Insufficient Impact: Limited Implementation of Federal Regulatory Changes to Methadone and Buprenorphine Access in Arizona During COVID-19

Introduction: This study examined the impact of federal regulatory changes on methadone and buprenorphine treatment during COVID-19 in Arizona. Methods: A cohort study of methadone and buprenorphine providers from September 14, 2021 to April 15, 2022 measured the proportion of 6 treatment accommodations implemented at 3 time periods: before COVID-19, during Arizona's COVID-19 shutdown, and at the time of the survey completion. Accommodations included (1) telehealth, (2) telehealth buprenorphine induction, (3) increased multiday dosing, (4) license reciprocity, (5) home medications delivery, and (6) off-site dispensing. A multilevel model assessed the association of treatment setting, rurality, and treatment with accommodation implementation time. Results: Over half (62.2%) of the 74-provider sample practiced in healthcare settings not primarily focused on addiction treatment, 19% practiced in methadone clinics, and 19% practiced in treatment clinics not offering methadone. Almost half (43%) were unaware of the regulatory changes allowing treatment accommodation. Telehealth was most frequently reported, increasing from 30% before COVID-19 to 80% at the time of the survey. Multiday dosing was the only accommodation substantially retracted after COVID-19 shutdown: from 41% to 23% at the time of the survey. Providers with higher patient limits were 2.5–3.2 times as likely to implement telehealth services, 4.4 times as likely to implement buprenorphine induction through telehealth, and 15.2–20.9 times as likely to implement license reciprocity as providers with lower patient limits. Providers of methadone implemented 12% more accommodations and maintained a higher average proportion of implemented accommodations during the COVID-19 shutdown period but were more likely to reduce the proportion of implemented accommodations (a 17-percentage point gap by the time of the survey). Conclusions: Federal regulatory changes are not sufficient to produce a substantive or sustained impact on provider accommodations, especially in methadone medical treatment settings. Practice change interventions specific to treatment settings should be implemented and studied for their impact

Pattern-Sensitive Epilepsy. I: A Demonstration of a Spatial Frequency Selective Epileptic Response to Gratings

Rare individuals suffer epileptic seizures when they view certain images, particularly stripes. Contrast-threshold functions (the ability to see faint stripes of various widths) were determined for two pattern-sensitive brothers, and the epileptogenicity of various patterns was assessed for one of them. Sine wave grating contrast-detection thresholds for the two subjects were essentially normal, with lowest thresholds at approximately 2 cycles/ degree (c/deg). Epileptiform discharges occurred maximally at 5 c/deg with a 1-octave 50% bandwidth. Pattern epileptogenicity was increased by the addition of a third harmonic sine wave grating to its fundamental, but was unaffected by the phase relation of the two gratings. The frequency selectivity of epileptic responsiveness was quantitatively similar to a “spatial frequency channel.” Inhibitory interactions were not present. The findings suggest relations between the phenomena of pattern-sensitive epilepsy and hypothesized spatial frequency channels which merit further exploration. RESUMEN De manera excepcional, hay personas que pueden tener ataques epilÉpticos cuando ven ciertas imÁgenes, particularmente rayas. Se determinaron los umbrales para contrastes (la capacidad de ver rayas de diversas anchuras y muy tenues) en dos hermanos sensibles a patrones y se estableciÓ la epileptogeneidad de di versos patrones en uno de ellos. Los umbrales para contrastes fueron esencialmente normales en los dos sujetos cuando se utilizeÓ una rejilla hecha con ondas sinusoidales, siendo el umbral inferior unos 2 ciclos/ grado (c/deg). Descargas epileptiformes tuvieron lugar de modo mÁximo a 5 c/deg con una amplitud de banda del 50% de una octava. la capacidad epileptogÉnica del partÓn aumentÓ cuando se aÑadiÓ una tercera sinusoide armÓnica a la rejilla base pero esa capacidad no se viÓ alterada por la relaciÓn de fase entre las dos rejillas. La selectividad de la frecuencia de la respuesta epileptogÉnica fue cuantitativamente similar al “canal de frecuencia espacial”. No se observaron interacciones inhibitorias. Los hallazgos sugieren que hay relaciones entre la epilepsyÍa secundaria a patrones visuales y los hipotÉticos canales de frecuencia espacial, lo cual merece mÁs investigaciÓn.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65270/1/j.1528-1157.1980.tb04075.x.pd

The DISC1 Pathway Modulates Expression of Neurodevelopmental, Synaptogenic and Sensory Perception Genes

Genetic and biological evidence supports a role for DISC1 across a spectrum of major mental illnesses, including schizophrenia and bipolar disorder. There is evidence for genetic interplay between variants in DISC1 and in biologically interacting loci in psychiatric illness. DISC1 also associates with normal variance in behavioral and brain imaging phenotypes.Here, we analyze public domain datasets and demonstrate correlations between variants in the DISC1 pathway genes and levels of gene expression. Genetic variants of DISC1, NDE1, PDE4B and PDE4D regulate the expression of cytoskeletal, synaptogenic, neurodevelopmental and sensory perception proteins. Interestingly, these regulated genes include existing targets for drug development in depression and psychosis.Our systematic analysis provides further evidence for the relevance of the DISC1 pathway to major mental illness, identifies additional potential targets for therapeutic intervention and establishes a general strategy to mine public datasets for insights into disease pathways

Integrated stratigraphy of the Waitakian-Otaian Stage boundary stratotype, Early Miocene, New Zealand

The base of the type section of the Otaian Stage at Bluecliffs, South Canterbury, is recognised as the stratotype for the boundary between the Waitakian and Otaian Stages. Principal problems with the boundary are the restriction of existing bioevent proxies to shelf and upper slope environments and its uncertain age. These topics are addressed by a multidisplinary study of a 125 m section about the boundary, which examines its lithostratigraphy, depositional setting, biostratigraphy, correlation, and geochronology. The lower siltstone lithofacies (0-38.5 m) was deposited at upper bathyal depths (200-600 m) in a marginal basin which was partially sheltered from fully oceanic circulation by a submarine high and islands. The site was covered by cool-temperate water and was probably adjacent to the Subtropical Convergence. This unit is succeeded by the banded lithofacies (38.5-106 m) and the upper siltstone lithofacies (basal 19 m studied). Paleodepth probably declined up-sequence, but deposition at shelf depths is not definitely indicated. A cyclic pattern of abundance spikes in benthic and planktonic foraminifera commences 9 m above base and extends to 73 m in the banded lithofacies. Oxygen isotope excursions (up to 2.08%) in Euuvigerina miozea and Cibicides novozelandicus are greatest within the interval containing the abundance spikes. The stage boundary occurs in the banded lithofacies at the highest abundance spike (73 m). Although condensed intervals might affect the completeness of the section, they are not associated with sedimentary discontinuities, and we consider that the section is suitable as a biostratigraphic reference. Spores, pollens, dinoflagellates, calcareous nannofossils, foraminifera, bryozoans, and ostracods are preserved near the boundary, but molluscs principally occur higher, in the shallower upper siltstone lithofacies. Siliceous microfossils are rare. There is considerable scope for further biostratigraphic research. The primary event marking the boundary at 73 m is the appearance of the benthic foraminifer Ehrenbergina marwicki. This is a distinctive and widely distributed event but is restricted to shelf and upper bathyal environments. Supplementary events in planktonic foraminifera and calcareous nannofossils were researched. Highest occurrences of Globigerina brazieri and G. euapertura are recorded at 47 and 58 m. There is a marked decline in relative abundance of Paragloborotalia spp. at 62 m. Helicosphaera carteri becomes more abundant than H. euphratis between 56 and 87 m. These events are not exact proxies for the boundary but they may usefully indicate proximity to it. They occur in the interval of prominent spikes in foraminiferal abundance. The Waitakian-Otaian boundary is dated at 21.7 Ma by strontium isotopes. Stable primary remanence could not be determined in a pilot paleomagnetic study of Bluecliffs specimens. However, specimens trended towards reversed polarity, and remagnetisation great circle analysis will allow directions to be calculated in future collections

Incipient Resistance of Helicoverpa punctigera to the Cry2Ab Bt Toxin in Bollgard II® Cotton

Combinations of dissimilar insecticidal proteins (“pyramids”) within transgenic plants are predicted to delay the evolution of pest resistance for significantly longer than crops expressing a single transgene. Field-evolved resistance to Bacillus thuringiensis (Bt) transgenic crops has been reported for first generation, single-toxin varieties and the Cry1 class of proteins. Our five year data set shows a significant exponential increase in the frequency of alleles conferring Cry2Ab resistance in Australian field populations of Helicoverpa punctigera since the adoption of a second generation, two-toxin Bt cotton expressing this insecticidal protein. Furthermore, the frequency of cry2Ab resistance alleles in populations from cropping areas is 8-fold higher than that found for populations from non-cropping regions. This report of field evolved resistance to a protein in a dual-toxin Bt-crop has precisely fulfilled the intended function of monitoring for resistance; namely, to provide an early warning of increases in frequencies that may lead to potential failures of the transgenic technology. Furthermore, it demonstrates that pyramids are not ‘bullet proof’ and that rapid evolution to Bt toxins in the Cry2 class is possible

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

Endogenous sex hormones and prostate cancer: a quantitative review of prospective studies

This paper presents a quantitative review of the data from eight prospective epidemiological studies, comparing mean serum concentrations of sex hormones in men who subsequently developed prostate cancer with those in men who remained cancer free. The hormones reviewed have been postulated to be involved in the aetiology of prostate cancer: androgens and their metabolites testosterone (T), non-SHBG-bound testosterone (non-SHBG-bound T), di-hydrotestosterone (DHT), androstanediol glucuronide (A-diol-g), androstenedione (A-dione), dehydroepiandrosterone sulphate (DHEAS), sex hormone binding globulin (SHBG), the oestrogens, oestrone and oestradiol, luteinizing hormone (LH) and prolactin. The ratio of the mean hormone concentration in prostate cancer cases to that of controls (and its 95% confidence interval (CI)) was calculated for each study, and the results summarized by calculating the weighted average of the log ratios. No differences in the average concentrations of the hormones were found between prostate cancer cases and controls, with the possible exception of A-diol-g which exhibited a 5% higher mean serum concentration among cases relative to controls (ratio 1.05, 95% CI 1.00-1.11), based on 644 cases and 1048 controls. These data suggest that there are no large differences in circulating hormones between men who subsequently go on to develop prostate cancer and those who remain free of the disease. Further research is needed to substantiate the small difference found in A-diol-g concentrations between prostate cancer cases and controls

Lung development in laminin γ2 deficiency: abnormal tracheal hemidesmosomes with normal branching morphogenesis and epithelial differentiation

BACKGROUND: Laminin γ2 (Lamc2), one of the polypeptides in laminin-332 (laminin-5), is prominent in the basement membrane of alveolar walls and airways of developing and adult lung. Laminins are important for lung morphogenesis and based on its localization, a function for laminin γ2 in lung development has been hypothesized. Targeted deletion of the laminin γ2 gene in mice results in skin blistering and neonatal death at 3–5 days after birth due to failure to thrive. METHODS: Examination of lung development in Lamc2-/- mice through 1–2 days postnatal was accomplished by morphometric analysis, lung bud culture, electron microscopy, immunohistochemical and immunofluorescence staining. RESULTS: Compared to littermate controls, Lamc2-/- lungs were similar in morphology during embryonic life. At post-natal day 1–2, distal saccules were mildly dilated by chord length measurements. Epithelial differentiation as evaluated by immunohistochemical staining for markers of ciliated cells, Clara cells, alveolar type I cells and alveolar type II cells did not reveal a difference between Lamc2-/- and littermate control lungs. Likewise, vascular development, smooth muscle cell differentiation, and elastic fiber formation looked similar, as did airway basement membrane ultrastructure. Branching morphogenesis by lung bud culture was similar in Lamc2-/- and littermate control lungs. Since laminin-332 is important for hemidesmosome formation, we examined the structure of tracheal hemidesmosomes by transmission electron microscopy. Compared to littermate controls, Lamc2-/- tracheal hemidesmosomes were less organized and lacked the increased electron density associated with the basement membrane abutting the hemidesmosome. CONCLUSION: These findings indicate that laminin γ2 and laminin-332, despite their prominence in the lung, have a minimal role in lung development through the saccular stage

U-Shaped Relation between Plasma Oxytocin Levels and Behavior in the Trust Game

10.1371/journal.pone.0051095PLoS ONE712