Twisting the Purposes of Discovery: Expert Witnesses and the Deposition Dilemma

The system of discovery that the Federal Rules establish theoretically entitles all parties in civil actions, prior to commencement of trial, to disclosure of all relevant nonprivileged information in he possession of any person. Thus, federal discovery rules should not force litigants to choose between failing to depose a party-opponent\u27s expert witness and thereby preparing inadequately for trial, and deposing the expert witness and consequently risking that opposing counsel will use the deposition against him at trial without the benefit of cross-examination. Part H of this Note reviews common law disagreement over the appropriateness of expert witness discovery and the acceptance of the principle under the Federal Rules. Part III discusses the procedural mechanics of discovering an expert witness and demonstrates the potential for use of such a deposition against the discovering party. Part IV reviews the judicial history of the expert witness deposition problem and demonstrates that courts have ignored the policy reasons that favor remedying this procedural problem. Part V discusses the in-equities that the expert witness deposition problem causes. It concludes that courts, by admitting discovery depositions of expert witnesses against the deposing party, not only have controverted the basic purposes of pretrial discovery, but also erroneously have eliminated the process of deposing the witness of a party-opponent as a pretrial discovery technique by effectively recharacterizing it as an extension of formal trial proceedings that presume the deposing party engaged in full pretrial preparation. Part V then explores several possible methods courts and rule makers could em-ploy to solve this problem, including an amendment to rule 26

School Reform and Coaching: Identifying Structures for Successful Implementation of a Data Informed Decision-Making Program

During the past 50 years, the landscape of education shifted from a rank order model to a system where all students are expected to achieve at a minimum level. This led to reforms in the way schools operate and teachers teach. One change to teaching is the use of data to inform instructional practices and student groupings. The need for teachers to increase their data use and change their instruction has prompted the need for professional development practices to be more effective. Coaching has been shown to be an effective professional development strategy to help teachers transfer new skills into their practice. This mixed-methods study examined one urban school district\u27s two-year attempt to implement a data informed decision-making model of instruction in 20 schools through the use of instructional coaches. The study used two data sets - archival literacy benchmark scores and coach surveys - to identify a purposive selection of interview participants. The interviews were conducted to determine what structures and factors increased the implementation of the data informed decision-making initiative. Findings indicate professional development and leadership structures were needed for successful implementation of the data initiative. Results of this study showed the factors of trust, focus, coach-principal relationship, and assessment literacy contributed to the coaches\u27 ability to implement the data initiative successfully

The National Rise in Residential Segregation

Exploiting complete census manuscript files, we derive a new segregation measure using the racial similarity of next-door neighbors. The fineness of our measure reveals new facts not captured by traditional segregation indices. First, segregation doubled nationally from 1880 to 1940. Second, contrary to prior estimates, Southern urban areas were the most segregated in the country and remained so over time. Third, increasing segregation in the twentieth century was not strictly driven by urbanization, black migration, or white flight: it resulted from increasing racial sorting at the household level. In all areas-North and South, urban and rural-segregation increased dramatically

Compositional characteristics and spatial distribution of enriched Icelandic mantle components

Author Posting. © The Authors, 2010. This is the author's version of the work. It is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Journal of Petrology 51 (2010): 1447-1475, doi:10.1093/petrology/egq025.We present compositional data on a suite of 18 primitive neovolcanic alkali basalts from three flank zone regions in Iceland (Vestmannaeyjar in the south, Snæfell in the east, and Snæfellsnes in the west) that are peripheral to the main rift zones that are dominated by tholeiitic basalts. This study integrates He isotope data with radiogenic isotope data (Sr-Nd-Pb-Hf), stable isotope data (δ18O), and trace element data to characterise the compositional features of the trace-elementenriched components of the Icelandic mantle. We also present high-precision Pb isotope data on an additional 57 lava samples from the flank zones (including Öræfajökull in the south-east) and the Northern and Eastern rift zones. Most Icelandic lavas have negative Δ207Pb (–4 to –1), with higher values (–1 to +4) found only in samples from Öræfajökull, Snæfell, and parts of the Reykjanes Peninsula. At Snæfell, this EM1-type component is characterised by a low δ18Oolivine signature (+4.1‰ to +4.6‰), moderate 206Pb/204Pb values (18.4-18.6) and MORB-like 3He/4He (6.9-7.5 R/RA). Samples from Vestmannaeyjar and Snæfellsnes have mantle-like δ18Oolivine (+4.9‰ to +5.0‰), and radiogenic 206Pb/204Pb values (18.9-19.3) that fall on the NHRL for 208Pb/204Pb (Δ208Pb –5 to +5). Compared to the Vestmannaeyjar lavas, Snæfellsnes lavas have higher La/YbN (5-11 vs. 3-5), lower εNd (5.5-6.5 vs. 6.8-7.6) and lower 3He/4He (6.3-8.6 R/RA vs. 11.4-13.5 R/RA). Therefore, the most trace element enriched components in the Icelandic mantle are not the carriers of the high 3He/4He values (> 15 R/RA) found in some lavas on Iceland and the adjacent ridges, and instead are consistent with degassed, recycled components. Even after excluding the EM1-type high Δ207Pb samples, high-precision Pb isotope data produce a kinked array on an 206Pb/204Pb vs. 208Pb/204Pb plot, which is not consistent with simple binary mixing between two end-members. This requires significant lateral heterogeneity within the Icelandic mantle and the presence of more than just two compositionally-distinct local mixing end-member components. Samples from each of the main axial rift zones define different trends. Despite the tectonic continuity between the Northern Volcanic Zone and the Eastern Volcanic Zone, lavas from these two rift zones define separate sub-parallel linear arrays. Lavas from the adjacent Western Volcanic Zone and the Eastern Volcanic Zone define oblique linear arrays that converge on a common local end-member that is not involved in the magmatism of the Northern Volcanic Zone. Therefore, there is a distinct NE-SW compositional heterogeneity within the Icelandic mantle.work was funded primarily by the Danish National Research Foundation through a grant to the former Danish Lithosphere Centre, with additional funding from the University of Iowa for the oxygen isotope analyses

A murine model of Charcot-Marie-Tooth disease 4F reveals a role for the C-terminus of periaxin in the formation and stabilization of Cajal bands

Charcot-Marie-Tooth (CMT) disease comprises up to 80 monogenic inherited neuropathies of the peripheral nervous system (PNS) that collectively result in demyelination and axon degeneration. The majority of CMT disease is primarily either dysmyelinating or demyelinating in which mutations affect the ability of Schwann cells to either assemble or stabilize peripheral nerve myelin. CMT4F is a recessive demyelinating form of the disease caused by mutations in the Periaxin (PRX) gene. Periaxin (Prx) interacts with Dystrophin Related Protein 2 (Drp2) in an adhesion complex with the laminin receptor Dystroglycan (Dag). In mice the Prx/Drp2/Dag complex assembles adhesive domains at the interface between the abaxonal surface of the myelin sheath and the cytoplasmic surface of the Schwann cell plasma membrane. Assembly of these appositions causes the formation of cytoplasmic channels called Cajal bands beneath the surface of the Schwann cell plasma membrane. Loss of either Periaxin or Drp2 disrupts the appositions and causes CMT in both mouse and man. In a mouse model of CMT4F, complete loss of Periaxin first prevents normal Schwann cell elongation resulting in abnormally short internodal distances which can reduce nerve conduction velocity, and subsequently precipitates demyelination. Distinct functional domains responsible for Periaxin homodimerization and interaction with Drp2 to form the Prx/Drp2/Dag complex have been identified at the N-terminus of Periaxin. However, CMT4F can also be caused by a mutation that results in the truncation of Periaxin at the extreme C-terminus with the loss of 391 amino acids. By modelling this in mice, we show that loss of the C-terminus of Periaxin results in a surprising reduction in Drp2. This would be predicted to cause the observed instability of both appositions and myelin, and contribute significantly to the clinical phenotype in CMT4F

Nickel and helium evidence for melt above the core–mantle boundary

High ^(3)He/^(4)He ratios in some basalts have generally been interpreted as originating in an incompletely degassed lower-mantle source. This helium source may have been isolated at the core–mantle boundary region since Earth’s accretion. Alternatively, it may have taken part in whole-mantle convection and crust production over the age of the Earth; if so, it is now either a primitive refugium at the core–mantle boundary or is distributed throughout the lower mantle. Here we constrain the problem using lavas from Baffin Island, West Greenland, the Ontong Java Plateau, Isla Gorgona and Fernandina (Galapagos). Olivine phenocryst compositions show that these lavas originated from a peridotite source that was about 20 per cent higher in nickel content than in the modern mid-ocean-ridge basalt source. Where data are available, these lavas also have high ^(3)He/^(4)He. We propose that a less-degassed nickel-rich source formed by core–mantle interaction during the crystallization of a melt-rich layer or basal magma ocean, and that this source continues to be sampled by mantle plumes. The spatial distribution of this source may be constrained by nickel partitioning experiments at the pressures of the core–mantle boundary

Mutation in the Gene Encoding Ubiquitin Ligase LRSAM1 in Patients with Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730–129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy

IMPORTANCE: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. OBJECTIVE: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. DESIGN, SETTING, AND PARTICIPANTS: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group. INTERVENTIONS: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). MAIN OUTCOMES AND MEASURES: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. RESULTS: Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P < .001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. CONCLUSIONS AND RELEVANCE: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10

Step-Wise Loss of Bacterial Flagellar Torsion Confers Progressive Phagocytic Evasion

Phagocytosis of bacteria by innate immune cells is a primary method of bacterial clearance during infection. However, the mechanisms by which the host cell recognizes bacteria and consequentially initiates phagocytosis are largely unclear. Previous studies of the bacterium Pseudomonas aeruginosa have indicated that bacterial flagella and flagellar motility play an important role in colonization of the host and, importantly, that loss of flagellar motility enables phagocytic evasion. Here we use molecular, cellular, and genetic methods to provide the first formal evidence that phagocytic cells recognize bacterial motility rather than flagella and initiate phagocytosis in response to this motility. We demonstrate that deletion of genes coding for the flagellar stator complex, which results in non-swimming bacteria that retain an initial flagellar structure, confers resistance to phagocytic binding and ingestion in several species of the gamma proteobacterial group of Gram-negative bacteria, indicative of a shared strategy for phagocytic evasion. Furthermore, we show for the first time that susceptibility to phagocytosis in swimming bacteria is proportional to mot gene function and, consequently, flagellar rotation since complementary genetically- and biochemically-modulated incremental decreases in flagellar motility result in corresponding and proportional phagocytic evasion. These findings identify that phagocytic cells respond to flagellar movement, which represents a novel mechanism for non-opsonized phagocytic recognition of pathogenic bacteria

Genetic spectrum of hereditary neuropathies with onset in the first year of life

Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine–Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot–Marie–Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot–Marie–Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot–Marie–Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset