Widespread presence of direction-reversing neurons in the mouse visual system

Direction selectivity, the preference of motion in one direction over the opposite, is a fundamental property of visual neurons across species. We find that a substantial proportion of direction selective neurons in the mouse visual system reverse their preferred direction of motion in response to drifting gratings at different spatiotemporal parameters. A spatiotemporally asymmetric filter model recapitulates our experimental observations

Widespread presence of direction-reversing neurons in the mouse visual system

Direction selectivity, the preference of motion in one direction over the opposite, is a fundamental property of visual neurons across species. We find that a substantial proportion of direction selective neurons in the mouse visual system reverse their preferred direction of motion in response to drifting gratings at different spatiotemporal parameters. A spatiotemporally asymmetric filter model recapitulates our experimental observations

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Morphologic and histologic characterization of sheep and porcine TMJ as large animal models for tissue engineering applications.

ObjectiveThe aim of this study was to compare and characterize the structural and ultrastructural organization of the temporomandibular joint (TMJ) between two large animal models for use in the development of tissue engineering strategies.Materials and methodsWhole TMJs from sheep and pigs were evaluated with micro-computed tomography (μCT) for morphology and quantitative analyses of bone parameters. Histological examination was performed on the TMJ disc and its attachments to investigate regional distribution of collagen, elastin, and glycosaminoglycans (GAGs).ResultsμCT analyses demonstrate higher bone mineral density (BMD) in the temporal fossa compared to the mandibular condyle in both species, with this variable being significantly higher in sheep than pig. Quantitative morphometry of the trabecular condyle reveals no statistical differences between the species. Histology demonstrates similar structural organization of collagen and elastin between species. Elastin staining was nearly twofold greater in sheep than in the pig disc. Finally, Safranin-O staining for GAGs in the TMJ disc was localized to the intermediate zone in the sheep but was absent from the porcine disc.ConclusionsOur findings show some important differences in the pig and sheep TMJ μCT variables and histology and composition of the disc and discal attachment. These disparities likely reflect differences in masticatory and TMJ functional loading patterns between the two species and provide insights into large animal models towards human applications.Clinical relevanceAs with the established pig model, the sheep is a suitable large animal model for TMJ research such as regenerative strategies, with specific considerations for design parameters appropriate for human-analog applications

Mechanistic Phenotypes: An Aggregative Phenotyping Strategy to Identify Disease Mechanisms Using GWAS Data

<div><p>A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1) non-synonymous SNPs (nsSNPs) associated with “mechanistic phenotypes”, comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1) thrombosis, evaluated in a population of 1,655 African Americans; and (2) four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs), and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03), driven by the <i>F5, P2RY12</i> and <i>F2RL2</i> genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10−5, FDR p = 0.03) (<i>POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L</i>) while the additive model showed enrichment related to chromatid segregation (p = 4×10−6, FDR p = 0.005) (<i>KIF25, PINX1</i>). We were able to replicate nsSNP associations for <i>POLG/FANCI, BRCA1, FANCA</i> and <i>CHD1L</i> in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.</p></div

Enriched ontologies for genes associated with the cancer phenotypes in whites.

<p> All ontologies with an FDR p<0.05 are shown.</p><p> (1) The association p-value cut-off that gave the strongest enrichment.</p><p> (2) Number of genes with p-values below the p-value cut-off.</p><p> (3) Number of genes with the ontology.</p

Association of DNA repair genes in independent data sets.

<p> (1) This model compared minor allele homozygotes to matched common allele homozygotes.</p><p> = 3,092 subjects). (2) Genotype data for this nsSNP was only available for one eMERGE site (n</p

Overview of the nsSNP association approaches.

<p>Panel (a) describes key features of the SNP association approaches used. Panel (b) shows, for a single hypothetical SNP, how assignment of affection status for homozygotes for the minor allele (HZMAs) varies by the approaches. The table lists cancer codes present among the HZMAs, the number of HZMAs that have the cancer code and the Fisher's p-value comparing the proportion of affected HZMAs with the cancer to the proportion in the common allele homozygotes. For this example, all of the listed cancers are assumed to be constituents of the mechanistic phenotype. For the standard genetic models, all subjects with any of the cancers are classified as cases. In contrast, the 2 reverse genetics approaches only analyze subsets of these subjects with cancers meeting pre-specified criteria, as designated by the brackets.</p

Population characteristics.

<p> = 16), Primary hypercoagulable state (n = 13), Budd-Chiari syndrome (n = 3), Thrombophlebitis migrans (n = 1), other congenital deficiencies (n = 2), congenital factor IX disorder (n = 1), other coagulation defects (n = 6), congenital factor VIII disorder (n = 3). (1) Includes: Defibrination syndrome (n</p

Double-stranded DNA repair pathway.

<p>Genes identified in the analyses are shown in red. When DNA is damaged, damage sensors promote recruitment and assembly of a repair complex comprised of Fanconi Anemia (FA) genes, BRCA1 and other proteins to the site of damage.</p