warts. To evaluate the efficacy and safety of intralesional vitamin D treatment for plantar warts. Twenty patients with single or multiple plantar warts were included in this study. Vitamin D(3) (0.2 mL, 7.5 mg/mL) was injected into the base of the warts after prilocaine (0.1 mL, 20 mg/mL) injection. A maximum of 5 warts were treated in 1 session, with at maximum 2 injections performed at 4-week intervals. In total, 16 of 20 patients (80%) showed complete resolution of warts, and 1 patient showed partial resolution. Three patients failed to show any response. No recurrence or serious adverse effects were observed. Intralesional vitamin D(3) may be an effective treatment option for warts.


Diagnosis of microvillous inclusion disease: a case report and literature review with significance for oman.
Microvillous Inclusion Disease (MVID) is one of the congenital diarrheal disorders (CDD) caused by genetic defects in enterocyte differentiation and polarization. Its prevalence is higher in countries with a high degree of consanguinity. It causes severe, intractable secretory diarrhea leading to permanent and definitive intestinal failure with resultant dependency on parenteral nutrition (PN). Small bowel transplantation is the only curative treatment. The gold standard for diagnosis are the typical morphological abnormalities in small bowel biopsies on light and electron microscopy (EM). In recent times, histochemistry and immunohistochemistry have shown sufficient diagnostic accuracy replacing EM if the facility is unavailable or EM findings are inconclusive. We describe a neonate with CDD who was diagnosed to have MVID on the duodenal biopsy by morphohistochemical and immunophenotypic methods used for the first time in Oman. By utilizing such easy and accessible diagnostic methods, a rare genetic disorder could be diagnosed with certainty and the family could be counseled accordingly. With a high degree of consanguinity in the region, the prevalence of MVID in Oman needs to be identified once these patients are diagnosed by utilizing appropriate investigations. Care of such patients necessitates improving current parenteral nutrition services and addressing the future need for small bowel transplantation (SBTx), in Oman.


Transcriptome for photobiological hydrogen production induced by sulfur deprivation in the green alga Chlamydomonas reinhardtii.
Photobiological hydrogen production using microalgae is being developed into a promising clean fuel stream for the future. In this study, microarray analyses were used to obtain global expression profiles of mRNA abundance in the green alga Chlamydomonas reinhardtii at different time points before the onset and during the course of sulfur-depleted hydrogen production. These studies were followed by real-time quantitative reverse transcription-PCR and protein analyses. The present work provides new insights into photosynthesis, sulfur acquisition strategies, and carbon metabolism-related gene expression during sulfur-induced hydrogen production. A general trend toward repression of transcripts encoding photosynthetic genes was observed. In contrast to all other LHCBM genes, the abundance of the LHCBM9 transcript (encoding a major light-harvesting polypeptide) and its protein was strongly elevated throughout the experiment. This suggests a major remodeling of the photosystem II light-harvesting complex as well as an important function of LHCBM9 under sulfur starvation and photobiological hydrogen production. This paper presents the first global transcriptional analysis of C. reinhardtii before, during, and after photobiological hydrogen production under sulfur deprivation.


Zinc-induced cardiomyocyte relaxation in a rat model of hyperglycemia is independent of myosin isoform.
It has been reported previously that diabetic cardiomyopathy can be inhibited or reverted with chronic zinc supplementation. In the current study, we hypothesized that total cardiac calcium and zinc content is altered in early onset diabetes mellitus characterized in part as hyperglycemia (HG) and that exposure of zinc ion (Zn2+) to isolated cardiomyocytes would enhance contraction-relaxation function in HG more so than in nonHG controls. To better control for differential cardiac myosin isoform expression as occurs in rodents after β-islet cell necrosis, hypothyroidism was induced in 16 rats resulting in 100% β-myosin heavy chain expression in the heart. β-Islet cell necrosis was induced in half of the rats by streptozocin administration. After 6 wks of HG, both HG and nonHG controls rats demonstrated similar myofilament performance measured as thin filament calcium sensitivity, native thin filament velocity in the myosin motility assay and contractile velocity and power. Extracellular Zn2+ reduced cardiomyocyte contractile function in both groups, but enhanced relaxation function significantly in the HG group compared to controls. Most notably, a reduction in diastolic sarcomere length with increasing pacing frequencies, i.e., incomplete relaxation, was more pronounced in the HG compared to controls, but was normalized with extracellular Zn2+ application. This is a novel finding implicating that the detrimental effect of HG on cardiomyocyte Ca2+ regulation can be amelioration by Zn2+. Among the many post-translational modifications examined, only phosphorylation of ryanodine receptor (RyR) at S-2808 was significantly higher in HG compared to nonHG. We did not find in our hypothyroid rats any differentiating effects of HG on myofibrillar protein phosphorylation, lysine acetylation, O-linked N-acetylglucosamine and advanced glycated end-products, which are often implicated as complicating factors in cardiac performance due to HG. Our results suggest that the relaxing effects of Zn2+ on cardiomyocyte function are more pronounced in the HG state due an insulin-dependent effect of enhancing removal of cytosolic Ca2+ via SERCA2a or NCX or by reducing Ca2+ influx via L-type channel or Ca2+ leak through the RyR. Investigations into the effects of Zn2+ on these mechanisms are now underway.


Repetitive magnetic stimulation: a novel therapeutic approach for myofascial pain syndrome.
The aim of this study was to evaluate the short, medium and long-term effects of peripheral repetitive magnetic stimulation (rMS) on myofascial pain compared with transcutaneous electrical nerve stimulation (TENS).Fifty-three subjects with myofascial trigger points (TPs) at the level of the superior trapezius muscle were allocated randomly to three groups. The first group (n=17) was treated with rMS, the second (n=18) with TENS and the third (n=18) received a placebo treatment. Each treatment consisted of ten daily 20-minute sessions. Patients were evaluated before and immediately following treatment, and at one and three months after the end of treatment. Outcome measures were: the "neck pain and disability visual analogue scale" (NPDVAS), an algometric evaluation of pain, an evaluation of the TP characteristics, and the range of cervical bending and rotation contralateral to the affected trapezius muscle. At the end of treatment, the rMS group showed a significant improvement in the NPDVAS, algometry, TP characteristics, and cervical contralateral rotation. This improvement also persisted at one and three months post-therapy. After treatment, the TENS group showed significant improvement in the same outcome measures except for algometry. At the one month follow-up visit, this improvement had returned to non significant levels in all outcome measures with the exception of NPDVAS. No significant effect of TENS was seen at the three-month follow-up visit. The placebo group showed no significant improvement in any measure. Our results strongly suggest that at medium and longer term intervals peripheral rMS may be more effective than TENS for the treatment of myofascial pain.


The Effects of Distance to Dentists and Dentist Supply on Children's Use of Dental Care.
To examine the effects of distance to dentists and dentist supply on dental services use among children with Medicaid coverage in Iowa. Iowa Medicaid claims for enrolled children between 2000 and 2009. The study sample included 41,554 children (providing 158,942 child-year observations) who were born in Iowa between 2000 and 2006 and enrolled from birth in the Iowa Medicaid program. Children were followed through 2009. We used logistic regression to simultaneously examine the effects of distance (miles to nearest dentist) and county-level dentist supply on a broad range of dental services controlling for key confounders. Additional models only used within-child variation over time to remove unobservable time-invariant confounders. Distance was related to lower utilization of comprehensive dental exams (2 percent lower odds per 1 mile increase in distance), an effect that also held in models using within-child variation only. Dentist supply was positively related to comprehensive exams and other preventive services and negatively related to major dental treatments; however, these associations became smaller and insignificant when examining within-child changes except for other preventive services. Longer distance to dentists is a barrier for use of comprehensive dental exams, conditional on dentist supply.


Laser spectral characterization in multiphoton microscopy.
Spectral and temporal characterization is a fundamental task when a tunable Ti:sapphire ultrafast laser system is operated for multiphoton microscopy applications. In the present paper simple procedures are reported that perform laser-peak-emission wavelength and bandwidth measurements without the need of any further instrumentation but a simple and inexpensive diffraction grating, by taking advantage of the confocal microscope imaging capabilities.


On the road to a neuroprosthetic hand: a novel hand grasp orthosis based on functional electrical stimulation.
To patients who have lost the functionality of their hands as a result of a severe spinal cord injury or brain stroke, the development of new techniques for grasping is indispensable for reintegration and independency in daily life. Functional Electrical Stimulation (FES) of residual muscles can reproduce the most dominant grasping tasks and can be initialized by brain signals. However, due to the very complex hand anatomy and current limitations in FES-technology with surface electrodes, these grasp patterns cannot be smoothly executed. In this paper, we present an adaptable passive hand orthosis which is capable of producing natural and smooth movements when coupled with FES. It evenly synchronizes the grasping movements and applied forces on all fingers, allowing for naturalistic gestures and functional grasps of everyday objects. The orthosis is also equipped with a lock, which allows it to remain in the desired position without the need for long-term stimulation. Furthermore, we quantify improvements offered by the orthosis compare them with natural grasps on healthy subjects.


A systematic review of the sensitivity and specificity of the toe-brachial index for detecting peripheral artery disease.
The toe-brachial index (TBI) is used as an adjunct to the ankle-brachial index (ABI) for non-invasive lower limb vascular screening. With increasing evidence suggesting limitations of the ABI for diagnosis of vascular complications, particularly in specific populations including diabetes cohorts, the TBI is being used more widely. The aim of this review was to determine the sensitivity and specificity of the TBI for detecting peripheral artery disease (PAD) in populations at risk of this disease. A database search was conducted to identify current work relating to the sensitivity and specificity of toe-brachial indices up to July 2015. Only studies using valid diagnostic imaging as a reference standard were included. The QUADAS-2 tool was used to critically appraise included articles. Seven studies met the inclusion criteria. Sensitivity of the TBI for PAD was reported in all seven studies and ranged from 45% to 100%; specificity was reported by five studies only and ranged from 16% to 100%. In conclusion, this review suggests that the TBI has variable diagnostic accuracy for the presence of PAD in specific populations at risk of developing the disease. There was a notable lack of large-scale diagnostic accuracy studies determining the diagnostic accuracy of the TBI in detecting PAD in different at-risk cohorts. However, standardised normal values need to be established for the TBI to conclusively determine the diagnostic accuracy of this test.


Activity counts from accelerometers do not add value to energy expenditure predictions in sedentary overweight individuals during weight loss interventions.
Knowing the total energy expenditure (TEE) of overweight adults is important for prescribing weight loss interventions. However, objective measurements of TEE may not always be readily available and can be expensive. This study aimed to investigate the validity of RT3 accelerometers in predicting the TEE of sedentary overweight adults, and to identify any sensitivity to anthropometric changes. The analysis used data from a 12-week weight loss study. At baseline and 12-week, TEE was predicted using RT3 accelerometers during whole room calorimeter stays. Bias between 2 methods was compared at and between the baseline and 12-week measurement points. Multiple regression analyses of TEE data were conducted. Predicted and measured values for TEE were not different at baseline (P = .677) but were significantly different after weight loss (P = .007). However, the mean bias between methods was small (<100 kcal/d) and was not significantly different between 2 time-points. RT3 activity counts explained an additional 2% of the variation in TEE at 12-week but not at baseline. RT3 accelerometers are not sensitive to body composition changes and do not explain variation in TEE of overweight and obese individuals in a sedentary environment.


Heart rate variability and daytime functioning in insomniacs and normal sleepers: preliminary results.
This study examined the differences in heart rate variability (HRV) and daytime functioning between insomniacs and normal sleepers. All participants underwent an interview, a medical examination, and a sleep measurement protocol during which they wore an actigraph and logged a sleep diary for a 7-day period to verify their eligibility. Included in the study were 18 insomniacs and 21 normal sleepers. During a laboratory session, these participants completed four paper-pencil tests of sleepiness, anxiety, fatigue, and concentration difficulty and the Wisconsin Card Sorting Test. Resting HRV was recorded under paced breathing. Neither did insomniacs experience cognitive impairment nor did they experience excessive daytime sleepiness compared with normal sleepers. However, insomniacs experienced higher frequency of fatigue [effect size (ES)=1.14, P=.002] compared with normal sleepers. There was also a trend toward higher trait anxiety score (ES=0.62) and concentration difficulty (ES=0.59) in insomniacs than in normal sleepers. Although a tendency toward lower resting high- frequency (HF) HRV (ES=-0.57) in insomniacs than in normal sleepers was noted, neither the resting low-frequency (LF) HRV nor the LF/HF ratio were different between groups. Subjective sleep estimates correlated to self-reported daytime consequences such as fatigue and concentration difficulty but not cognitive function. On the contrary, objective sleep estimates correlated to problem-solving/conceptualization and learning but not self-reported daytime consequences. Insomniacs are not sleepier during the day than normal sleepers. However, they may experience such a daytime symptom as fatigue although cognitive function remains unimpaired.


Non-linear Dynamical Analysis of Intraspinal Pressure Signal Predicts Outcome After Spinal Cord Injury.
The injured spinal cord is a complex system influenced by many local and systemic factors that interact over many timescales. To help guide clinical management, we developed a technique that monitors intraspinal pressure from the injury site in patients with acute, severe traumatic spinal cord injuries. Here, we hypothesize that spinal cord injury alters the complex dynamics of the intraspinal pressure signal quantified by computing hourly the detrended fluctuation exponent alpha, multiscale entropy, and maximal Lyapunov exponent lambda. 49 patients with severe traumatic spinal cord injuries were monitored within 72 h of injury for 5 days on average to produce 5,941 h of intraspinal pressure data. We computed the spinal cord perfusion pressure as mean arterial pressure minus intraspinal pressure and the vascular pressure reactivity index as the running correlation coefficient between intraspinal pressure and arterial blood pressure. Mean patient follow-up was 17 months. We show that alpha values are greater than 0.5, which indicates that the intraspinal pressure signal is fractal. As alpha increases, intraspinal pressure decreases and spinal cord perfusion pressure increases with negative correlation between the vascular pressure reactivity index vs. alpha. Thus, secondary insults to the injured cord disrupt intraspinal pressure fractality. Our analysis shows that high intraspinal pressure, low spinal cord perfusion pressure, and impaired pressure reactivity strongly correlate with reduced multi-scale entropy, supporting the notion that secondary insults to the injured cord cause de-complexification of the intraspinal pressure signal, which may render the cord less adaptable to external changes. Healthy physiological systems are characterized by edge of chaos dynamics. We found negative correlations between the percentage of hours with edge of chaos dynamics (-0.01 ≤ lambda ≤ 0.01) vs. high intraspinal pressure and vs. low spinal cord perfusion pressure; these findings suggest that secondary insults render the intraspinal pressure more regular or chaotic. In a multivariate logistic regression model, better neurological status on admission, higher intraspinal pressure multi-scale entropy and more frequent edge of chaos intraspinal pressure dynamics predict long-term functional improvement. We conclude that spinal cord injury is associated with marked changes in non-linear intraspinal pressure metrics that carry prognostic information.


Comparison of fractional exhaled nitric oxide, spirometry, and Asthma Control Test, in predicting asthma exacerbations: A prospective cohort study.
Fractional exhaled nitric oxide (FeNO) is a noninvasive test for airway inflammation in asthma. The usefulness of FeNO in predicting exacerbations is uncertain. The study aims to assess and compare the ability of FeNO, spirometry, and asthma control test (ACT) in predicting future exacerbations of asthma and their correlation with each other. This prospective, cohort study was conducted at the Department of Respiratory Medicine, Kasturba Medical College, Manipal. Adult asthma patients of age 18-65 years were included. Patients with a smoking history of >10 pack-years and those in whom spirometry was contraindicated were excluded. Patients who consented underwent FeNO and spirometry. The control of asthma was assessed using the ACT questionnaire. We captured the number of exacerbations in the follow-up period of 4 months. Mann-Whitney test was used to compare the utility of FeNO, spirometry, ACT in predicting exacerbations and Spearman's correlation coefficient was used to ascertain the correlation among them. Of 154 study patients, 28% had exacerbations. We found that there was no significant difference in FeNO in patients with and without exacerbations. The median (interquartile range [IQR]) FEV1% in the patients with and without exacerbations were 68 (55-79) and 75 (65-88), respectively (P = 0.013). The median (IQR) ACT score in patients with exacerbations was 12 (10-16) which was significantly lower than in those without exacerbation in whom it was 16 (14-18) (P = 0.003). There was a negative correlation of ACT with FeNO (Correlation coefficient: -0.167, P = 0.038). The median (IQR) FeNO level (ppb) was lower in patients who were on inhaled corticosteroid (ICS) than in the other group values being 22 (14-38) and 30 (17-58), respectively (P = 0.05). In our study, FEV1% and ACT score could predict exacerbations of asthma whereas FeNO could not. FeNO level correlated inversely with ACT score. FeNO level decreased with inhaled corticosteroid usage.


Acupuncture for migraine prophylaxis.
Acupuncture is often used for migraine prophylaxis but its effectiveness is still controversial. This review (along with a companion review on 'Acupuncture for tension-type headache') represents an updated version of a Cochrane review originally published in Issue 1, 2001, of The Cochrane Library. To investigate whether acupuncture is a) more effective than no prophylactic treatment/routine care only; b) more effective than 'sham' (placebo) acupuncture; and c) as effective as other interventions in reducing headache frequency in patients with migraine. The Cochrane Pain, Palliative & Supportive Care Trials Register, CENTRAL, MEDLINE, EMBASE and the Cochrane Complementary Medicine Field Trials Register were searched to January 2008. We included randomized trials with a post-randomization observation period of at least 8 weeks that compared the clinical effects of an acupuncture intervention with a control (no prophylactic treatment or routine care only), a sham acupuncture intervention or another intervention in patients with migraine. Two reviewers checked eligibility; extracted information on patients, interventions, methods and results; and assessed risk of bias and quality of the acupuncture intervention. Outcomes extracted included response (outcome of primary interest), migraine attacks, migraine days, headache days and analgesic use. Pooled effect size estimates were calculated using a random-effects model. Twenty-two trials with 4419 participants (mean 201, median 42, range 27 to 1715) met the inclusion criteria. Six trials (including two large trials with 401 and 1715 patients) compared acupuncture to no prophylactic treatment or routine care only. After 3 to 4 months patients receiving acupuncture had higher response rates and fewer headaches. The only study with long-term follow up saw no evidence that effects dissipated up to 9 months after cessation of treatment. Fourteen trials compared a 'true' acupuncture intervention with a variety of sham interventions. Pooled analyses did not show a statistically significant superiority for true acupuncture for any outcome in any of the time windows, but the results of single trials varied considerably. Four trials compared acupuncture to proven prophylactic drug treatment. Overall in these trials acupuncture was associated with slightly better outcomes and fewer adverse effects than prophylactic drug treatment. Two small low-quality trials comparing acupuncture with relaxation (alone or in combination with massage) could not be interpreted reliably. In the previous version of this review, evidence in support of acupuncture for migraine prophylaxis was considered promising but insufficient. Now, with 12 additional trials, there is consistent evidence that acupuncture provides additional benefit to treatment of acute migraine attacks only or to routine care. There is no evidence for an effect of 'true' acupuncture over sham interventions, though this is difficult to interpret, as exact point location could be of limited importance. Available studies suggest that acupuncture is at least as effective as, or possibly more effective than, prophylactic drug treatment, and has fewer adverse effects. Acupuncture should be considered a treatment option for patients willing to undergo this treatment.


Association between urinary calculi and erectile dysfunction: a case-control study.
Stone disease is associated with systemic metabolic and hormonal disorders that share common risk factors with erectile dysfunction (ED); however, few studies have investigated the association between ED and urinary calculi (UC). This case-control study aims to estimate the association of ED with UC using a nationwide, population-based database in Taiwan. We identified 5,620 patients with ED as the study group and randomly selected 16,860 patients as the controls. We estimated the odds ratio (OR) and 95% confidence interval (CI) of having previously been diagnosed with UC according to the presence/absence of ED using conditional logistic regression after adjusting for hypertension, diabetes, coronary heart disease, and hyperlipidemia. We measured the prevalence and risk of UC between the cases and controls. We only included UC cases if the UC diagnosis was made previous to the index date. Of the sampled patients, 3,855 (17.2%) were found to have been diagnosed with UC prior to the index date; 1,251 (22.3%) ED patients and 2,604 (15.4%) controls had been diagnosed with UC, respectively. After adjusting for confounders, the OR in ED patients who had prior UC was 1.46 (95% CI = 1.35-1.58) when compared with controls. The ORs of UC for ED patients were somewhat higher in younger groups. In particular, when compared with controls the adjusted OR in ED patients between 40 and 49 years old for prior UC was 1.73 (95% CI = 1.48-2.02). ED is associated with cases having a prior diagnosis of UC, particularly in younger populations.


Total antioxidant capacity from diet and risk of myocardial infarction: a prospective cohort of women.
There are no previous studies investigating the effect of all dietary antioxidants in relation to myocardial infarction. The total antioxidant capacity of diet takes into account all antioxidants and synergistic effects between them. The aim of this study was to examine how total antioxidant capacity of diet and antioxidant-containing foods were associated with incident myocardial infarction among middle-aged and elderly women. In the population-based prospective Swedish Mammography Cohort of 49-83-year-old women, 32,561 were cardiovascular disease-free at baseline. Women completed a food-frequency questionnaire, and dietary total antioxidant capacity was calculated using oxygen radical absorbance capacity values. Information on myocardial infarction was identified from the Swedish Hospital Discharge and the Cause of Death registries. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazard models. During the follow-up (September 1997-December 2007), we identified 1114 incident cases of myocardial infarction (321,434 person-years). In multivariable-adjusted analysis, the HR for women comparing the highest quintile of dietary total antioxidant capacity to the lowest was 0.80 (95% CI, 0.67-0.97; P for trend=0.02). Servings of fruit and vegetables and whole grains were nonsignificantly inversely associated with myocardial infarction. These data suggest that dietary total antioxidant capacity, based on fruits, vegetables, coffee, and whole grains, is of importance in the prevention of myocardial infarction.


Correlating acupuncture FMRI in the human brainstem with heart rate variability.
Past neuroimaging studies of acupuncture have demonstrated variable results for important brainstem nuclei. We have employed cardiac-gated fMRI with T1-variability correction to study the processing of acupuncture by the human brain. Furthermore, our imaging experiments collected simultaneous ECG data in order to correlate heart rate variability (HRV) with fMRI signal intensity. Subjects experienced one of three stimulations over a 31.5 minute fMRI run: (1) electro-acupuncture at 2Hz/15Hz over the acupoint ST-36 (2) electro-acupuncture at a sham non-acupoint, or (3) sensory control tapping over ST-36. The ECG was analyzed with power spectral methods for low frequency and high frequency components, which reflect the balance in the autonomic nervous system. The HRV data was then correlated with the time-varying fMRI signal intensity. Our data suggests that fMRI activity in the hypothalamus, the dorsal raphe nucleus, the periaqueductal gray, and the rostroventral medulla showed significant correlation with LF/HF ratio calculated from simultaneous HRV data. The correlation of time-varying fMRI response with physiological parameters may provide insight into connections between acupuncture modulation of the autonomic nervous system and neuroprocessing.


Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy.
Nonalcoholic fatty liver disease (NAFLD) has become a major public health issue. The goal of this study was to assess the clinical use of liver stiffness measurement (LSM) evaluated by supersonic shear imaging (SSI), FibroScan, and acoustic radiation force impulse (ARFI) in a cohort of NAFLD patients who underwent liver biopsy. A total of 291 NAFLD patients were prospectively enrolled from November 2011 to February 2015 at 2 French university hospitals. LSM was assessed by SSI, FibroScan (M probe), and ARFI within two weeks prior to liver biopsy. Calculations of the area under the receiver operating curve (AUROC) were performed and compared for the staging of liver fibrosis. AUROC for SSI, FibroScan, and ARFI were 0.86, 0.82, and 0.77 for diagnoses of ≥F2; 0.89, 0.86, and 0.84 for ≥F3; and 0.88, 0.87, and 0.84 for F4, respectively. SSI had a higher accuracy than ARFI for diagnoses of significant fibrosis (≥F2) (P = 0.004). Clinical factors related to obesity such as body mass index ≥ 30 kg/m(2) , waist circumference ≥102 cm or increased parietal wall thickness were associated with LSM failures when using SSI or FibroScan and with unreliable results when using ARFI. In univariate analysis, FibroScan values were slightly correlated with NAFLD activity score and steatosis (R = 0.28 and 0.22, respectively), whereas SSI and ARFI were not; however, these components of NAFLD did not affect LSM results in multivariate analysis. The cutoff values for SSI and FibroScan for staging fibrosis with a sensitivity ≥90% were very close: 6.3/6.2 kPa for ≥F2, 8.3/8.2 kPa for ≥F3, and 10.5/9.5 kPa for F4. Although obesity is associated with an increase in LSM failure, the studied techniques and especially SSI provide high value for the diagnosis of liver fibrosis in NAFLD patients. (Hepatology 2016;63:1817-1827).


Disruption of Nrf2 Synergizes with High Glucose to Cause Heightened Myocardial Oxidative Stress and Severe Cardiomyopathy in Diabetic Mice.
High glucose-induced oxidative stress is a major contributing mechanism to the development of diabetic cardiomyopathy. Nrf2 is an emerging critical regulator of cellular defense against oxidative damage. The role of Nrf2 in diabetic cardiomyopathy was investigated in vivo. Streptozotocin (STZ) induced diabetes in Nrf2 knockout (KO) mice that rapidly progressed to severe conditions with high mortality within two weeks of injection; whereas, in wild type (WT) mice, diabetes was less severe with no death. Severe myocardial lesions were observed in diabetic KO mice that had high, sublethal levels of blood glucose including: (a) irregular myocardial arrangements, myofibrillar discontinuation, and cell death; (b) reduced electron density, discontinuation of myocardial fibers, and mitochondrial damage; and (c) markedly reduced contractility of the cardiomyocytes to β-agonist stimulation. Parallel to severe cardiomyopathy, the diabetic KO hearts showed: (a) increased apoptosis as revealed by TUNEL and PARP1 cleavage assays; (b) infiltration of granulocytes and macrophages as well as fibrosis indicating robust inflammatory response; and (c) heightened oxidative stress as evidenced by increased levels of 8-hydroxydeoxyquanine, free malondialdehyde, and 3-nitrotyrosine. Increased oxidative stress in the KO hearts was attributed to decrease or loss of the basal and induced expression of Nrf2-dependent cytoprotective genes. Our findings demonstrate that loss of Nrf2 function synergizes with high glucose to cause heightened oxidative stress in the heart leading to severe diabetic cardiomyopathy.


Solastalgia: living with the environmental damage caused by natural disasters.
Forced separation from one's home may trigger emotional distress. People who remain in their homes may experience emotional distress due to living in a severely damaged environment. These people experience a type of 'homesickness' similar to nostalgia because the land around them no longer resembles the home they knew and loved. What they lack is solace or comfort from their home; they long for the home environment to be the way it was before. "Solastalgia" is a term created to describe feelings which arise in people when an environment changes so much that it negatively affects an individual's quality of life. Such changed environments may include drought-stricken areas and open-cut mines. The aim of this article is to describe how solastalgia, originally conceptualized as the result of man-made environmental change, can be similarly applied to the survivors of natural disasters. Using volcanic eruptions as a case example, the authors argue that people who experience a natural disaster are likely to suffer from solastalgia for a number of reasons, which may include the loss of housing, livestock and farmland, and the ongoing danger of living in a disaster-prone area. These losses and fears challenge people's established sense of place and identity and can lead to feelings of helplessness and depression.


Generation and tight focusing of hybridly polarized vector beams.
We propose and experimentally demonstrate the generation of hybridly polarized beams by transmitting radially polarized light through a wave plate. We show that such beams span a closed circle on the surface of the Poincaré sphere whose center coincides with the center of the sphere. In addition we numerically investigate the field and energy density distribution across the focal plane of a high NA lens illuminated by such a hybrid beam. The results show an interesting polarization distribution with 3D orientation and space variant ellipticity. This kind of polarization distributions may be used for a variety of applications, e.g. particle orientation analysis, microscopy and in atomic systems.


Sensitization to common allergens and its association with allergic disorders at age 4 years: a whole population birth cohort study.
Atopy is defined as the genetic propensity to develop immunoglobulin E antibodies in response to exposure to allergens and assessed by skin prick test responses to common allergens. Although it is generally agreed that atopy is an important risk factor for allergic diseases such as asthma, rhinitis, and eczema, the extent to which atopy accounts for these diseases is controversial. We aim to describe the prevalence of sensitization to common allergens and investigate the degree of association of atopy (as defined by positive skin prick test to 1 or more common allergens) to asthma, rhinitis, and eczema in a birth cohort at the age of 4 years. A birth cohort of 1456 children was recruited over a 14-month period (1989-1990). These children have been seen previously at 1 and 2 years of age. At 4 years, 1218 children were reviewed and an interview was administered or postal questionnaire was completed for the presence of allergic diseases (asthma, rhinitis, and eczema). Additionally, in 981 children, skin prick tests with a battery of 12 common allergens were performed. Allergens were house dust mite (Dermatophagoides pteronyssimus), grass pollen mix, cat, dog, Alternaria alternata, Cladosporium herbarum, cow's milk, hen's egg, soya, cod, wheat, and peanut. A mean wheal diameter of at least 3 mm greater than the negative control was taken as positive. This analysis is confined to the 981 (67% of the original population) who also had skin prick tests to the standard battery. chi(2) tests were used to test the univariate association between each allergic disease and positive skin test. Multiple logistic regression analysis was performed to obtain the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the independent effect of sensitization to each allergen on allergic disease, adjusting for the effect of sensitization to other allergens. To ascertain how much of allergic disease is attributable to atopy, we estimated the population-attributable risk. This was calculated with the formula: P(R - 1) where R is the OR for the allergic disease under consideration and P is the proportion of atopy in children with that disease. Children who were skin prick-tested at 4 years were similar in most characteristics to the rest of the population, except that they had a higher prevalence of allergic disease. Allergic disorders (asthma, rhinitis, and eczema) were present in 276 (28.1%) of 981. One hundred ninety-two (19.6%) children were atopic (positive reaction to 1 or more allergens). Sensitization to inhalant allergens was relatively common (19.2%) as compared with food allergens (3.5%). House dust mite (11.9%), grass pollen (7.8%), and cat (5.8%) were the most common positive reactions. A test to the 4 most common allergens (house dust mite, grass pollen, cat, and A alternata) could detect 94% of the atopic children. Sensitization to the 4 most common allergens was strongly associated with the presence of allergic disorders. There was a graded effect with the potent allergens, such as house dust mite, having the greatest impact. For example, 50% of children sensitized to house dust mite had asthma as opposed to 44% sensitized to cat, 42% sensitized to grass pollen, and 32% sensitized to A alternata. Overall, 68.4% of children sensitized to house dust mite had asthma, eczema, and/or rhinitis. The respective figures for grass pollen, cat, and A alternata were 64.9%, 66.7%, and 57.4%. The proportion of children sensitized to cat was not higher in households with cat ownership (households with cats: 5.1% [19/374]; households without cats: 6.2% [36/580]; not significant [NS]). Similarly, no difference was seen in sensitization to dog in households with and without dogs (households with dogs: 1.8% [5/282]; households without dogs: 2.8% [19/673]; NS). Boys were atopic more often than girls at this age (male: 112 of 497 [22.5%] vs female: 80 of 484 [16.5%]; OR: 1.47, 95% CI: 1.07-2.02). Male preponderance was observed with most allergens, but this was statistically significant only for house dust mite (male: 75/497 [15.1%] vs female: 42/484 [8.7%]; OR: 1.87; CI: 1.25-2.79) and grass pollen (male: 51/497 [10.3%] vs female: 26/484 [5.4%]; OR: 2.01; CI: 1.23-3.29). An independent effect of allergen sensitization on asthma was observed only with house dust mite with an OR of 8.07 (CI: 4.60-14.14). The highest independent risk for rhinitis was sensitization to grass pollen (OR: 5.02; CI: 2.21-11.41), and for eczema, sensitization to peanut (OR: 4.65; CI: 1.02-21.34). The majority of children (98/192) were sensitized to >1 allergen. A graded effect was observed with the risk of allergic disease in the child increasing with the number of positive skin prick test reactions. This effect was consistent throughout the spectrum of allergic diseases (asthma, eczema, and rhinitis). (ABSTRACT TRUNCATED)


Numerical simulations of in vitro nanoparticle toxicity - the case of poly(amido amine) dendrimers.
A phenomenological rate equation model is constructed to numerically simulate nanoparticle uptake and subsequent cellular response. Polyamidoamine dendrimers (generations 4-6) are modelled and the temporal evolution of the intracellular cascade of; increased levels of reactive oxygen species, intracellular antioxidant species, caspase activation, mitochondrial membrane potential decay, tumour necrosis factor and interleukin generation is simulated, based on experimental observations. The dose and generation dependence of several of these response factors are seen to well represent experimental observations at a range of time points. The model indicates that variations between responses of different cell-lines, including murine macrophages, human keratinocytes and colon cells, can be simulated and understood in terms of different intracellular antioxidant levels, and, within a given cell-line, varying responses of different cytotoxicity assays can be understood in terms of their sensitivities to different intracellular cascade events. The model serves as a tool to interpolate and visualise the range of dose and temporal dependences and elucidate the mechanisms underlying the in vitro cytotoxic response to nanoparticle exposure and describes the interaction in terms of independent nanoparticle properties and cellular parameters, based on reaction rates. Such an approach could be a valid alternative to that of effective concentrations for classification of nanotoxicity and may lay the foundation for future quantitative structure activity relationships and predictive nanotoxicity models.


Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2.
Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by using the pluripotency factors Oct4, Sox2, Klf4 and c-Myc (together referred to as OSKM). iPSC reprogramming erases somatic epigenetic signatures—as typified by DNA methylation or histone modification at silent pluripotency loci—and establishes alternative epigenetic marks of embryonic stem cells (ESCs). Here we describe an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as Nanog and Esrrb. By day 4 after transduction with OSKM, two epigenetic modification factors necessary for iPSC generation, namely poly(ADP-ribose) polymerase-1 (Parp1) and ten-eleven translocation-2 (Tet2), are recruited to the Nanog and Esrrb loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: Parp1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas Tet2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC (refs 3,4). Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts, our data, and also studies of Tet2-mutant human tumour cells, argue in favour of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, Parp1 and Tet2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas Parp1 induction further promotes accessibility to the Oct4 reprogramming factor. These findings suggest that Parp1 and Tet2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.


Predictors of Exceptional Longevity: Effects of Early-Life and Midlife Conditions, and Familial Longevity.
Knowledge of strong predictors of mortality and longevity is very important for actuarial science and practice. Earlier studies found that parental characteristics as well as early-life conditions and midlife environment play a significant role in survival to advanced ages. However, little is known about the simultaneous effects of these three factors on longevity. This ongoing study attempts to fill this gap by comparing centenarians born in the United States in 1890-1891 with peers born in the same years who died at age 65. The records for centenarians and controls were taken from computerized family histories, which were then linked to 1900 and 1930 U.S. censuses. As a result of this linkage procedure, 765 records of confirmed centenarians and 783 records of controls were obtained. Analysis with multivariate logistic regression found the existence of both general and gender-specific predictors of human longevity. General predictors common for men and women are paternal and maternal longevity. Gender-specific predictors of male longevity are occupation as a farmer at age 40, Northeastern region of birth in the United States, and birth in the second half of year. A gender-specific predictor of female longevity is the availability of radio in the household according to the 1930 U.S. census. Given the importance of familial longevity as an independent predictor of survival to advanced ages, we conducted a comparative study of biological and nonbiological relatives of centenarians using a larger sample of 1,945 validated U.S. centenarians born in 1880-1895. We found that male gender of centenarian has a significant positive effect on survival of adult male relatives (brothers and fathers) but not female blood relatives. Life span of centenarian siblings-in-law is lower compared to life span of centenarian siblings and does not depend on centenarian gender. Wives of male centenarians (who share lifestyle and living conditions) have a significantly better survival compared to wives of centenarians' brothers. This finding demonstrates an important role of shared familial environment and lifestyle in human longevity. The results of this study suggest that familial background, some early-life conditions and midlife characteristics play an important role in longevity.


U.K. Clergy and people in mental distress: community and patterns of pastoral care.
Despite the advance of secularizing influences in many western societies, religion and faith-based organizations play a significant role in the lives of many individuals and communities. Despite this, little is known about what clergy do when faced with mental health problems among their communities. Based on an analysis of in-depth interviews with U.K. Christian, Muslim and Jewish clergy this article examines models of pastoral care provided within different faith groups. The provision of such care was generally influenced by religious tradition and beliefs, community integrity and mission. Implications of the findings for collaboration with pastoral care are discussed.


Emerging investigator series: influence of marine emissions and atmospheric processing on individual particle composition of summertime Arctic aerosol over the Bering Strait and Chukchi Sea.
The Arctic is rapidly transforming due to sea ice loss, increasing shipping activity, and oil and gas development. Associated marine and combustion emissions influence atmospheric aerosol composition, impacting complex aerosol-cloud-climate feedbacks. To improve understanding of the sources and processes determining Arctic aerosol composition, atmospheric particles were collected aboard the Korean icebreaker R/V Araon cruising within the Bering Strait and Chukchi Sea during August 2016. Offline analyses of individual particles by microspectroscopic techniques, including scanning electron microscopy with energy dispersive X-ray spectroscopy and atomic force microscopy with infrared spectroscopy, provided information on particle size, morphology, and chemical composition. The most commonly observed particle types were sea spray aerosol (SSA), comprising ∼60-90%, by number, of supermicron particles, and organic aerosol (OA), comprising ∼50-90%, by number, of submicron particles. Sulfate and nitrate were internally mixed within both SSA and OA particles, consistent with particle multiphase reactions during atmospheric transport. Within the Bering Strait, SSA and OA particles were more aged, with greater number fractions of particles containing sulfate and/or nitrate, compared to particles collected over the Chukchi Sea. This is indicative of greater pollution influence within the Bering Strait from coastal and inland sources, while the Chukchi Sea is primarily influenced by marine sources.


Hospital Medicine Point of Care Ultrasound Credentialing: An Example Protocol.
Though the use of point-of-care ultrasound (POCUS) has increased over the last decade, formal hospital credentialing for POCUS may still be a challenge for hospitalists. This document details the Hospital Medicine Department Ultrasound Credentialing Policy from Regions Hospital, which is part of the HealthPartners organization in Saint Paul, Minnesota. National organizations from internal medicine and hospital medicine (HM) have not published recommended guidelines for POCUS credentialing. Revised guidelines for POCUS have been published by the American College of Emergency Physicians, though these are not likely intended to guide hospitalists when working with credentialing committees and medical boards. This document describes the scope of ultrasound in HM and our training, credentialing, and quality assurance program. This report is intended to be used as a guide for hospitalists as they work with their own credentialing committees and will require modification for each institution. However, the overall process described here should assist in the establishment of POCUS at various institutions.


Black hole physics. Black hole lightning due to particle acceleration at subhorizon scales.
Supermassive black holes with masses of millions to billions of solar masses are commonly found in the centers of galaxies. Astronomers seek to image jet formation using radio interferometry but still suffer from insufficient angular resolution. An alternative method to resolve small structures is to measure the time variability of their emission. Here we report on gamma-ray observations of the radio galaxy IC 310 obtained with the MAGIC (Major Atmospheric Gamma-ray Imaging Cherenkov) telescopes, revealing variability with doubling time scales faster than 4.8 min. Causality constrains the size of the emission region to be smaller than 20% of the gravitational radius of its central black hole. We suggest that the emission is associated with pulsar-like particle acceleration by the electric field across a magnetospheric gap at the base of the radio jet.


A statistical design for testing transgenerational genomic imprinting in natural human populations.
Genomic imprinting is a phenomenon in which the same allele is expressed differently, depending on its parental origin. Such a phenomenon, also called the parent-of-origin effect, has been recognized to play a pivotal role in embryological development and pathogenesis in many species. Here we propose a statistical design for detecting imprinted loci that control quantitative traits based on a random set of three-generation families from a natural population in humans. This design provides a pathway for characterizing the effects of imprinted genes on a complex trait or disease at different generations and testing transgenerational changes of imprinted effects. The design is integrated with population and cytogenetic principles of gene segregation and transmission from a previous generation to next. The implementation of the EM algorithm within the design framework leads to the estimation of genetic parameters that define imprinted effects. A simulation study is used to investigate the statistical properties of the model and validate its utilization. This new design, coupled with increasingly used genome-wide association studies, should have an immediate implication for studying the genetic architecture of complex traits in humans.


A spontaneous increase in intracellular Ca2+ in metaphase II human oocytes in vitro can be prevented by drugs targeting ATP-sensitive K+ channels.
Could drugs targeting ATP-sensitive K(+) (K(ATP)) channels prevent any spontaneous increase in intracellular Ca(2+) that may occur in human metaphase II (MII) oocytes under in vitro conditions? Pinacidil, a K(ATP) channel opener, and glibenclamide, a K(ATP) channel blocker, prevent a spontaneous increase in intracellular Ca(2+) in human MII oocytes. The quality of the oocyte and maintenance of this quality during in vitro processing in the assisted reproductive technology (ART) laboratory is of critical importance to successful embryo development and a healthy live birth. Maintenance of Ca(2+) homeostasis is crucial for cell wellbeing and increased intracellular Ca(2+) levels is a well-established indicator of cell stress. Supernumerary human oocytes (n = 102) collected during IVF/ICSI treatment that failed to fertilize were used from October 2013 to July 2015. All experiments were performed on mature (MII) oocytes. Dynamics of intracellular Ca(2+) levels were monitored in oocytes in the following experimental groups: (i) Control, (ii) Dimethyl sulfoxide (DMSO; used to dissolve pinacidil, glibenclamide and 2,4-Dinitrophenol (DNP)), (iii) Pinacidil, (iv) Glibenclamide, (v) DNP: an inhibitor of oxidative phosphorylation, (vi) Pinacidil and DNP and (vii) Glibenclamide and DNP. Oocytes were collected under sedation as part of routine treatment at an assisted conception unit from healthy women (mean ± SD) age 34.1 ± 0.6 years, n = 41. Those surplus to clinical use were donated for research. Oocytes were loaded with Fluo-3 Ca(2+)-sensitive dye, and monitored by laser confocal microscopy for 2 h at 10 min intervals. Time between oocyte collection and start of Ca(2+) monitoring was 80.4 ± 2.1 h. Intracellular levels of Ca(2+) increased under in vitro conditions with no deliberate challenge, as shown by Fluo-3 fluorescence increasing from 61.0 ± 11.8 AU (AU = arbitrary units; n = 23) to 91.8 ± 14.0 AU (n = 19; P < 0.001) after 2 h of monitoring. Pinacidil (100 µM) inhibited this increase in Ca(2+) (85.3 ± 12.3 AU at the beginning of the experiment, 81.7 ± 11.0 AU at the end of the experiment; n = 13; P = 0.616). Glibenclamide (100 µM) also inhibited the increase in Ca(2+) (74.7 ± 10.6 AU at the beginning and 71.8 ± 10.9 AU at the end of the experiment; n = 13; P = 0.851. DNP (100 mM) induced an increase in intracellular Ca(2+) that was inhibited by glibenclamide (100 µM; n = 9) but not by pinacidil (100 µM; n = 5). Owing to clinical and ethical considerations, it was not possible to monitor Ca(2+) in MII oocytes immediately after retrieval. MII oocytes were available for our experimentation only after unsuccessful IVF or ICSI, which was, on average, 80.4 ± 2.1 h (n = 102 oocytes) after the moment of retrieval. As the MII oocytes used here were those that were not successfully fertilized, it is possible that they may have been abnormal with impaired Ca(2+) homeostasis and, furthermore, the altered Ca(2+) homeostasis might have been associated solely with the protracted incubation. These results show that maintenance of oocytes under in vitro conditions is associated with intracellular increase in Ca(2+), which can be counteracted by drugs targeting K(ATP) channels. As Ca(2+) homeostasis is crucial for contributing to a successful outcome of ART, these results suggest that K(ATP) channel openers and blockers should be tested as drugs for improving success rates of ART. University of Dundee, MRC (MR/K013343/1, MR/012492/1), NHS Tayside. Funding NHS fellowship (Dr Sarah Martins da Silva), NHS Scotland. The authors declare no conflicts of interest.


Reproduction of Pratylenchus penetrans on 24 Common Weeds in Potato Fields in Québec.
Twenty-four weeds commonly found in commercial potato fields in Quebec were evaluated for their host suitability to the root-lesion nematode, Pratylenchus penetrans, under greenhouse conditions. Brown mustard (Brassica juncea) and rye (Secale cereale) were included as susceptible controls and forage pearl millet hyb. CFPM 101 (Pennisetum glaucum) as a poor host. Pratylenchus penetrans multiplied well on 22 of the 24 weed species tested (Pf/Pi >/= rye or brown mustard). Cirsium arvense, Leucanthemum vulgare and Matricaria discoida were classified as very good hosts with a Pf/Pi ranging from 1.60 to 2.54, while Ambrosia artemisiifolia and Cyperus esculentus were classified as poor hosts with a Pf/Pi from 0.01 to 0.15. Amaranthus powellii, A. retrqflexus, Raphanus raphanistrum, Rorippa palustris, Cerastium fontanum, Spergula arvensis, Stellaria media, Chenopodium album, Vicia cracca, Elytrigia repens, Digitaria ischaemum, Echinochloa crusgalli, Panicum capillare, Setaria faberii, S. pumila, S. viridis, Polygonum convolvulus, P. scabrum and P. persicaria were intermediate hosts with Pf/Pi values ranging from 0.33 to 2.01. The plant species and the botanical family had a significant impact on nematode reproduction. The Brassicaceae family resulted in the greatest reproduction of P. penetrans, and the Cyperaceae resulted in the least. The plant life-cycle (annual vs. perennial) had no impact on nematode population.


Calculations of mechanisms for balance control during narrow and single-leg standing in fit older adults: A reliability study.
For older people balance control in standing is critical for performance of activities of daily living without falling. The aims were to investigate reliability of quantification of the usage of the two balance mechanisms M(1) 'moving the centre of pressure' and M(2) 'segment acceleration' and also to compare calculation methods based on a combination of kinetic (K) and kinematic (Km) data, (K-Km), or Km data only concerning M(2). For this purpose nine physically fit persons aged 70-78 years were tested in narrow and single-leg standing. Data were collected by a 7-camera motion capture system and two force plates. Repeated measure ANOVA and Tukey's post hoc tests were used to detect differences between the standing tasks. Reliability was estimated by ICCs, standard error of measurement including its 95% CI, and minimal detectable change, whereas Pearson's correlation coefficient was used to investigate agreement between the two calculation methods. The results indicated that for the tasks investigated, M(1) and M(2) can be measured with acceptable inter- and intrasession reliability, and that both Km and K-Km based calculations may be useful for M(2), although Km data may give slightly lower values. The proportional M(1):M(2) usage was approximately 9:1, in both anterio-posterior (AP) and medio-lateral (ML) directions for narrow standing, and about 2:1 in the AP and of 1:2 in the ML direction in single-leg standing, respectively. In conclusion, the tested measurements and calculations appear to constitute a reliable way of quantifying one important aspect of balance capacity in fit older people.


SGLT2 inhibitor dapagliflozin limits podocyte damage in proteinuric nondiabetic nephropathy.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have pleiotropic properties beyond blood glucose-lowering effects and modify important nonglycemic pathways, leading to end-organ protection. SGLT2 inhibitors display renoprotective effects in diabetic kidney disease, which creates a rationale for testing the therapeutic potential of this drug class in nondiabetic chronic kidney disease. Here, we have shown that dapagliflozin provided glomerular protection in mice with protein-overload proteinuria induced by bovine serum albumin (BSA), to a similar extent as an ACE inhibitor used as standard therapy for comparison. Dapagliflozin limited proteinuria, glomerular lesions, and podocyte dysfunction and loss. We provide the observation that SGLT2 was expressed in podocytes and upregulated after BSA injections. Through in vitro studies with cultured podocytes loaded with albumin we have identified what we believe to be a novel mechanism of action for SGLT2 inhibitor that directly targets podocytes and relies on the maintenance of actin cytoskeleton architecture. Whether SGLT2 inhibitors represent a possible future therapeutic option for some patients with proteinuric glomerular disease who do not have as yet an effective treatment will require ad hoc clinical studies.


Retrospective review of modafinil use for cerebral palsy.
A retrospective review was undertaken at Texas Tech University Health Sciences Center regarding the use of modafinil for the treatment of spasticity associated with cerebral palsy. Neurology clinic records were reviewed from January 1, 2000, until October 1, 2001. Thirty pediatric patients with cerebral palsy were identified who were treated empirically with modafinil during this time period. Twenty-three (76%) patients reported diminished spasticity with treatment, which was confirmed by physical examination; these patients had improved joint mobility. Seventeen (56%) patients continued treatment with modafinil by the end of the formal review period (September 30, 2001). Twenty-three percent (seven) of the patients stopped taking modafinil during the study owing to one of the following: decreased sleep time (four), decreased appetite (one), hyperactivity, and irritability (two). Thus, this retrospective review shows a reduction in spasticity from cerebral palsy, with only minor and reversible side effects noted from modafinil. A blinded, crossover study using modafinil for spastic cerebral palsy is planned.


Self-assessed physical function levels of women with fibromyalgia: a national survey.
We sought to determine the self-reported physical function level of women with fibromyalgia (FM). We performed a secondary analysis using data from an Internet-based survey posted on the National Fibromyalgia Association website. Data used for this study included women (n = 1,735) aged 31-78 years who reported being diagnosed with FM. More than 25% of women reported having difficulty taking care of personal needs and bathing, and >60% reported difficulty doing light household tasks, going up/down 1 flight of stairs, walking (1/2) mile, and lifting or carrying 10 lbs. More than 90% of women reported having difficulty doing heavy household tasks, lifting or carrying 25 lbs, and doing strenuous activities. Women with lower functional ability reported higher levels of fatigue, pain, spasticity, depression, restless legs, balance problems, dizziness, fear of falling, and bladder problems. The average woman in this sample reported having less functional ability related to activities of daily living and instrumental activities of daily living than the average community-dwelling woman in her 80s. Several symptoms/conditions were found to be associated with functional limitation in women with FM. Targeting these-singly or in clusters-may potentially be important in terms of future interventions.


Using Nonfiction Narratives in an English Course to Teach the Nature of Science and Its Importance to Communicating About Science.
The nature of science (NOS) is a foundational framework for understanding scientific ideas and concepts. This framework includes scientific methodology, the process of revising and interpreting data, and the ways in which science is a social endeavor. Nature of science literature treats science as a way of knowing that is based on observable phenomenon. While discipline-specific coursework teaches the factual information of science, it may fall short on teaching scientific literacy, a key component of which is understanding NOS. We have designed an English course that features nonfiction narratives describing the early days of epidemiology, hygiene awareness, and the current controversy surrounding vaccination. Using a validated assessment of student understanding of NOS, the Student Understanding of Science and Scientific Inquiry (SUSSI), we have determined that this science-themed English composition course was effective in teaching NOS. Student understanding of NOS increased between the beginning and the end of the course in eight of the nine parameters of NOS measured, with the greatest gains in understanding the role of revision and of creativity in science. Our data imply that the course helped students develop a slightly less naïve understanding of the nature of science and its importance in the development and dissemination of scientific ideas and concepts.


Titrated oral misoprostol for augmenting labour to improve maternal and neonatal outcomes.
Labour dystocia is associated with a number of adverse maternal and neonatal outcomes. Augmentation of labour is a commonly used intervention in cases of labour dystocia. Misoprostol is an inexpensive and stable prostaglandin E1 analogue that can be administered orally, vaginally, sublingually or rectally. Misoprostol has proven to be effective at stimulating uterine contractions although it can have serious, and even life-threatening side-effects. Titration refers to the process of adjusting the dose, frequency, or both, of a medication on the basis of frequent review to achieve optimal outcomes. Studies have reported on a range of misoprostol titration regimens used for labour induction and titrated misoprostol may potentially be effective and safe for augmentation of labour. To examine the effects and safety of titrated oral misoprostol compared with placebo, oxytocin, other interventions, or no active treatment, in women with labour dystocia. The Trials Search Co-ordinator of the Cochrane Pregnancy and Childbirth Group searched the Cochrane Pregnancy and Childbirth Group's Trials Register; date of search: 29 May 2013. We also searched the reference lists of retrieved studies Randomised trials (including quasi-randomised and cluster-randomised trials) comparing titrated oral misoprostol with placebo, other interventions (e.g. oxytocin, other prostaglandins), or no treatment in women requiring augmentation of labour were eligible for inclusion. Two review authors independently assessed eligibility for inclusion, carried out data extraction and assessed risk of bias in included studies. Data were entered by one author and checked for accuracy. We included two randomised trials with a total of 581 women each comparing different regimens of titrated oral misoprostol with intravenous oxytocin. One study compared 20 mcg doses of misoprostol dissolved in water (repeated every hour up to four hours, after which the dose was increased to 40 mcg per hour up to a maximum total dose of 1600 mcg), while the second study gave women 75 mcg doses (repeated after four hours provided there were no adverse effects observed).Neither trial reported maternal death, severe maternal morbidity, or fetal/neonatal mortality outcomes, and only a few fetal/neonatal morbidity outcomes were considered, none of which were significantly different between groups. For several outcomes (such as maternal side-effects, instrumental birth, maternal blood transfusion for hypovolaemia and epidural analgesia), the number of events was generally too low for sufficient statistical power to be achieved. Maternal satisfaction was not reported in either trial. One trial reported a slight reduction in the median duration of labour from the start of augmentation to vaginal delivery in the oxytocin group.Neither trial reported significantly higher rates of caesarean section (CS) in the oral misoprostol group. Rates of vaginal delivery within 12 and 24 hours of commencing augmentation were not significantly different in the trial using a 20 mcg misoprostol dose. Neither trial had significantly higher rates of uterine hyperstimulation with fetal heart rate changes in the titrated oral misoprostol group. However, the rates of this outcome varied so greatly between the two studies as to suggest that other factors were at play. The only significant differences between groups related to uterine hyperstimulation (without fetal heart rate changes), and results were not consistent in the two trials. In the trial examining the higher dose of misoprostol, more women in the misoprostol group experienced hyperstimulation of labour measured over a 10-minute period compared with those receiving oxytocin (risk ratio (RR) 1.17, 95% confidence interval (CI) 1.02 to 1.35, 350 women). In the study examining the lower titrated dose of misoprostol, there was a lower incidence of tachysystole when labour was augmented with titrated oral misoprostol than with oxytocin (RR 0.39, 95% CI 0.17 to 0.91, 231 women) with no occurrences of hypertonus in either group of women. Important uncertainties still exist on the safety and acceptability of titrated oral misoprostol compared with intravenous oxytocin regimens in women with dystocia following spontaneous onset of labour. Although in facilities where electronic oxytocin infusion is not available, low-dose titrated misoprostol may offer a better alternative to an uncontrolled oxytocin infusion to avoid hyperstimulation. Further research is needed in both high- and low-resource settings More trials should be conducted to evaluate the effect of a standard titration oral misoprostol regimen, both following spontaneous labour and labour induction. Comparisons with other augmentation methods are also warranted, as are any effects on women's birth experiences.


Yoga compared to non-exercise or physical therapy exercise on pain, disability, and quality of life for patients with chronic low back pain: A systematic review and meta-analysis of randomized controlled trials.
Chronic low back pain (CLBP) is a common and often disabling musculoskeletal condition. Yoga has been proven to be an effective therapy for chronic low back pain. However, there are still controversies about the effects of yoga at different follow-up periods and compared with other physical therapy exercises. To critically compare the effects of yoga for patients with chronic low back pain on pain, disability, quality of life with non-exercise (e.g. usual care, education), physical therapy exercise. This study was registered in PROSPERO, and the registration number was CRD42020159865. Randomized controlled trials (RCTs) of online databases included PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase which evaluated effects of yoga for patients with chronic low back pain on pain, disability, and quality of life were searched from inception time to November 1, 2019. Studies were eligible if they assessed at least one important outcome, namely pain, back-specific disability, quality of life. The Cochrane risk of bias tool was used to assess the methodological quality of included randomized controlled trials. The continuous outcomes were analyzed by calculating the mean difference (MD) or standardized mean difference (SMD) with 95% confidence intervals (CI) according to whether combining outcomes measured on different scales or not. A total of 18 randomized controlled trials were included in this meta-analysis. Yoga could significantly reduce pain at 4 to 8 weeks (MD = -0.83, 95% CI = -1.19 to -0.48, p<0.00001, I2 = 0%), 3 months (MD = -0.43, 95% CI = -0.64 to -0.23, p<0.0001, I2 = 0%), 6 to 7 months (MD = -0.56, 95% CI = -1.02 to -0.11, p = 0.02, I2 = 50%), and was not significant in 12 months (MD = -0.52, 95% CI = -1.64 to 0.59, p = 0.36, I2 = 87%) compared with non-exercise. Yoga was better than non-exercise on disability at 4 to 8 weeks (SMD = -0.30, 95% CI = -0.51 to -0.10, p = 0.003, I2 = 0%), 3 months (SMD = -0.31, 95% CI = -0.45 to -0.18, p<0.00001, I2 = 30%), 6 months (SMD = -0.38, 95% CI = -0.53 to -0.23, p<0.00001, I2 = 0%), 12 months (SMD = -0.33, 95% CI = -0.54 to -0.12, p = 0.002, I2 = 9%). There was no significant difference on pain, disability compared with physical therapy exercise group. Furthermore, it suggested that there was a non-significant difference on physical and mental quality of life between yoga and any other interventions. This meta-analysis provided evidence from very low to moderate investigating the effectiveness of yoga for chronic low back pain patients at different time points. Yoga might decrease pain from short term to intermediate term and improve functional disability status from short term to long term compared with non-exercise (e.g. usual care, education). Yoga had the same effect on pain and disability as any other exercise or physical therapy. Yoga might not improve the physical and mental quality of life based on the result of a merging.


Sasquatch: predicting the impact of regulatory SNPs on transcription factor binding from cell- and tissue-specific DNase footprints.
In the era of genome-wide association studies (GWAS) and personalized medicine, predicting the impact of single nucleotide polymorphisms (SNPs) in regulatory elements is an important goal. Current approaches to determine the potential of regulatory SNPs depend on inadequate knowledge of cell-specific DNA binding motifs. Here, we present Sasquatch, a new computational approach that uses DNase footprint data to estimate and visualize the effects of noncoding variants on transcription factor binding. Sasquatch performs a comprehensive k-mer-based analysis of DNase footprints to determine any k-mer's potential for protein binding in a specific cell type and how this may be changed by sequence variants. Therefore, Sasquatch uses an unbiased approach, independent of known transcription factor binding sites and motifs. Sasquatch only requires a single DNase-seq data set per cell type, from any genotype, and produces consistent predictions from data generated by different experimental procedures and at different sequence depths. Here we demonstrate the effectiveness of Sasquatch using previously validated functional SNPs and benchmark its performance against existing approaches. Sasquatch is available as a versatile webtool incorporating publicly available data, including the human ENCODE collection. Thus, Sasquatch provides a powerful tool and repository for prioritizing likely regulatory SNPs in the noncoding genome.