Successful host defense against pathogens requires innate immune recognition of the correct pathogen associated molecular patterns (PAMPs) by pathogen recognition receptors (PRRs) to trigger the ...appropriate gene program tailored to the pathogen. While many PRR pathways contribute to the innate immune response to specific pathogens, the relative importance of each pathway for the complete transcriptional program elicited has not been examined in detail. Herein, we used RNA-sequencing with wildtype and mutant macrophages to delineate the innate immune pathways contributing to the early transcriptional response to Staphylococcus aureus, a ubiquitous microorganism that can activate a wide variety of PRRs. Unexpectedly, two PRR pathways-the Toll-like receptor (TLR) and Stimulator of Interferon Gene (STING) pathways-were identified as dominant regulators of approximately 95% of the genes that were potently induced within the first four hours of macrophage infection with live S. aureus. TLR signaling predominantly activated a pro-inflammatory program while STING signaling activated an antiviral/type I interferon response with live but not killed S. aureus. This STING response was largely dependent on the cytosolic DNA sensor cyclic guanosine-adenosine synthase (cGAS). Using a cutaneous infection model, we found that the TLR and STING pathways played opposite roles in host defense to S. aureus. TLR signaling was required for host defense, with its absence reducing interleukin (IL)-1β production and neutrophil recruitment, resulting in increased bacterial growth. In contrast, absence of STING signaling had the opposite effect, enhancing the ability to restrict the infection. These results provide novel insights into the complex interplay of innate immune signaling pathways triggered by S. aureus and uncover opposing roles of TLR and STING in cutaneous host defense to S. aureus.
Alpha-fetoprotein (AFP) predicts hepatocellular carcinoma (HCC) recurrence after liver transplant (LT) but remains an imperfect biomarker. The role of DCP (des-gamma-carboxyprothrombin) and AFP-L3 ...(AFP bound to Lens culinaris agglutinin) in predicting HCC recurrence remains incompletely characterized. AFP-L3 and DCP could identify patients at high risk of post-transplant HCC recurrence and serve as liver transplant exclusion criteria to defer transplant until patients receive additional risk-reducing pre-transplant locoregional therapy.
This prospective cohort study included consecutive patients with HCC who underwent LT (within or down-staged to Milan criteria) between 2017 and 2022. Pre-transplant AFP, AFP-L3, and DCP measurements were obtained. The primary endpoint was the ability of biomarkers to predict HCC recurrence-free survival.
This cohort included 285 patients with a median age of 67 (IQR 63-71). At LT, median biomarker values were AFP 5.0 ng/ml (IQR 3.0-12.1), AFP-L3 6.7% (0.5-13.2), and DCP 1.0 ng/ml (0.3-2.8). Most (94.7%) patients received pre-LT locoregional therapy. After a median post-LT follow-up of 3.1 years, HCC recurrence was observed in 18 (6.3%) patients. AFP-L3 and DCP outperformed AFP with C-statistics of 0.81 and 0.86 respectively, compared with 0.74 for AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted 61.1% of HCC recurrences, whereas HCC only recurred in 7 of 265 (2.6%) patients not meeting this threshold. The Kaplan-Meier recurrence-free survival rate at 3 years post-LT was 43.7% for patients with dual-positive biomarkers compared to 97.0% for all others (p <0.001).
Dual-positivity for AFP-L3 ≥15% and DCP ≥7.5 strongly predicted post-LT HCC recurrence. This model could refine LT selection criteria and identify high-risk patients who require additional locoregional therapy prior to LT.
Alpha-fetoprotein (AFP) is used to predict hepatocellular carcinoma (HCC) recurrence after liver transplant, but it remains an imperfect biomarker. In this prospective study, the biomarkers DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) strongly predicted early HCC recurrence and outperformed AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted the majority of recurrences and could be used to further refine liver transplant eligibility criteria.
Through experiences with hospital visitor restrictions during the COVID-19 pandemic, a group of frontline trainees at the University of California San Francisco (UCSF) uncovered patient stories ...highlighting the unique challenges that patients with limited English proficiency (LEP) face in the hospital, particularly their vulnerability to social isolation. Here, we recount patient stories illustrative of this isolation, generated by insufficient professional interpreter use, ad hoc interpretation, and scarcity of media in preferred languages. When confronted with the social isolation faced by all patients during COVID-19, we more clearly saw the healthcare disparities affecting patients with LEP. A trainee-led videoconferencing initiative facilitating social calls between patients at UCSF and their loved ones proved especially helpful in reducing the disconnection that patients with LEP experience in the hospital. Motivated by the findings of this project, we advocate for other institutions to take similar action, such as hiring inpatient telehealth navigators and providing tablets for ad lib use. Enacting these changes will keep patients with LEP connected to their families and communities while in the hospital, an essential step towards establishing an equitable experience for patients with LEP.
Mild traumatic brain injury (mTBI) poses risk to the neurocognitive, emotional, and financial well‐being of affected individuals. While aggression and impulsivity have been examined in relation to ...mTBI, little work has been done to evaluate the relationship between history of mTBI and personality disorder (PD). The authors examined the associations between history of mTBI and PD in a control group without history of mTBI (N = 1189) and individuals with history of mTBI (N = 267). Results demonstrated that any PD diagnosis is a significant risk factor for mTBI (p < 0.001). Cluster B diagnoses, particularly borderline and antisocial PD, were independently significant risk factors for mTBI. These data suggest a role for screening for a history of mTBI in patients with PDs and associated traits.
Background:
More than a dozen countries have now legalized some form of assisted dying, and additional jurisdictions are considering similar legislations or expanding eligibility criteria. Despite ...the persistent controversies about the relationship between medicine, palliative care, and assisted dying, many people are interested in assisted dying. Understanding how end-of-life care discussions between patients and specialist palliative care providers may be affected by such legislation can inform end-of-life care delivery in the evolving socio-cultural and legal environment.
Aim:
To explore how the Canadian Medical Assistance in Dying legislation affects end-of-life care discussions between patients and multidisciplinary specialist palliative care providers.
Design:
Qualitative thematic analysis of semi-structured interviews.
Participants:
Forty-eight specialist palliative care providers from Vancouver (n = 26) and Toronto (n = 22) were interviewed in person or by phone. Participants included physicians (n = 22), nurses (n = 15), social workers (n = 7), and allied health professionals (n = 4).
Results:
Qualitative thematic analysis identified five notable considerations associated with Medical Assistance in Dying affecting end-of-life care discussions: (1) concerns over having proactive conversations about the desire to hasten death, (2) uncertainties regarding wish-to-die statements, (3) conversation complexities around procedural matters, (4) shifting discussions about suffering and quality of life, and (5) the need and challenges of promoting open-ended discussions.
Conclusion:
Medical Assistance in Dying challenges end-of-life care discussions and requires education and support for all concerned to enable compassionate health professional communication. It remains essential to address psychosocial and existential suffering in medicine, but also to provide timely palliative care to ensure suffering is addressed before it is deemed irremediable. Hence, clarification is required regarding assisted dying as an intervention of last resort. Furthermore, professional and institutional guidance needs to better support palliative care providers in maintaining their holistic standard of care.
In the United States, candidates with hepatocellular carcinoma (HCC) meeting standardized qualifying criteria receive similar priority on the liver transplant waiting list through Model for End-Stage ...Liver Disease exception points, without consideration of the dropout risk or relative expected benefit from liver transplantation. A more nuanced allocation scheme for HCC is needed to better represent the individual urgency for liver transplant and optimize organ utility. In this review, we discuss the development of HCC risk prediction models for practical use in liver allocation.
HCC is a heterogenous disease that requires improved risk stratification for patients who fall within current transplant eligibility criteria. Several models have been proposed, though none have been adopted in clinical practice or liver allocation to date, due to various limitations.
Improved HCC risk stratification for liver transplant candidates is needed to more accurately represent their urgency for transplant, with continued attention to the potential impact on post-liver transplant outcomes. Plans to implement a continuous distribution model for liver allocation in the United States may provide an opportunity to re-consider a more equitable allocation scheme for patients with HCC.
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