Disparate Impact and the Use of Racial Proxies in Post-MCRI Admissions

The Michigan Civil Rights Initiative (“MCRI”) amended the Michigan Constitution to provide that public universities, colleges, and school districts may not “discriminate against, or grant preferential treatment to, any individual or group on the basis of race, sex, color, ethnicity, or national origin in the operation of . . . public education.” We argue that, in addition to prohibiting the overt use of racial preferences in admissions, the MCRI also prohibits using racial proxies such as socioeconomic status or a “Ten Percent Plan” that aim to prefer minorities in admissions. Though the MCRI does not expressly say so, we stipulate for this paper that its language prohibits universities from overtly considering race in any way when making admissions decisions. It remains unclear, however, what other conduct might be barred by the MCRI. In particular, it is unsettled whether the MCRI would prohibit using proxies or other race-neutral criteria designed to aid minority candidates in admissions. Would a plan similar to the “Texas Ten Percent Plan,” which accepts all in-state students who graduate at the top of their high school classes, violate the MCRI as a proxy for racial preference? What about giving applicants a bonus for socioeconomic disadvantage or overcoming adversity? Does purpose matter? These questions are vital to universities trying to achieve racial diversity in a post- MCRI world. The answers will depend mostly on how state courts interpret the MCRI’s language on “discrimination” and “preferential treatment.

Disparate Impact and the Use of Racial Proxies in Post-MCRI Admissions

The Michigan Civil Rights Initiative (“MCRI”) amended the Michigan Constitution to provide that public universities, colleges, and school districts may not “discriminate against, or grant preferential treatment to, any individual or group on the basis of race, sex, color, ethnicity, or national origin in the operation of . . . public education.” We argue that, in addition to prohibiting the overt use of racial preferences in admissions, the MCRI also prohibits using racial proxies such as socioeconomic status or a “Ten Percent Plan” that aim to prefer minorities in admissions. Though the MCRI does not expressly say so, we stipulate for this paper that its language prohibits universities from overtly considering race in any way when making admissions decisions. It remains unclear, however, what other conduct might be barred by the MCRI. In particular, it is unsettled whether the MCRI would prohibit using proxies or other race-neutral criteria designed to aid minority candidates in admissions. Would a plan similar to the “Texas Ten Percent Plan,” which accepts all in-state students who graduate at the top of their high school classes, violate the MCRI as a proxy for racial preference? What about giving applicants a bonus for socioeconomic disadvantage or overcoming adversity? Does purpose matter? These questions are vital to universities trying to achieve racial diversity in a post- MCRI world. The answers will depend mostly on how state courts interpret the MCRI’s language on “discrimination” and “preferential treatment.

Can hydraulic design explain patterns of leaf water isotopic enrichment in C3 plants?

H2 18 O enrichment develops when leaves transpire, but an accurate generalized mechanistic model has proven elusive. We hypothesized that leaf hydraulic architecture may affect the degree to which gradients in H2 18 O develop within leaves, influencing bulk leaf stable oxygen isotope enrichment (ΔL ) and the degree to which the Péclet effect is relevant in leaves. Leaf hydraulic design predicted the relevance of a Péclet effect to ΔL in 19 of the 21 species tested. Leaves with well-developed hydraulic connections between the vascular tissue and the epidermal cells through bundle sheath extensions and clear distinctions between palisade and spongy mesophyll layers (while the mesophyll is hydraulically disconnected) may have velocities of the transpiration stream such that gradients in H2 18 O develop and are expressed in the mesophyll. In contrast, in leaves where the vascular tissue is hydraulically disconnected from the epidermal layers, or where all mesophyll cells are well connected to the transpiration stream, velocities within the liquid transport pathways may be low enough that gradients in H2 18 O are very small. Prior knowledge of leaf hydraulic design allows informed selection of the appropriate ΔL modelling framework.K.E.L. was supported by an Australian Postgraduate Award and A.S. was supported by an Australian Postgraduate Award and International Postgraduate Research Support. Australian Research Council, Grant/Award Number: DP17010427

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

The effects on isotopic composition of leaf water and transpiration of adding a gas-exchange cuvette

An expression was earlier derived for the non-steady state isotopic composition of a leaf when the composition of the water entering the leaf was not necessarily the same as that of the water being transpired (Farquhar and Cernusak 2005). This was relevant to natural conditions because the associated time constant is typically sufficiently long to ensure that the leaf water composition and fluxes of the isotopologues are rarely steady. With the advent of laser-based measurements of isotopologues, leaves have been enclosed in cuvettes and time courses of fluxes recorded. The enclosure modifies the time constant by effectively increasing the resistance to the one-way gross flux out of the stomata because transpiration increases the vapour concentration within the chamber. The resistance is increased from stomatal and boundary layer in series, to stomata, boundary layer and chamber resistance, where the latter is given by the ratio of leaf area to the flow rate out of the chamber. An apparent change in concept from one-way to net flux, introduced by Song, Simonin, Loucos and Barbour (2015) is resolved, and shown to be unnecessary, but the value of their data is reinforced. This article is protected by copyright. All rights reserved.This work was supported by a grant, ARC DP170104276, to Professors Barbour and Farquhar