A Bicultural Community-Academic Partnership to Improve the Latina/o Physician Workforce in Washington State (2019-2021).

From July 2019 through April 2021, the Latino Center for Health, a bicultural population health research center at the University of Washington, partnered with community stakeholders to generate evidence to inform elected officials about the need to increase the diversity of the state's physician workforce and ultimately improve Latina/o health in Washington state. Legislative efforts resulted in legislation creating goals for the state's medical schools to admit students representative of the state's population diversity and the creation of a new residency pathway for international medical graduates. (Am J Public Health. 2024;114(S6):S467-S471. https://doi.org/10.2105/AJPH.2024.307627) [Formula: see text].

Insufficient duration of insecticidal efficacy of Yahe® insecticide-treated nets in Papua New Guinea.

BACKGROUND: Insecticide-treated nets (ITNs) are the backbone of anti-malarial vector control in Papua New Guinea (PNG). Over recent years the quality and performance of ITNs delivered to PNG decreased, which has likely contributed to the stagnation in the malaria control effort in the country. The present study reports results from the first 24 months of a durability study with the ITN product Yahe LN® in PNG. METHODS: The durability study was conducted in four villages on the northern coast of PNG, in an area with high malaria parasite transmission, following WHO-recommended methodology adapted to the local scenario. A cohort of n = 500 individually identifiable Yahe® ITNs was distributed by the PNG National Malaria Control Programme from October to December 2021. Insecticidal efficacy of the ITNs was tested using cone bioassays with fully pyrethroid susceptible Anopheles farauti colony mosquitoes at baseline and at 6 months intervals, alongside evaluation of physical integrity and the proportion of ITNs lost to follow-up. A questionnaire was used to collect information on ITN end user behaviour, such as the frequency of use and washing. The observations from the durability study were augmented with simulated laboratory wash assays. RESULTS: Gradual uptake and replacement of previous campaign nets by the communities was observed, such that at 6 months 45% of all newly distributed nets were in use in their designated households. Insecticidal efficacy of the Yahe® nets, expressed as the percent 24 h mortality in cone bioassays decreased from 91 to 45% within the first 6 months of distribution, even though > 90% of study nets had never been washed. Insecticidal efficacy decreased further to < 20% after 24 months. ITNs accumulated physical damage (holes) at a rate similar to previous studies, and 35% were classified as 'too torn' by proportional hole index after 24 months. ITNs were lost to follow-up such that 61% of cohort nets were still present after 24 months. Laboratory wash assays indicated a rapid reduction in insecticidal performance with each consecutive wash such that average 24 h mortality was below 20% after 10 washes. CONCLUSION: Yahe® ITNs are not performing as per label claim in an area with fully pyrethroid susceptible vectors, and should be investigated more comprehensively and in other settings for compliance with currently recommended durability and efficacy thresholds. The mass distribution of low quality ITN products with variable performance is one of the major ongoing challenges for global malaria control in the last decade.

Barriers to Community-Based Eradication of Helicobacter pylori Infection.

Helicobacter pylori (HP) is a causative agent in gastric cancer (GC).1 In the United States, HP is more prevalent in racial and ethnic minorities, including African Americans, Asian Americans, Latinos, and immigrants, the same groups that are more likely to develop and die from GC.2 Although screening for HP is not presently performed in the United States, there are plausible benefits to doing so, because HP is considered a group 1 carcinogen by the World Health Organization, and its link to GC parallels that of human papilloma virus and cervical cancer.1 HP eradication as a means of preventing GC also fulfils the Wilson and Jungner criteria for a successful screening program, and literature has consistently demonstrated that HP eradication reduces GC risk and death from GC.3 In fact, in countries with a high burden of GC, HP eradication is considered primary prevention for GC. As such, targeted HP testing in the United States may reduce GC burden in high-risk groups.4 We evaluate the results of community-based HP testing in an at-risk, underserved population.

C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types.

Introduction: A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis. Methods: We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, and cerebellum) with average gene expression values for 15,633 protein-coding genes, including 54 genes known to be associated with ALS, FTD, or ALS-FTD. We then performed imaging transcriptomic analyses to evaluate whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n = 19) compared to controls (n = 23). Lastly, we explored whether genes with significant C9orf72 imaging transcriptomic correlations (i.e., "C9orf72 imaging transcriptomic network") were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways. Results: A total of 2,120 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 imaging transcriptomic network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic neurons in the spinal cord and brainstem and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with protein ubiquitination, autophagy, cellular response to DNA damage, endoplasmic reticulum to Golgi vesicle-mediated transport, among others. Conclusion: Considered together, we identified a network of C9orf72 associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.

Waste to energy, indispensable cornerstone for circular economy: A mini-review.

This mini-review aims at proving that waste-to-energy (WtE) is an essential cornerstone for circular economy (CE). Based on literature, the history of thermal waste treatment over the last 150 years is investigated, from open burning to WtE with resource recovery and final sink function. The results show that in the past incineration solved the issues it was designed for but often created new and sometimes even worse problems: The introduction of incineration in the 19th century improved urban sanitation, decreased waste volume and prolonged operational life of landfills. But it also polluted the environment, triggering an unprecedented scientific and engineering effort of all stakeholders. Today, WtE is one of the best investigated and optimized technologies in waste management. It enables the recovery of energy as heat and electric power and facilitates the 'cleaning' of cycles by the destruction of hazardous organic substances. Recent developments in resource recovery from WtE residues allow to recycle metals and, in the case of sewage sludge, even phosphorus by thermal recycling. Combined with carbon capture and storage technology, WtE stands for a quantifiable contribution to greenhouse gas reduction. Today, WtE is indispensable to reach the goals of CE, namely recycling of energy and materials, supplying safe final sinks for persistent organic substances and minimizing the need for sinks for hazardous inorganic substances.

Biofilm formation and desiccation survival of Listeria monocytogenes with microbiota on mushroom processing surfaces and the effect of cleaning and disinfection.

Microbial multispecies communities consisting of background microbiota and Listeria monocytogenes could be established on materials used in food processing environments. The presence, abundance and diversity of the strains within these microbial multispecies communities may be affected by mutual interactions and differences in resistance towards regular cleaning and disinfection (C&D) procedures. Therefore, this study aimed to characterize the growth and diversity of a L. monocytogenes strain cocktail (n = 6) during biofilm formation on polyvinyl chloride (PVC) and stainless steel (SS) without and with the presence of a diverse set of background microbiota (n = 18). L. monocytogenes and background microbiota strains were isolated from mushroom processing environments and experiments were conducted in simulated mushroom processing environmental conditions using mushroom extract as growth medium and ambient temperature (20 °C) as culturing temperature. The L. monocytogenes strains applied during monospecies biofilm incubation formed biofilms on both PVC and SS coupons, and four cycles of C&D treatment were applied with a chlorinated alkaline cleaning agent and a disinfection agent based on peracetic acid and hydrogen peroxide. After each C&D treatment, the coupons were re-incubated for two days during an incubation period for 8 days in total, and C&D resulted in effective removal of biofilms from SS (reduction of 4.5 log CFU/cm2 or less, resulting in counts below detection limit of 1.5 log CFU/cm2 after every C&D treatment), while C&D treatments on biofilms formed on PVC resulted in limited reductions (reductions between 1.2 and 2.4 log CFU/cm2, which equals a reduction of 93.7 % and 99.6 %, respectively). Incubation of the L. monocytogenes strains with the microbiota during multispecies biofilm incubation led to the establishment of L. monocytogenes in the biofilm after 48 h incubation with corresponding high L. monocytogenes strain diversity in the multispecies biofilm on SS and PVC. C&D treatments removed L. monocytogenes from multispecies biofilm communities on SS (reduction of 3.5 log CFU/cm2 or less, resulting in counts below detection limit of 1.5 log CFU/cm2 after every C&D treatment), with varying dominance of microbiota species during different C&D cycles. However, C&D treatments of multispecies biofilm on PVC resulted in lower reductions of L. monocytogenes (between 0.2 and 2.4 log CFU/cm2) compared to single species biofilm, and subsequent regrowth of L. monocytogenes and stable dominance of Enterobacteriaceae and Pseudomonas. In addition, planktonic cultures of L. monocytogenes were deposited and desiccated on dry surfaces without and with the presence of planktonic background microbiota cultures. The observed decline of desiccated cell counts over time was faster on SS compared to PVC. However, the application of C&D resulted in counts below the detection limit of 1.7 log CFU/coupon on both surfaces (reduction of 5.9 log CFU/coupon or less). This study shows that L. monocytogenes is able to form single and multispecies biofilms on PVC with high strain diversity following C&D treatments. This highlights the need to apply more stringent C&D regime treatments for especially PVC and similar surfaces to efficiently remove biofilm cells from food processing surfaces.

Domain structure and cross-linking in a giant adhesin from the Mobiluncus mulieris bacterium.

Cell-surface proteins known as adhesins enable bacteria to colonize particular environments, and in Gram-positive bacteria often contain autocatalytically formed covalent intramolecular cross-links. While investigating the prevalence of such cross-links, a remarkable example was discovered in Mobiluncus mulieris, a pathogen associated with bacterial vaginosis. This organism encodes a putative adhesin of 7651 residues. Crystallography and mass spectrometry of two selected domains, and AlphaFold structure prediction of the remainder of the protein, were used to show that this adhesin belongs to the family of thioester, isopeptide and ester-bond-containing proteins (TIE proteins). It has an N-terminal domain homologous to thioester adhesion domains, followed by 51 immunoglobulin (Ig)-like domains containing ester- or isopeptide-bond cross-links. The energetic cost to the M. mulieris bacterium in retaining such a large adhesin as a single gene or protein construct suggests a critical role in pathogenicity and/or persistence.

It's about time: small mammal communities and Lyme disease emergence.

Theory predicts that biodiversity changes due to climate warming can mediate the rate of disease emergence. The mechanisms linking biodiversity-disease relationships have been described both theoretically and empirically but remain poorly understood. We investigated the relations between host diversity and abundance and Lyme disease risk in southern Quebec, a region where Lyme disease is rapidly emerging. We found that both the abundance of small mammal hosts and the relative abundance of the tick's natural host, the white-footed mouse (Peromyscus leucopus), influenced measures of disease risk in tick vectors (Borrelia burgdorferi infection abundance and prevalence in tick vectors). Our results suggest that the increase in Lyme disease risk is modulated by regional processes involving the abundance and composition of small mammal assemblages. However, the nature and strength of these relationships was dependent both on time and geographic area. The strong effect of P. leucopus abundance on disease risk we report here is of significant concern, as this competent host is predicted to increase in abundance and occurrence in the region, with the northern shift in the range of North American species under climate warming.

C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types.

Introduction: A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis. Methods: We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, cerebellum) with average gene expression values for 15,633 protein-coding genes, including 50 genes known to be associated with ALS, FTD, or ALS-FTD. We then evaluated whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n=19). Lastly, we explored whether genes with significant C9orf72 radiogenomic correlations (i.e., 'C9orf72 gene network') were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways. Results: A total of 1,748 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 gene network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic motor neurons in the spinal cord, and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with multiple neurotransmitter systems, protein ubiquitination, autophagy, and MAPK signaling, among others. Conclusions: Considered together, we identified a network of C9orf72-associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.

Tobacco Use Patterns From Adolescence to Young Adulthood Among Latinx Youth From Rural Communities.

PURPOSE: To examine patterns in adolescent and young adult tobacco use, comparing Latinx foreign-born children and children of foreign-born parents (i.e., children of immigrants(COI)) to Latinx US-born children of US-born parents (i.e., children of nonimmigrants,(CONI)) and to CONI White youth who grew up in small and rural towns. METHODS: Data were from youth who lived in control communities that participated in a community-randomized trial of the Communities That Care prevention system. We compared Latinx CONI (n = 154) with Latinx COI (n = 316) and with non-Latinx White CONI (n = 918). We examined tobacco use in adolescence (any adolescent use, early onset, and chronic use) and young adulthood (any past-year tobacco use, any daily smoking, any nicotine dependence symptoms) with mixed-effects logistic regressions. RESULTS: In adolescence, Latinx CONI had a higher prevalence of any and chronic tobacco use relative to Latinx COI, and of any and early onset tobacco use relative to non-Latinx White CONI. In young adulthood, Latinx CONI were more likely to report tobacco use in the past year, any symptoms of nicotine dependence, and daily smoking relative to Latinx COI; and more likely to report daily smoking relative to non-Latinx White CONI. Generation differences in young adult tobacco use were explained by chronic tobacco use in adolescence. DISCUSSION: The study suggests targeting chronic tobacco use in adolescence to prevent disparities in tobacco outcomes among Latinx young adults from rural communities.

Variability in growth and biofilm formation of Listeria monocytogenes in Agaricus bisporus mushroom products.

Foods and food production environments can be contaminated with Listeria monocytogenes and may support growth of this foodborne pathogen. This study aims to characterize the growth and biofilm formation of sixteen L. monocytogenes strains, isolated from mushroom production and processing environments, in filter-sterilized mushroom medium. Strain performance was compared to twelve L. monocytogenes strains isolated from other sources including food and human isolates. All twenty-eight L. monocytogenes strains showed rather similar growth performance at 20 °C in mushroom medium, and also significant biofilm formation was observed for all strains. HPLC analysis revealed the presence of mannitol, trehalose, glucose, fructose and glycerol, that were all metabolized by L. monocytogenes, except mannitol, in line with the inability of L. monocytogenes to metabolize this carbohydrate. Additionally, the growing behavior of L. monocytogenes was tested on whole, sliced and smashed mushroom products to quantify performance in the presence of product-associated microbiota. A significant increase of L. monocytogenes was observed with higher increase of counts when the mushroom products were more damaged, even with the presence of high background microbiota counts. This study demonstrated that L. monocytogenes grows well in mushroom products, even when the background microbiota is high, highlighting the importance to control (re)contamination of mushrooms.

Growth performance of Listeria monocytogenes and background microbiota from mushroom processing environments.

Interaction between Listeria monocytogenes and resident background microbiota may occur in food processing environments and may influence the survival of this pathogen in a factory environment. Therefore the aim of this study was to characterize the growth performance of microbiota isolated from the processing environments of frozen sliced mushrooms, and to investigate the competitive performance of L. monocytogenes when co-cultured with accompanying environmental microbiota. Acinetobacter, Enterobacteriaceae, Lactococcus and Pseudomonas were the most prominent background microbiota isolated from the processing environment of frozen sliced mushrooms. All individual microbiota strains were able to grow and form biofilm in filter-sterilized mushroom medium, with the mannitol-consumers Raoultella and Ewingella as top performers, reaching up to 9.6 and 9.8 log CFU/mL after 48 h incubation at room temperature. When L. monocytogenes mushroom isolates were co-cultured with the microbiota strains, L. monocytogenes counts ranged from 7.6 to 8.9 log CFU/mL after 24 h of incubation, while counts of the microbiota strains ranged from 5.5 to 9.0 log CFU/mL. Prolonged incubation up to 48 h resulted in further increase of L. monocytogenes counts when co-cultured with non-acidifying species Pseudomonas and Acinetobacter reaching 9.1 to 9.2 log CFU/mL, while a decrease of L. monocytogenes counts reaching 5.8 to 7.7 log CFU/mL was observed in co-culture with Enterobacteriaceae and acidifying Lactococcus representatives. In addition, L. monocytogenes grew also in spent mushroom media of the microbiota strains, except in acidified spent media of Lactococcus strains. These results highlight the competitive ability of L. monocytogenes during co-incubation with microbiota in fresh and in spent mushroom medium, indicative of its invasion and persistence capacity in food processing factory environments.

A 3D human co-culture to model neuron-astrocyte interactions in tauopathies.

BACKGROUND: Intraneuronal tau aggregation is the major pathological hallmark of neurodegenerative tauopathies. It is now generally acknowledged that tau aggregation also affects astrocytes in a cell non-autonomous manner. However, mechanisms involved are unclear, partly because of the lack of models that reflect the situation in the human tauopathy brain. To accurately model neuron-astrocyte interaction in tauopathies, there is a need for a model that contains both human neurons and human astrocytes, intraneuronal tau pathology and mimics the three-dimensional architecture of the brain. RESULTS: Here we established a novel 100-200 µm thick 3D human neuron/astrocyte co-culture model of tau pathology, comprising homogenous populations of hiPSC-derived neurons and primary human astrocytes in microwell format. Using confocal, electron and live microscopy, we validate the procedures by showing that neurons in the 3D co-culture form pre- and postsynapses and display spontaneous calcium transients within 4 weeks. Astrocytes in the 3D co-culture display bipolar and stellate morphologies with extensive processes that ensheath neuronal somas, spatially align with axons and dendrites and can be found perisynaptically. The complex morphology of astrocytes and the interaction with neurons in the 3D co-culture mirrors that in the human brain, indicating the model's potential to study physiological and pathological neuron-astrocyte interaction in vitro. Finally, we successfully implemented a methodology to introduce seed-independent intraneuronal tau aggregation in the 3D co-culture, enabling study of neuron-astrocyte interaction in early tau pathogenesis. CONCLUSIONS: Altogether, these data provide proof-of-concept for the utility of this rapid, miniaturized, and standardized 3D model for cell type-specific manipulations, such as the intraneuronal pathology that is associated with neurodegenerative disorders.

An unprecedented function for a tungsten-containing oxidoreductase.

Five tungstopterin-containing oxidoreductases were characterized from the hyperthermophile Pyrococcus furiosus. Each enzyme catalyzes the reversible conversion of one or more aldehydes to the corresponding carboxylic acid, but they have different specificities. The physiological functions of only two of these enzymes are known: one, termed GAPOR, is a glycolytic enzyme that oxidizes glyceraldehyde-3-phosphate, while the other, termed AOR, oxidizes multiple aldehydes generated during peptide fermentation. Two of the enzymes have known structures (AOR and FOR). Herein, we focus on WOR5, the fifth tungstopterin enzyme to be discovered in P. furiosus. Expression of WOR5 was previously shown to be increased during cold shock (growth at 72 â„ƒ), although the physiological substrate is not known. To gain insight into WOR5 function, we sought to determine both its structure and identify its intracellular substrate. Crystallization experiments were performed with a concentrated cytoplasmic extract of P. furiosus grown at 72 â„ƒ and the structure of WOR5 was deduced from the crystals that were obtained. In contrast to a previous report, WOR5 is heterodimeric containing an additional polyferredoxin-like subunit with four [4Fe-4S] clusters. The active site structure of WOR5 is substantially different from that of AOR and FOR and the significant electron density observed adjacent to the tungsten cofactor of WOR5 was modeled as an aliphatic sulfonate. Biochemical assays and product analysis confirmed that WOR5 is an aliphatic sulfonate ferredoxin oxidoreductase (ASOR). A catalytic mechanism for ASOR is proposed based on the structural information and the potential role of ASOR in the cold-shock response is discussed.

Pattern ERGs suggest a possible retinal contribution to the visual acuity loss in acute optic neuritis.

PURPOSE: Macular involvement in optic neuritis (ON) is well-recognised but poorly understood and may be of clinical relevance. This study explores macular structure-function correlates in acute ON. METHODS: This cross-sectional cohort study recruited ON patients within 14 days of symptom onset. Subjects underwent pattern electroretinography (PERG), pattern visual evoked potentials (PVEP) and optical coherence tomography (OCT) imaging. PERG P50 and N95 components were correlated with OCT data. RESULTS: Twenty-six individuals with ON were recruited, comprising eleven multiple sclerosis (MS-ON), six myelin oligodendrocyte glycoprotein associated (MOG-ON) and nine with isolated ON. These were compared with 28 healthy controls. PVEPs were undetectable in 11 (42%) of individuals with ON. When detectable, PVEP P100 was delayed (median 136 ms range 110-173 ms) and amplitude reduced (median 6 µV, range 3-14 µV) in ON compared with controls (both p < 0.001). PERG P50 component amplitudes, largely reflecting macular function, were reduced in affected eyes (median 2.3 µV; range 0.8-5.0 µV) compared with controls (3.3 µV; range 2.8-5.7 µV) and compared with fellow eyes (p < 0.001). The N95:P50 ratio was below the reference range in the affected eyes of five patients. Eight cases (32%) had subnormal P50 amplitudes (< 2.0 µV), and these patients had poorer visual acuity (p = 0.020). P50 amplitudes were positively correlated with an increase in inner nuclear layer thickness (rs = 0.36; p = 0.009) and macular ganglion cell and inner plexiform layer (mGCIPL) thickness (rs = 0.44, p = 0.022). CONCLUSION: PERG P50 component reduction reveals dysfunction of inner macular layers in acute ON and correlates with structural alterations on OCT. These early macular pathologic processes are likely to contribute to the visual loss.

The Cytoarchitecture of the Tectal-Related Pallium of Squirrelfish, Holocentrus sp.

The squirrelfish, which live in visually complex coral reefs, have very large eyes and a special dual-system "day and night vision" retina. They also have atypical expansions of brain areas involved in processing visual information. The midbrain tectum sends information via diencephalic relay to two enlarged dorsal telencephalic regions. The latter include a superficial dorsal/lateral "cortex-like area" of small to medium-sized cells [area dorsalis telencephali, pars lateralis-dorsal region (dorsal segment); Dld1] which projects to an underlying dorsocentral region of relatively large cells (the area dorsalis telencephali, pars centralis-dorsal region; Dcd) which in turn reconnects with the tectum. Additionally, the cerebellum is also involved in this pathway. The hypertrophied pallial regions, termed the tectal-related pallium (TRP), most likely exert major influences on a variety of visually-related sensorimotor systems. This research aimed at better establishing the cellular structures and possible connections within the TRP. Nissl and rapid Golgi staining, biotinylated dextran amine tracing and cell-filling, and electron microscopy were used in this study. For gross observation of the pallial areas and plotting of the study sites, a mini-atlas of transverse and horizontal sections was constructed. This research better documented the known cellular elements of the TRP and defined two novel cell types. Species differences in the TRP may be related to possible differences in behavior and ecology.

Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors.

Patient-derived organoids (PDOs) recapitulate tumor architecture, contain cancer stem cells and have predictive value supporting personalized medicine. Here we describe a large-scale functional screen of dual-targeting bispecific antibodies (bAbs) on a heterogeneous colorectal cancer PDO biobank and paired healthy colonic mucosa samples. More than 500 therapeutic bAbs generated against Wingless-related integration site (WNT) and receptor tyrosine kinase (RTK) targets were functionally evaluated by high-content imaging to capture the complexity of PDO responses. Our drug discovery strategy resulted in the generation of MCLA-158, a bAb that specifically triggers epidermal growth factor receptor degradation in leucine-rich repeat-containing G-protein-coupled receptor 5-positive (LGR5+) cancer stem cells but shows minimal toxicity toward healthy LGR5+ colon stem cells. MCLA-158 exhibits therapeutic properties such as growth inhibition of KRAS-mutant colorectal cancers, blockade of metastasis initiation and suppression of tumor outgrowth in preclinical models for several epithelial cancer types.

Health inequities and the inappropriate use of race in nephrology.

Chronic kidney disease is an important clinical condition beset with racial and ethnic disparities that are associated with social inequities. Many medical schools and health centres across the USA have raised concerns about the use of race - a socio-political construct that mediates the effect of structural racism - as a fixed, measurable biological variable in the assessment of kidney disease. We discuss the role of race and racism in medicine and outline many of the concerns that have been raised by the medical and social justice communities regarding the use of race in estimated glomerular filtration rate equations, including its relationship with structural racism and racial inequities. Although race can be used to identify populations who experience racism and subsequent differential treatment, ignoring the biological and social heterogeneity within any racial group and inferring innate individual-level attributes is methodologically flawed. Therefore, although more accurate measures for estimating kidney function are under investigation, we support the use of biomarkers for determining estimated glomerular filtration rate without adjustments for race. Clinicians have a duty to recognize and elucidate the nuances of racism and its effects on health and disease. Otherwise, we risk perpetuating historical racist concepts in medicine that exacerbate health inequities and impact marginalized patient populations.