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Abstract Objective Examine the influence of household income on health‐related quality of life (HRQOL) among children with newly diagnosed acute myeloid leukemia (AML). Design Secondary analysis of data prospectively collected from pediatric patients receiving treatment for AML at 14 hospitals across the United States. Exposure Household income was self‐reported on a demographic survey. The examined mediators included the acuity of presentation and treatment toxicity. Outcome Caregiver proxy reported assessment of patient HRQOL from the Peds QL 4.0 survey. Result Children with AML (n = 131) and caregivers were prospectively enrolled to complete PedsQL assessments. HRQOL scores were better for patients in the lowest versus highest income category (mean ± SD: 76.0 ± 14 household income

The non-breeding season is an understudied, yet likely critical, period for many species. Understanding species’ resource requirements, and determining when limited resources and increased densities may lead to intraspecific competition and demographic partitioning, may aid species conservation efforts. Monitoring species’ resource requirements during the non-breeding season may be more important in highly modified ecosystems, such as intensive agricultural landscapes, where anthropogenic pressures may further limit resources. The Loggerhead Shrike ( Lanius ludovicianus ) is a rapidly declining avian species that winters in agricultural areas in the southeastern United States, but little is known about their ecology or potential demographic partitioning in this context. To fill these knowledge gaps, we compared multi-scale habitat selection, survival, and space use across age and sex classes of shrikes inhabiting an agricultural landscape in Arkansas, USA. We found that habitat selection differed among demographic classes. Specifically, females preferred areas with more fallow cover, utility wires, and anthropogenic perches, whereas males preferred areas with more agricultural fields and ditches and less soybean cover. However, overall, shrikes exhibited numerous similarities in habitat selection, generally preferring areas with greater developed land cover (within a predominantly agricultural landscape), greater water availability, and taller perches. Despite the observed variability in habitat selection, no differences in apparent seasonal and annual survival rates or home range size existed among groups. However, non-breeding dispersal distance between years differed by age class, with older individuals being more site faithful than younger individuals. We suggest that the demographic habitat partitioning we detected may reflect adaptive differential life history strategies associated with age and sex classes, but further study of habitat selection by Loggerhead Shrikes across seasons and habitat types will help clarify the variation, importance, and potential carry-over effects of non-breeding habitat partitioning.

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous and persistent environmental contaminants originating from many everyday products. Perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are two PFAS that are commonly found at high concentrations in aquatic environments. Both chemicals have previously been shown to be toxic to fish, as well as having complex and largely uncharacterized mixture effects. However, limited information is available on marine and estuarine species. In this study, embryonic and larval sheepshead minnows (Cyprinodon variegatus) were exposed to several PFAS mixtures to assess lethal and sublethal effects. PFOS alone was acutely toxic to larvae, with a 96 h LC50 of 1.97 mg/L (1.64–2.16). PFOS + PFOA resulted in a larval LC50 of 3.10 (2.62–3.79) mg/L, suggesting an antagonistic effect. These observations were supported by significant reductions in malondialdehyde (105% ± 3.25) and increases in reduced glutathione concentrations (43.8% ± 1.78) in PFOS + PFOA exposures compared to PFOS-only treatments, indicating reduced oxidative stress. While PFOA reduced PFOS-induced mortality (97.0% ± 3.03), perfluorohexanoic acid (PFHxA) and perfluorobutanoic acid (PFBA) did not. PFOS alone did not affect expression of peroxisome proliferator-activated receptor alpha (pparα) but significantly upregulated apolipoprotein A4 (apoa4) (112.4% ± 17.8), a downstream product of pparα, while none of the other individually tested PFAS affected apoa4 expression. These findings suggest that there are antagonistic interactions between PFOA and PFOS that may reduce mixture toxicity in larval sheepshead minnows through reduced oxidative stress. Elucidating mechanisms of toxicity and interactions between PFAS will aid environmental regulation and management of these ubiquitous pollutants.

Summary: Presynaptic plasticity adjusts neurotransmitter (NT) liberation. Short-term facilitation (STF) tunes synapses to millisecond repetitive activation, while presynaptic homeostatic potentiation (PHP) of NT release stabilizes transmission over minutes. Despite different timescales of STF and PHP, our analysis of Drosophila neuromuscular junctions reveals functional overlap and shared molecular dependence on the release-site protein Unc13A. Mutating Unc13A’s calmodulin binding domain (CaM-domain) increases baseline transmission while blocking STF and PHP. Mathematical modeling suggests that Ca2+/calmodulin/Unc13A interaction plastically stabilizes vesicle priming at release sites and that CaM-domain mutation causes constitutive stabilization, thereby blocking plasticity. Labeling the functionally essential Unc13A MUN domain reveals higher STED microscopy signals closer to release sites following CaM-domain mutation. Acute phorbol ester treatment similarly enhances NT release and blocks STF/PHP in synapses expressing wild-type Unc13A, while CaM-domain mutation occludes this, indicating common downstream effects. Thus, Unc13A regulatory domains integrate signals across timescales to switch release-site participation for synaptic plasticity.

Microscopic symbionts represent crucial links in biological communities. However, they present technical challenges in high-throughput sequencing (HTS) studies due to their small size and minimal high-quality DNA yields, hindering our understanding of host–symbiont coevolution at microevolutionary and macroevolutionary scales. One approach to overcome those barriers is to pool multiple individuals from the same infrapopulation (i.e., individual host) and sequence them together (Pool-Seq), but individual-level information is then compromised. To simultaneously address both issues (i.e., minimal DNA yields and loss of individual-level information), we implemented a strategic Pool-Seq approach to assess variation in sequencing performance and categorize genetic diversity (single nucleotide polymorphisms (SNPs)) at both the individual-level and infrapopulation-level for microscopic feather mites. To do so, we collected feathers harboring mites (Proctophyllodidae: Amerodectes protonotaria) from four individual Prothonotary Warblers (Parulidae: Protonotaria citrea). From each of the four hosts (i.e., four mite infrapopulations), we conducted whole-genome sequencing on three extraction pools consisting of different numbers of mites (1 mite, 5 mites, and 20 mites). We found that samples containing pools of multiple mites had more sequencing reads map to the feather mite reference genome than did the samples containing only a single mite. Mite infrapopulations were primarily genetically structured by their associated individual hosts (not pool size) and the majority of SNPs were shared by all pools within an infrapopulation. Together, these results suggest that the patterns observed are driven by evolutionary processes occurring at the infrapopulation level and are not technical signals due to pool size. In total, despite the challenges presented by microscopic symbionts in HTS studies, this work highlights the value of both individual-level and infrapopulation-level sequencing toward our understanding of host–symbiont coevolution at multiple evolutionary scales.

Feather mites are ubiquitous, permanent, obligate ectosymbionts of avian hosts and are a valuable natural system for studying host-symbiont evolutionary and ecological dynamics at multiple levels of biological organization. However, a lack of a sequenced genome impedes molecular studies using this system. Therefore, we present the first draft genome of a symbiotic feather mite, Amerodectes protonotaria Hernandes 2018. The genome sequence data presented here were derived from an individual female mite that was collected in the field from Protonotaria citrea, its only known host species. Short read sequence data were obtained using an Illumina NovaSeq 6000 platform. From these data, we assembled a 59,665,063 bp draft genome consisting of 2,399 contigs. Raw short reads and the assembled genome sequence are available at the National Center for Biotechnology Information (NCBI)’s Sequence Read Archive (SRA) under BioProject PRJNA884722. The data presented here are beneficial for future research on the biology and evolution of closely related mites and the genomics of host-symbiont interactions.

Abstract For nearly all organisms, dispersal is a fundamental life‐history trait that can shape their ecology and evolution. Variation in dispersal capabilities within a species exists and can influence population genetic structure and ecological interactions. In fungus‐gardening (attine) ants, co‐dispersal of ants and mutualistic fungi is crucial to the success of this obligate symbiosis. Female‐biased dispersal (and gene flow) may be favored in attines because virgin queens carry the responsibility of dispersing the fungi, but a paucity of research has made this conclusion difficult. Here, we investigate dispersal of the fungus‐gardening ant Trachymyrmex septentrionalis using a combination of maternally (mitochondrial DNA) and biparentally inherited (microsatellites) markers. We found three distinct, spatially isolated mitochondrial DNA haplotypes; two were found in the Florida panhandle and the other in the Florida peninsula. In contrast, biparental markers illustrated significant gene flow across this region and minimal spatial structure. The differential patterns uncovered from mitochondrial DNA and microsatellite markers suggest that most long‐distance ant dispersal is male‐biased and that females (and concomitantly the fungus) have more limited dispersal capabilities. Consequently, the limited female dispersal is likely an important bottleneck for the fungal symbiont. This bottleneck could slow fungal genetic diversification, which has significant implications for both ant hosts and fungal symbionts regarding population genetics, species distributions, adaptive responses to environmental change, and coevolutionary patterns.

In this study, the conformational behavior of N-benzyl-N-(furan-2-ylmethyl) acetamide in chloroform was addressed by using a combined experimental/theoretical strategy using NMR spectroscopy and quantum chemical calculations. The 1H and 13C one-dimensional NMR spectra, as well as the two-dimensional HSQC-DEPT and HMBC-DEPT NMR spectra, evinced the presence of a hindered cis(E)-trans(Z) rotational equilibrium in solution. DFT calculations were performed at different theoretical levels using the polarizable continuum model (PCM) and predicted nine (four Z and five E structures) stable conformations. The interconversion dynamics among the different confirmations were established in terms of four different rotational equilibria in CDCl3. The chemical shifts in the 1H and 13C NMR spectra of the compound are similar to the values calculated for the two most abundant conformational equilibria at room temperature, one caused by two Z rotamers and the other by two E rotamers. The compound was also characterized for the first time by FTIR, Raman spectroscopy, and GC/MS spectrometry. Additionally, several acylation methodologies for synthesizing the title compound from N-benzyl-1-(furan-2-yl)methanamine were tested which resulted in high yields (> 90%) under very convenient conditions (10 min, at room temperature).

Abstract Objective The objective of this study is to develop and identify polymorphic microsatellite markers for fungus-gardening (attine) ants in the genus Trachymyrmex sensu lato. These ants are important ecosystem engineers and have been a model group for understanding complex symbiotic systems, but very little is understood about the intraspecific genetic patterns across most North American attine species. These microsatellite markers will help to better study intraspecific population genetic structure, gene flow, mating habits, and phylogeographic patterns in these species and potentially other congeners. Results Using next-generation sequencing techniques, we identified 17 and 12 polymorphic microsatellite markers from T. septentrionalis and Mycetomoellerius (formerly Trachymyrmex) turrifex, respectively, and assessed the genetic diversity of each marker. We also analyzed the cross-amplification success of the T. septentrionalis markers in two other closely related Trachymyrmex species, and identified 10 and 12 polymorphic markers for T. arizonensis and T. pomonae, respectively.

The reaction of N-phenyl-1-(pyridin-2-yl)methanimine with copper chloride dihydrate produced the title neutral complex, [CuCl2(C12H10N2)(H2O)]·H2O. The CuII ion is five-coordinated in a distorted square-pyramidal geometry, in which the two N atoms of the bidentate Schiff base, as well as one chloro and a water molecule, form the irregular base of the pyramidal structure. Meanwhile, the apical chloride ligand interacts through a strong hydrogen bond with a water molecule of crystallization. In the crystal, molecules are arranged in pairs, forming a stacking of symmetrical cyclic dimers that interact in turn through strong hydrogen bonds between the chloride ligands and both the coordinated and the crystallization water molecules. The molecular and electronic structures of the complex were also studied in detail using EPR (continuous and pulsed), FT–IR and Raman spectroscopy, as well as magnetization measurements. Likewise, Hirshfeld surface analysis was used to investigate the intermolecular interactions in the crystal packing.

Raw milk adulteration with cheese whey is a major problem that affects the dairy industry. The objective of this work was to evaluate the adulteration of raw milk with the cheese whey obtained from the coagulation process, with chymosin enzyme using casein glycomacropeptide (cGMP) as an HPLC marker. Milk proteins were precipitated with 24% TCA; with the supernatant obtained, a calibration curve was established by mixing raw milk and whey in different percentages, which were passed through a KW-802.5 Shodex molecular exclusion column. A reference signal, with a retention time of 10.8 min, was obtained for each of the different percentages of cheese whey; the higher the concentration, the higher the peak. Data analysis was adjusted to a linear regression model, with an R2 of 0.9984 and equation to predict dependent variable (cheese whey percentage in milk) values. The chromatography sample was collected and analyzed by three tests: a cGMP standard HPLC analysis, MALDI-TOF spectrometry, and immunochromatography assay. The results of these three tests confirmed the presence of the cGMP monomer in adulterated samples with whey, which was obtained from chymosin enzymatic coagulation. As a contribution to food safety, the molecular exclusion chromatography technique presented is reliable, easy to implement in a laboratory, and inexpensive, compared with other methodologies, such as electrophoresis, immunochromatography, and HPLC-MS, thus allowing for the routine quality control of milk, an important product in human nutrition.

Quality is an essential element for any company that wants to be recognized successfully; because of this, the companies undergo a certification process under a quality standard such as ISO 9001 that allows them to improve the performance of its operation, differentiate itself from its competitors, achieve a better position in the market and export quickly. In this sense, making and maintaining such certification can be under high pressure over the company, up to become a source of corruption risk, since, in emerging markets, companies may be tempted to perform unethical practices such as falsifying or adulterating documents to maintain their certifications and the benefits derived from it. Besides, considering that the quality management system audit process is based on the verification made by a third party of the documents and records of the company against the quality standard, it becomes necessary to reinforce with technology the audit process to minimize this kind of risk. Given this, a software architecture for a quality management system supported in BPMN and Blockchain technology is proposed to guarantee the integrity and immutability of the system and information, which allows exposing any attempt at fraud and facilitates the audit process's automation.

The spatial extent of seagrass is poorly mapped, and knowledge of historical loss is limited. Here, we collated empirical and qualitative data using systematic review methods to provide unique analysis on seagrass occurrence and loss in the United Kingdom. We document 8,493 ha of recently mapped seagrass in the United Kingdom since 1998. This equates to an estimated 0.9 Mt of carbon, which, in the current carbon market represents about £22 million. Using simple models to estimate seagrass declines triangulated against habitat suitability models, we provide evidence of catastrophic seagrass loss; at least 44% of United Kingdom’s seagrasses have been lost since 1936, 39% since the 1980’s. However, losses over longer time spans may be as high as 92%. Based on these estimates, historical seagrass meadows could have stored 11.5 Mt of carbon and supported approximately 400 million fish. Our results demonstrate the vast scale of losses and highlight the opportunities to restore seagrass to support a range of ecosystems services.

Energetic nutrients are oxidized to sustain high intracellular NADPH/NADP+ ratios. NADPH-dependent reduction of thioredoxin-1 (Trx1) disulfide and glutathione disulfide by thioredoxin reductase-1 (TrxR1) and glutathione reductase (Gsr), respectively, fuels antioxidant systems and deoxyribonucleotide synthesis. Mouse livers lacking both TrxR1 and Gsr sustain these essential activities using an NADPH-independent methionine-consuming pathway; however, it remains unclear how this reducing power is distributed. Here, we show that liver-specific co-disruption of the genes encoding Trx1, TrxR1, and Gsr (triple-null) causes dramatic hepatocyte hyperproliferation. Thus, even in the absence of Trx1, methionine-fueled glutathione production supports hepatocyte S phase deoxyribonucleotide production. Also, Trx1 in the absence of TrxR1 provides a survival advantage to cells under hyperglycemic stress, suggesting that glutathione, likely via glutaredoxins, can reduce Trx1 disulfide in vivo. In triple-null livers like in many cancers, deoxyribonucleotide synthesis places a critical yet relatively low-volume demand on these reductase systems, thereby favoring high hepatocyte turnover over sustained hepatocyte integrity.

CAR-T targeting CD19 have been successfully used in a variety of B-cell malignancies but patients may eventually relapse. Here, the authors show that CD19 CAR-T resistance in pre-B cell ALL can be due to the induction of a myeloid lineage switch through an epigenetic alterations in master regulators of B cell development.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. While frontline chemotherapy regimens are generally very effective, the prognosis for patients whose leukemia returns remains poor. The presence of measurable residual disease (MRD) in bone marrow at the completion of induction therapy is the strongest predictor of relapse, suggesting that strategies to eliminate the residual leukemic blasts from this niche could reduce the incidence of recurrence. We have previously reported that toll-like receptor (TLR) agonists achieve durable T cell-mediated protection in transplantable cell line-based models of B cell precursor leukemia (B-ALL). However, the successful application of TLR agonist therapy in an MRD setting would require the induction of anti-leukemic immune activity specifically in the bone marrow, a site of the chemotherapy-resistant leukemic blasts. In this study, we compare the organ-specific depletion of human and mouse primary B-ALL cells after systemic administration of endosomal TLR agonists. Despite comparable splenic responses, only the TLR9 agonist induced strong innate immune responses in the bone marrow and achieved a near-complete elimination of B-ALL cells. This pattern of response was associated with the most significantly prolonged disease-free survival. Overall, our findings identify innate immune activity in the bone marrow that is associated with durable TLR-induced protection against B-ALL outgrowth.

Informed consent has remained one of the more debated topics within research ethics. Many scholars and bioethicists have wondered the best way to obtain it, who should give it, and if it is even necessary at all. Feminist scholarship has remained similarly engaged in questions surrounding consent, with particular focus on sex and sexuality. This year, in the wake of the #MeToo movement, we have witnessed a cultural shift towards a willingness to address the perils of sexual consent under patriarchy. In the context of this cultural reckoning, I see no better time to apply feminist epistemology to the fraught nature of consent to a bioethical framework. Feminist bioethicists, such as Susan Sherwin, have long argued for a wider consent model that privileges justice over a focus on autonomy. Using radical feminist theorist Catherine MacKinnon’s work on consent and sexual harassment, I will support Sherwin’s claim by arguing for a more nuanced understanding of power and structural social hierarchy that exists in every aspect of our society, including research. It should be noted I am not trying to conflate engagement in sex/sexual violence with engagement in research. However, I am attempting to find useful parallels to dissect the broader issue that applies equally to both, which is an issue of meaningful agreement across power differentials. There is a false idea, within research ethics and our society at large, that consent is the gatekeeper of a just and reciprocal experience. As feminist theorist Catherine MacKinnon writes, “The presence of consent does not make an interaction equal. It makes it tolerated, or the less costly of alternatives out of the control, or beyond the construction, of the one who consents” [1]. A new model incorporating radical feminist scholarship and focusing on structural inequality as opposed to individual choice is necessary to ensure truly ethical research practices. Informed consent is a widely discussed topic in research ethics, one that presents many challenges. According to U.S. law and the principles of bioethics, physicians, scientists and researchers are required to obtain the informed consent of their patients or subjects before initiating treatment or collecting scientific data. True informed consent, as defined in bioethics, requires the disclosure of all relevant information to a competent participant who is capable and permitted to make a totally voluntary and educated choice. Typically, as Paul Appelbaum writes, “such disclosure includes the nature of the patient’s condition, the nature and purpose of the proposed treatment, and the risks and benefits of the proposed treatment and of alternative treatments, including the option of no treatment at all” [2]. In other words, the participant is supposedly free to utilize their full autonomy in determining what they do, and do not, want to be done with their body. Informed consent in research ethics is often framed under the specific lens of the preservation of autonomy, and, consequentially, autonomy is usually heralded as the most important of bioethical principles with regards to consent. There are obvious cases in which informed consent, as defined, cannot be reasonably given due to limited autonomy. Traditional bioethics tends to focus on cases of limited autonomy as individual circumstances of language barrier, cognitive impairment, or mental instability. As Appelbaum writes, “when patients lack the competence to make a decision about treatment, substitute decision makers must be sought. Hence, the determination of whether patients are competent is critical in striking a proper balance between respecting the autonomy of patients who are capable of making informed decisions and protecting those with cognitive impairment” [2]. Typically, the determination of limited autonomy is defined on individualistic terms based on a subject’s specific health limitations. I propose this is not a useful enough starting point, as this idea of individualistic autonomy has many limitations, namely, the exaltation of autonomy assumes falsely that every individual has the same operational ‘access’ to it. We need to be considering autonomy in a structural, rather than individualistic framework. Furthermore, the recognition on the part of traditional bioethicists that autonomy is not universally equally distributed already reveals a soft admission to the fact that autonomy is not the best model upon which to rely. However, by choosing to focus only on the more ‘obvious’ examples of limited autonomy such as dementia, and mental capacity, as opposed to larger social determinants of a type of compromised autonomy such as in the case of gender, race, and class, traditional bioethics reveals an unwillingness to address larger societal issues of justice and power. Arguably, the space in which the most prolific theorizing on the role and perils of consent and autonomy in society has been feminist theory. Radical feminist theory, a line of thought emerging out of the second-wave feminist movement, specifically has grappled with the concept of “consent” and “free-choice” under uneven power structures. As radical feminist scholarship considers the mechanisms underlying rape and sexual harassment, the notion of consent as a fraught concept is brought into unique focus. Catherine MacKinnon, one of the most prominent radical feminist and legal scholars, and the inventor of the term “sexual harassment” has written prolifically on this subject. In her work, MacKinnon theorizes on the illusion of female choice under patriarchy given gender oppression and uneven power structures and argues that the presence of consent is not a robust enough concept to differentiate rape from sex because women are not truly free to make unencumbered choices with regard to their sexuality. She writes, The law of rape presents consent as free exercise of sexual choice under conditions of equality of power without exposing the underlying structure of constraint and disparity…if rape is less a question of unwanted sex than of unequal sex, if equality not autonomy is its primary issue, if internal psychology is less determinant of these criminal acts than leverages external conditions and gendered social behaviors, the existing conceptual framework together with its lexicon of examples, has been fundamentally beside the point all along” [3]. According to MacKinnon, the concept of consent is beside the point: in order for consent to even be possible, the two actors entering into an agreement must be equal in power. Since this equality is nonexistent, the discussion should instead involve the leveling of the playing field before we can worry about coming to an agreement. These ideas from second wave feminist theory have recently reemerged as a way to discuss the fallout from the revelations of the #MeToo movement. As Brit Marling published in The Atlantic in response to the Harvey Weinstein sexual assault scandal, “the things that happen in hotel rooms and board rooms all over the world (and in every industry) between women seeking employment or trying to keep employment and men holding the power to grant it or take it away exist in a gray zone where words like ‘consent’ cannot fully capture the complexity of the encounter. Because consent is a function of power. You have to have a modicum of power to give it” [4]. This reiterates MacKinnon’s claim that obtaining consent is inadequate in addressing inequality across power differentials. Without an equality of power positions, consent is not only meaningless, but presents a red herring. Even if we falsely accept the equality of the two parties, consent as a concept inherently implies a differential in power, as one agent necessarily initiates as another acquiesces. In fact, The Oxford English Dictionary defines consent as the “voluntarily acquiesce in what another proposes or desires” [3]. Similarly, Black’s Law Dictionary defines consent as “voluntarily yielding the will to the proposition of another” [3]. Therefore, using consent as a marker for an equal exchange is a fundamental misconception. As MacKinnon writes, “intrinsic to consent is the actor and the acted-upon, with no guarantee of any kind of equality between them, whether of circumstance or condition or interaction [3]. While some may argue discussions of sexual consent are too specific to be applied to issues of research consent, this is not the case. Research, like gender dynamics under a patriarchal social system, is rife with inequities of power. Doctors and researchers similarly occupy a traditionally masculine role of paternalism and authority over their subjects, just as men hold power over women under patriarchy. It is also important to note the history of colonial abuses in academic and biomedical research that has contributed to this contemporary power imbalance. As Indigenous theorist Lina Tuhiwai Smith writes, “from the vantage point of the colonized…the term ‘research’ is inextricably linked to European imperialism and colonialism” [5]. She continues: Research is one of the ways in which the underlying code of imperialism and colonialism is both regulated and realized. It is regulated through the formal rules of individual scholarly disciplines and scientific paradigms, and the institutions that support them (including the state). It is realized in the myriad of representations and ideological constructions of the Other in scholarly and ‘popular’ works, and in the principles which help to select and re-contextualize those constructions in such things as the media, official histories and school curricula [5]. Research is not a neutral truth-seeker, but rather a historically situated institution built off the values of imperialism. Much of the establishment of research as a field has relied heavily on the stratification of the colonizers (researchers) from the colonized (subjects). While the goal of this paper is not to argue for the conflation of sexual consent with research consent, it should be noted that there are meaningful historical and contemporary examples of patients, particularly women, who have been taken advantage of in the name of science in manners that are sexual in nature. Consider the performance of pelvic exams by medical students on anesthetized women without their consent: according to an article published in 2012, women undergoing gynecological surgeries were asked to give consent to allowing medical students be involved in their care, but not explicitly allowing them to do educational exams on them while unconscious. As a medical student stated, “For three weeks, four to five times a day, I was asked to, and did, perform pelvic examinations on anesthetized women," whom had only given implicit consent to his presence during surgery [6]. According to the United States Department of Justice the legal definition of rape is "penetration, no matter how slight, of the vagina or anus with anybody part or object without the consent of the consent of the victim” [7]. Accepting this definition, what these patients endured was ostensibly a form of rape. In the United States, there are only four states (Hawaii, California, Illinois and Virginia) “where doctors are legally required to obtain specific consent for pelvic exams under anesthesia” [6]. Furthermore, a study found that medical students who had completed a clerkship in obstetrics or gynecology did not believe consent for pelvic exams under anesthesia were warranted [8]. These attitudes suggest that while issues surrounding sexual consent and research consent are distinct, there are important overlaps that point to a larger structural problem in society. Research is not created in a vacuum. It is created by and for the culture in which it is produced; in this case, the same culture that also permits and encourages gendered sexual abuse. Taking a cue from feminist theory, we can see that by focusing only on autonomy and ignoring issues of structured oppression and violence, the current model of informed consent in medical research is fundamentally skewed in favor of the powerful. As feminist bioethicist Susan Sherwin writes, “autonomy language is often used to hide the workings of privilege and mask the barriers of oppression” [9]. By choosing to focus only on issues of autonomy we artificially make research ethics an individualistic issue rather than a systemic one. Like MacKinnon, Sherwin too argues that the idea of choice under systems of oppression is illusory. She writes, the “illusion of ‘choice’ in the context of informed consent can operate as a mechanism to insure compliance with care provider’s preferences” [9]. Not only is the ontology of choice illusory, the framework of emphasizing autonomy often serves to blame victims for their own mistreatment. According to Sherwin, in emphasizing choice as the gatekeeper of impartiality, advocates “not only fail to deflect responsibility from victims, but rather attribute it to them” [9]. This phenomenon can be clearly seen in the recent discussion surrounding the prevalence of sexual assault in the work place. In response to Harvey Weinstein’s outspoken victims, many have asked questions to the tune of, “if she felt uncomfortable, why didn’t she just leave” or “why didn’t she tell anyone?” Not only does this unimaginatively ignore the realities of power differentials, it also serves to blame victims for being victimized. Focusing on the victims’ choices as if they were as free and unencumbered as Weinstein’s is wrong, and misses the point entirely. The emphasis on women’s autonomy here insidiously and paradoxically serves not to embolden, but rather undermine, their subjectivity. Sherwin writes that “the concept of autonomy, rather than working to empower the oppressed and exploited among us, in practice often serves to protect the privileges of the most powerful” [9]. Additionally, Sherwin writes that “theories that place priority on autonomy—at least as the concept is commonly interpreted—must be understood as primarily protecting the autonomy of those who are already well-situated, while sacrificing the necessary prerequisite for autonomy for others” [10]. Assuming both parties have ‘equal’ access to autonomy in this situation is not only callously inappropriate, it also relies on clumsy reasoning that serves only to bolster power differentials rather than level them. And this, of course, does not merely apply to women subjects but to other marginalized groups be they based on race, class, sexuality, etc. An emphasis on autonomy not only serves to unfairly place blame on the victim, it also obscures structural oppression that limits autonomy in the first place. As Sherwin explains, This individualistic approach to autonomy makes it very easy for people of privilege to remain ignorant of the social arrangements the support their own sense of independence, such as the institutions that provide them with the exceptionally good education and a relatively high degree of personal safety. Encouraged to focus on their own sense of individual accomplishment, they are inclined to blame less well-situated people for their lack of comparable success rather than to appreciate the cost of oppression. This familiar sort of thinking tends to interfere with people’s ability to see the importance of supportive social conditions for fostering autonomous action. [11] Our project as bioethicists should rely less on maintaining and bolstering what is ultimately the golden rule of autonomy myth, and focus rather on enlightening and unmasking the various power structures at play that limit various groups’ access to power. Rather than a focus on individual choice, “we need to question how much control individual patients really have over the determination of their treatment within the stressful world of health care services” [11]. Overall, the current model of informed consent as it is currently understood at best misses the point, and at worst promotes damaging neoliberal notions that place blame on individuals rather than on structural inequality. In the case of research ethics, consent and its function as a measurement of autonomy fails because the power between the researcher and subject is inherently unequal. This is not to suggest that in this scenario autonomy is actively stripped from the subject by the researcher, but rather that the dice were loaded before either entered the room. Autonomy, regardless of the efforts of bioethics, is simply not equally accessed in our society as it stands today. The incorporation of feminist theory serves to challenge the current model by accurately and forcefully confronting the realities of our unequal world. Not only does this application reveal parallels in how power is negotiated similarly throughout different realms in society, it also helps to illuminate the larger ethical issues that warrant attention. As Sherwin writes, “feminist health care ethics does not only change the way we handle traditional bioethical problems; it also changes the agenda of the discipline by making visible a whole range of new ethical problems [11]. Taking a feminist approach to bioethics reveals a need to move toward a justice model and away from an autonomy model in order to more vigorously account for structural inequality within biomedical research. Photo by Miguel Bruna on Unsplash Works Cited [1] MacKinnon, Catherine. “Rape: On Coercion and Consent .” Www.julietdavis.com, www.julietdavis.com/oldsite/WST383/rape.pdf. [2] Appelbaum, Paul S. “Assessment of Patients' Competence to Consent to Treatment — NEJM.” New England Journal of Medicine, www.nejm.org/doi/full/10.1056/NEJMcp074045. [3] MacKinnon, Catherine. “Rape Redefined.” Http://Harvardlpr.com/Wp-Content/Uploads/2016/06/10.2_6_MacKinnon.Pdf. [4] Marling, Brit. “Harvey Weinstein and the Economics of Consent.” The Atlantic, Atlantic Media Company, 23 Oct. 2017, www.theatlantic.com/entertainment/archive/2017/10/harvey-weinstein-and-the-economics-of-consent/543618/. [5] Smith , Linda Tuhiwai. “Decolonizing Methodologies.” Google Books, books.google.com/books/about/Decolonizing_Methodologies.html?id=Nad7afStdr8C. [6] Rowan, Karen. “Pelvic Exams While Under Anesthesia Sparks Debate.” LiveScience, Purch, 5 Oct. 2012, www.livescience.com/23749-pelvic-exams-anesthesia-medical-students.html./.latest_citation_text [7] “An Updated Definition of Rape.” The United States Department of Justice, 6 Jan. 2012, www.justice.gov/archives/opa/blog/updated-definition-rape./.latest_citation_text [8] Ubel, Peter A.; Jepson, Christopher; Silver-Isenstadt, Ari. “Don't Ask, Don't Tell: A Change in Medical Student Attitudes after Obstetrics/Gynecology Clerkships toward Seeking Consent for Pelvic Examinations on an Anesthetized Patient, American Journal of Obstetrics and Gynecology.” DeepDyve, Elsevier, 1 Feb. 2003, www.deepdyve.com/lp/elsevier/don-t-ask-don-t-tell-a-change-in-medical-student-attitudes-after-ty00XBCuEa./.latest_citation_text [9] Humphreys, Janice. “Family Violence and Nursing Practice, Second Edition 2nd Edition.” Family Violence and Nursing Practice, Second Edition: 9780826118288: Medicine & Health Science Books @ Amazon.com, www.amazon.com/Family-Violence-Nursing-Practice-Second/dp/0826118283. 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PurposeA cohort of pediatric patients with AML treated at hospitals contributing to the Pediatric Health Information System was used to evaluate differences in opioid utilization by sex, age, race, and insurance.MethodsBilling data were used to compute the prevalence of opioid exposure and to quantify rates of utilization among those exposed to opioids as days of use per 1000 inpatient days. Multivariable regressions were used to compare opioid prevalence, and rates of utilization among those exposed.ResultsOn average across courses, 95.2% of patients were exposed to analgesics, 84.7% were exposed to non-opioid analgesics and 77.7% were exposed to opioids. The proportion of opioid-exposed patients increased with age, but did not differ by gender, race, or insurance status. Analyses limited to patients exposed to opioids revealed modest differences in days of opioid use among female patients (adjusted rate ratio (aRR) = 1.19, 95% CI: 1.11, 1.28), patients ConclusionAdditional work is needed to discern whether observed differences in opioid utilization by age and race reflect a difference in treatment or a difference in the experience of pain. Future studies should also explore the factors which guide decisions on opioid selections in an attempt to explain the variability across institutions.

Mature B-cell non-Hodgkin lymphoma (B-NHL) constitutes a collection of relatively rare pediatric malignancies. In order to utilize administrative data to perform large-scale epidemiologic studies within this population, a two-step process was used to assemble a 12-year cohort of B-NHL patients treated between 2004 and 2015 within the Pediatric Health Information System database. Patients were identified by ICD-9 codes, and their chemotherapy data were then manually reviewed against standard B-NHL treatment regimens. A total of 1,409 patients were eligible for cohort inclusion. This process was validated at a single center, utilizing both an institutional tumor registry and medical record review as the gold standards. The validation demonstrated appropriate sensitivity (91.5%) and positive predictive value (95.1%) to allow for the future use of this cohort for epidemiologic and comparative effectiveness research.

Anthropogenic alterations to bottomland forests in the United States that occurred post-European settlement likely negatively affected many avian species. The Prothonotary Warbler (Protonotaria citrea), a secondary cavity nester that breeds predominantly in these forests, has steadily declined over the past 60 years, and our ability to mitigate this trend is partially limited by a lack of basic biological data. Although much research has been devoted to Prothonotary Warblers, most studies have focused on local breeding populations that use nest boxes; we lack information about habitat selection behavior and demographic parameters of individuals that use natural cavities, which includes the vast majority of the global population. We studied warblers nesting both in boxes and natural cavities in central Arkansas, USA. We aimed to evaluate: (1) microhabitat features important for nest site selection, (2) relationships between these features and nest survival, and (3) demographic parameters of individuals breeding in natural cavities versus nest boxes. We hypothesized (1) selected nest site characteristics are associated with nest survival, and (2) natural cavities and nest boxes provide similar nest features related to clutch size and number fledged, but that predation protection differs. We found that warblers preferred nesting in dead trees with cavities that were higher and shallower than available random cavities, and that canopy cover within 5 m of nests was inversely related to nest survival. Demographic parameters did not differ between natural cavities and nest boxes; however, when excluding flooded nests, boxes experienced lower rates of nest depredation. We believe that forest management strategies that increase the number of suitable dead nest trees and restore the natural hydrology of these ecosystems would create and improve habitat for this iconic species. We advocate multiscale experimental canopy cover manipulation to explore the causal mechanism(s) of the relationship we found between canopy cover and nest survival.

This study is a pharmacoepidemiologic description of pediatric bortezomib use. Exposure was identified through billing codes in patients admitted to US children's hospitals that participated with the Pediatric Health Information System between 2004 and 2013. Associated information on underlying diseases, demographics, institutional use, mortality, and physician type was collected. Exposure to bortezomib was identified in 314 patients. Hematologist/Oncologists prescribed half of the bortezomib used. Use increased during the study period. Inpatient volume was positively correlated with bortezomib utilization. Bortezomib use in pediatrics is increasing for a variety of diseases. Variation in use exists across institutions. Further studies are needed to characterize bortezomib's efficacy in pediatric diseases.

The neuroinvasive Herpes simplex virus type 1 (HSV-1) utilizes intergenomic recombination in order to diversify viral populations. Research efforts to assess HSV-1 recombination are often complicated by the use of attenuating mutations, which differentiate viral progeny but unduly influence the replication and spread. In this work, we generated viruses with markers that allowed for classification of viral progeny with limited attenuation of viral replication. We isolated viruses, harboring either a cyan (C) or yellow (Y) fluorescent protein (FP) expression cassette inserted in two different locations within the viral genome, in order to visually quantify the recombinant progeny based on plaque fluorescence. We found that the FP marked genomes had a limited negative affect on the viral replication and production of progeny virions. A co-infection of the two viruses resulted in recombinant progeny that was dependent on the multiplicity of infection and independent of the time post infection, at a rate that was similar to previous reports. The sequential passage of mixed viral populations revealed a limited change in the distribution of the parental and recombinant progeny. Interestingly, the neuroinvasive spread within neuronal cultures and an in vivo mouse model, revealed large, random shifts in the parental and recombinant distributions in viral populations. In conclusion, our approach highlights the utility of FP expressing viruses in order to provide new insights into mechanisms of HSV-1 recombination.

PURPOSE:Clinical trials data from National Cancer Institute (NCI)-funded cooperative oncology group trials could be enhanced by merging with external data sources. Merging without direct patient identifiers would provide additional patient privacy protections. We sought to develop and validate a matching algorithm that uses only indirect patient identifiers. METHODS:We merged the data from two Phase III Children's Oncology Group (COG) trials for de novo acute myeloid leukemia (AML) with the Pediatric Health Information Systems (PHIS). We developed a stepwise matching algorithm that used indirect identifiers including treatment site, gender, birth year, birth month, enrollment year and enrollment month. Results from the stepwise algorithm were compared against the direct merge method that used date of birth, treatment site, and gender. The indirect merge algorithm was developed on AAML0531 and validated on AAML1031. RESULTS:Of 415 patients enrolled on the AAML0531 trial at PHIS centers, we successfully matched 378 (91.1%) patients using the indirect stepwise algorithm. Comparison to the direct merge result suggested that 362 (95.7%) matches identified by the indirect merge algorithm were concordant with the direct merge result. When validating the indirect stepwise algorithm using the AAML1031 trial, we successfully matched 157 out of 165 patients (95.2%) and 150 (95.5%) of the indirectly merged matches were concordant with the directly merged matches. CONCLUSIONS:These data demonstrate that patients enrolled on COG clinical trials can be successfully merged with PHIS administrative data using a stepwise algorithm based on indirect patient identifiers. The merged data sets can be used as a platform for comparative effectiveness and cost effectiveness studies.

In the title molecule, C19H21BrN2O, the piperidone ring adopts a chair conformation with a total puckering amplitude QT of 0.554 (2) Å. The dihedral angle between the benzene rings is 64.10 (7)°. There are no significant intermolecular interactions.

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.

Equal access to clinical trial enrollment is important to ensure that findings are generalizable to the broader population. This study aimed to evaluate disparities in enrollment on pediatric oncology clinical trials. We assessed the relationship between patient characteristics and enrollment on COG trial AAML1031 in a cohort of pediatric patients with AML in the Pediatric Health Information System. The associations of enrollment with outcomes were evaluated. Non-Hispanic Black patients, infants, and patients from zip codes with a lower proportion of poverty were less likely to enroll (30% vs. 61%, p = .004; 34% vs. 58%, p = .003; 46% vs. 58%, p = .02). On-therapy mortality was similar among enrolled and nonenrolled patients (7.3% vs. 8.9%, p = .47). Differences in early mortality were more pronounced among nonenrolled patients compared to enrolled patients (3.0% vs. 0.5%, p = .03). Understanding the etiology of these disparities will inform strategies to ensure balanced access to clinical trials across patient populations.

BackgroundBlack patients with acute myeloid leukemia (AML) are more likely to present with high acuity and consequently experience higher rates of induction mortality than white patients. Given the consistently identified racial disparities in overall survival (OS) among patients with AML, we aimed to evaluate whether there were sustained on-therapy racial differences in inpatient mortality, intensive care unit (ICU) requirements, or supportive care beyond initial induction.ProcedureWithin a retrospective cohort of 1239 children diagnosed with AML between 2004 and 2014 in the Pediatric Health Information System (PHIS) database who survived their initial course of induction chemotherapy, we compared on-therapy inpatient mortality, ICU-level care requirements, treatment course duration, cumulative length of hospital stay (LOS), and resource utilization after induction I by race.ResultsOver the period from the start of induction II through completion of frontline chemotherapy, there were no significant differences in mortality (adjusted odds ratios [OR], 1.01; 95% confidence intervals [CI], 0.41-2.48), ICU-level care requirements (adjusted OR, 0.93; 95% CI, 0.69-1.26), LOS (adjusted mean difference, 3.2 days; 95% CI, -2.3-9.6), or supportive care resource utilization for black patients relative to white patients. Course-specific analyses also demonstrated no differences by race.ConclusionAlthough black patients have higher acuity at presentation and higher induction mortality, such disparities do not persist over subsequent frontline chemotherapy treatment. This finding allows interventions aimed at reducing disparities to be directed at presentation and induction.