Eugenics,Epigenetics, and Obesity Predisposition among Mexican Mestizos

ABSTRACT

We compare the discourses on obesity found in early- and mid-twentieth century Mexican public discourse with those of Mexican geneticists and doctors today. We argue that postgenomic shifts towards non-determinism, apparently contained in current openness to epigenetics, need to be considered alongside the persistence of racialized genetic determinisms, and alongside the potential for epigenetic environmental determinisms. By exploring the environmentalist explanations of earlier eugenic thinking about obesity, we trace continuities in the gendered and racialized framings of obesity, which risk stigmatizing indigenous ancestry and attributing blame to individual mothers.     

Intranasal hydromorphone for treatment of acute pain in children: A pilot study

ObjectivesWe aimed to describe the analgesic efficacy, duration of analgesia, and adverse event profile associated with intranasal hydromorphone in children with acute pain presenting to an emergency department.MethodsProspective dose titration pilot study of otherwise healthy children 4 to 17-years-old with moderate to severe pain who required a parenteral opioid. All patients received an initial intranasal hydromorophone dose of 0.03 mg/kg. The need for additional analgesia was assessed at 15 and 30 min; an additional 0.015 mg/kg was given at each assessment, if required. Need for rescue analgesic, pain intensity and adverse events were assessed until 6 h after hydromorphone administration or until patients were discharged, underwent a procedure to treat their painful condition, or received a rescue analgesic.ResultsWe enrolled 35 children. Fifteen, 11, and 9 children required a total dose of 0.03, 0.045, and 0.06 mg/kg, respectively. Patients in each dose group experienced an absolute decrease in pain score of ≥3/10 and percent reduction >40% within 5–15 min of completing dose-titration administration of hydromorphone. Duration of analgesia (i.e. time until rescue analgesic administered) >1 h was observed in 85.7% of patients. Patients not requiring rescue analgesics had mild or no pain until discharged or their painful conditions were treated. Three (8.6%) patients required a rescue analgesic <1 h after hydromorphone administration. There were no major adverse events.ConclusionsIntranasal hydromorphone led to rapid, clinically significant and frequently sustained decreases in pain intensity in children. No major adverse events were observed in this preliminary sample.Clinical Trials Registration Number: NCT02437669     

The impact of chronic kidney disease on lower extremity bypass outcomes in patients with critical limb ischemia

Objective

Patient selection for open lower extremity revascularization in patients with chronic kidney disease (CKD) remains a clinical challenge. This study investigates the impact of CKD on early graft failure, postoperative complications, and mortality in patients undergoing lower extremity bypass for critical limb ischemia.

Challenges for Research into Military Investigations

In cases of suspected violations of rules, regulations or the law by armed forces personnel, investigations are invariably mandatory. Military investigations differ from well-researched civilian criminal investigations. Differing from civilian police detectives, most military investigators – as disciplinary supervisors and military police personnel – have a number of tasks to accomplish, which include leading in combat and ensuring military readiness. Military investigations can lead to substantive negative or positive consequences for military readiness, including mental health, unit cohesion and subjective legal certainty. This impact on unit cohesion and mental health is influenced by any prior history of distress or trauma; military investigations are often preceded by contravention of internal disciplinary acts, complaints and traumatic events. This study explores factors in the differing military and legal systems of Germany and the United Kingdom (UK) that might help military personnel to successfully conduct investigations while ensuring deployment readiness and maintaining human rights.     

Midterm results of endovascular aneurysm sealing to treat abdominal aortic aneurysm

Background

Endovascular aneurysm sealing (EVAS) represents a novel approach to the treatment of abdominal aortic aneurysms. It uses polymer technology to achieve an anatomic seal within the sac of the aneurysm. This cohort study reports the early clinical outcomes, technical refinements, and learning curve during the initial EVAS experience at a single institution.

Health Care Utilization After Ventricular Tachycardia Ablation: A Propensity Score-Matched Cohort Study

Background

Catheter ablation of ventricular tachycardia (VT) can reduce the burden of ventricular arrhythmia (VA) but its effect on health care utilization and costs after such therapy is poorly known. We sought to compare the rates of cardiovascular (CV)-related hospitalizations, survival, and health care costs in patients with recurrent VT treated either with VT ablation or with medical therapy.

Sex bias of females in survival from cancer and infections. Is X the answer?

Major differences in survival of men and women from infectious diseases and cancers have been highlighted by death rates from COVID-19 infections. In cancer, attention has been focussed on differences in gene expression from X chromosomes in men and women with a preponderance of genes involved in immune responses being expressed in women. Important findings have been that some of the genes are important epigenetic regulators that play fundamental roles in immune responses.Subject terms: Cancer epigenetics, Oncology

One of the striking features of the coronavirus disease 2019 (COVID-19) outbreak has been the higher death rates in men even though the infection rates seem similar between men and women.¹ Similar findings were reported from Wuhan where men had 2.4 times the death rate of women² and in New York where press releases stated twice the death rate of men compared with women.³ Although men had higher rates of comorbidities, these differences were not considered sufficient to explain the higher death rates and other explanations have been sort. Women are considered to have stronger immune responses against infective diseases and a higher rate of autoimmune diseases, so this has questioned whether the lower death rate may have an immune basis.A sex bias is not only seen in infections, but also in cancers where a strong sex bias in survival from cancer is well documented.^4,5 For example, women in Australia have approximately half the death rates from melanoma as males.⁶ A number of explanations have been proposed to account for these major differences in melanoma, such as higher sun exposure in males⁷ and higher mutation rates⁸ in melanoma from males. When stringent statistical analyses are carried out, however, female sex remains as the major contributor to longer survival.⁴Melanoma is not the only cancer to show improved survival in females and previous researchers have asked whether this may be due to differences in the sex chromosomes between male and females. In a mammoth study, Dunford and colleagues examined information in The Cancer Genome Atlas (TCGA) from 21 different tumour types from 4100 cancers.⁵ They found that 6 out of 783 X chromosome genes had loss-of-function mutations with tumour-suppressive function in males but not in females. There were no similar differences in 18,055 non-X autosomal genes. Importantly, four of the six genes were known epigenetic regulators, such as KDM6A (lysine-specific demethylase 6A), KDM5C (lysine-specific demethylase 5C), ATRX (Alpha thalassaemia/mental retardation syndrome X-linked) and DDX3X (DEAD-box helicase 3 X-linked).⁵These findings point to important differences in X chromosomes between the sexes. The Y chromosome codes mainly for genes that determine male sex, but X chromosomes are quite large and code for >800 genes many of which are involved in immune responses.⁹ To equalise the number of genes between the sexes, one of the X chromosomes in females undergoes inactivation (Xi) of its genes.¹⁰ The silencing process is, however, not perfect and between 10 and 20% of the genes on the X may be expressed in females depending on the tissue involved. It is probably of significance that failure to silence genes may be particularly high in activated lymphocytes.¹¹ As a result of this phenomenon, females have double expression of many genes involved in immune responses compared with males. Biologists have speculated that this is an evolutionary mechanism to protect the species by enhancing immune responses in females against harmful infections.Analysis of data in the TCGA on 458 melanoma patients revealed that KDM6A expression was strongly related to improved survival from melanoma in female patients. ATRX had prognostic significance in both sexes. Analysis of another series of 678 patients with earlier melanoma referred to as the Leeds Melanoma Cohort confirmed the association with KDM6A expression and also identified KDM5C and DDX3X as being related to improved survival.¹² Immune responses are known to be critical in survival from melanoma and the TCGA analysis allowed us to link high KDM6A to components of the immune system considered important in killing of melanoma. This was particularly so in the production of interferon γ in female patients which is a key cytokine needed by the immune system to kill cancer cells. Gene set analysis also showed downregulation of Myc and other oncogenic pathways that may have contributed to the improvement in survival.¹²These data add to a number of studies implicating KDM6A in immune responses against viral infections and in autoimmune diseases.¹³ At a molecular level, KDM6A is known to have an opposing role to EZH2 (enhancer of Zeste homologue 2) in the PRC2 complex in methylation of Lys 27 on H3 histone. This role may explain some of the effects of KDM6A on the immune system in that we previously reported that EZH2 was associated with the repression of several genes associated with antigen presentation and chemokines involved in T cell responses.¹⁴Although these studies are compelling in linking KDM6A to immune responses, it is still questionable whether it has a role in immune responses against COVID-19. If this was the case, we would expect that women being treated for severe COVID-19 infections in intensive care would have lower KDM6A expression than those with infections not requiring such care.¹⁵ We examined the RNA-seq data from blood samples of 102 COVID-19 patients. This included 38 women and 64 men, where 17 women and 34 men were admitted to intensive care unit. The analysis of KDM6A levels in the women showed that treatment in intensive care unit was associated with higher KDM6A expression ({"type":"entrez-geo","attrs":{"text":"GSE157103","term_id":"157103"}}GSE157103,¹⁵ data not shown). Although this was unexpected, it may indicate that KDM6A expression was linked to stronger responses causing higher inflammation in organs such as the lungs. No differences in KDM6A levels were detected in men irrespective of whether they were admitted to intensive care or not.Female patients with bi-allelic expression of KDM6A may induce the expression of interferon γ pathways which enhance anti-tumour immunity by recruiting immune modulatory cells (Fig. 1). These results point to the need for a better understanding of the role of X-linked genes in immune responses and whether EZH2-mediated suppression of immune modulatory genes have a role in infections as well as in cancer. In cancers and infections that have worst outcomes in males versus females, one approach might be to target (inhibit) the EZH2 epigenetic regulator that opposes KDM6A (Fig. 1). Another option may be to increase levels of KDM6A by administration of oestrogens. Oestrogen α receptors are expressed in practically all lymphocytes and were shown to physically interact with KDM6A to create a permissive chromatin state on endoplasmic reticulum (ER) targets such as C-X-C chemokine motif receptor 4.¹⁶ It was transactivated by ER to form a feed-forward loop. Administration of 17β-oestradiol has been suggested by others as treatment for COVID-19 infections.¹⁷Open in a separate windowFig. 1Proposed model of sex-biased role of the X-linked KDM6A gene in promoting immunity.Males harbour one X chromosome with no functional Y chromosome homologue. Hence, mutation in the X-linked epigenetic modifier KDM6A with tumour-suppressive or immunomodulatory role will probably lead to cancer or infection in males. Immune-related genes will be repressed by EZH2-mediated H3K27me3 deposition resulting in low KDM6A protein and immune evasion in male patients. In females, with two X chromosome, [one active (Xa) and one inactive (Xi)], a single mutation (m) in KDM6A is less likely to develop cancer or infections since another functional allele escapes X inactivation. Cells with high KDM6A level would be expected to demethylate H3K27me3 resulting in activation of the interferon γ pathway resulting in inactivation of natural killer (NK), dendritic or cytotoxic T cells to induce anti-tumour immunity and adaptive immunity against virus-infected cells.These studies have therefore raised many questions that require more detailed study to identify how the powerful survival benefits of the X-linked epigenetic regulators might be used to improve the therapeutic outcome in patients.     

Black beans and red kidney beans induce positive postprandial vascular responses in healthy adults: A pilot randomized cross-over study

Background and aimsConsuming pulses (dry beans, dry peas, chickpeas, lentils) over several weeks can improve vascular function and decrease cardiovascular disease risk; however, it is unknown whether pulses can modulate postprandial vascular responses. The objective of this study was to compare different bean varieties (black, navy, pinto, red kidney) and white rice for their acute postprandial effects on vascular and metabolic responses in healthy individuals.Methods and resultsThe study was designed as a single-blinded, randomized crossover trial with a minimum 6 days between consumption of the food articles. Vascular tone (primary endpoint), haemodynamics and serum biochemistry (secondary endpoints) were measured in 8 healthy adults before and at 1, 2, and 6 h after eating ¾ cup of beans or rice. Blood pressure and pulse wave velocity (PWV) were lower at 2 h following red kidney bean and pinto bean consumption compared to rice and navy bean, respectively (p < 0.05). There was greater vasorelaxation 6 h following consumption of darker-coloured beans, as shown by decreased vascular tone: PWV was lower after consuming black bean compared to pinto bean, augmentation pressure was lower after consuming black bean compared to rice and pinto bean, and wave reflection magnitude was lower after consuming red kidney bean and black bean compared to rice, navy bean, and pinto bean (p < 0.05). LDL-cholesterol concentrations were lower 6 h after black bean consumption compared to rice (p < 0.05).ConclusionOverall, red kidney and black beans, the darker-coloured beans, elicited a positive effect on the tensile properties of blood vessels, and this acute response may provide insight for how pulses modify vascular function.     

The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence

Brain metastases are a major cause of melanoma-related mortality and morbidity. We undertook whole-exome sequencing of 50 tumours from patients undergoing surgical resection of brain metastases presenting as the first site of visceral disease spread and validated our findings in an independent dataset of 18 patients. Brain metastases had a similar driver mutational landscape to cutaneous melanomas in TCGA. However, KRAS was the most significantly enriched driver gene, with 4/50 (8%) of brain metastases harbouring non-synonymous mutations. Hotspot KRAS mutations were mutually exclusive from BRAF^V600, NRAS and HRAS mutations and were associated with a reduced overall survival from the resection of brain metastases (HR 10.01, p = 0.001). Mutations in KRAS were clonal and concordant with extracranial disease, suggesting that these mutations are likely present within the primary. Our analyses suggest that KRAS mutations could help identify patients with primary melanoma at higher risk of brain metastases who may benefit from more intensive, protracted surveillance.Subject terms: CNS cancer, Metastasis, Melanoma, Tumour biomarkers, Cancer     

A second wave of COVID-19 in Cook County: What lessons can be applied?

During the ongoing public health crisis, many agencies are reporting COVID-19 health outcome information based on the overall population. This practice can lead to misleading results and underestimation of high risk areas. To gain a better understanding of spatial and temporal distribution of COVID-19 deaths; the long term care facility (LTCF) and household population (HP) deaths must be used. This approach allows us to better discern high risk areas and provides policy makers with reliable information for community engagement and mitigation strategies. By focusing on high-risk LTCFs and residential areas, protective measures can be implemented to minimize COVID-19 spread and subsequent mortality.  These areas should be a high priority target when COVID-19 vaccines become available

During the current public health crisis, many agencies and media outlets are reporting COVID-19 health outcome information based on the overall population of Cook County. As we have demonstrated, overall COVID-19 case counts and mortality can be misleading (details in >Story Map 1). Moreover, they offer little guidance for delivering public health interventions to high risk populations, a critical need during this second and potentially more devastating wave of the pandemic. The University of Illinois Chicago School of Public Health’s Public Health Geographic Information System Program (UIC-SPH-PHGIS) and Purdue research team has been examining spatial and temporal patterns of COVID-19 mortality with a focus on the significant loss of life from COVID-19 among Long-Term Care Facility (LTCF) residents in contrast to mortality in the community among residents of private households (non-LTCF; referred to as household population, HP). The goals of the study are:

• Improve the accuracy of commonly quoted COVID-19 mortality indicators;
• Gain a better understanding of spatial and temporal distribution of COVID-19 deaths;
• Examine the role of race, ethnicity, and socioeconomic status in COVID-19 mortality;
• Identify population and organizational parameters that can inform strategies for public health interventions.

Prioritizing the allocation of resources based on reliable information is a prerequisite of a successful mitigation strategy and immunization plan. Findings from our research have significant practical implications. The state and federal government face a series of policy decisions both due to the recent surge in positive cases and, when the time comes, the need to rationalize distribution of vaccines to high priority groups beyond healthcare workers and nursing home residents in critical areas. The research team seeks to modify prevailing practices in order to derive reliable information that guides policy decisions. At this stage of the study, we identified high-risk LTCFs and residential areas (HP) of Cook County from readily available, real-time mortality data.