Microbiota-dependent activation of CD4+ T cells induces CTLA-4 blockade-associated colitis via Fcγ receptors.

Immune checkpoint inhibitors can stimulate antitumor immunity but can also induce toxicities termed immune-related adverse events (irAEs). Colitis is a common and severe irAE that can lead to treatment discontinuation. Mechanistic understanding of gut irAEs has been hampered because robust colitis is not observed in laboratory mice treated with checkpoint inhibitors. We report here that this limitation can be overcome by using mice harboring the microbiota of wild-caught mice, which develop overt colitis following treatment with anti-CTLA-4 antibodies. Intestinal inflammation is driven by unrestrained activation of IFNγ-producing CD4+ T cells and depletion of peripherally induced regulatory T cells through Fcγ receptor signaling. Accordingly, anti-CTLA-4 nanobodies that lack an Fc domain can promote antitumor responses without triggering colitis. This work suggests a strategy for mitigating gut irAEs while preserving antitumor stimulating effects of CTLA-4 blockade.

Engineering Equity Into the Promise of Xenotransplantation.

Two of the greatest challenges facing kidney transplantation are the lack of donated organs and inequities in who receives a transplant. Xenotransplantation holds promise as a treatment approach that could solve the supply problem. Major advances in gene-editing procedures have enabled several companies to raise genetically engineered pigs for organ donation. These porcine organs lack antigens and have other modifications that should reduce the probability of immunological rejection when transplanted into humans. The US Food and Drug Administration and transplantation leaders are starting to chart a path to test xenotransplants in clinical trials and later integrate them into routine clinical care. Here we provide a framework that industry, regulatory authorities, payers, transplantation professionals, and patient groups can implement to promote equity during every stage in this process. We also call for immediate action. Companies developing xenotransplant technology should assemble patient advocacy boards to bring the concerns of individuals with end-stage kidney disease to the forefront. For trials, xenotransplantation companies should partner with transplant programs with substantial patient populations of racial and ethnic minority groups and that have reciprocal relationships with those communities. Those companies and transplant programs should reach out now to those communities to inform them about xenotransplantation and try to address their concerns. These actions have the potential to make these communities full partners in the promise of xenotransplantation.

Prevalence and predictors of shared decision-making in goals-of-care clinician-family meetings for critically ill neurologic patients: a multi-center mixed-methods study.

BACKGROUND: Shared decision-making is a joint process where patients, or their surrogates, and clinicians make health choices based on evidence and preferences. We aimed to determine the extent and predictors of shared decision-making for goals-of-care discussions for critically ill neurological patients, which is crucial for patient-goal-concordant care but currently unknown. METHODS: We analyzed 72 audio-recorded routine clinician-family meetings during which goals-of-care were discussed from seven US hospitals. These occurred for 67 patients with 72 surrogates and 29 clinicians; one hospital provided 49/72 (68%) of the recordings. Using a previously validated 10-element shared decision-making instrument, we quantified the extent of shared decision-making in each meeting. We measured clinicians' and surrogates' characteristics and prognostic estimates for the patient's hospital survival and 6-month independent function using post-meeting questionnaires. We calculated clinician-family prognostic discordance, defined as ≥ 20% absolute difference between the clinician's and surrogate's estimates. We applied mixed-effects regression to identify independent associations with greater shared decision-making. RESULTS: The median shared decision-making score was 7 (IQR 5-8). Only 6% of meetings contained all 10 shared decision-making elements. The most common elements were "discussing uncertainty"(89%) and "assessing family understanding"(86%); least frequent elements were "assessing the need for input from others"(36%) and "eliciting the context of the decision"(33%). Clinician-family prognostic discordance was present in 60% for hospital survival and 45% for 6-month independent function. Univariate analyses indicated associations between greater shared decision-making and younger clinician age, fewer years in practice, specialty (medical-surgical critical care > internal medicine > neurocritical care > other > trauma surgery), and higher clinician-family prognostic discordance for hospital survival. After adjustment, only higher clinician-family prognostic discordance for hospital survival remained independently associated with greater shared decision-making (p = 0.029). CONCLUSION: Fewer than 1 in 10 goals-of-care clinician-family meetings for critically ill neurological patients contained all shared decision-making elements. Our findings highlight gaps in shared decision-making. Interventions promoting shared decision-making for high-stakes decisions in these patients may increase patient-value congruent care; future studies should also examine whether they will affect decision quality and surrogates' health outcomes.

Prognostic Language in Critical Neurologic Illness: A Multicenter Mixed-Methods Study.

BACKGROUND AND OBJECTIVES: There are no evidence-based guidelines for discussing prognosis in critical neurologic illness, but in general, experts recommend that clinicians communicate prognosis using estimates, such as numerical or qualitative expressions of risk. Little is known about how real-world clinicians communicate prognosis in critical neurologic illness. Our primary objective was to characterize prognostic language clinicians used in critical neurologic illness. We additionally explored whether prognostic language differed between prognostic domains (e.g., survival, cognition). METHODS: We conducted a multicenter cross-sectional mixed-methods study analyzing deidentified transcripts of audio-recorded clinician-family meetings for patients with neurologic illness requiring intensive care (e.g., intracerebral hemorrhage, traumatic brain injury, severe stroke) from 7 US centers. Two coders assigned codes for prognostic language type and domain of prognosis to each clinician prognostic statement. Prognostic language was coded as probabilistic (estimating the likelihood of an outcome occurring, e.g., "80% survival"; "She'll probably survive") or nonprobabilistic (characterizing outcomes without offering likelihood; e.g., "She may not survive"). We applied univariate and multivariate binomial logistic regression to examine independent associations between prognostic language and domain of prognosis. RESULTS: We analyzed 43 clinician-family meetings for 39 patients with 78 surrogates and 27 clinicians. Clinicians made 512 statements about survival (median 0/meeting [interquartile range (IQR) 0-2]), physical function (median 2 [IQR 0-7]), cognition (median 2 [IQR 0-6]), and overall recovery (median 2 [IQR 1-4]). Most statements were nonprobabilistic (316/512 [62%]); 10 of 512 prognostic statements (2%) offered numeric estimates; and 21% (9/43) of family meetings only contained nonprobabilistic language. Compared with statements about cognition, statements about survival (odds ratio [OR] 2.50, 95% CI 1.01-6.18, p = 0.048) and physical function (OR 3.22, 95% 1.77-5.86, p < 0.001) were more frequently probabilistic. Statements about physical function were less likely to be uncertainty-based than statements about cognition (OR 0.34, 95% CI 0.17-0.66, p = 0.002). DISCUSSION: Clinicians preferred not to use estimates (either numeric or qualitative) when discussing critical neurologic illness prognosis, especially when they discussed cognitive outcomes. These findings may inform interventions to improve prognostic communication in critical neurologic illness.

Association Between Shared Decision-Making During Family Meetings and Surrogates' Trust in Their ICU Physician.

BACKGROUND: Although trust is central to successful physician-family relationships in ICUs, little is known about how to promote surrogates' trust of ICU physicians in this setting. RESEARCH QUESTION: Does the conduct of family conferences and physicians' use of shared decision-making (SDM) within family conferences impact surrogates' trust in the physician? STUDY DESIGN AND METHODS: A mixed-methods secondary analysis was done of a multicenter prospective cohort study of 369 surrogate decision-makers of 204 decisionally incapacitated patients at high risk of death or severe functional impairment within 13 ICUs at six US medical centers between 2008 and 2012. Surrogates completed the Abbreviated Wake Forest Physician Trust Scale (range, 5-25) before and after an audio-recorded family conference conducted within 5 days of ICU admission. We qualitatively coded transcribed conferences to determine physicians' use of five SDM behaviors: discussing surrogate's role, explaining medical condition and prognosis, providing emotional support, assessing understanding, and eliciting patient's values and preferences. Using multivariable linear regression with adjustment for clustering, we assessed whether surrogates' trust in the physician increased after the family meeting; we also examined whether the number of SDM behaviors used by physicians during the family meeting impacted trust scores. RESULTS: In adjusted models, conduct of a family meeting was associated with increased trust (average change, pre- to post family meeting: 0.91 point [95% CI, 0.4-1.4; P < .01]). Every additional element of SDM used during the family meeting, including discussing surrogate's role, providing emotional support, assessing understanding, and eliciting patient's values and preferences, was associated with a 0.37-point increase in trust (95% CI, 0.08-0.67; P = .01). If all four elements were used, trust increased by 1.48 points. Explaining medical condition or prognosis was observed in nearly every conference (98.5%) and was excluded from the final model. INTERPRETATION: The conduct of family meetings and physicians' use of SDM behaviors during meetings were both associated with increases in surrogates' trust in the treating physician.

Clinical Medical Ethics: How Did We Start? Where Are We Heading?

The author presents his view of the start of clinical medical ethics and ideas on where the broader field of bioethics is heading. In addition to clinical medical ethics, people with training in clinical ethics can enlarge the scope of their work in order to have additional real-world impact. Important opportunities abound in empirical research on medical ethics, the ethics of healthcare institutions, ethical issues regarding biomedical research, and public policy. Three topics for bioethics scholars to address are artificial intelligence in clinical care, health disparities, and communicating persuasively to broader audiences beyond academia.

Mitigating Racial Bias in Machine Learning.

When applied in the health sector, AI-based applications raise not only ethical but legal and safety concerns, where algorithms trained on data from majority populations can generate less accurate or reliable results for minorities and other disadvantaged groups.

Variability of Prognostic Communication in Critically Ill Neurologic Patients: A Pilot Multicenter Mixed-Methods Study.

IMPORTANCE: Withdrawal-of-life-sustaining treatments (WOLST) rates vary widely among critically ill neurologic patients (CINPs) and cannot be solely attributed to patient and family characteristics. Research in general critical care has shown that clinicians prognosticate to families with high variability. Little is known about how clinicians disclose prognosis to families of CINPs, and whether any associations exist with WOLST. OBJECTIVES: Primary: to demonstrate feasibility of audio-recording clinician-family meetings for CINPs at multiple centers and characterize how clinicians communicate prognosis during these meetings. Secondary: to explore associations of 1) clinician, family, or patient characteristics with clinicians' prognostication approaches and 2) prognostication approach and WOLST. DESIGN SETTING AND PARTICIPANTS: Forty-three audio-recorded clinician-family meetings during which prognosis was discussed from seven U.S. centers for 39 CINPs with 88 family members and 27 clinicians. MAIN OUTCOMES AND MEASURES: Two investigators qualitatively coded transcripts using inductive methods (inter-rater reliability > 80%) to characterize how clinicians prognosticate. We then applied univariate and multivariable multinomial and binomial logistic regression. RESULTS: Clinicians used four distinct prognostication approaches: Authoritative (21%; recommending treatments without discussing values and preferences); Informational (23%; disclosing just the prognosis without further discussions); advisory (42%; disclosing prognosis followed by discussion of values and preferences); and responsive (14%; eliciting values and preferences, then disclosing prognosis). Before adjustment, prognostication approach was associated with center (p < 0.001), clinician specialty (neurointensivists vs non-neurointensivists; p = 0.001), patient age (p = 0.08), diagnosis (p = 0.059), and meeting length (p = 0.03). After adjustment, only clinician specialty independently predicted prognostication approach (p = 0.027). WOLST decisions occurred in 41% of patients and were most common under the advisory approach (56%). WOLST was more likely in older patients (p = 0.059) and with more experienced clinicians (p = 0.07). Prognostication approach was not independently associated with WOLST (p = 0.198). CONCLUSIONS AND RELEVANCE: It is feasible to audio-record sensitive clinician-family meetings about CINPs in multiple ICUs. We found that clinicians prognosticate with high variability. Our data suggest that larger studies are warranted in CINPs to examine the role of clinicians' variable prognostication in WOLST decisions.

Promoting equity with a multi-principle framework to allocate scarce ICU resources.

We wholeheartedly agree with Schmidt and colleagues' efforts to promote equity in intensive care unit (ICU) triage. We also take issue with their characterisation of the New Jersey (NJ) allocation framework for ICU beds and ventilators, which is modelled after the multi-principle allocation framework we developed early in the pandemic. They characterise it as a two-criterion allocation framework and claim-without evidence-that it will 'compound disadvantage for black patients'. However, the NJ triage framework-like the model allocation policy we developed-actually contains four allocation criteria: the two criteria that the authors mentioned (chances for survival and near-term prognosis) and two criteria that they failed to mention which we included to promote equity: giving priority to frontline essential workers and giving priority to younger patients. These omissions are problematic both for reasons of factual accuracy and because the two criteria they failed to acknowledge would likely mitigate rather than exacerbate racial disparities during triage.

Structural Inequities, Fair Opportunity, and the Allocation of Scarce ICU Resources.

The September-October 2021 issue of the Hastings Center Report highlights the important topic of allocating scarce critical care resources during the Covid-19 pandemic. The article by Alex Rajczi and colleagues urges that policy-makers use public reasoning, not private reasoning, when developing triage policies. We completely agree. We show how the allocation framework we developed as private scholars, the "Pittsburgh framework," has been supported by public reasoning. The article by MaryKatherine Gaurke and colleagues criticizes rationing based on maximizing life-years saved and mistakenly claims that our framework recommended this approach. We explain that our framework never contained such a criterion but instead included a more limited consideration of near-term prognosis. In December 2020, in response to emerging data and important criticisms, we modified our framework to further strengthen equity. We are committed to improving allocation guidelines during crisis standards of care through reflective discussions and debates.

Bacterial-fungal interactions in the neonatal gut influence asthma outcomes later in life.

Bacterial members of the infant gut microbiota and bacterial-derived short-chain fatty acids (SCFAs) have been shown to be protective against childhood asthma, but a role for the fungal microbiota in asthma etiology remains poorly defined. We recently reported an association between overgrowth of the yeast Pichia kudriavzevii in the gut microbiota of Ecuadorian infants and increased asthma risk. In the present study, we replicated these findings in Canadian infants and investigated a causal association between early life gut fungal dysbiosis and later allergic airway disease (AAD). In a mouse model, we demonstrate that overgrowth of P. kudriavzevii within the neonatal gut exacerbates features of type-2 and -17 inflammation during AAD later in life. We further show that P. kudriavzevii growth and adherence to gut epithelial cells are altered by SCFAs. Collectively, our results underscore the potential for leveraging inter-kingdom interactions when designing putative microbiota-based asthma therapeutics.

Mitigating Inequities and Saving Lives with ICU Triage during the COVID-19 Pandemic.

The burdens of the coronavirus disease (COVID-19) pandemic have fallen disproportionately on disadvantaged groups, including the poor and Black, Latinx, and Indigenous communities. There is substantial concern that the use of existing ICU triage protocols to allocate scarce ventilators and critical care resources-most of which are designed to save as many lives as possible-may compound these inequities. As governments and health systems revisit their triage guidelines in the context of impending resource shortages, scholars have advocated a range of alternative allocation strategies, including the use of a random lottery to give all patients in need an equal chance of ICU treatment. However, both the save-the-most-lives approach and random allocation are seriously flawed. In this Perspective, we argue that ICU triage policies should simultaneously promote population health outcomes and mitigate health inequities. These ethical goals are sometimes in conflict, which will require balancing the goals of maximizing the number of lives saved and distributing health benefits equitably across society. We recommend three strategies to mitigate health inequities during ICU triage: introducing a correction factor into patients' triage scores to reduce the impact of baseline structural inequities; giving heightened priority to individuals in essential, high-risk occupations; and rejecting use of longer-term life expectancy and categorical exclusions as allocation criteria. We present a practical triage framework that incorporates these strategies and attends to the twin public health goals of promoting population health and social justice.

Ethical Framework for Assessing Manual and Digital Contact Tracing for COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has challenged the traditional public health balance between benefiting the good of the community through contact tracing and restricting individual liberty. This article first analyzes important technical and ethical issues regarding new smartphone apps that facilitate contact tracing and exposure notification. It then presents a framework for assessing contact tracing, whether manual or digital: the effectiveness at mitigating the pandemic; acceptability of risks, particularly privacy; and equitable distribution of benefits and risks. Both manual and digital contact tracing require public trust, engagement of minority communities, prompt COVID-19 testing and return of results, and high adherence with physical distancing and use of masks.