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ABSTRACT Although the medical profession strives for equal treatment of all patients, disparities in health care are prevalent. Cultural stereotypes may not be consciously endorsed, but their mere existence influences how information about an individual is processed and leads to unintended biases in decision-making, so called “implicit bias”. All of society is susceptible to these biases, including physicians. Research suggests that implicit bias may contribute to health care disparities by shaping physician behavior and producing differences in medical treatment along the lines of race, ethnicity, gender or other characteristics. We review the origins of implicit bias, cite research documenting the existence of implicit bias among physicians, and describe studies that demonstrate implicit bias in clinical decision-making. We then present the bias-reducing strategies of consciously taking patients’ perspectives and intentionally focusing on individual patients’ information apart from their social group. We conclude that the contribution of implicit bias to health care disparities could decrease if all physicians acknowledged their susceptibility to it, and deliberately practiced perspective-taking and individuation when providing patient care. We further conclude that increasing the number of African American/Black physicians could reduce the impact of implicit bias on health care disparities because they exhibit significantly less implicit race bias.

Dyslexia is a common learning impairment with a genetic basis that affects word reading and spelling. An increasing list of loci and genes have been implicated, but analyses to-date have investigated only limited genomic variation within each locus with no confirmed pathogenic variants identified. Our study is the first to comprehensively sequence both coding and cis-acting regulatory regions of such genes in a large study sample. In a collection of >2000 participants in families from three independent sites, we performed targeted capture and comprehensive sequencing of all exons and some regulatory elements of five candidate risk genes ( DNAAF4 , CYP19A1 , DCDC2 , KIAA0319 and GRIN2B ) for which prior evidence for a role in dyslexia exists from more than one sample. We evaluated evidence for association in each of six dyslexia-related quantitative phenotypes (traits) using both individual common single nucleotide polymorphisms and aggregated rare variants. We detected no promoter alterations and few deleterious variants in the coding exons, none of which showed evidence of association with any trait. Single variant and aggregate testing of DNAAF4 failed to detect significant evidence of association with any of the traits. The other four genes provided evidence of association with one or more traits. A common variant downstream of CYP19A1 showed significant evidence of association with multiple traits with or without verbal IQ (VIQ) adjustment. A haplotype that stretches from the downstream region of KIAA0319 to the second intron of DCDC2 was associated with reduced performance on timed real word reading. Finally, rare exonic variants in GRIN2B were associated with performance on spelling, with or without adjustment for VIQ. Our findings from this large-scale sequencing study complement those from genome-wide association studies, argue against the causative involvement of large-effect coding variants in these five candidate genes, support a multigenic etiology, and suggest a role of transcriptional regulation.

Shark populations have declined across the Caribbean region, with negative associations between shark abundance and human population density, open access to fishing, and proximity to large markets (‘market gravity’). This decline is frequently attributed to fishing mortality, which increases in areas closer to humans and outside marine reserves. Although it is difficult to disentangle the effects of fishing mortality from other anthropogenic pressures on sharks, comparing shark abundance and diversity in jurisdictions with near zero fishing mortality versus prevalent shark fishing can demonstrate the role of overfishing. We used baited remote underwater video systems to compare shark abundance and diversity on coral reefs in 2 Caribbean nations with contrasting levels of shark exploitation: Belize (shark fishing) and The Bahamas (shark sanctuary). The abundance of targeted shark species and diversity were significantly higher in The Bahamas than in Belize. Caribbean reef and nurse shark abundance in Belize were best predicted by fishing-related factors (marine reserves, market gravity, their interaction). In The Bahamas, abiotic factors (depth, sea surface temperature) best predicted nurse shark abundance, while depth, market gravity, and its interaction with marine reserves predicted Caribbean reef shark abundance. These results indicate that fishing mortality reduces shark abundance and diversity in Belize, while lower fishing mortality in The Bahamas has greatly reduced but not eliminated human impacts on sharks. Future work should elucidate the indirect effects of humans to develop holistic shark conservation plans. We suggest minimizing shark fishing through multi national management plans to improve shark abundance and diversity, especially on reefs near densely populated areas.

Background COVID-19 outbreaks have occurred in homeless shelters across the US, highlighting an urgent need to identify the most effective infection control strategy to prevent future outbreaks. Methods We developed a microsimulation model of SARS-CoV-2 transmission in a homeless shelter and calibrated it to data from cross-sectional polymerase chain reaction (PCR) surveys conducted during COVID-19 outbreaks in five homeless shelters in three US cities from March 28 to April 10, 2020. We estimated the probability of averting a COVID-19 outbreak when an exposed individual is introduced into a representative homeless shelter of 250 residents and 50 staff over 30 days under different infection control strategies, including daily symptom-based screening, twice-weekly PCR testing, and universal mask wearing. Results The proportion of PCR-positive residents and staff at the shelters with observed outbreaks ranged from 2.6 to 51.6%, which translated to the basic reproduction number ( R 0 ) estimates of 2.9–6.2. With moderate community incidence (~ 30 confirmed cases/1,000,000 people/day), the estimated probabilities of averting an outbreak in a low-risk ( R 0 = 1.5), moderate-risk ( R 0 = 2.9), and high-risk ( R 0 = 6.2) shelter were respectively 0.35, 0.13, and 0.04 for daily symptom-based screening; 0.53, 0.20, and 0.09 for twice-weekly PCR testing; 0.62, 0.27, and 0.08 for universal masking; and 0.74, 0.42, and 0.19 for these strategies in combination. The probability of averting an outbreak diminished with higher transmissibility ( R 0 ) within the simulated shelter and increasing incidence in the local community. Conclusions In high-risk homeless shelter environments and locations with high community incidence of COVID-19, even intensive infection control strategies (incorporating daily symptom screening, frequent PCR testing, and universal mask wearing) are unlikely to prevent outbreaks, suggesting a need for non-congregate housing arrangements for people experiencing homelessness. In lower-risk environments, combined interventions should be employed to reduce outbreak risk.

Targeted anticancer drug hope for melanoma PLX4032, a small-molecule inhibitor being developed by Plexxikon of California and Roche Pharmaceuticals in New Jersey ( http://go.nature.com/QnVGQx ), selectively targets B-RAFV600E, a mutant form of the B-RAF protein kinase common in several human cancers. In this issue of Nature , Gideon Bollag and colleagues report promising results for PLX4032 in an early clinical trial in melanoma patients who carry this B-RAF mutation. They also describe the structure and function of PLX4032 and present translational data from a phase I trial to show that clinical efficacy requires a drug concentration that is sufficient to cause a substantial degree of inhibition of the ERK pathway downstream of B-RAF. The study demonstrates how the design of early clinical trials based on the biological mechanisms underlying tumour formation has the potential to speed up the process by which anticancer drugs can reach the clinic. PLX4032 is a selective inhibitor of the B-RAF protein that has shown promising results in an early clinical trial in melanoma patients with an activating mutation in B-RAF. Now the structure and function of this inhibitor are described. Translational data from a phase I trial show that clinical efficacy requires a substantial degree of inhibition of the ERK pathway downstream of B-RAF. The data also show that BRAF -mutant melanomas are highly dependent on B-RAF activity. B-RAF is the most frequently mutated protein kinase in human cancers 1 . The finding that oncogenic mutations in BRAF are common in melanoma 2 , followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway 3 , offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts 4 . Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032 (ref. 5 ). In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumour regressions. At higher drug exposures afforded by a new amorphous drug formulation 4 , 5 , greater than 80% inhibition of ERK phosphorylation in the tumours of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily 5 . These data demonstrate that BRAF -mutant melanomas are highly dependent on B-RAF kinase activity.

Konstantinos Lazaridis, Carl Anderson and colleagues report results of a genome-wide association study of primary sclerosing cholangitis (PSC). They identify four new susceptibility loci for PSC and quantify the correlation of common genetic variation shared between PSC and inflammatory bowel diseases. Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A , with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation ( r G ) between PSC and ulcerative colitis (UC) ( r G = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) ( r G = 0.04) ( P = 2.55 × 10 −15 ). UC and CD were genetically more similar to each other ( r G = 0.56) than either was to PSC ( P < 1.0 × 10 −15 ). Our study represents a substantial advance in understanding of the genetics of PSC.

Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer 1 , 2 . The success of poly-ADP ribose polymerase inhibitors in the treatment of breast cancers that are deficient in homologous recombination exemplifies the utility of synthetically lethal genetic interactions in the treatment of breast cancers that are driven by genomic instability 3 . Given that defects in homologous recombination are present in only a subset of breast cancers, there is a need to identify additional driver mechanisms for genomic instability and targeted strategies to exploit these defects in the treatment of cancer. Here we show that centrosome depletion induces synthetic lethality in cancer cells that contain the 17q23 amplicon, a recurrent copy number aberration that defines about 9% of all primary breast cancer tumours and is associated with high levels of genomic instability 4 – 6 . Specifically, inhibition of polo-like kinase 4 (PLK4) using small molecules leads to centrosome depletion, which triggers mitotic catastrophe in cells that exhibit amplicon-directed overexpression of TRIM37 . To explain this effect, we identify TRIM37 as a negative regulator of centrosomal pericentriolar material. In 17q23-amplified cells that lack centrosomes, increased levels of TRIM37 block the formation of foci that comprise pericentriolar material—these foci are structures with a microtubule-nucleating capacity that are required for successful cell division in the absence of centrosomes. Finally, we find that the overexpression of TRIM37 causes genomic instability by delaying centrosome maturation and separation at mitotic entry, and thereby increases the frequency of mitotic errors. Collectively, these findings highlight TRIM37- dependent genomic instability as a putative driver event in 17q23-amplified breast cancer and provide a rationale for the use of centrosome-targeting therapeutic agents in treating these cancers. TRIM37 overexpression promotes centrosome dysfunction that drives genomic instability in breast cancer cell lines containing the recurrent 17q23 amplicon, revealing a vulnerability that can be targeted to eliminate cancer cells.

UK good practice recommendations for outpatient parenteral antimicrobial therapy (OPAT) were published in 2012 and 2015 for adult and paediatric patients, respectively. Here we update the initial good practice recommendations in a combined document based on a further review of the OPAT literature and an extensive consultation process. As with the previous good practice recommendations, these updated recommendations are intended to provide pragmatic guidance for new and established OPAT services across a range of settings and to act as a set of quality indicators for service evaluation and quality improvement.

Background Chronic kidney disease (CKD) is characterized by dysbiosis, elevated levels of uremic toxins, systemic inflammation, and increased markers of oxidative stress. These factors lead to an increased risk of cardiovascular disease (CVD) which is common among CKD patients. Supplementation with high amylose maize resistant starch type 2 (RS-2) can change the composition of the gut microbiota, and reduce markers of inflammation and oxidative stress in patients with end-stage renal disease. However, the impact of RS-2 supplementation has not been extensively studied in CKD patients not on dialysis. Aerobic exercise training lowers certain markers of inflammation in CKD patients. Whether combining aerobic training along with RS-2 supplementation has an additive effect on the aforementioned biomarkers in predialysis CKD patients has not been previously investigated. Methods The study is being conducted as a 16-week, double-blind, placebo controlled, parallel arm, randomized controlled trial. Sixty stage 3–4 CKD patients (ages of 30–75 years) are being randomized to one of four groups: RS-2 & usual care, RS-2 & aerobic exercise, placebo (cornstarch) & usual care and placebo & exercise. Patients attend four testing sessions: Two baseline (BL) sessions with follow up visits 8 (wk8) and 16 weeks (wk16) later. Fasting blood samples, resting brachial and central blood pressures, and arterial stiffness are collected at BL, wk8 and wk16. A stool sample is collected for analysis of microbial composition and peak oxygen uptake is assessed at BL and wk16. Blood samples will be assayed for p-cresyl sulphate and indoxyl sulphate, c-reactive protein, tumor necrosis factor α, interleukin 6, interleukin 10, monocyte chemoattractant protein 1, malondialdehyde, 8-isoprostanes F2a, endothelin-1 and nitrate/nitrite. Following BL, subjects are randomized to their group. Individuals randomized to conditions involving exercise will attend three supervised moderate intensity (55–65% peak oxygen uptake) aerobic training sessions (treadmills, bikes or elliptical machine) per week for 16 weeks. Discussion This study has the potential to yield information about the effect of RS-2 supplementation on key biomarkers believed to impact upon the development of CVD in patients with CKD. We are examining whether there is an additive effect of exercise training and RS-2 supplementation on these key variables. Trial registration Clinicaltrials.gov Trial registration# NCT03689569 . 9/28/2018, retrospectively registered.

PurposeRecent advances in cancer treatment have resulted in greatly improved survival, and yet many patients in the USA have not benefited due to poor access to healthcare and difficulty accessing timely care across the cancer care continuum. Recognizing these issues and the need to facilitate discussions on how to improve navigation services for patients with cancer, the National Cancer Policy Forum of the National Academies of Sciences, Engineering, and Medicine (NASEM) held a workshop entitled, “Establishing Effective Patient Navigation Programs in Oncology. The purpose of this manuscript is to disseminate the conclusions of this workshop while providing a clinically relevant review of patient navigation in oncology.DesignNarrative literature review and summary of workshop discussionsResultsPatient navigation has been shown to be effective at improving outcomes throughout the spectrum of cancer care. Work remains to develop consensus on scope of practice and evaluation criteria and to align payment incentives and policy.ConclusionPatient navigation plays an essential role in overcoming patient- and system-level barriers to improve access to cancer care and outcomes for those most in need.