Cardiac abnormalities in children with malignancies at Kenyatta National Hospital.
This was a cross-sectional survey in which 80 children with malignancies were studied at the Kenyatta National Hospital to determine cardiac status before and during cancer therapy. An equal number of age and sex matched subjects admitted to the surgical wards for minor procedures was recruited as a comparison group. All the subjects underwent clinical cardiac assessment. Chest radiographs, electrocardiograms (ECG), echocardiograms, haemograms and renal function tests were also performed. Overall, 13 cases (16.3%) had abnormal cardiac findings compared to 7 (8%) in the comparison group (p = 0.429). Sixteen, two and five subjects had abnormal velocity of circumferential fibre shortening, ejection fraction and pericardial effusion respectively. Three out of the five subjects with pericardial effusion were cancer patients who had not undergone treatment. Mitral valve prolapse with regurgitation was diagnosed in one cancer patient. Though not statistically significant, children with malignancies appear to have a higher frequency of acquired cardiac abnormalities than those without cancers. Since a larger proportion of the abnormalities occurred in cancer children before commencement of treatment, the pathology is more likely to have resulted from the malignancies than therapy. There was no evidence to suggest that cancer treatment contributed to cardiac morbidity. We recommend that all oncology patients undergo cardiac evaluation on admission.


Semienclosed Tube Cultures of Bean Plants (Phaseolus vulgaris L.) for Enumeration of Rhizobium phaseoli by the Most-Probable-Number Technique.
The semienclosed tube culture technique of Gibson was modified to permit growth of common bean (Phaseolus vulgaris L.) roots in humid air, enabling enumeration of the homologous (nodule forming) symbiont, Rhizobium phaseoli, by the most-probable-number plant infection method. A bean genotype with improved nodulation characteristics was used as the plant host. This method of enumeration was accurate when tubes were scored 3 weeks after inoculation with several R. phaseoli strains diluted from aqueous suspensions, peat-based inoculants, or soil. A comparison of population sizes obtained by most-probable-number tube cultures and plate counts indicated that 1 to 3 viable cells of R. phaseoli were a sufficient inoculant to induce nodule formation.


Direct determination of native proteins in miniaturized capillary electrophoresis system.
Lysozyme (14.4 kDa), BSA (66.4 kDa) and beta-galactosidase (116 kDa) were successfully separated and determined directly within 80 seconds using a laboratory-made miniaturized capillary electrophoresis apparatus provided with a confocal fluorescence spectrometry. Several parameters controlling on the detection limits, including focusing effect, laser power and buffer composition were tested and optimized. Separation buffer was 10 mM phosphate containing 4 mM CTAB at pH 2.5. The LOD values for lysozyme, beta-galactosidase and BSA were found as 9.0, 13.0 and 55 fg/microl, respectively. This miniaturized CE system offers a lot of advantages for protein analysis. First; it provides reproducible separation reducing wall-adsorption effects at low pH. Second, the analysis time observed from our system is in the range of chip electrophoresis applications. And finally, LOD values for standard proteins are much more lower than that of obtained from traditional gel electrophoresis method.


X-ray absorption spectroscopy with time-tagged photon counting: application to study the structure of a Co(i) intermediate of H2 evolving photo-catalyst.
In order to probe the structure of reaction intermediates of photochemical reactions a new setup for laser-initiated time-resolved X-ray absorption (XAS) measurements has been developed. With this approach the arrival time of each photon in respect to the laser pulse is measured and therefore full kinetic information is obtained. All X-rays that reach the detector are used to measure this kinetic information and therefore the detection efficiency of this method is high. The newly developed setup is optimized for time-resolved experiments in the microsecond range for samples with relatively low metal concentration (∼1mM). This setup has been applied to study a multicomponent photocatalytic system with a Co(dmgBF(2))(2) catalyst (dmg(2-) = dimethylglyoximato dianion), [Ru(bpy)(3)](2+) chromophore (bpy = 2,2'-bipyridine) and methyl viologen as the electron relay. On the basis of the analysis of hundreds of Co K-edge XAS spectra corresponding to different delay times after the laser excitation of the chromophore, the presence of a Co(i) intermediate is confirmed. The calculated X-ray transient signal for a model of Co(i) state with a 0.14 Å displacement of Co out of the dmg ligand plane and with the closest solvent molecule at a distance of 2.06 Å gives reasonable agreement with the experimental data.


Posterior reversible encephalopathy syndrome: associated clinical and radiologic findings.
To identify and define clinical associations and radiologic findings of posterior reversible encephalopathy syndrome (PRES). Patients prospectively diagnosed as having PRES from October 1, 2005, through April 30, 2009, were pooled with retrospectively identified patients admitted from August 1, 1999, through September 30, 2005. We performed a detailed review of clinical information, including demographics, presenting symptoms, medical history, and risk factors. All patients underwent computed tomography of the brain or magnetic resonance imaging. Findings on magnetic resonance imaging were analyzed independently by 2 neuroradiologists. We identified 120 cases of PRES in 113 patients (mean age, 48 years). Mean peak systolic blood pressure was 199 mm Hg (minimum-maximum, 160-268 mm Hg), and mean peak diastolic blood pressure was 109 mm Hg (minimum-maximum, 60-144 mm Hg). Etiologies of PRES included hypertension (n=69 [61%]), cytotoxic medications (n=21 [19%]), sepsis (n=8 [7%]), preeclampsia or eclampsia (n=7 [6%]), and multiple organ dysfunction (n=1 [1%]). Autoimmune disease was present in 51 patients (45%). Clinical presentations included seizures (n=84 [74%]), encephalopathy (n=32 [28%]), headache (n=29 [26%]), and visual disturbances (n=23 [20%]). In the 115 cases (109 patients) for which magnetic resonance imaging findings were available, the parieto-occipital regions were the most commonly involved (n=108 [94%]), followed by the frontal lobe (n=88 [77%]), temporal lobe (n=74 [64%]), and cerebellum (n=61 [53%]). Cerebellar involvement was significantly more frequent in patients with a history of autoimmunity (P=.008), and patients with sepsis were more likely to have cortical involvement (P<.001). A substantial proportion of patients with PRES have underlying autoimmune conditions that may support endothelial dysfunction as a pathophysiologic mechanism. On brain imaging, the location and severity of vasogenic edema were mostly similar for the different clinical subgroups.


Dendrites of rod bipolar cells sprout in normal aging retina.
The aging nervous system is known to manifest a variety of degenerative and regressive events. Here we report the unexpected growth of dendrites in the retinas of normal old mice. The dendrites of many rod bipolar cells in aging mice were observed to extend well beyond their normal strata within the outer plexiform layer to innervate the outer nuclear layer where they appeared to form contacts with the spherules of rod photoreceptors. Such dendritic sprouting increased with age and was evident at all retinal eccentricities. These results provide evidence of retinal plasticity associated with normal aging.


Adoptive T cell transfer of autoimmune nonobese diabetic mouse diabetes does not require recruitment of host B lymphocytes.
The autoimmune nonobese diabetic mouse, a model of human juvenile type I diabetes mellitus, exhibits features of both B and T cell autoreactivity against insulin-producing cells. Using the neonatal cell transfer model of the disease, which we have described previously, we have shown that B cell suppression of newborn recipients by anti-mu treatment did not affect the transfer of diabetes by means of T cells. B cell-depleted, purified T cells from diabetic adults were injected into newborns treated with either IR-52, a control rat myeloma protein, or LOMM.9, a rat anti-mouse mu-chain mAb. Both groups developed diabetes over a similar time scale. Although the pancreases in both groups showed massive infiltration by T lymphocytes, B lymphocytes, presumably recruited in the host, were present in the IR-52-treated group, whereas they were absent in the LOMM.9-treated group. Anti-mu-treated diabetic animals showed substantial B cell suppression in vivo and in vitro when compared with IR-52-treated controls. These results suggest that B cell autoreactivity is a secondary phenomenon that is unimportant during the effector phase of diabetes in nonobese diabetic mice.


ReaLigands: A Ligand Library Cultivated from Experiment and Intended for Molecular Computational Catalyst Design.
Computational catalyst design requires identification of a metal and ligand that together result in the desired reaction reactivity and/or selectivity. A major impediment to translating computational designs to experiments is evaluating ligands that are likely to be synthesized. Here, we provide a solution to this impediment with our ReaLigands library that contains >30,000 monodentate, bidentate (didentate), tridentate, and larger ligands cultivated by dismantling experimentally reported crystal structures. Individual ligands from mononuclear crystal structures were identified using a modified depth-first search algorithm and charge was assigned using a machine learning model based on quantum-chemical calculated features. In the library, ligands are sorted based on direct ligand-to-metal atomic connections and on denticity. Representative principal component analysis (PCA) and uniform manifold approximation and projection (UMAP) analyses were used to analyze several tridentate ligand categories, which revealed both the diversity of ligands and connections between ligand categories. We also demonstrated the utility of this library by implementing it with our building and optimization tools, which resulted in the very rapid generation of barriers for 750 bidentate ligands for Rh-hydride ethylene migratory insertion.


Zygomatic bone-to-implant contact in 77 patients with partially or completely edentulous maxillas.
Specifically with zygomatic implants, the bone-to-implant contact (BIC) at the zygomatic bone correlates with the survival of the implant because there is little anchorage at the alveolus. The purpose of this retrospective study was to view and measure the BIC of zygomatic implants in the zygomatic bone. The patients in this study received zygomatic implants at a single private dental implant center. All patients were treated with the same immediate-loading protocol followed by postoperative cone beam computed tomography. The scans were exported to a computer-aided design system, where the BICs could be measured digitally. The BIC was analyzed by gender, and any statistical difference was determined by analysis of variance. The study sample was composed of 77 patients (62.3% women) receiving 173 zygomatic implants. The mean age of the sample was 59 ± 8.7 years. The mean BIC was 15.3 ± 5.6 mm (range, 4.9 to 32.9 mm) in the zygomatic bone. On average, 35.9% ± 11.7% (range, 12.2% to 67.3%) of the implant came into contact with the zygomatic bone. The average BIC in men was 16.5 ± 6.0 mm, and the average BIC in women was 14.7 ± 5.4 mm, a statistically significant difference by analysis of variance (P < .05). Evidence from this report indicates the zygomatic BIC varies greatly from patient to patient. These data show that the typical male patient has a greater zygomatic BIC than the typical female patient; however, these data do not support the hypothesis that the zygomatic BIC influences the zygomatic implant survival rate.


Addressing modifiable risk factors for coronary heart disease in primary care: an evidence-base lost in translation.
Risk factors for cardiovascular disease can be modified in primary care. Electronic patient record (EPR) systems include embedded cardiovascular risk factor calculators and should facilitate this process. To observe how the evidence base for assessing and managing cardiovascular risk is implemented in practice. We compared the different risk calculators promoted for calculating cardiovascular risk in primary care using four test cases. We looked to see how these calculators were implemented in primary care EPR systems. We explored through a workshop which risk factors GPs thought were important and felt motivated to address as part of clinical care. The risk calculators reviewed use different sets of risk factors and the levels of risk calculated for the same test patient profiles vary by up to 100%. The risk factor calculators embedded within UK computer systems all include the Framingham equation though there is variation in interface, default values and patient groups included. GPs showed consensus around the importance of managing smoking, blood pressure, obesity (body mass index), diabetes and cholesterol but also stressed the importance of providing personalized care and exercising professional judgement. There appears to be an evidence-base lost in translation. Different guidelines calculate risk differently, and even when the same guideline is used, variation in implementation leads to further variation. Education and development of improved risk calculators should enable the most appropriate calculator to be used for an individual patient; accreditation of implementation could be achieved through the use of a standard set of test cases.


Can empirical hypertonic saline or sodium bicarbonate treatment prevent the development of cardiotoxicity during serious amitriptyline poisoning? Experimental research.
The aim of this experimental study was to investigate whether hypertonic saline or sodium bicarbonate administration prevented the development of cardiotoxicity in rats that received toxic doses of amitriptyline. Thirty-six Sprague Dawley rats were used in the study. The animals were divided into six groups. Group 1 received toxic doses of i.p. amitriptyline. Groups 2 and 3 toxic doses of i.p. amitriptyline, plus i.v. sodium bicarbonate and i.v. hypertonic saline, respectively. Group 4 received only i.v. sodium bicarbonate, group 5 received only i.v. hypertonic saline, and group 6 was the control. Electrocardiography was recorded in all rats for a maximum of 60 minutes. Blood samples were obtained to measure the serum levels of sodium and ionised calcium. The survival time was shorter in group 1. In this group, the animals' heart rates also decreased over time, and their QRS and QTc intervals were significantly prolonged. Groups 2 and 3 showed less severe changes in their ECGs and the rats survived for a longer period. The effects of sodium bicarbonate or hypertonic saline treatments on reducing the development of cardiotoxicity were similar. The serum sodium levels decreased in all the amitriptyline-applied groups. Reduction of serum sodium level was most pronounced in group 1. Empirical treatment with sodium bicarbonate or hypertonic saline can reduce the development of cardiotoxicity during amitriptyline intoxication. As hypertonic saline has no adverse effects on drug elimination, it should be considered as an alternative to sodium bicarbonate therapy.


Set size effects in the macaque striate cortex.
Attentive processing is often described as a competition for resources among stimuli by mutual suppression. This is supported by findings that activity in extrastriate cortex is suppressed when several stimuli are presented simultaneously, compared to a single stimulus. In this study, we randomly varied the number of simultaneously presented figures (set size) in an attention-demanding change detection task, while we recorded multiunit activity in striate cortex (V1) in monkeys. After figure-background segregation, activity was suppressed as set size increased. This effect was stronger and started earlier among cells stimulated by the background than those stimulated by the figures themselves. As a consequence, contextual modulation, a correlate of figure-background segregation, increased with set size, approximately 100 msec after its initial generation. The results indicate that suppression of responses under increasing attentional demands differentially affects figure and background responses in area V1.


Feasibility of using microencapsulated phase change materials as filler for improving low temperature performance of rubber sealing materials.
The feasibility of a novel composite rubber sealing material to improve sealing under transient cooling (in a so-called blowdown scenario) is investigated here. A composite of hydrogenated nitrile butadiene rubber (HNBR) filled with Micro Encapsulated Phase Change Materials (MEPCM) is described. The fillers contain phase change materials that release heat during the phase transformation from liquid to solid while cooling. This exotherm locally heats the rubber and may improve the function of the seal during a blowdown event. A representative HNBR-MEPCM composite was made and the critical thermal and mechanical properties were obtained by simulating the temperature distribution during a blowdown event. Simulations predict that the MEPCM composites can delay the temperature decrease in a region of the seal during the transient blowdown. A sensitivity analysis of material properties is also presented which highlights possible avenues of improvement of the MEPCMs for sealing applications.


Left auditory cortex gamma synchronization and auditory hallucination symptoms in schizophrenia.
Oscillatory electroencephalogram (EEG) abnormalities may reflect neural circuit dysfunction in neuropsychiatric disorders. Previously we have found positive correlations between the phase synchronization of beta and gamma oscillations and hallucination symptoms in schizophrenia patients. These findings suggest that the propensity for hallucinations is associated with an increased tendency for neural circuits in sensory cortex to enter states of oscillatory synchrony. Here we tested this hypothesis by examining whether the 40 Hz auditory steady-state response (ASSR) generated in the left primary auditory cortex is positively correlated with auditory hallucination symptoms in schizophrenia. We also examined whether the 40 Hz ASSR deficit in schizophrenia was associated with cross-frequency interactions. Sixteen healthy control subjects (HC) and 18 chronic schizophrenia patients (SZ) listened to 40 Hz binaural click trains. The EEG was recorded from 60 electrodes and average-referenced offline. A 5-dipole model was fit from the HC grand average ASSR, with 2 pairs of superior temporal dipoles and a deep midline dipole. Time-frequency decomposition was performed on the scalp EEG and source data. Phase locking factor (PLF) and evoked power were reduced in SZ at fronto-central electrodes, replicating prior findings. PLF was reduced in SZ for non-homologous right and left hemisphere sources. Left hemisphere source PLF in SZ was positively correlated with auditory hallucination symptoms, and was modulated by delta phase. Furthermore, the correlations between source evoked power and PLF found in HC was reduced in SZ for the LH sources. These findings suggest that differential neural circuit abnormalities may be present in the left and right auditory cortices in schizophrenia. In addition, they provide further support for the hypothesis that hallucinations are related to cortical hyperexcitability, which is manifested by an increased propensity for high-frequency synchronization in modality-specific cortical areas.


A Systematic Review of the Physiological Effects of the Effortful Swallow Maneuver in Adults With Normal and Disordered Swallowing.
Purpose This systematic review summarizes the biomechanical and functional effects of the effortful swallow in adults with and without dysphagia, highlighting clinical implications and future research needs. Specifically, the effects of the effortful swallow on swallowing physiology, safety, and efficiency were identified, as well as the strengths and limitations of current research. Method Recommendations specified by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses were followed. A literature search of three databases and relevant articles cited in the searched studies was performed. Two evaluators independently analyzed the studies for eligibility criteria, and final inclusion of studies was decided by consensus. Evaluators also assessed each study for quality of evidence. Results Twenty-three studies were included in this systematic review. Main findings indicated that the effortful swallow generated greater pressures in the tongue-to-palate, pharynx, upper esophageal sphincter, and esophageal regions. Inconsistent results for hyolaryngeal excursion were reported, as well as for swallowing function. Instructions of the effortful swallow varied greatly across studies. Two of the 23 studies were judged to be of high quality, and the remaining studies were of medium quality based on the quality indicators of this review. Conclusions Biomechanical effects of the effortful swallow included increased pressures in the oral, pharyngeal, and esophageal regions. Future investigations should address the effects of the effortful swallow in individuals with dysphagia and its potential role as a rehabilitative maneuver. Moreover, standardization of the effortful swallow instructions based on its physiological and functional effects is essential.


Comprehension of climate change and environmental attitudes across the lifespan.
Given the coincidence of the demographic change and climate change in the upcoming decades the aging voter gains increasing importance in climate change mitigation and adaptation processes. It is generally assumed that information status and comprehension of complex processes underlying climate change are prerequisites for adopting pro-environmental attitudes and taking pro-environmental actions. In a cross-sectional study, we investigated in how far (1) environmental knowledge and comprehension of feedback processes underlying climate change and (2) pro-environmental attitudes change as a function of age. Our sample consisted of 92 participants aged 25-75 years (mean age 49.4 years, SD 17.0). Age was negatively related to comprehension of system structures inherent to climate change, but positively associated with level of fear of consequences and anxiousness towards climate change. No significant relations were found between environmental knowledge and pro-environmental attitude. These results indicate that, albeit understanding of relevant structures of the climate system is less present in older age, age is not a limiting factor for being engaged in the complex dilemma of climate change. Results bear implications for the communication of climate change and pro-environmental actions in aging societies.


Chondroitin proteoglycans are involved in cell division of Caenorhabditis elegans.
Glycosaminoglycans such as heparan sulphate and chondroitin sulphate are extracellular sugar chains involved in intercellular signalling. Disruptions of genes encoding enzymes that mediate glycosaminoglycan biosynthesis have severe consequences in Drosophila and mice. Mutations in the Drosophila gene sugarless, which encodes a UDP-glucose dehydrogenase, impairs developmental signalling through the Wnt family member Wingless, and signalling by the fibroblast growth factor and Hedgehog pathways. Heparan sulphate is involved in these pathways, but little is known about the involvement of chondroitin. Undersulphated and oversulphated chondroitin sulphate chains have been implicated in other biological processes, however, including adhesion of erythrocytes infected with malaria parasite to human placenta and regulation of neural development. To investigate chondroitin functions, we cloned a chondroitin synthase homologue of Caenorhabditis elegans and depleted expression of its product by RNA-mediated interference and deletion mutagenesis. Here we report that blocking chondroitin synthesis results in cytokinesis defects in early embryogenesis. Reversion of cytokinesis is often observed in chondroitin-depleted embryos, and cell division eventually stops, resulting in early embryonic death. Our findings show that chondroitin is required for embryonic cytokinesis and cell division.


Paeoniflorin, a Natural Product With Multiple Targets in Liver Diseases-A Mini Review.
Paeoniflorin is derived from Paeonia suffruticosa Andr., Paeonia lactiflora Pall., or Paeonia veitchii Lynch and has been used in traditional medical applications for more than 2,000 years. Paeoniflorin is a monoterpenoid glycoside with various effects on liver diseases. Recent studies have revealed that paeoniflorin demonstrates a wide range of activities, including hepatic protection, cholestasis alleviation, liver fibrosis attenuation, nonalcoholic fatty liver disease prevention, and hepatocellular carcinoma inhibition involved in multiple pathways. Moreover, anti-inflammation, antioxidation, and immune regulation with the regulation of TLR4-NF-κB, ROCK/NF-κB, HO-1, mitochondria-dependent as well as HMGB1-TLR4 signaling pathways are correlated with hepatic protection in liver injury and nonalcoholic fatty liver disease. Antioxidative mechanisms, anti-inflammation, and hepatic transporter regulation involved in NOX4, PI3K/Akt/Nrf2, NF-κB, NTCP, BSEP, as well as MRP2 signals are mainly relevant to the anticholestatic effect of paeoniflorin. The inhibition of hepatic stellate cell activation and alleviation of extracellular matrix deposition via vast signals such as mTOR/HIF-1α, TGF-β1/Smads, and JAK2/STAT6 are primarily involved in the antifibrotic effect of paeoniflorin. The regulation of macrophages also contributes to the alleviation effect on liver fibrosis. In addition, the reduction of invasion, metastasis, and adhesion and the induction of apoptosis-related targets, including Bax, Bcl-2, and caspase-3, are related to its effect on hepatocellular carcinoma. The literature indicates that paeoniflorin might have potent efficacy in complex liver diseases and demonstrates the profound medicinal value of paeoniflorin.


A survey of vascular specialists' practice patterns of inferior vena cava filter placement and retrieval.
The placement of inferior vena cava filters (IVCF) continues to rise. Vascular specialists adopt different practices based on local expertise. This study was performed to assess the attitudes of vascular specialists towards the placement and retrieval of IVCF. An online survey of 28 questions related to practice patterns regarding IVCF was administered to 1429 vascular specialists. Vascular specialists were categorized as low volume if they place less than three IVCF per month and high volume if they place at least three IVCF per month. The responses of high volume and low volume were compared using two-sample t-tests and Chi-square tests. A total of 259 vascular specialists completed the survey (18% response rate). There were 191 vascular surgeons (74%) and 68 interventional radiologists (26%). The majority of responders were in academic practice (67%) and worked in tertiary care centers (73%). The retrievable IVCF of choice was Celect (27%) followed by Denali (20%). Forty-two percent used a temporary IVCF and left it in situ instead of using a permanent IVCF. Eighty-two percent preferred placing the tip of the IVCF at or just below the lowest renal vein. Thirty-one percent obtained a venous duplex of the lower extremities prior to retrieval while 24% did not do any imaging. There were 132 (51%) low volume vascular specialists and 127 (49%) high volume vascular specialists. Compared to low volume vascular specialists, significantly more high volume vascular specialists reported procedural times of less than 30 min for IVCF retrieval (57% vs. 42%, P = 0.026). There was a trend for high volume to have fewer unsuccessful attempts at IVCF retrieval but that did not reach statistical significance ( P = .061). High volume were more likely to have attempted multiple times to retrieve an IVCF (66% vs. 33%, P < .001), and to have used bronchoscopy forceps (32% vs. 14%, P = .001) or a laser sheath (14% vs. 2%, P < .001) for IVCF retrieval. In general, vascular specialists were not comfortable using bronchoscopy forceps (65%) or a laser sheath (82%) for IVCF retrieval. This study underscores significant variability in vascular specialists practice patterns regarding IVCF. More studies and societal guidelines are needed to define best practices.


Implant Complications After Magnetically Controlled Growing Rods for Early Onset Scoliosis: A Multicenter Retrospective Review.
Traditional growing rods have a reported wound and implant complication rate as high as 58%. It is unclear whether the use of magnetically controlled growing rods (MCGR) will affect this rate. This study was performed to characterize surgical complications following MCGR in early onset scoliosis. A multicenter retrospective review of MCGR cases was performed. Inclusion criteria were: (1) diagnosis of early onset scoliosis of any etiology; (2) 10 years and younger at time of index surgery; (3) preoperative major curve size >30 degrees; (4) preoperative thoracic spine height <22 cm. Complications were categorized as wound related and instrumentation related. Complications were also classified as early (<6 mo from index surgery) versus late (>6 mo). Distraction technique and interval of distraction was surgeon preference without standardization across sites. Fifty-four MCGR patients met inclusion criteria. There were 30 primary and 24 conversion procedures. Mean age at initial surgery was 7.3 years (range, 2.4 to 11 y), and mean duration of follow-up 19.4 months. Twenty-one (38.8%) of 54 patients had at least 1 complication. Fifteen (27.8%) had at least 1 revision surgery. Six (11.1%) had broken rods (2 to 4.5 and 4 to 5.5 mm rods); two 5.5 mm rods failed early (4 mo) and 4 late (mean=14.5 mo). Six (11.1%) patients experienced 1 episode of lack or loss of lengthening, of which 4 patients subsequently lengthened. Seven patients (13.0%) had either proximal or distal fixation-related complication at average of 8.4 months. Two patients (3.7%) had infections requiring incision and drainage; 1 early (2 wk) with wound drainage and 1 late (8 mo). The late case required removal of one of the dual rods. This study shows that compared with traditional growing rods, MCGR has a lower infection rate (3.7% vs. 11.1%). MCGR does not appear to prevent common implant-related complications such as rod or foundation failure. The long-term implication remains to be determined. Level IV.


Antimicrobial-resistant bacterial infections from foods of animal origin: understanding and effectively communicating to consumers.
Consumers are increasingly interested in the attributes of the food they consume. This includes what is in the food and how it was raised; and at least some consumers are willing to pay a premium for products with specific attributes. However, the current plethora of labels on the market does not adequately address this issue; rather than providing actionable information, most labels add to the consumer confusion. In addition, there is a tendency toward "absence labels" that can contribute to a negative consumer perception of conventional products that may or may not include the attribute in question. Communication with consumers about the complex and highly technical issue of antimicrobial resistance (AMR) is challenging, and experiences from communication efforts about food safety-related issues demonstrate exactly how challenging this is to communicate clearly. General lessons learned from the science of risk communication can help guide efforts to communicate about the challenging issue of AMR. There are efforts underway to chart out a new approach. A new labeled animal production certification program is under development to provide choice for consumers, while reducing consumer confusion, which mandates antibiotic stewardship practices.


Development of a novel, high-affinity ssDNA trypsin inhibitor.
Inhibitors of serine proteases are not only extremely useful in the basic research but are also applied extensively in clinical settings. Using Systematic Evolution of Ligands by Exponential Enrichment (SELEX) approach we developed a family of novel, single-stranded DNA aptamers capable of specific trypsin inhibition. Our most potent candidate (T24) and its short version (T59) were thoroughly characterised in terms of efficacy. T24 and T59 efficiently inhibited bovine trypsin with Ki of 176 nM and 475 nM, respectively. Interestingly, in contrast to the majority of known trypsin inhibitors, the selected aptamers have superior specificity and did not interact with porcine trypsin or any human proteases tested. These included plasmin and thrombin characterised by trypsin-like substrate specificity. Our results demonstrate that SELEX may be successfully employed in the development of potent and specific DNA based protease inhibitors.


A comparison of multifactor dimensionality reduction and L1-penalized regression to identify gene-gene interactions in genetic association studies.
Recently, the amount of high-dimensional data has exploded, creating new analytical challenges for human genetics. Furthermore, much evidence suggests that common complex diseases may be due to complex etiologies such as gene-gene interactions, which are difficult to identify in high-dimensional data using traditional statistical approaches. Data-mining approaches are gaining popularity for variable selection in association studies, and one of the most commonly used methods to evaluate potential gene-gene interactions is Multifactor Dimensionality Reduction (MDR). Additionally, a number of penalized regression techniques, such as Lasso, are gaining popularity within the statistical community and are now being applied to association studies, including extensions for interactions. In this study, we compare the performance of MDR, the traditional lasso with L1 penalty (TL1), and the group lasso for categorical data with group-wise L1 penalty (GL1) to detect gene-gene interactions through a broad range of simulations. We find that each method has both advantages and disadvantages, and relative performance is context dependent. TL1 frequently over-fits, identifying false positive as well as true positive loci. MDR has higher power for epistatic models that exhibit independent main effects; for both Lasso methods, main effects tend to dominate. For purely epistatic models, GL1 has the best performance for lower minor allele frequencies, but MDR performs best for higher frequencies. These results provide guidance of when each approach might be best suited for detecting and characterizing interactions with different mechanisms.


Endocytosis, intracellular traffic and fate of cell penetrating peptide based conjugates and nanoparticles.
The insides of cells can be viewed as a treasure trove of targets for therapeutic intervention of diseases or as deposits for contrasting agents. Increasingly the molecules that need to be delivered to the inside of cells for these purposes are macromolecular and membrane impermeable. Cell penetrating peptides (CPPs) have proven abilities to deliver a range of macromolecular cargo into cells thus raising their profile as potential delivery vectors for wide-ranging applications. There is evidence to suggest that CPPs first enter cells through endocytosis and that cytosolic delivery is mediated across endolysosomal membranes. Their capacity to do this, over direct plasma membrane translocation, is likely to depend on the nature and size of the cargo. Cells use a range of endocytic routes to facilitate entry from well characterised pathways regulated by clathrin to more recently discovered and less characterised pathways regulated by clathrin independent mechanisms. These are likely to determine the intracellular fate of cell delivery vectors including those based on cell penetrating peptides. Thus gaining accurate knowledge of their endocytic uptake and traffic is an important characterisation criteria for progress in this field. This review describes the different endocytic pathways that have been identified in mammalian cells and specific reports that have studied the uptake mechanisms and endocytic traffic of cell penetrating peptides and their associated cargo. These cargoes range from short peptides to an increasing library of nanoparticles such as quantum dots, liposomes and polymeric dendrimers. The studies highlight the effectiveness of cell penetrating peptides for delivering these entities into a diverse array of cell types using different endocytic pathways. This is shown using microscopy based colocalisation analysis with the few specific endocytic probes available, and chemical inhibitors of endocytosis that suffer from lack of specificity. Overall, more specific probes, inhibitors and novel technologies are required for accurate characterisation of cellular dynamics of cell penetrating peptide conjugates thus allowing them to reach their full potential as vectors for therapeutics and other payloads.


Thymomas: a cytological and immunohistochemical study, with emphasis on lymphoid and neuroendocrine markers.
The current study correlates cytologic morphology with histologic type and describes immunophenotypes with a focus on epithelial, neuroendocrine, and lymphoid characteristics in an institutional series of surgically excised thymomas. Fine needle aspirates (FNAs) and surgical specimens were retrospectively analyzed, and immunohistochemical stains were performed for EMA, cytokeratin 7, cytokeratin 20, CD57 CD5, bcl-2, calretinin, vimentin, CD3, CD20, CD1a, CD99 and Ki67. Tumors were classified by WHO criteria. There were eleven male and six female patients with an age range of 41 to 84 years (mean, 61 years) and a male to female ratio of 1.8:1. Four thymomas (4/17, 23.5%) were associated with neuromuscular disease: myasthenia gravis (n = 3) and limbic encephalitis (n = 1). FNA, under CT guidance, was performed in 7 cases. The positive predictive value for thymoma by FNA cytology was 100% and the sensitivity was 71%. Thymomas associated with neuromuscular disorders were WHO types B2 (n = 1) and B3 (n = 3), and showed a strong expression of CD57 in the majority of neoplastic epithelial cells accompanied by large numbers of CD20+ intratumoral B lymphocytes. Two of seventeen (11.7%) thymomas (all sporadic B3 type) contained numerous neoplastic epithelial cells positive for CD5 and bcl-2. Our results suggest that thymomas associated with autoimmune disorders contain a significant population of CD20+ intratumoral B lymphocytes. Strong CD57 positivity in thymomas may suggest a concomitant neuromuscular disorder, notably myasthenia gravis. CD5 expression is of limited value in the differential diagnosis of primary thymic epithelial neoplasms since both thymic carcinomas and thymomas may express CD5.


High-throughput sheathless and three-dimensional microparticle focusing using a microchannel with arc-shaped groove arrays.
Sheathless particle focusing which utilises the secondary flow with a high throughput has great potential for use in microfluidic applications. In this work, an innovative particle focusing method was proposed. This method makes use of a mechanism that takes advantage of secondary flow and inertial migration. The device was a straight channel with arrays of arc-shaped grooves on the top surface. First, the mechanism and expected focusing phenomenon are explained using numerical simulation of the flow field and force balance. A simulation of particle trajectories was conducted as a reference, and then a series of experiments was designed and the effects of changes in particle size, flow rate and quantity of the groove structure were discussed. The microscopic images show that this particle focusing method performed well for different size particles, and the results agreed well with the theory and simulated results. Finally, the channel successfully concentrated Jurkat cells, which showed a good compatibility in the biological assay field. In this work, the arc-shaped groove channel was demonstrated to have the ability to achieve high-throughput, sheathless and three-dimensional particle focusing with simple operations.


Paintball ocular injuries.
Six cases of ocular injury following paintball injuries sustained during war games are described. A CO2-powered rifle shoots a 14 mm plastic-coated paintball at participants. The muzzle velocity of the gun is 250 ft/sec (76 m/sec). Locally manufactured paintballs are harder than the more expensive imported varieties and may account for the severity of our reported injuries. Six patients presented to a retinal specialist with various ocular injuries, predominantly of the posterior pole. All patients were young males. There were no cases of ocular penetration. A variety of retinal pathologies was noted, with three cases requiring surgery; however this did not significantly improve the visual outcome. These cases highlight the severe ocular injuries that may occur from paintball injuries. Recommendations to avoid ocular injury are made.


Effects of changes in membrane sodium flux on virulence gene expression in Vibrio cholerae.
The expression of several virulence factors of Vibrio cholerae is coordinately regulated by the ToxT molecule and the membrane proteins TcpP/H and ToxR/S, which are required for toxT transcription. To identify proteins that negatively affect toxT transcription, we screened transposon mutants of V. cholerae carrying a chromosomally integrated toxT::lacZ reporter construct for darker blue colonies on media containing 5-bromo-4-chlor-3-indolyl beta-D galactoside (X-gal). Two mutants had transposon insertions in a region homologous to the nqr gene cluster of Vibrio alginolyticus, encoding a sodium-translocating NADH-ubiquinone oxidoreductase (NQR). In V. alginolyticus, NQR is a respiration-linked Na+ extrusion pump generating a sodium motive force that can be used for solute import, ATP synthesis, and flagella rotation. Inhibition of NQR enzyme function in V. cholerae by the specific inhibitor 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO) resulted in elevated toxT::lacZ activity. Increased toxT::lacZ expression in an nqr mutant strain compared with the parental strain was observed when the TcpP/H molecules alone were strongly expressed, suggesting that the negative effect of the NQR complex on toxT transcription is mediated through TcpP/H. However, the ability of the TcpP/H proteins to activate the toxT::lacZ reporter construct was greatly diminished in the presence of high NaCl concentrations in the growth medium. The flagellar motor of V. cholerae appears to be driven by a sodium motive force, and modulation of flagella rotation by inhibitory drugs, high media viscosity, or specific mutations resulted in increases of toxT::lacZ expression. Thus, the regulation of the main virulence factors of V. cholerae appears to be modulated by endogenous and exogenous sodium levels in a complex way.


Classification and assessment of retrieved electron density maps in coherent X-ray diffraction imaging using multivariate analysis.
Coherent X-ray diffraction imaging (CXDI) is one of the techniques used to visualize structures of non-crystalline particles of micrometer to submicrometer size from materials and biological science. In the structural analysis of CXDI, the electron density map of a sample particle can theoretically be reconstructed from a diffraction pattern by using phase-retrieval (PR) algorithms. However, in practice, the reconstruction is difficult because diffraction patterns are affected by Poisson noise and miss data in small-angle regions due to the beam stop and the saturation of detector pixels. In contrast to X-ray protein crystallography, in which the phases of diffracted waves are experimentally estimated, phase retrieval in CXDI relies entirely on the computational procedure driven by the PR algorithms. Thus, objective criteria and methods to assess the accuracy of retrieved electron density maps are necessary in addition to conventional parameters monitoring the convergence of PR calculations. Here, a data analysis scheme, named ASURA, is proposed which selects the most probable electron density maps from a set of maps retrieved from 1000 different random seeds for a diffraction pattern. Each electron density map composed of J pixels is expressed as a point in a J-dimensional space. Principal component analysis is applied to describe characteristics in the distribution of the maps in the J-dimensional space. When the distribution is characterized by a small number of principal components, the distribution is classified using the k-means clustering method. The classified maps are evaluated by several parameters to assess the quality of the maps. Using the proposed scheme, structure analysis of a diffraction pattern from a non-crystalline particle is conducted in two stages: estimation of the overall shape and determination of the fine structure inside the support shape. In each stage, the most accurate and probable density maps are objectively selected. The validity of the proposed scheme is examined by application to diffraction data that were obtained from an aggregate of metal particles and a biological specimen at the XFEL facility SACLA using custom-made diffraction apparatus.


Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.
Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.


Orienting attention in audition and between audition and vision: young and elderly subjects.
This study examined 30 young and 10 elderly subjects to test whether orienting of attention could be measured in audition. Orienting in a mixed-modal condition in which stimuli were either auditory or visual was also tested. The dependent measure was the reaction time (RT) to lateralized targets when the locations were predicted by antecedent arrow cues that were correct (valid), were incorrect (invalid), or provided no lateralizing information (neutral). A comparison between the two groups among the different conditions showed that elderly subjects had longer RTs than the younger participants, but the pattern of results was similar in both groups. In addition, a similar RT pattern was found for each modal condition: Valid trials elicited the fastest responses and invalid trials the slowest. These findings suggest that the mechanisms involved in orienting attention operate in audition and that individuals may allocate their processing resources among multiple sensory pools. Moreover, effects seen in orienting attention in audition were similar to those found in vision and are interpretable with the same types of models. Orienting attention appears to be relatively resistant to the aging process in the sample of subjects tested in this study.


Effect size and power for clinical trials that measure years of healthy life.
Some clinical trials perform repeated measurements on patients over time, plot those measures against time, and summarize the results in terms of the area under the curve. If the measured variable is health status, the summary outcome is sometimes referred to as years of healthy life (YHL), or quality-adjusted life years (QALY). This paper investigates some theoretical and practical aspects of randomized trials designed to assess measures such as YHL. We first derived algebraic expressions for the effect size of YHL measures under several theoretical models of the treatment's effect on health. We used these expressions to examine how the length of the study, the number of measurements per person and the correlations among health measurements over time influence the effect size. We also explored the relative statistical power of analyses based on YHL versus analyses based on change-scores using the same data. We present an example. Findings suggest that: (i) the number of measurements per person need not be large; (ii) high correlation among measures over time tends to lower the power of a study using YHL; (iii) a longer study will not always provide more power than a shorter study, and (iv) analyses based on YHL may have less power than change-score analyses. Some of these findings depend on the model of change in health status caused by the treatment. Such models require further study.


On the origin of the solid-state thermochromism and thermal fatigue of polycyclic overcrowded enes.
Aimed at unraveling the relative contribution of the folding, twisting and bending in the mechanism of the solid-state thermochromism of overcrowded polycyclic aromatic enes (PAEs), the structures of two typical heteromeric and homomeric representatives, 2-(thioxanthen-9-ylidene)indane-1,3-dione (1) and 9,9'-bi-9(10H)-anthracenylidene-10,10'-dione (bianthrone, 2), were studied by temperature-resolved single crystal X-ray diffraction (120-530 K) and solid-state UV-visible spectroscopy. Aside from negligibly small unfolding of the tricyclic moiety of 1, this first direct diffraction study of the high-temperature structures of solid PAEs did not unravel any significant and detectable changes in the time- and space-averaged intramolecular structures, thus, showing that the PAE-type thermochromism is not due to phase transitions or to major and permanent molecular distortions of a large portion of the material that would be caused by folding, twisting and/or bending. Instead, the experimental observations and theoretical modeling indicated that the color change is probably due to a dynamic process, where the absorption spectrum changes as a result of enhanced thermal oscillations of the two halves of the molecules around the central bridge. In addition to the reversible coloration, we also observed irreversible processes of thermal fatigue that afford stable chemical products that absorb in the visible region. We showed that the stable products are conductive and they act electrocatalytically toward oxidation of several biomarkers.


Is there still a glass ceiling for women in academic surgery?
Despite the dramatically increased entry of women into general surgery and surgical subspecialties, traditionally male-dominated fields, there remains a gross under-representation of women in the leadership positions of these departments. Women begin their careers with fewer academic resources and tend to progress through the ranks slower than men. Female surgeons also receive significantly lower salaries than their male counterparts and are more vulnerable to discrimination, both obvious and covert. Although some argue that female surgeons tend to choose their families over careers, studies have actually shown that women are as eager as men to assume leadership positions, are equally qualified for these positions as men, and are as good as men at leadership tasks.Three major constraints contribute to the glass-ceiling phenomenon: traditional gender roles, manifestations of sexism in the medical environment, and lack of effective mentors. Gender roles contribute to unconscious assumptions that have little to do with actual knowledge and abilities of an individuals and they negatively influence decision-making when it comes to promotions. Sexism has many forms, from subtle to explicit forms, and some studies show that far more women report being discriminately against than do men. There is a lack of same-sex mentors and role models for women in academic surgery, thereby isolating female academicians further. This review summarizes the manifestation of the glass-ceiling phenomenon, identifies some causes of these inequalities, and proposes different strategies for continuing the advancement of women in academic surgery and to shatter the glass ceiling.


Orientation Control of Block Copolymers Using Surface Active, Phase-Preferential Additives.
Orientation control of thin film nanostructures derived from block copolymers (BCPs) are of great interest for various emerging technologies like separation membranes, nanopatterning, and energy storage. While many BCP compositions have been developed for these applications, perpendicular orientation of these BCP domains is still very challenging to achieve. Herein we report on a new, integration-friendly approach in which small amounts of a phase-preferential, surface active polymer (SAP) was used as an additive to a polycarbonate-containing BCP formulation to obtain perpendicularly oriented domains with 19 nm natural periodicity upon thermal annealing. In this work, the vertically oriented BCP domains were used to demonstrate next generation patterning applications for advanced semiconductor nodes. Furthermore, these domains were used to demonstrate pattern transfer into a hardmask layer via commonly used etch techniques and graphoepitaxy-based directed self-assembly using existing lithographic integration schemes. We believe that this novel formulation-based approach can easily be extended to other applications beyond nanopatterning.


Direct control of paralysed muscles by cortical neurons.
A potential treatment for paralysis resulting from spinal cord injury is to route control signals from the brain around the injury by artificial connections. Such signals could then control electrical stimulation of muscles, thereby restoring volitional movement to paralysed limbs. In previously separate experiments, activity of motor cortex neurons related to actual or imagined movements has been used to control computer cursors and robotic arms, and paralysed muscles have been activated by functional electrical stimulation. Here we show that Macaca nemestrina monkeys can directly control stimulation of muscles using the activity of neurons in the motor cortex, thereby restoring goal-directed movements to a transiently paralysed arm. Moreover, neurons could control functional stimulation equally well regardless of any previous association to movement, a finding that considerably expands the source of control signals for brain-machine interfaces. Monkeys learned to use these artificial connections from cortical cells to muscles to generate bidirectional wrist torques, and controlled multiple neuron-muscle pairs simultaneously. Such direct transforms from cortical activity to muscle stimulation could be implemented by autonomous electronic circuitry, creating a relatively natural neuroprosthesis. These results are the first demonstration that direct artificial connections between cortical cells and muscles can compensate for interrupted physiological pathways and restore volitional control of movement to paralysed limbs.


Versatile Reversible Cross-Linking Strategy to Stabilize CCMV Virus Like Particles for Efficient siRNA Delivery.
Virus like particles obtained from the Cowpea Chlorotic Mottle Virus (CCMV) represent an innovative platform for drug delivery applications. Their unique reversible self-assembly properties as well as their suitability for both cargo loading and functionalization make them a versatile scaffold for numerous purposes. One of the main drawbacks of this platform is however its limited stability at physiological conditions. Herein, we report the development of a general reversible cross-linking strategy involving the homobifunctional cross-linker DTSSP (3,3'-dithiobis (sulfosuccinimidylpropionate)) which is suitable for particle stabilization. This methodology is adaptable to different CCMV variants in the presence or absence of a stabilizing cargo without varying neither particle shape nor size thus extending the potential use of these protein cages in nanomedical applications. Cross-linked particles are stable at neutral pH and 37 °C and they are capable of protecting loaded cargo against enzymatic digestion. Furthermore, the reversible nature of the cross-linking ensures particle disassembly when they are taken up by cells. This was demonstrated via the highly effective delivery of active siRNA into cells.


Seasonality of retinal detachment incidence and its associations with climate: an 11-year nationwide population-based study.
This study aimed to examine the seasonal variability of retinal detachment (RD) in Taiwan by using an 11-yr nationwide population database. This study also investigated the association of weather conditions, i.e., ambient temperature, relative humidity, rainfall, monthly hours of sunshine, and atmospheric pressure, with RD. Data were retrospectively collected from the Taiwan National Health Insurance Research Database. The study sample included 23 718 RD hospitalizations between January 1999 and December 2009. The incidence rate of RD/100 000 people over the 132 months was computed according to sex and age groupings of <20, 20-39, 40-59, and ≥60 yrs. Then, the association between climatic factors and the monthly RD incidence rate was examined. The ARIMA (autoregressive integrated moving average) method was also employed to test the seasonality of RD incidence rates and their association with climatic factors. The annual RD incidence rates were between 7.8 and 10.8 cases/100 000 people during the study period. A fairly similar seasonal pattern of monthly RD incidence rates was apparent for males and females and males and females combined. Rates were highest August through October, decreasing in November, and lowest in February. After adjusting for time, trend, and month, the ARIMA regression models for the male, female, and males and females combined consistently revealed the monthly RD incidence rate was significantly and positively associated with ambient temperature, but negatively associated with atmospheric pressure. The authors conclude that the monthly RD incidence rates were significantly associated with seasonality. The monthly RD incidence rates were positively associated with ambient temperature and negatively associated with atmospheric pressure.


Identification of Salivary Microbiota and Its Association With Host Inflammatory Mediators in Periodontitis.
Periodontitis is a microbial-induced chronic inflammatory disease, which may not only result in tooth loss, but can also contribute to the development of various systemic diseases. The transition from healthy to diseased periodontium depends on microbial dysbiosis and impaired host immune response. Although periodontitis is a common disease as well as associated with various systemic inflammatory conditions, the taxonomic profiling of the salivary microbiota in periodontitis and its association with host immune and inflammatory mediators has not been reported. Therefore, the aim of this study was to identify key pathogens and their potential interaction with the host's inflammatory mediators in saliva samples for periodontitis risk assessment. The microbial 16S rRNA gene sequencing and the levels of inflammatory mediators were performed in saliva samples from patients with chronic periodontitis and periodontally healthy control subjects. The salivary microbial community composition differed significantly between patients with chronic periodontitis and healthy controls. Our analyses identified a number of microbes, including bacteria assigned to Eubacterium saphenum, Tannerella forsythia, Filifactor alocis, Streptococcus mitis/parasanguinis, Parvimonas micra, Prevotella sp., Phocaeicola sp., and Fretibacterium sp. as more abundant in periodontitis, compared to healthy controls. In samples from healthy individuals, we identified Campylobacter concisus, and Veillonella sp. as more abundant. Integrative analysis of the microbiota and inflammatory mediators/cytokines revealed associations that included positive correlations between the pathogens Treponema sp. and Selenomas sp. and the cytokines chitinase 3-like 1, sIL-6Rα, sTNF-R1, and gp130/sIL-6Rβ. In addition, a negative correlation was identified between IL-10 and Filifactor alocis. Our results reveal distinct and disease-specific patterns of salivary microbial composition between patients with periodontitis and healthy controls, as well as significant correlations between microbiota and host-mediated inflammatory cytokines. The positive correlations between the pathogens Treponema sp. and Selenomas sp. and the cytokines chitinase 3-like 1, sIL-6Rα, sTNF-R1, and gp130/sIL-6Rβ might have the future potential to serve as a combined bacteria-host salivary biomarker panel for diagnosis of the chronic infectious disease periodontitis. However, further studies are required to determine the capacity of these microbes and inflammatory mediators as a salivary biomarker panel for periodontitis.


Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial.
In the SPARTAN trial, addition of apalutamide to androgen deprivation therapy, as compared with placebo plus androgen deprivation therapy, significantly improved metastasis-free survival in men with non-metastatic castration-resistant prostate cancer who were at high risk for development of metastases. We aimed to investigate the effects of apalutamide versus placebo added to androgen deprivation therapy on health-related quality of life (HRQOL). SPARTAN is a multicentre, international, randomised, phase 3 trial. Participants were aged 18 years or older, with non-metastatic castration-resistant prostate cancer, a prostate-specific antigen doubling time of 10 months or less, and a prostate-specific antigen concentration of 2 ng/mL or more in serum. Patients were randomly assigned (2:1) to 240 mg oral apalutamide per day plus androgen deprivation therapy, or matched oral placebo plus androgen deprivation therapy, using an interactive voice randomisation system. Permuted block randomisation was used according to the three baseline stratification factors: prostate-specific antigen doubling time (>6 months vs ≤6 months), use of bone-sparing drugs (yes vs no), and presence of local-regional nodal disease (N0 vs N1). Each treatment cycle was 28 days. The primary endpoint was metastasis-free survival. The trial was unblinded in July, 2017. In this prespecified exploratory analysis we assessed HRQOL using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires, which we collected at baseline, day 1 of cycle 1 (before dose), day 1 of treatment cycles 1-6, day 1 of every two cycles from cycles 7 to 13, and day 1 of every four cycles thereafter. This study is registered with ClinicalTrials.gov, number NCT01946204. Between Oct 14, 2013, and Dec 15, 2016, we randomly assigned 1207 patients to receive apalutamide (n=806) or placebo (n=401). The clinical cutoff date, as for the primary analysis, was May 19, 2017. Median follow-up for overall survival was 20·3 months (IQR 14·8-26·6). FACT-P total and subscale scores were associated with a preservation of HRQOL from baseline to cycle 29 in the apalutamide group; there were similar results for EQ-5D-3L. At baseline, the mean for FACT-P total score in both the apalutamide and placebo groups were consistent with the FACT-P general population norm for US adult men. Group mean patient-reported outcome scores over time show that HRQOL was maintained from baseline after initiation of apalutamide treatment and was similar over time among patients receiving apalutamide versus placebo. Least-squares mean change from baseline shows that HRQOL deterioration was more apparent in the placebo group. In asymptomatic men with high-risk non-metastatic castration-resistant prostate cancer, HRQOL was maintained after initiation of apalutamide treatment. Considered with findings from SPARTAN, patients who received apalutamide had longer metastasis-free survival and longer time to symptomatic progression than did those who received placebo, while preserving HRQOL. Janssen Research & Development.


Time series analysis of sexual assault case characteristics and the 2007-2008 period of post-election violence in Kenya.
Following the declaration that President Mwai Kibaki was the winner of the Kenyan presidential election held on December 27, 2007, a period of post-election violence (PEV) took place. In this study, we aimed to identify whether the period of PEV in Kenya was associated with systematic changes in sexual assault case characteristics. Medical records of 1,615 patients diagnosed with sexual assault between 2007 and 2011 at healthcare facilities in Eldoret (n = 569), Naivasha (n = 534), and Nakuru (n = 512) were retrospectively reviewed to examine characteristics of sexual assault cases over time. Time series and linear regression were used to examine temporal variation in case characteristics relative to the period of post-election violence in Kenya. Key informant interviews with healthcare workers at the sites were employed to triangulate findings. The time series of sexual assault case characteristics at these facilities were examined, with a specific focus on the December 2007-February 2008 period of post-election violence. Prais-Winsten estimates indicated that the three-month period of post-election violence was associated with a 22 percentage-point increase in cases where survivors did not know the perpetrator, a 20 percentage-point increase in cases with more than one perpetrator, and a 4 percentage-point increase in cases that had evidence of abdominal injury. The post-election violence period was also associated with an 18 percentage-point increase in survivors waiting >1 month to report to a healthcare facility. Sensitivity analyses confirmed that these characteristics were specific to the post-election violence time period. These results demonstrate systematic patterns in sexual assault characteristics during the PEV period in Kenya.


Adherence to HIV medications in a cohort of men who have sex with men: impact of September 11th.
Adherence to highly active antiretroviral therapy (HAART) regimens remains a challenge for people living with human immunodeficiency virus (HIV). Severe traumas like that of September 11, 2001, can exacerbate the difficulties already associated with adherence. A community-based sample of 68 HIV-seropositive men who have sex with men (MSM) living in New York City who were on protease inhibitor HAART regimens completed quantitative assessments to examine adherence in the aftermath of September 11th. Data were drawn from a larger study of drug use and HIV medication adherence. Assessments conducted from September 24, 2001 to October 24, 2001 were compared to assessments taken 2-4 months prior to September 11th. Repeated measures analyses of variance were used to analyze the number of missed and suboptimal doses (doses taken outside the prescribed time by +/-4 hours) reported in the 2 weeks prior to each respective assessment. The results indicated a significant increase in the number of missed doses and the number of suboptimal doses immediately after the events of September 11th. Differences in adherence were not influenced, however, by sociodemographic characteristics. These results suggest that the events of September 11th had an impact on adherence to HIV medications among MSM in New York City and provide further support for the notion that the events of September 11th may have adversely impacted the lives of seropositive individuals. Attention should be paid by clinicians working with HIV-positive individuals on how this event has been incorporated into lives of individuals already burdened by a chronic and demanding disease.


CdEr2Se4: a new erbium spin ice system in a spinel structure.
Here we present a detailed study of the spinel CdEr2Se4 and show it to be a new instance of spin ice, the first one in an erbium material and the first one in a spinel. Definitive experimental evidence comes from the temperature dependence of the magnetic entropy, which shows an excellent agreement with the predicted behavior for a spin ice state. Crystal field calculations demonstrate that the change in the local environment from that of the titanates completely alters the rare-earth anisotropy giving rise, in the case of Er3+, to the required Ising anisotropy, when Er2Ti2O7 behaves as an XY antiferromagnet. This finding opens up the possibility of new exotic ground states within the CdR2Se4 and CdR2Se4 families.


My Caregiver the Cobot: Comparing Visualization Techniques to Effectively Communicate Cobot Perception to People with Physical Impairments.
Nowadays, robots are found in a growing number of areas where they collaborate closely with humans. Enabled by lightweight materials and safety sensors, these cobots are gaining increasing popularity in domestic care, where they support people with physical impairments in their everyday lives. However, when cobots perform actions autonomously, it remains challenging for human collaborators to understand and predict their behavior, which is crucial for achieving trust and user acceptance. One significant aspect of predicting cobot behavior is understanding their perception and comprehending how they "see" the world. To tackle this challenge, we compared three different visualization techniques for Spatial Augmented Reality. All of these communicate cobot perception by visually indicating which objects in the cobot's surrounding have been identified by their sensors. We compared the well-established visualizations Wedge and Halo against our proposed visualization Line in a remote user experiment with participants suffering from physical impairments. In a second remote experiment, we validated these findings with a broader non-specific user base. Our findings show that Line, a lower complexity visualization, results in significantly faster reaction times compared to Halo, and lower task load compared to both Wedge and Halo. Overall, users prefer Line as a more straightforward visualization. In Spatial Augmented Reality, with its known disadvantage of limited projection area size, established off-screen visualizations are not effective in communicating cobot perception and Line presents an easy-to-understand alternative.


Variation and change in the meaning of oral health related quality of life: a 'grounded' systems approach.
Changes in concepts of health and disease have led to increased interest in health related quality of life in medicine. Quality of life measures tend to treat quality of life as a stable construct that can be measured externally. They do not consider people's differing expectations and assume that what quality of life means to people is stable over time. This paper reports on a study which aimed to find out how measures of oral health related quality of life (OHRQoL) vary between and change within individuals. Longitudinal semi-structured open-ended interviews were carried out with twenty people with socially noticeable broken, decayed or missing teeth who were or were not seeking dental treatment. The data were collected and analysed using the iterative processes of grounded systems theory based on Glaserian (Theoretical Sensitivity, The Sociology Press, Mill Valley, CA, 1978) grounded theory and Luhmann's (Social Systems, Stanford University, Stanford, 1984) social systems theory. During the data analysis it emerged that participants' were adopting positions on seven dimensions of oral health relating to the positions that people would adopt with respect norm, attribution, trust, accessibility, commodity, authenticity, and character. The core distinction that accommodated people's varying positions was that people constructed their own margins of relevance of oral health. The margins of relevance indicated a variable from a hypothetical extreme of 'super-relevant' to the other extreme of 'not relevant'. The margins of relevance could shift, meaning that assessments of quality of life would vary. Oral health related quality of life is therefore defined as the cyclical and self-renewing interaction between the relevance and impact of oral health in everyday life.


Gastrointestinal stromal tumor and leiomyoma of the ileum mimicking adnexal mass: a report of two cases.
Adnexal masses are formations seen in women of all ages; they most often include cystic elements. Medical history, physical examination, different imaging methods, and tumor marker determinations must be used together for preoperative evaluation of an adnexal mass. Both benign and malignant tumors of the small intestine are more rarely encountered than malignant tumors of other gastrointestinal system components; although advanced imaging methods and other diagnostic techniques are used, they do not always allow these tumors to be differentiated from adnexal masses. We report here on two cases operated on with the preliminary diagnosis of an adnexal mass, in which the presence of a gastrointestinal stromal tumor and a leiomyoma of the ileum, respectively, was established.


Controlled Osteogenic Differentiation of Human Mesenchymal Stem Cells Using Dexamethasone-Loaded Light-Responsive Microgels.
Human mesenchymal stem cells (hMSCs), which have the ability to differentiate into osteoblasts, show promise for bone tissue engineering and bone defect treatment. While there are a number of approaches currently available to accomplish this, e.g., utilizing biodegradable materials loaded with the synthetic glucocorticoid osteogenic inducer dexamethasone (DEX), there are still many disadvantages with the current technologies. Here, we generated light-responsive microgels that we showed are capable of loading and releasing DEX in a light-triggered fashion, with the released DEX being able to induce hMSC differentiation into osteoblasts. Specifically, light-responsive poly(N-isopropylacrylamide-co-nitrobenzyl methacrylate) (pNIPAm-co-NBMA) microgels were synthesized via free radical precipitation polymerization and their size, morphology, and chemical composition were characterized. We then went on to show that the microgels could be loaded with DEX (via what we think are hydrophobic interactions) and released upon exposure to UV light. We went on to show that the DEX released from the microgels was still capable of inducing osteogenic differentiation of hMSCs using an alamarBlue assay and normalized alkaline phosphatase (ALP) activity assay. We also investigated how hMSC differentiation was impacted by intermittent DEX released from UV-exposed microgels. Finally, we confirmed that the microgels themselves were not cytotoxic to hMSCs. Taken together, the DEX-loaded light-responsive microgels reported here may find a use for niche clinical applications, e.g., bone tissue repair.


Missed strokes using computed tomography imaging in patients with vertigo: population-based cohort study.
The purpose of this study was to determine the proportion of emergency department (ED) patients with a diagnosis of peripheral vertigo who received computed tomography (CT) head imaging in the ED and to examine whether strokes were missed using CT imaging. This population-based retrospective cohort study assessed patients who were discharged from an ED in Ontario, Canada, with a diagnosis of peripheral vertigo, April 2006 to March 2011. Patients who received CT imaging (exposed) were matched by propensity score methods to patients who did not (unexposed). If performed, CT imaging was presumed to be negative for stroke because brain stem/cerebellar stroke would result in hospitalization. We compared the incidence of stroke within 30, 90, and 365 days subsequent to ED discharge between groups, to determine whether the exposed group had a higher frequency of early strokes than the matched unexposed group. Among 41 794 qualifying patients, 8596 (20.6%) received ED head CT imaging, and 99.8% of these patients were able to be matched to a control. Among exposed patients, 25 (0.29%) were hospitalized for stroke within 30 days when compared with 11 (0.13%) among matched nonexposed patients. The relative risk of a 30- and 90-day stroke among exposed versus unexposed patients was 2.27 (95% confidence interval, 1.12-4.62) and 1.94 (95% confidence interval, 1.10-3.43), respectively. There was no difference between groups at 1 year. Strokes occurred at a median of 32.0 days (interquartile range, 4.0-33.0 days) in exposed patients, compared with 105 days (interquartile range, 11.5-204.5) in unexposed patients. One fifth of patients diagnosed with peripheral vertigo in Ontario received imaging that is not recommended in guidelines, and that imaging was associated with missed strokes.


Theory of nonionic hydrophobic solutes in mixture solvent: Solvent-mediated interaction and solute-induced phase separation.
We present a theory of nonionic solutes in a mixture solvent composed of water-like and alcohol-like species. First, we show the relationship among the solvation chemical potential, the partial volumes vi, the Kirkwood-Buff integrals, the second osmotic virial coefficient, and the Gibbs transfer free energy. We examine how the solute density n3 is coupled to the solvent densities n1 and n2 in thermodynamics. In the limit of small compressibility, we show that the space-filling condition ∑i vini = 1 nearly holds for inhomogeneous densities ni, where the concentration fluctuations of the solvent can give rise to a large solute-solute attractive interaction. We also derive a solute spinodal density n3spi for solute-induced instability. Next, we examine gas-liquid and liquid-liquid phase transitions induced by a small amount of a solute using the Mansoori, Carnahan, Starling, and Leland model for hard-sphere mixtures [J. Chem. Phys. 54, 1523-1525 (1971)]. Here, we assume that the solvent is close to its gas-liquid coexistence and the solute interacts repulsively with the water-like species but attractively with the alcohol-like one. We calculate the binodal and spinodal curves in the phase diagrams and examine nucleation for these two phase transitions.


Spatial models for the rational allocation of routinely distributed bed nets to public health facilities in Western Kenya.
In high to moderate malaria transmission areas of Kenya, long-lasting insecticidal nets (LLINs) are provided free of charge to pregnant women and infants during routine antenatal care (ANC) and immunization respectively. Quantities of LLINs distributed to clinics are quantified based on a combination of monthly consumption data and population size of target counties. However, this approach has been shown to lead to stock-outs in targeted clinics. In this study, a novel LLINs need quantification approach for clinics in the routine distribution system was developed. The estimated need was then compared to the actual allocation to identify potential areas of LLIN over- or under-allocation in the high malaria transmission areas of Western Kenya. A geocoded database of public health facilities was developed and linked to monthly LLIN allocation. A network analysis approach was implemented using the location of all public clinics and topographic layers to model travel time. Estimated travel time, socio-economic and ANC attendance data were used to model clinic catchment areas and the probability of ANC service use within these catchments. These were used to define the number of catchment population who were likely to use these clinics for the year 2015 equivalent to LLIN need. Actual LLIN allocation was compared with the estimated need. Clinics were then classified based on whether allocation matched with the need, and if not, whether they were over or under-allocated. 888 (70%) public health facilities were allocated 591,880 LLINs in 2015. Approximately 682,377 (93%) pregnant women and infants were likely to have attended an LLIN clinic. 36% of the clinics had more LLIN than was needed (over-allocated) while 43% had received less (under-allocated). Increasing efficiency of allocation by diverting over supply of LLIN to clinics with less stock and fully covering 43 clinics that did not receive nets in 2015 would allow for complete matching of need with distribution. The proposed spatial modelling framework presents a rationale for equitable allocation of routine LLINs and could be used for quantification of other maternal and child health commodities applicable in different settings. Western Kenya region received adequate LLINs for routine distribution in line with government of Kenya targets, however, the model shows important inefficiencies in the allocation of the LLINs at clinic level.


Failure of selected endocrine organ ablation to modify the natriuresis of blood volume expansion in the dog.
1. Selected organ-ablation experiments were performed in dogs in an attempt to identify the source of the natriuretic hormone postulated to participate in the natriuresis of blood volume expansion. 2. An isolated dog kidney perfused with blood from the femoral artery of deoxycorticosterone-loaded dogs subjected to acute volume expansion with equilibrated blood served as the bioassay system for the natriuretic factor. Four groups were studied after the following procedures: group I, no ablation; group II, thyroparathyroidectomy; group III, hypophysectomy; group IV, adrenalectomy. 3. In all groups, the administration of equilibrated blood promoted a significant increase in sodium chloride excretion in the isolated kidney. The natriuresis was unrelated to changes in glomerular filtration rate, renal blood flow, renal arterial pressure, plasma protein concentration or packed cell volume. In the absence of volume expansion, sodium chloride excretion in the isolated kidney did not change or decreased. 4. These results argue against the thyroid, parathyroid, adrenal and pituitary glands as the source of natriuretic hormone.


Recognition of an ERAD-L substrate analyzed by site-specific in vivo photocrosslinking.
Misfolded, luminal endoplasmic reticulum (ER) proteins must be recognized before being degraded by a process called ERAD-L. Using site-specific photocrosslinking in Saccharomyces cerevisiae, we tested luminal interactions of a glycosylated ERAD-L substrate with potential recognition components. Major interactions were observed with Hrd3p. These are independent of the glycan and of other ERAD components, and can occur throughout the length of the unfolded substrate. The lectin Yos9p only interacts with a polypeptide segment distant from the degradation signal. Hrd3p may thus be the first substrate-recognizing component. Der1p appears to have a role in a pathway that is parallel to that involving Hrd3p.


Characteristics of adults with and without cystic fibrosis-related diabetes.
The prevalence of diabetes in adults with cystic fibrosis (CF) approximates 25%, yet few studies have defined risk factors. We examined the association between biochemical and clinical factors and CF-related diabetes. We performed a study in adults with CF in 2004 in Cambridgeshire, UK. Of 160 individuals, 51 had diabetes (cases) on the basis of medical history or screening using a 75-g oral glucose tolerance test, and 107 did not have diabetes (control subjects); two were excluded. We used logistic regression to model the cross-sectional association between potential risk factors and diabetes. The mean age was 26 (16-58) years, mean body mass index (BMI) was 21 (16-28) kg/m(2), and mean forced expiratory volume in 1 s was 60 +/- 24% (mean +/- sd). All of the cases and 88% of control subjects had pancreatic insufficiency. Cases did not differ from control subjects with respect to age, sex, body mass index, or dose of oral pancreatic enzymes. Cases were more likely to have low serum magnesium, haemoglobin, and pulmonary function, and higher serum gamma-glutamyl transferase (GGT) activity, plasma fibrinogen levels, erythrocyte sedimentation rate, use of oral corticosteroids, and number of CF-related complications. In multivariate analyses, GGT, previous organ transplantation, plasma fibrinogen and the presence of CF-related complications were independently associated with diabetes, after controlling for corticosteroid use. These data confirm the high prevalence of diabetes in adults with CF, and identify plasma fibrinogen and GGT, and organ transplantation as factors independently associated with CF-related diabetes. A prospective study would clarify the nature of these associations.


A systematic review and meta-analysis of the impact of cash transfers on subjective well-being and mental health in low- and middle-income countries.
Cash transfers (CTs) are increasingly recognized as a scalable intervention to alleviate financial hardship. A large body of evidence evaluates the impact of CTs on subjective well-being (SWB) and mental health (MH) in low- and middle-income countries. We undertook a systematic review, quality appraisal and meta-analysis of 45 studies examining the impact of CTs on self-reported SWB and MH outcomes, covering a sample of 116,999 individuals. After an average follow-up time of two years, we find that CTs have a small but statistically significant positive effect on both SWB (Cohen's d = 0.13, 95% confidence interval (CI) 0.09, 0.18) and MH (d = 0.07, 95% CI 0.05, 0.09) among recipients. CT value, both relative to previous income and in absolute terms, is a strong predictor of the effect size. Based on this review and the large body of existing research demonstrating a positive impact of CTs on other outcomes (for example, health and income), there is evidence to suggest that CTs improve lives. To enable comparisons of the relative efficacy of CTs to improve MH and SWB, future research should meta-analyse the effects of alternative interventions in similar contexts.


Organizational culture and staff outcomes in services for people with intellectual disabilities.
Organizational culture has been shown by organizational psychology to influence important aspects of staff behaviour. In particular, mismatches between staff perceptions of real and ideal organizational cultures have been shown to be associated with a range of negative outcomes for staff, such as stress, sickness and staff turnover. The present study investigates organizational culture in services for people with intellectual disabilities. The aim was to discover the prevalent organizational cultures in these services, and associations between organizational culture and staff outcomes. As part of a large-scale survey of staff in services for people with intellectual disabilities, information concerning organizational culture and staff outcomes was collected from 450 staff. A self-report measure of real and ideal organizational culture produced nine dimensions of organizational culture: (I) tolerant/staff-oriented; (2) achievement-oriented; (3) innovative; (4) analytical; (5) social relationships; (6) rewarding staff; (7) stable work environment; (8) demanding; and (9) conflict management. These nine dimensions of organizational culture showed generally adequate psychometric properties. While there was some variation in organizational culture across services, there is little variation across staff with different job titles. Overall, the staff rated real organizational cultures to be relatively high in achievement orientation and fostering social relationships, and relatively low in managing conflict and providing rewards for staff. Staff rated ideal organizational cultures to be high in rewarding staff, being tolerant/staff-oriented and fostering social relationships, and low in demands on staff. Except for the dimension of making demands on staff, where staff rated organizations as considerably higher than ideal, staff generally rated organizations as being less than ideal on all dimensions of organizational culture. Organizational psychology theory predicts that poor 'person-organization fit' (i.e. a greater mismatch between real and ideal organizational culture) will be associated with a range of negative staff outcomes. This theory was largely supported by findings of the present study. The implications for practice and for future research are discussed.


Towards population screening for Cerebral Visual Impairment: Validity of the Five Questions and the CVI Questionnaire.
Cerebral Visual Impairment (CVI) is the most common cause of visual impairment in children in the developed world and appears to be more prevalent in children with additional support needs (ASN). There is an urgent need for routine screening for CVI, particularly in children with ASN, however, current screening questionnaires for CVI have limited validation. The aim of this study was to evaluate two screening tools: the Five Questions and the CVI Questionnaire. Additionally, the distribution of CVI across neurodevelopmental disorders is unknown. This too was investigated. An online survey was completed by 535 parents. The survey was advertised via social media, CVI websites and parent email systems of four schools. The survey comprised of the Five Questions, the CVI Questionnaire and additional questions regarding the child's diagnoses. Whether or not a child had a diagnosis of CVI and/or additional neurodevelopmental disorders was based on parental report. Based on parent reports, both the screening tools accurately screened for CVI diagnoses in children. The Five Questions and the CVI Questionnaire have construct validity (as determined through factor analysis), high internal consistency (as determined by Cronbach's alpha) and convergent validity (as determined by correlation analysis of the raw scores of each questionnaire). This study also highlights that among children with neurodevelopmental disorders, a large proportion have parent-reported CVI (23%-39%) and potential CVI (6.59-22.53%; as identified by the questionnaires). The current study demonstrates that the Five Questions and CVI Questionnaire have good convergent validity, internal consistency and a reliable factor structure and may therefore be suitable as screening tools. The study also highlights that reported or potential CVI is evident in a large proportion of children with neurodevelopmental disorders.


Structural weakening of the colonic mucus barrier is an early event in ulcerative colitis pathogenesis.
The colonic inner mucus layer protects us from pathogens and commensal-induced inflammation, and has been shown to be defective in active UC. The aim of this study was to determine the underlying compositional alterations, their molecular background and potential contribution to UC pathogenesis. In this single-centre case-control study, sigmoid colon biopsies were obtained from patients with UC with ongoing inflammation (n=36) or in remission (n=28), and from 47 patients without colonic disease. Mucus samples were collected from biopsies ex vivo, and their protein composition analysed by nanoliquid chromatography-tandem mass spectrometry. Mucus penetrability and goblet cell responses to microbial stimulus were assessed in a subset of patients. The core mucus proteome was found to consist of a small set of 29 secreted/transmembrane proteins. In active UC, major structural mucus components including the mucin MUC2 (p<0.0001) were reduced, also in non-inflamed segments. Active UC was associated with decreased numbers of sentinel goblet cells and attenuation of the goblet cell secretory response to microbial challenge. Abnormal penetrability of the inner mucus layer was observed in a subset of patients with UC (12/40; 30%). Proteomic alterations in penetrable mucus samples included a reduction of the SLC26A3 apical membrane anion exchanger, which supplies bicarbonate required for colonic mucin barrier formation. Core mucus structural components were reduced in active UC. These alterations were associated with attenuation of the goblet cell secretory response to microbial challenge, but occurred independent of local inflammation. Thus, mucus abnormalities are likely to contribute to UC pathogenesis.


Identification of the catalytic triad in the haloalkane dehalogenase from Sphingomonas paucimobilis UT26.
The haloalkane dehalogenase from Sphingomonas paucimobilis UT26 (LinB) is the enzyme involved in the gamma-hexachlorocyclohexane degradation. This enzyme hydrolyses a broad range of halogenated aliphatic compounds via an alkyl-enzyme intermediate. LinB is believed to belong to the family of alpha/beta-hydrolases which employ a catalytic triad, i.e. nucleophile-histidine-acid, during the catalytic reaction. The position of the catalytic triad within the sequence of LinB was probed by a site-directed mutagenesis. The catalytic triad residues of the haloalkane dehalogenase LinB are proposed to be D108, H272 and E132. The topological location of the catalytic acid (E132) is after the beta-strand six which corresponds to the location of catalytic acid in the pancreatic lipase, but not in the haloalkane dehalogenase of Xanthobacter autotrophicus GJ10 which contains the catalytic acid after the beta-strand seven.


Child Marriages and Unions in Latin America: Understanding the Roles of Agency and Social Norms.
Child marriages and unions can infringe upon adolescent and youth sexual and reproductive health (AYSRH). Interventions increasingly promote strategies to transform social norms or foster the agency of adolescent girls. Recent empirical studies call for further understanding of how social norms and agency interact in ways that influence these practices, especially in contexts where girls' agency is central. A secondary cross-case analysis of three qualitative studies (in Brazil, Guatemala, Honduras) was conducted to inform the investigation of how norms and agency may relate in sustaining or mitigating child marriage. Social norms dictating how girls/young women and how men should act indirectly led to child marriages and unions. The data showed that (1) social norms regulated girls' acceptable actions and contributed to their exercise of "oppositional" agency; (2) social norms promoted girls' "accommodating" agency; and (3) girls exercised "transformative" agency to resist harmful social norms. Research should advance frameworks to conceptualize how social norms interact with agency in nuanced and context-specific ways. Practitioners should encourage equitable decision-making; offer confidential, adolescent-friendly AYSRH services; and address the social norms of parents, men and boys, and community members.


Extracorporal Shock Waves Activate Migration, Proliferation and Inflammatory Pathways in Fibroblasts and Keratinocytes, and Improve Wound Healing in an Open-Label, Single-Arm Study in Patients with Therapy-Refractory Chronic Leg Ulcers.
Chronic leg ulcers (CLUs) are globally a major cause of morbidity and mortality with increasing prevalence. Their treatment is highly challenging, and many conservative, surgical or advanced therapies have been suggested, but with little overall efficacy. Since the 1980s extracorporal shock wave therapy (ESWT) has gained interest as treatment for specific indications. Here, we report that patients with CLU showed wound healing after ESWT and investigated the underlying molecular mechanisms. We performed cell proliferation and migration assays, FACS- and Western blot analyses, RT-PCR, and Affymetrix gene expression analyses on human keratinocytes and fibroblasts, and a tube formation assay on human microvascular endothelial cells to assess the impact of shock waves in vitro. In vivo, chronic therapy-refractory leg ulcers were treated with ESWT, and wound healing was assessed. Upon ESWT, we observed morphological changes and increased cell migration of keratinocytes. Cell-cycle regulatory genes were upregulated, and proliferation induced in fibroblasts. This was accompanied by secretion of pro-inflammatory cytokines from keratinocytes, which are known to drive wound healing, and a pro-angiogenic activity of endothelial cells. These observations were transferred "from bench to bedside", and 60 consecutive patients with 75 CLUs with different pathophysiologies (e.g. venous, mixed arterial-venous, arterial) were treated with ESWT. In this setting, 41% of ESWT-treated CLUs showed complete healing, 16% significant improvement, 35% improvement, and 8% of the ulcers did not respond to ESWT. The induction of healing was independent of patient age, duration or size of the ulcer, and the underlying pathophysiology. The efficacy of ESWT needs to be confirmed in controlled trials to implement ESWT as an adjunct to standard therapy or as a stand-alone treatment. Our results suggest that EWST may advance the treatment of chronic, therapy-refractory ulcers.