Tolerance is established in polyclonal CD4(+) T cells by distinct mechanisms, according to self-peptide expression patterns.

Studies of repertoires of mouse monoclonal CD4(+) T cells have revealed several mechanisms of self-tolerance; however, which mechanisms operate in normal repertoires is unclear. Here we studied polyclonal CD4(+) T cells specific for green fluorescent protein expressed in various organs, which allowed us to determine the effects of specific expression patterns on the same epitope-specific T cells. Peptides presented uniformly by thymic antigen-presenting cells were tolerated by clonal deletion, whereas peptides excluded from the thymus were ignored. Peptides with limited thymic expression induced partial clonal deletion and impaired effector T cell potential but enhanced regulatory T cell potential. These mechanisms were also active for T cell populations specific for endogenously expressed self antigens. Thus, the immunotolerance of polyclonal CD4(+) T cells was maintained by distinct mechanisms, according to self-peptide expression patterns.

Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection.

A naive CD4(+) T cell population specific for a microbial peptide:major histocompatibility complex II ligand (p:MHCII) typically consists of about 100 cells, each with a different T cell receptor (TCR). Following infection, this population produces a consistent ratio of effector cells that activate microbicidal functions of macrophages or help B cells make antibodies. We studied the mechanism that underlies this division of labor by tracking the progeny of single naive T cells. Different naive cells produced distinct ratios of macrophage and B cell helpers but yielded the characteristic ratio when averaged together. The effector cell pattern produced by a given naive cell correlated with the TCR-p:MHCII dwell time or the amount of p:MHCII. Thus, the consistent production of effector cell subsets by a polyclonal population of naive cells results from averaging the diverse behaviors of individual clones, which are instructed in part by the strength of TCR signaling.

T cell receptor cross-reactivity between similar foreign and self peptides influences naive cell population size and autoimmunity.

T cell receptor (TCR) cross-reactivity between major histocompatibility complex II (MHCII)-binding self and foreign peptides could influence the naive CD4(+) T cell repertoire and autoimmunity. We found that nonamer peptides that bind to the same MHCII molecule only need to share five amino acids to cross-react on the same TCR. This property was biologically relevant because systemic expression of a self peptide reduced the size of a naive cell population specific for a related foreign peptide by deletion of cells with cross-reactive TCRs. Reciprocally, an incompletely deleted naive T cell population specific for a tissue-restricted self peptide could be triggered by related microbial peptides to cause autoimmunity. Thus, TCR cross-reactivity between similar self and foreign peptides can reduce the size of certain foreign peptide-specific T cell populations and might allow T cell populations specific for tissue-restricted self peptides to cause autoimmunity after infection.

Is Suffering a Useless Concept?

"Suffering" is a central concept within bioethics and often a crucial consideration in medical decision making. As used in practice, however, the concept risks being uninformative, ambiguous, or even misleading. In this paper, we consider a series of cases in which "suffering" is invoked and analyze them in light of prominent theories of suffering. We then outline ethical hazards that arise as a result of imprecise usage of the concept and offer practical recommendations for avoiding them. Appeals to suffering are often getting at something ethically important. But this is where the work of ethics begins, not where it ends.

Caregiver survey in glioblastoma focused on cognitive dysfunction: development and results from a multicenter study.

Aim: To develop a cognitive dysfunction (CD) focused questionnaire to evaluate caregiver burden in glioblastoma. Materials & methods: The survey was developed from stakeholder consultations and a pilot study, and disseminated at eight US academic cancer centers. Caregivers self-reported caring for an adult with glioblastoma and CD. Results: The 89-item survey covered demographics, CD symptoms and caregiver burden domains. Among 185 caregivers, most were white, educated females and reported memory problems as the most common CD symptom. An exposure-effect was observed, with increase in number of CD symptoms significantly associated with greater caregiver burden. Conclusion: This questionnaire could guide caregiver interventions and be adapted for use longitudinally, in community cancer settings, and in patients with brain metastases.

Glioblastoma (GBM) is a very aggressive brain cancer. People who have GBM have trouble remembering things and are unable to do things they used to do. These changes can be very hard. Researchers are trying to better understand what it is like for people who take care of people with GBM (or caregivers). In this study, researchers created a new survey for caregivers. The survey included questions about what caregivers see happening in their loved one with GBM. Caregivers said that memory problems were common. Also, when the patient had more problems the caregiver had a harder time, too. Researchers hope to improve the survey and use it in the future for more studies.

Symptomatic idiopathic intracranial hypertension triggered by Ramadan intermittent fasting: a case report.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a disorder that primarily affects obese women of reproductive age. The exact pathogenesis of IIH is unknown though multiple etiologies have been proposed. CASE PRESENTATION: We report a case of IIH triggered by first-time Ramadan intermittent fasting (RIF) in an 18-year-old woman. Our patient developed new onset headaches, diplopia, and pulsatile tinnitus with examination notable for bilateral papilledema and lumbar puncture revealing an elevated opening pressure. Her symptoms resolved after cessation of RIF, apart from persistent left sided tinnitus which later resolved with acetazolamide administration. CONCLUSION: This case report uniquely illustrates that RIF may provoke symptomatic IIH. We hypothesize that a decreased concentration of glucagon-like peptide-1 (GLP-1) induced by fasting results in decreased GLP-1 receptor activation in the choroid plexus, allowing for increased CSF secretion into the ventricles invoking increased intracranial pressure (ICP). This theoretical mechanism provides further insight as to the possible underlying pathophysiology of IIH.

From Bridge to Destination? Ethical Considerations Related to Withdrawal of ECMO Support over the Objections of Capacitated Patients.

Extracorporeal membrane oxygenation (ECMO) is typically viewed as a time-limited intervention-a bridge to recovery or transplant-not a destination therapy. However, some patients with decision-making capacity request continued ECMO support despite a poor prognosis for recovery and lack of viability as a transplant candidate. In response, critical care teams have asked for guidance regarding the ethical permissibility of unilateral withdrawal over the objections of a capacitated patient. In this article, we evaluate several ethical arguments that have been made in favor of withdrawal, including distributive justice, quality of life, patients' rights, professional integrity, and the Equivalence Thesis. We find that existing justifications for unilateral withdrawal of ECMO support in capacitated patients are problematic, which leads us to conclude that either: (1) additional ethical arguments are necessary to defend this approach or (2) the claim that it is not appropriate to use ECMO as a destination therapy should be questioned.

Bioethics and the Moral Authority of Experience.

While experience often affords important knowledge and insight that is difficult to garner through observation or testimony alone, it also has the potential to generate conflicts of interest and unrepresentative perspectives. We call this tension the paradox of experience. In this paper, we first outline appeals to experience made in debates about access to unproven medical products and disability bioethics, as examples of how experience claims arise in bioethics and some of the challenges raised by these claims. We then motivate the idea that experience can be an asset by appealing to themes in feminist and moral epistemology, distinguishing between epistemic and justice-based appeals. Next, we explain the concern that experience may be a liability by appealing to empirical work on cognitive biases and theoretical work about the problem of partial representation. We conclude with preliminary recommendations for addressing the paradox and offer several questions for future discussion.

Missing Voices: What Early Career Hospitalists View as Essential in Hospital Medicine-Focused Education.

OBJECTIVES: Acknowledging that a successful career in hospital medicine (HM) requires specialized skills, residency programs have developed hospital medicine-focused education (HMFE) programs. Surveys of Internal Medicine residency leaders have described HMFE curricula but are limited to that specialty and lack perspectives from early career hospitalists (ECHs) who recently completed this training. As such, we surveyed multispecialty ECHs to evaluate their preferences for HMFE and to identify gaps in standard residency training and career development that HMFE can bridge. The objectives of our study were to describe multispecialty ECH needs and preferences for HMFE and to identify gaps in standard residency training and career development that HMFE can bridge. METHODS: From February to March 2021, ECHs (defined as hospitalists within 0-5 years from residency) were surveyed using the Society of Hospital Medicine's listserv. Respondents identified as having participated in HMFE or not during residency (defining them as HMFE participants or non-HMFE participants). RESULTS: From 257 respondents, 84 (33%) ECHs met inclusion criteria. Half (n = 42) were HMFE participants. ECHs ranked clinical hospitalist career preparation (86%) and mentorship from HM faculty (85%) as the most important gaps in standard residency training and career development that HMFE can bridge. Other key components of HMFE included exposure to quality improvement, patient safety, and high-value care (67%); provision of autonomy through independent rounding (54%); and preparation for the job application process (70%). CONCLUSIONS: Multispecialty ECHs describe HMFE as positively influencing their decision to pursue a hospitalist career and increasing their preparedness for practice. HMFE may be particularly well suited to foster advanced clinical skills such as independent rounding, critical thinking, and self-reflection. We propose an organizing framework for HMFE in residency that may assist in the implementation and innovation of HMFE programs nationwide and in the development of standardized HMFE competencies.

Consistently Inconsistent: Does Inconsistency Really Indicate Incapacity?

While it is not explicitly included in capacity assessment tools, "consistency" has come to feature as a central concern when assessing patients' capacity. In order to determine whether inconsistency indicates incapacity, clinicians must determine the source of the inconsistency with respect to the process or content of a patient's decision-making. In this paper, we outline common types of inconsistency and analyze them against widely accepted elements of capacity. We explore the question of whether inconsistency necessarily entails a deficiency in a patient's capacity. While inconsistency may count as prima facie evidence of incapacity-enough evidence to justify a closer look-when making such determinations, it is important for clinicians to slow down, inquire about the reasons underlying the inconsistency and clearly show which of the elements of capacity the patient fails to satisfy.

Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline.

Bedaquiline is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation-addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi-lab reproducibility led to optimized reaction conditions that feature an unusual base-salt pairing and afford a doubling of the yield of racemic bedaquiline. We anticipate that implementation of these improvements on manufacturing scale will be facile, thereby substantially increasing the accessibility of this essential medication.

Two Minds, One Patient: Clearing up Confusion About "Ambivalence".

Patients who experience difficulty making medical decisions are often referred to as "ambivalent." However, the current lack of attention to the nuances between a cluster of phenomena that resemble ambivalence means that we are not always recognizing what is really going on with a patient. Importantly, different kinds of "ambivalence" may call for different approaches. In this paper, we present a taxonomy of ambivalence-related phenomena, provide normative analysis of some of the effects of-and common responses to-such mental states, and sketch some practical strategies for addressing ambivalence. In applying lessons from the philosophical literature and decision theory, our aim is to provide ethicists and clinicians with the tools to better understand and effectively intervene in cases of ambivalence.

Building Effective Mentoring Relationships During Clinical Ethics Fellowships: Pedagogy, Programs, and People.

How should clinical ethicists be trained? Scholars have stated that clinical ethics fellowships create well-trained, competent ethicists. While this appears intuitive, few features of fellowship programs have been publicly discussed, let alone debated. In this paper, we examine how fellowships can foster effective mentoring relationships. These relationships provide the foundation for the fellow's transition from novice to competent professional. In this essay, we begin by discussing our pedagogical commitments. Next, we describe the structures our program has created to assist our fellows in becoming competent ethicists. We then outline the kinds of knowledge, skills, and professional attributes mentors should possess. Following this, we focus on the knowledge, skills, and professional attributes that fellows develop as they co-create effective mentoring relationships. We will not prescribe a single approach to fellowship training; instead, our perspective will, we hope, become a catalyst for further conversation on training and mentoring clinical ethics fellows.

Human Eosinophils Express a Distinct Gene Expression Program in Response to IL-3 Compared with Common ß-Chain Cytokines IL-5 and GM-CSF.

Despite recent advances in asthma management with anti-IL-5 therapies, many patients have eosinophilic asthma that remains poorly controlled. IL-3 shares a common ß subunit receptor with both IL-5 and GM-CSF but, through α-subunit-specific properties, uniquely influences eosinophil biology and may serve as a potential therapeutic target. We aimed to globally characterize the transcriptomic profiles of GM-CSF, IL-3, and IL-5 stimulation on human circulating eosinophils and identify differences in gene expression using advanced statistical modeling. Human eosinophils were isolated from the peripheral blood of healthy volunteers and stimulated with either GM-CSF, IL-3, or IL-5 for 48 h. RNA was then extracted and bulk sequencing performed. DESeq analysis identified differentially expressed genes and weighted gene coexpression network analysis independently defined modules of genes that are highly coexpressed. GM-CSF, IL-3, and IL-5 commonly upregulated 252 genes and downregulated 553 genes, producing a proinflammatory and survival phenotype that was predominantly mediated through TWEAK signaling. IL-3 stimulation yielded the most numbers of differentially expressed genes that were also highly coexpressed (n = 119). These genes were enriched in pathways involving JAK/STAT signaling. GM-CSF and IL-5 stimulation demonstrated redundancy in eosinophil gene expression. In conclusion, IL-3 produces a distinct eosinophil gene expression program among the ß-chain receptor cytokines. IL-3-upregulated genes may provide a foundation for research into therapeutics for patients with eosinophilic asthma who do not respond to anti-IL-5 therapies.

Erasing Workers' Identities: Comment on Blanck, Hyseni, and Altunkol Wise's National Study of the Legal Profession.

"Bring your whole self to work" remains a common mantra of supporters of workplace diversity, equity, and inclusion ("DEI").1 For example, disability rights advocates have long contended that hiding or downplaying one's disability from one's colleagues at work "create[s] an invisible layer of additional work for the individual" in being accepted at the job and negatively affects productivity.2 LGBTQ+ rights advocates have raised similar points, noting that hiding or downplaying one's sexual orientation or gender identity from one's colleagues hinders internal advancement of LGBTQ+ workers.3 As recently as 2019, however, a Deloitte study found that sixty-one percent of workers hid or downplayed one or more of their identities from their colleagues at work.4.

E-cigarette use increases susceptibility to bacterial infection by impairment of human neutrophil chemotaxis, phagocytosis, and NET formation.

E-cigarettes are portrayed as safer relative to conventional tobacco. However, burgeoning evidence suggests that E-cigarettes may adversely affect host defenses. However, the precise mechanisms by which E-cigarette vapor alters innate immune cell function have not been fully elucidated. We determined the effects of E-cigarette exposure on the function and responses to infectious challenge of the most abundant innate immune cell, the neutrophil, using isolated human neutrophils and a mouse model of gram-negative infection. Our results revealed that human neutrophils exposed to E-cigarette vapor had 4.2-fold reductions in chemotaxis toward the bacterial cell-well component f-Met-Leu-Phe (P < 0.001). F-actin polarization and membrane fluidity were also adversely affected by E-cigarette vapor exposure. E-cigarette-exposed human neutrophils exhibited a 48% reduction in production of reactive oxygen species (ROS; P < 0.001). Given the central role of ROS in neutrophil extracellular trap (NET) production, NET production was quantified, and E-cigarette vapor exposure was found to reduce NETosis by 3.5-fold (P < 0.01); formulations with and without nicotine containing propylene glycol exhibiting significant suppressive effects. However, noncanonical NETosis was unaffected. In addition, exposure to E-cigarette vapor lowered the rate of phagocytosis of bacterial bioparticles by 47% (P < 0.05). In our physiological mouse model of chronic E-cigarette exposure and sepsis, E-cigarette vapor inhalation led to reduced neutrophil migration in infected spaces and a higher burden of Pseudomonas. These findings provide evidence that E-cigarette use adversely impacts the innate immune system and may place E-cigarette users at higher risk for dysregulated inflammatory responses and invasive bacterial infections.

Adherence to Adjuvant Imatinib Therapy in Patients with Gastrointestinal Stromal Tumor in Clinical Practice: A Cross-Sectional Study.

BACKGROUND: Adherence to imatinib therapy has been significantly associated with disease progression and direct medical costs in gastrointestinal stromal tumor (GIST) patients. However, adherence to oral anticancer drugs is frequently hindered by the influence of various factors. The aim of this study was to evaluate the prevalence of imatinib adherence and its influencing factors among GIST patients in the adjuvant setting. METHODS: Adherence of GIST patients (receiving imatinib for ≥1 month) was assessed using the 8-item Morisky Medication Adherence Scale (MMAS), with a score <8 indicating nonadherence. Quality of life and social support were evaluated by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ C30) and Social Support Rating Scale (SSRS). Factors associated with nonadherence were identified by multivariate logistic regression analysis. Imatinib plasma concentrations were determined and compared between adherent and nonadherent groups. RESULTS: A total of 158 GIST patients were enrolled, 92 (58.2%) patients were considered nonadherent. Intentional nonadherence, especially feeling hassled by treatment plan (34.2% of patients), was common. In the multivariate logistic regression analysis, gender (OR 2.68, 95% CI 1.33-5.41; p = 0.0058), place of residence (OR 3.20, 95% CI 1.39-7.35; p = 0.0061), and global health status (OR 1.02, 95% CI 1.00-1.04; p = 0.0378) were significantly associated with nonadherence. Moreover, imatinib plasma concentrations in nonadherent patients were significantly lower than that in the good adherence group (p = 0.0338). CONCLUSIONS: Poor adherence to imatinib is a notable problem in Chinese GIST patients in the adjuvant therapy setting. The predominant indicators of nonadherence in this study were gender (female), living in a rural area, and harboring a low global health status score. These indicators may aid clinicians in determining where increased efforts in promoting adherence may be beneficial.

pH switch for OH-photoacidity in 5-amino-2-naphthol and 8-amino-2-naphthol.

Photoactive charge transfer compounds are of strong interest for their potential applications in material, chemical, and biological science and their abilities to elucidate fundamental charge transfer mechanisms. Aminonaphthols, photoacids with both oxygen (OH) and nitrogen-based (NH2) protonation sites, have been reported to undergo simultaneous excited-state proton transfer (ESPT) in water upon excitation. In this paper, the ESPT mechanism for zwitterion formation in 8-amino-2-naphthol (8N2OH) and 5-amino-2-naphthol (5N2OH) was examined using a combination of time-resolved emission spectroscopy and time-dependent density functional theory (TD-DFT) calculations. The measurements prompted a re-assignment of the zwitterion state in the steady-state emission spectra; analysis of the time-correlated single-photon counting emission data showed that the zwitterion was formed only from excitation of protonated 5N2OH and 8N2OH such that ESPT occurred only at the single hydroxyl group. The protonation state of the amino group dramatically altered the photoacidity of OH, such that the pH behaved as an on/off switch for photoacidity. In the protonated state (NH3+), the pKa*(OH) values of 5N2OH and 8N2OH were both 1.1 ± 0.2, while in the deprotonated state (NH2), the two pKa*(OH) values were similar to the ground state proton acidity, pKa(OH) = 9.5 ± 0.2. The switching of the photoacidity was investigated using TD-DFT calculations and the linear free energy Hammett relation. The latter was shown to not describe the excited state data over the broad pH range.