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Several life-threatening diseases of the kidney have their origins in mutational events that occur during embryonic development. In this study, we investigate the role of the Wolffian duct (WD), the earliest embryonic epithelial progenitor of renal tubules, in the etiology of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with a germline mutation of one of the two Pkd1 alleles. For the disease to occur, a second event that disrupts the expression of the other inherited Pkd1 allele must occur. We postulated that this secondary event can occur in the pronephric WD. Using Cre-Lox recombination, mice with WD-specific deletion of one or both Pkd1 alleles were generated. Homozygous Pkd1-targeted deletion in WD-derived tissues resulted in mice with large cystic kidneys and serologic evidence of renal failure. In contrast, heterozygous deletion of Pkd1 in the WD led to kidneys that were phenotypically indistinguishable from control in the early postnatal period. High-throughput sequencing, however, revealed underlying gene and microRNA (miRNA) changes in these heterozygous mutant kidneys that suggest a strong predisposition toward developing ADPKD. Bioinformatic analysis of this data demonstrated an upregulation of several miRNAs that have been previously associated with PKD; pathway analysis further demonstrated that the differentially expressed genes in the heterozygous mutant kidneys were overrepresented in signaling pathways associated with maintenance and function of the renal tubular epithelium. These results suggest that the WD may be an early epithelial target for the genetic or molecular signals that can lead to cyst formation in ADPKD.
The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
Antipseudomonal carbapenems are an important target for antimicrobial stewardship programs. We evaluated the impact of formulary restriction and preauthorization on relative carbapenem use for medical and surgical intensive care units at a large, urban academic medical center using interrupted time-series analysis.
This is a copy of the slides presented at the meeting but not formally written up for the volume.
Reflection high-energy electron diffraction (RHEED) is one of the most robust and widespread techniques used for in-situ monitoring during molecular beam epitaxy (MBE) growth. Thus, all MBE systems have an electron gun allowing additional electron-beam stimulated in-situ characterizations. At WVU we are developing two such techniques, spectral analysis of cathodoluminescence (CL) in wide bandgap semiconductors and reflection high-energy electron diffraction-total reflection angle x-ray spectroscopy (RHEED-TRAXS) for in-situ composition monitoring and control.A pressing issue remaining for epitaxial growth is real-time compositional control to a high level of accuracy. For many materials, such as multi-element nitrides and oxides with unity sticking coefficients, it would be extremely beneficial to monitor the composition to a fraction of a monolayer. This technique needs to be both element-specific and surface-sensitive. RHEED-TRAXS is a leading contender as such a technique. The electron beam from a RHEED gun impinges on the sample at a small angle of incidence approximately equal to the critical angle for x-ray reflection. This geometry ensures that the measurement is extremely surface sensitive. This technique can be used to obtain both structural information, via RHEED, and chemical information, via x-ray detection. We are currently developing a compact RHEED-TRAXS using a state-of-the-art Si P-intrinsic-N (PIN) photodiode technology. We have used this system to investigate Ga and In coverage during the growth of GaN, and have observed Ga bi-layer evolution during growth, Mg destabilization of the Ga wetting layer, and significant In surface segregation. We are also investigating the in-situ, real-time composition measurements in complex oxide systems such as YMnO3 with promising initial results.In-situ cathodoluminescence (CL) occurring during RHEED is a strong candidate to determine the growth temperature and alloy composition for wide bandgap semiconductors. CL is easily detected up to and beyond typical growth temperatures for GaN and InGaN, accurately and reproducibly determining sample temperature during growth. Room CL measurement at room temperature can also be used as a means to check the quality of the substrate by comparing intensities of the GaN band edge energy peak and defect peaks. We have performed a detailed study of the factors influencing high temperature CL, and find the reproducibility of CL data and ability for fast CL scanning provide strong advantages for use in the growth of GaN films. CL could also be observed during growth using a ccd camera. This could be used to see temperature inhomogenaities, and potentially to map alloy composition fluctuations. Using tunable narrow bandpass optical filters, we can obtain a spatial/spectral map of sample CL. We will present CL images of samples at differing temperatures.This work was supported by the AFOSR MURI F49620-03-1-0330 and by ONR Grant N00014-02-1-0974.
Background: There is an unmet need for blood-based biomarkers that can reliably detect MS disease activity. Serum Biomarkers of interest includ Neurofilament-light-chain (NfL), Glial-fibrillary-strocyte-protein(GFAP) and Tau. Bone Marrow Transplantation (BMT) is reserved for aggressive forms of MS and has been shown to halt detectable CNS inflammatory activity for prolonged periods. Significant pre-treatment tissue damage at followed by inflammatory disease abeyance should be reflected longitudinal sera collected from these patients. Methods: Sera were collected from 23 MS patients pre-treatment, and following BMT at 3, 6, 9 and 12-months in addition from 33 non-inflammatory neurological controls. Biomarker quantification was performed with SiMoA. Results: Pre-AHSCT levels of serum NfL and GFAP but not Tau were elevated compared to controls (p=0.0001), and NfL correlated with lesion-based disease activity (6-month-relapse, MRI-T2 and Gadolinium-enhancement). 3-months post-treatment, while NfL levels remained elevated, Tau/GFAP paradoxically increased (p=0.0023/0.0017). These increases at 3m correlated with MRI ‘pseudoatrophy’ at 6-months. NfL/Tau levels dropped to that of controls by 6-months (p=0.0036/0.0159). GFAP levels dropped progressively after 6-months although even at 12-months remained higher than controls (p=0.004). Conclusions: NfL was the closest correlate of MS disease activity and treatment response. Chemotherapy-related toxicity may account for transient increases in NfL, Tau and MRI brain atrophy post-BMT.
Recently, Anil Gupta raised several important objections against Wilfrid Sellars’s theory of perception. The purpose of this paper is to defend Sellars’s theory of perception against these objections. I admit that some aspects of his theory are problematic: for example, there are good reasons to reject Sellars’s view that the ultimate referent of a perceptual taking is a sense impression. Nonetheless, I argue that a Sellarsian account of perception is still a viable approach to perception, despite Gupta’s powerful objections.
We investigated whether neurobehavioral markers of risk for emotion dysregulation were evident among newborns, as well as whether the identified markers were associated with prenatal exposure to maternal emotion dysregulation. Pregnant women (N = 162) reported on their emotion dysregulation prior to a laboratory assessment. The women were then invited to the laboratory to assess baseline respiratory sinus arrhythmia (RSA) and RSA in response to an infant cry. Newborns were assessed after birth via the NICU Network Neurobehavioral Scale. We identified two newborn neurobehavioral factors—arousal and attention—via exploratory factor analysis. Low arousal was characterized by less irritability, excitability, and motor agitation, while low attention was related to a lower threshold for auditory and visual stimulation, less sustained attention, and poorer visual tracking abilities. Pregnant women who reported higher levels of emotion dysregulation had newborns with low arousal levels and less attention. Larger decreases in maternal RSA in response to cry were also related to lower newborn arousal. We provide the first evidence that a woman's emotion dysregulation while pregnant is associated with risks for dysregulation in her newborn. Implications for intergenerational transmission of emotion dysregulation are discussed.
This article aimed to address the feasibility of mentalization-based treatment (MBT) for patients with personality disorder in a non-specialist setting. The development and implementation of an MBT Programme is described.
A multidisciplinary Consult Group met to plan the implementation of the programme. Participants attended a psychoeducation group (MBT Introductory Group), then weekly individual and group therapy. Fourteen participants started the full programme with eight completing at least 9 months, complete data are available for five participants who completed 27 months (first cohort) and 21 months (second cohort). Data include quantitative measures and qualitative questionnaires/interviews. All had a diagnosis of personality dysfunction with co-morbid disorder including anxiety/depressive disorder, post-traumatic stress disorder and eating disorder.
Data on five participants revealed reductions in global level of distress, improvements in psychological well-being, less interpersonal difficulties and better work and social functioning. Qualitative data from feedback questionnaires (n = 18) and in-depth interview (n = 2) are discussed under the themes of mentalizing, treatment feedback/outcomes and group factors. Therapist reflections on the process identify the challenges involved in implementing a specialist psychotherapy programme within a general service and learning points from this are discussed.
MBT is an acceptable treatment for patients with personality dysfunction. Prior to the implementation of a programme, factors at the therapist, team and organizational level, as well as the wider context, need to be examined. This is to ensure that conditions are in place for proper adherence to the model to achieve the positive outcomes demonstrated in the RCT studies.
Resonant optical dipole antennas, consisting either of two arms coupled by a small gap or of a single, uncoupled arm only, are fabricated by the application of electron beam lithography and gold evaporation. Using dark-field microscopy, scattering spectra of structures with varied antenna arm length and varied gap size are obtained. The results show not only a spectral redshift for coupled structures compared to single arm structures, but also that the far-field scattering intensity is significantly higher for two arm structures with gap. In addition to the dipole structures, first fabrication results on quadrupole antennas and split-ring antennas are presented, offering novel pathways for an enhancement of the optical response function.
The second order nonlinear optical (NLO) properties of two different ionic selfassembled multilayer (ISAM) films combined with Ag nanoparticles have been investigated. The plasmon resonances in the Ag particles concentrate the incident light, markedly increasing in the NLO efficiencies of the films. We find that the efficiency enhancement is significantly larger in conventional ISAM films compared to films made using a hybrid covalent ISAM technique (HCISAM), even though the intrinsic bulk second order non-linear susceptibility (χ(2)) is much larger for HCISAM films. We attribute this to the interfaces in HCISAM films being much easier to disrupt by external perturbations such as the metal deposition by which the nanoparticles are fabricated. We conclude that because the plasmon decay length is very short, the plasmonic enhancement of NLO effects primarily occurs at and near the film-particle interface. To discern the importance of the interfaces, we surrounded thin ISAM and HCISAM films with NLOinactive buffer layers, which confirmed this hypothesis, particularly in the case of HCISAM films.
While much research has focused on crop damage following foliar exposure to auxin herbicides, reports documenting the risk posed by exposure via root uptake of irrigation water are lacking. Herbicide residues circulated in tailwater recovery systems may pose threats of cross-crop impacts to nonresistant cultivars with known sensitivity to auxins. An auxin-susceptible soybean [Glycine max (L.) Merr.] cultivar was grown in a controlled growth chamber environment and exposed to dicamba dissolved in irrigation water applied to the soil surface, simulating furrow irrigation. Five herbicide treatment concentrations, ranging from 0.05 to 5.0 mg L−1 and encompassing estimated field doses of 3.1 to 310g ha−1, were applied to the soil of potted soybean plants at V3/V4 or R1 growth stages. Plant injury (0% to 100%), dry mass, height, number of pods, and number of pod-bearing nodes were measured. Kruskal-Wallis and logistic regression analyses were performed to determine treatment differences and examine dose effects. Yield losses were projected using (1) 14 d after treatment plant injury assessments based on injury–yield relationships described for foliar exposures and (2) pod counts. Dicamba concentration was the main significant factor affecting all growth response metrics, and growth stage was a significant explanatory variable only for the height response metric. A nonlinear response to dicamba dose was observed, with the threshold response dose required to affect 50% of plants being three times greater for 40% crop injury compared with 20% injury. Yield projections derived from plant response to root uptake compared with foliar exposure indicate that soybean may express both magnitude of injury and specific symptomology differently when exposure occurs via root uptake. Drift exposure–based models may be incompatible to predict soybean yield loss when injury results from irrigation. Data are needed to develop correlations for predicting yield losses based on field-scale exposure to dicamba in irrigation water, as well as assessment of real-world concentrations of herbicide residues in tailwater recovery systems.
To determine the factors related to multiple ventilation tube insertions in children with otitis media with effusion.
A retrospective review was performed of 126 ears of 81 children aged less than 12 years who had undergone insertion of a Paparella type 1 ventilation tube for the first time between August 2012 and March 2018.
Mean age at the first operation was 4.0 ± 2.2 years, and the mean duration of otitis media with effusion before the first ventilation tube insertion was 5.4 ± 4.5 months. Among 126 ears, 80 (63.5 per cent) had a single ventilation tube insertion and 46 (36.5 per cent) had multiple insertions. On multivariate logistic regression, tympanic membrane retraction, serous middle-ear discharge, and early recurrence of otitis media with effusion were independent predictive factors of multiple ventilation tube insertions.
Tympanic membrane retraction, serous middle-ear discharge, and early recurrence of otitis media with effusion after the first tube extrusion are associated with multiple ventilation tube insertions.
The intensities of x-rays scattered by amorphous Fe80P13C7 and Fe40Ni40P14B6 samples have been measured as a function of photon energies E at fixed scattering angles 2θi using a Li-drifted Si detector and polychromatic x-rays generated by a 50KV full-wave rectified generator. The coherently scattered intensity per atom was calculated for free-standing samples as well as samples contained in a Be or pyrolytic graphite cell, after the evaluation of the energy dependence of the primary beam spectrum by an iterative process. The interference functions were then calculated from the data obtained in transmission and reflection, and compared with those measured with the conventional variable 2θ technique. Good agreement between energy-dispersive diffraction (also called variable wavelength technique) and variable 2θ diffraction was observed in all cases.
Characteristic x rays have been produced for a variety of samples by bombardment with protons in the energy range from 75 keV to 5 MeV. The experiments were performed with two accelerators. For the low-energy studies (less than 150 keV), a Cockcroft-Walton accelerator was used. The higher-energy studies were done with a 5 MV Van de Graaff. The x rays were measured with high-resolution Si(Li) and Ge(Li) detectors. Yields for the cross section of characteristic K- and L-shell ionizations were measured for titanium, vanadium, chromium, manganeses iron, cobalt, nickel, copper, silver, gold, bismuth, and uranium. The experimental cross-sections have been compared to the theoretical predictions of the Born approximation for an interaction of this type.
Trace element analysis by 4-MeV proton bombardment of samples in the 10-12 gm range has also been performed. Some comments with regard to analysis with these sensitivities will be made.
A new ESCA (electron spectroscopy for chemical analysis) instrument has been developed to provide high sensitivity and efficient operation for laboratory analysis of composition and chemical bonding in very thin surface layers of solid samples. High sensitivity is achieved by means of the high-intensity, efficient X-ray source described by Davies and Herglotz at the 1968 Denver X-Ray Conference, in combination with the new electron energy analyzer described by Lee at the 1972 Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy. A sample chamber designed to provide for rapid introduction and replacement of samples has adequate facilities for various sample treatments and conditioning followed immediafely by ESCA analysis of the sample.
Examples of application are presented, demonstrating the sensitivity and resolution achievable with this instrument. Its usefulness in trace surface analysis is shown and some “chemical shifts” measured by the instrument are compared with those obtained by X-ray spectroscopy.
X-ray diffraction techniques have been used for the structure characterization of Y-Ba-Cu-O and Tl-Ca-Ba-Cu-O thin films. A powder diffraction analysis of Y-Ba-Cu-O films showed that the films deposited at 650°C on Si are polycrystalline and have an orthorhambic structure similar to that of the YBa2Cu3O7 bulk superconductors. In addition to the conventional powder diffraction technique, both the rocking curve and the grazing incidence diffraction methods were used to characterize a YBa2Cu3O7 film on (110) SrTiO3 substrate. Results showed that the film was epitaxially grown and aligned with its substrate in a true epitaxy. Phase identification and line broadening analyses of Tl-Ca-Ba-Cu-O films showed that the films are comprised of one or more superconducting phases and probably contain stacking faults.
The use of transdiagnostic mental health treatments in low resource settings has been proposed as a possible aid in scaling up mental health services. Modular, multi-problem transdiagnostic treatments can be used to treat a range of mental health problems and are designed to handle comorbidity. Two randomized controlled trials have been completed on one treatment – the Common Elements Treatment Approach, or CETA – delivered by lay counsellors in Iraq and Thailand. This paper utilizes data from two clinical trials to explore the delivery of CETA by lay providers, examining fidelity and flexibility of element use. Data were collected at every therapy session. Clients completed a short symptom assessment and providers described the clinical elements delivered during sessions. Analyses included descriptive statistics of delivery including selection and sequencing of treatment elements, and the variance in element dose, clustering at the counsellor level, using multi-level models. Results indicate that lay providers in low resource settings (with supervision) demonstrated fidelity to the recommended CETA elements, order and dose, and occasionally added in elements and flexed dosage based on client presentation (i.e. flexibility). This modular approach did not result in significantly longer treatment duration. Our analysis suggests that lay providers were able to learn decision-making processes of CETA based on client presentation and adjust treatment as needed with supervision. As modular multi-problem transdiagnostic treatments continue to be explored in low resource settings, research should continue to focus on ‘unpacking’ lay counsellor delivery of these interventions, decision-making processes, and the level of supervision required.
A 1108.6 m long core was recovered at Site U1457 located on the Indus Fan in the Laxmi Basin of the eastern Arabian Sea during IODP Expedition 355. Shipboard examinations defined five lithologic units (I to V) of the lower Paleocene to Holocene sedimentary sequence. In this study, δ13C values of sedimentary organic matter (SOM) confirm the differentiation of the lithologic units and further divide units III and IV into two subunits (1 and 2). Based on the underlying assumption that the SOM is decided primarily by a mixture of marine and terrestrial origins, δ13CSOM values at Site U1457 provide information on the terrestrial catchment conditions since late Miocene time. Low δ13CSOM values from late Miocene to late Pleistocene times are similar (c. −22.0 ‰) for the most part, reflecting a consistent contribution of terrestrial organic matter from the catchment areas characterized by dominant C3 land plants. Significantly lower δ13CSOM values (c. −24.0 ‰) in Unit III-2 (∼8 to ∼7 Ma) might be due to a greater input of C3 terrestrial organic matter. The increase in δ13CSOM values at ∼7 Ma and the appearance of high δ13CSOM values (c. −18.0 ‰) within Unit III-1 (∼7 to ∼2 Ma) indicate that C4 biomass overwhelmed the terrestrial catchment environment as a result of enhanced terrestrial aridity in the Himalayan foreland. The three-end-member simple mixing model, estimating the relative contributions of SOM from terrestrial C3 and C4 plants and marine phytoplankton, supports our interpretation of the distribution of C3 and C4 land plants in the terrestrial catchment environment.