Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a virulent pathogen that induces rapid host death. Here we observed that host survival after infection with S. Typhimurium was enhanced in the absence of type I interferon signaling, with improved survival of mice deficient in the receptor for type I interferons (Ifnar1(-/-) mice) that was attributed to macrophages. Although there was no impairment in cytokine expression or inflammasome activation in Ifnar1(-/-) macrophages, they were highly resistant to S. Typhimurium-induced cell death. Specific inhibition of the kinase RIP1 or knockdown of the gene encoding the kinase RIP3 prevented the death of wild-type macrophages, which indicated that necroptosis was a mechanism of cell death. Finally, RIP3-deficient macrophages, which cannot undergo necroptosis, had similarly less death and enhanced control of S. Typhimurium in vivo. Thus, we propose that S. Typhimurium induces the production of type I interferon, which drives necroptosis of macrophages and allows them to evade the immune response.

Pandemic Forms.

Narrative structures, though invisible to the naked eye, guide our understanding of pandemics. Like curves and graphs, we can plot them, identify their patterns and organizing principles. These structures act upon our understanding of social and biological events just as much as the rhythms of viral replication and mutation. They order not only themselves but also social and health outcomes. This essay uses narrative precision to expand beyond Charles Rosenberg's influential dramaturgic model and develops new pandemic forms, scaled from the level of an individual line break to the multi-part series: Arc, a form of sequence. Cycle, a form of repetition. Sequel, a form of elongation. Caesura, a form of break. It investigates the potentialities and limitations of these forms, how they intersect, collide, and contradict, and how analysis of these interactions contributes to a deeper understanding of pandemics, their effects, and the diverse perspectives defining their structures. In doing so, it prototypes how literary methods offer conceptual frameworks for pandemic historiography and how a transdisciplinary, medical humanities analysis produces novel understandings at the intersection of health, culture, and society.

Virtuosic craft or clerical labour: the rise of the electronic health record and challenges to physicians' professional identity (1950-2022).

The electronic health record (EHR) is a focus of contentious debate, having become as essential to contemporary clinical practice as it is polarising. Debates about the EHR raise questions about physicians' professional identity, the nature of clinical work, evolution of the patient/practitioner relationship, and narratives of technological optimism and pessimism. The metaphors by which clinicians stake our identities-are we historians, detectives, educators, technicians, or something else?-animate the history of the early computer-based medical record in the mid-to-late twentieth-century USA. Proponents and detractors were equally interested in what the EHR revealed about clinician identity, and how it might fundamentally reshape it. This paper follows key moments in the history of the early computer-based patient record from the late 1950s to the EHR of the present day. In linking physician identity development, clinical epistemological structures, and the rise of the computer-based medical record in the USA in the mid-to-late twentieth century, we ask why the EHR is such a polarising entity in contemporary medicine, and situate clinician/EHR tensions in a longer history of aspirational physician identity and a kind of technological optimism that soon gave way to pessimism surrounding computer-based clinical work.

The Case of the Peculiar Story: Medical Investigation and the Detective in Edgar Allan Poe and Marguerite Duras.

In "The Murders in the Rue Morgue" (1841), Poe invents the detective story in English, introducing his gentleman sleuth Auguste Dupin as he solves the locked-room mystery of two women found brutally murdered in a Paris apartment. In L'Amante Anglaise (1967), Duras revisits the detective form, fictionalizing the true 1949 crime of a woman murdering and dismembering her cousin in Viorne, France. These literary detective stories highlight the powerful but unspoken role of affective experience in driving what appears, on the surface, to be a forensic medical or psychological investigation. In both tales, peculiarity is an affective and cognitive force that, contrary to what the majority of affect literature argues, inherently moves toward resolution and closure. Using peculiarity as an analytical concept, we argue that the concealment / discovery binary must acknowledge its affective origins, breaking a barrier between narrative scholarship and medical practice.

Historical Insights on Coronavirus Disease 2019 (COVID-19), the 1918 Influenza Pandemic, and Racial Disparities: Illuminating a Path Forward.

The coronavirus disease 2019 (COVID-19) pandemic is exacting a disproportionate toll on ethnic minority communities and magnifying existing disparities in health care access and treatment. To understand this crisis, physicians and public health researchers have searched history for insights, especially from a great outbreak approximately a century ago: the 1918 influenza pandemic. However, of the accounts examining the 1918 influenza pandemic and COVID-19, only a notable few discuss race. Yet, a rich, broader scholarship on race and epidemic disease as a "sampling device for social analysis" exists. This commentary examines the historical arc of the 1918 influenza pandemic, focusing on black Americans and showing the complex and sometimes surprising ways it operated, triggering particular responses both within a minority community and in wider racial, sociopolitical, and public health structures. This analysis reveals that critical structural inequities and health care gaps have historically contributed to and continue to compound disparate health outcomes among communities of color. Shifting from this context to the present, this article frames a discussion of racial health disparities through a resilience approach rather than a deficit approach and offers a blueprint for approaching the COVID-19 crisis and its afterlives through the lens of health equity.

Assessment of stability of sulphated lactosyl archaeol archaeosomes for use as a vaccine adjuvant.

Archaeosomes, composed of sulphated lactosyl archaeol (SLA) glycolipids, have been proven to be an effective vaccine adjuvant in multiple preclinical models of infectious disease or cancer. In addition to efficacy, the stability of vaccine components including the adjuvant is an important parameter to consider when developing novel vaccine formulations. To properly evaluate the potential of SLA glycolipids to be used as vaccine adjuvants in a clinical setting, a comprehensive evaluation of their stability is required. Herein, we evaluated the long term stability of preformed empty SLA archaeosomes prior to admixing with antigen at 4 °C or 37 °C for up to 6 months. In addition, the stability of adjuvant and antigen was evaluated for up to 1 month following admixing. Multiple analytical parameters evaluating the molecular integrity of SLA and the liposomal profile were assessed. Following incubation at 4 °C or 37 °C, the SLA glycolipid did not show any pattern of degradation as determined by mass spectroscopy, nuclear magnetic resonance (NMR) and thin layer chromatography (TLC). In addition, SLA archaeosome vesicle characteristics, such as size, zeta potential, membrane fluidity and vesicular morphology, were largely consistent throughout the course of the study. Importantly, following storage for 6 months at both 4 °C and 37 °C, the adjuvant properties of empty SLA archaeosomes were unchanged, and following admixing with antigen, the immunogenicity of the vaccine formulations was also unchanged when stored at both 4 °C and 37 °C for up to 1 month. Overall this indicates that SLA archaeosomes are highly stable adjuvants that retain their activity over an extended period of time even when stored at high temperatures.

In vitro evaluation of archaeosome vehicles for transdermal vaccine delivery.

Archaeosomes composed of archaeal total polar lipids (TPL) or semi-synthetic analog vesicles have been used as vaccine adjuvants and delivery systems in animal models for many years. Typically administered by intramuscular or subcutaneous injections, archaeosomes can induce robust, long-lasting humoral and cell-mediated immune responses against entrapped antigens and provide protection in murine models of infectious disease and cancer. Herein, we evaluated various archaeosomes for transdermal delivery, since this route may help eliminate needle-stick injuries and needle re-use, and therefore increase patient compliance. Archaeosomes composed of TPL from different archaea (Halobacterium salinarum, Methanobrevibacter smithii, Haloferax volcanii) and various semi-synthetic glycolipid combinations were evaluated for their ability to diffuse across the skin barrier using an ex vivo pig skin model and the results were compared to conventional synthetic ester liposomes. Physicochemical characteristics were determined for selected formulations including vesicle size, size distribution, zeta potential, fluidity, antigen (ovalbumin) incorporation efficiency and release. Archaeosomes, in particular those composed of M. smithii TPL or the synthetic glycolipid sulfated S-lactosylarchaeol (SLA) mixed with uncharged glycolipid lactosyl archaeol (LA), appeared to be effective carriers for ovalbumin, achieving much better antigen distribution and vesicle accumulation in the skin epidermis than conventional liposomes. The enhanced skin permeation of archaeosomes may be attributed to their chemical structure and physicochemical properties such as particle size, surface charge, stability, and fluidity of their lipid bilayer.

Segregating complex sound sources through temporal coherence.

A new approach for the segregation of monaural sound mixtures is presented based on the principle of temporal coherence and using auditory cortical representations. Temporal coherence is the notion that perceived sources emit coherently modulated features that evoke highly-coincident neural response patterns. By clustering the feature channels with coincident responses and reconstructing their input, one may segregate the underlying source from the simultaneously interfering signals that are uncorrelated with it. The proposed algorithm requires no prior information or training on the sources. It can, however, gracefully incorporate cognitive functions and influences such as memories of a target source or attention to a specific set of its attributes so as to segregate it from its background. Aside from its unusual structure and computational innovations, the proposed model provides testable hypotheses of the physiological mechanisms of this ubiquitous and remarkable perceptual ability, and of its psychophysical manifestations in navigating complex sensory environments.

Micro-Loans, Insecticide-Treated Bednets, and Malaria: Evidence from a Randomized Controlled Trial in Orissa, India.

We describe findings from the first large-scale cluster randomized controlled trial in a developing country that evaluates the uptake of a health-protecting technology, insecticide-treated bednets (ITNs), through micro-consumer loans, as compared to free distribution and control conditions. Despite a relatively high price, 52 percent of sample households purchased ITNs, highlighting the role of liquidity constraints in explaining earlier low adoption rates. We find mixed evidence of improvements in malaria indices. We interpret the results and their implications within the debate about cost sharing, sustainability and liquidity constraints in public health initiatives in developing countries.

Bioglass and nano bioglass: A next-generation biomaterial for therapeutic and regenerative medicine applications.

Biomaterials are an indispensable component in tissue engineering that primarily functions to resemble the extracellular matrix of any tissue targeted for regeneration. In the last five decades, bioglass has been extensively used in the field of therapeutic and tissue engineering. The doping of metal components into bioglass and the synthesizing of nano bioglass particles have found remarkable implications, both in vivo and in vitro. These include various medical and biological applications such as rejuvenating tissues, facilitating regeneration, and delivering biomolecules into cells and therapy, etc. Therefore, the current review discusses the various techniques used in synthesizing bioglass particles, trends of various ion-doped nano bioglass, and their applications in therapy as well as in regenerative medicine, specifically in the fields of dentistry, cardiovascular, skin, nervous, and respiratory systems. Apart from these, this review also emphasizes the bioglass combined with diverse natural polymers (like collagen, chitosan, etc.) and their applications. Furthermore, we discuss the effectiveness of bioglass properties such as antibacterial effects, biomolecular delivery systems, tissue compatibility, and regenerative material. Finally, the prospects and limitations are elaborated.

CD8+ T cells primed in the periphery provide time-bound immune-surveillance to the central nervous system.

After vaccination, memory CD8(+) T cells migrate to different organs to mediate immune surveillance. In most nonlymphoid organs, following an infection, CD8(+) T cells differentiate to become long-lived effector-memory cells, thereby providing long-term protection against a secondary infection. In this study, we demonstrated that Ag-specific CD8(+) T cells that migrate to the mouse brain following a systemic Listeria infection do not display markers reminiscent of long-term memory cells. In contrast to spleen and other nonlymphoid organs, none of the CD8(+) T cells in the brain reverted to a memory phenotype, and all of the cells were gradually eliminated. These nonmemory phenotype CD8(+) T cells were found primarily within the choroid plexus, as well as in the cerebrospinal fluid-filled spaces. Entry of these CD8(+) T cells into the brain was governed primarily by CD49d/VCAM-1, with the majority of entry occurring in the first week postinfection. When CD8(+) T cells were injected directly into the brain parenchyma, cells that remained in the brain retained a highly activated (CD69(hi)) phenotype and were gradually lost, whereas those that migrated out to the spleen were CD69(low) and persisted long-term. These results revealed a mechanism of time-bound immune surveillance to the brain by CD8(+) T cells that do not reside in the parenchyma.

Roles of natural resistance-associated macrophage protein-1 in modulating bacterial distribution and immune responses during Salmonella enterica serovar Typhimurium infection in murine pregnancy.

PROBLEM: Salmonella enterica serovar Typhimurium (S.Tm) infection in Nramp1+/+ mice during pregnancy can lead to profound bacterial growth in the feto-placental unit and adverse pregnancy outcomes, including fetal loss, maternal illness and death. The kinetics and mechanisms by which S.Tm gains entry within individual feto-placental unit, and disseminates through tissues leading to placental resorption and fetal demise remain unclear. METHOD OF STUDY: Mice were systemically infected with S.Tm. Bacterial burden within spleen and individual placentas, and placental/fetal resorptions were quantified. Flow cytometric analysis of immune cell types in the spleen and individual placentas was performed. Cytokine expression in maternal serum was determined through cytometric bead array. RESULTS: Systemic infection with S.Tm resulted in preferential bacterial proliferation in placentas compared to the spleen in Nramp1+/+ mice. At 24 h post-infection, the mean infection rate of individual placentas per mouse was ∼50%, increasing to >75% by 72 h post-infection, suggesting that initial infection in few sites progresses to rapid spread of infection through the uterine milieu. This correlated with a steady increase in placental/fetal resorption rates. Placental infection was associated with local increased neutrophil percentages, whereas numbers and percentages in the spleen remained unchanged, suggesting dichotomous modulation of inflammation between the systemic compartment and the feto-maternal interface. Reduced survival rates of pregnant mice during infection correlated with decreased serum IFN-γ but increased IL-10 levels relative to non-pregnant controls. CONCLUSION: Pregnancy compromises host resistance conferred by Nramp1 against S.Tm through compartment-specific regulation of maternal and placental cellular responses, and modulation of systemic cytokine expression.

A Pilot Study to Understand the Role of Medical Humanities in Medical Education.

Over the past 20 years, the number of colleges offering programs in medical humanities has increased, and through the Medical Humanities Initiative at Georgetown University, this pilot study sought to understand students perceived benefits of a medical humanities curriculum. Based on a qualitative thematic analysis of free-response survey reflections from students enrolled in three unique medical humanities courses, six themes emerged. The themes help capture the role that a medical humanities education can play in shaping future clinicians and demonstrate that these courses not only provided a distinct teaching methodology from the scientific classroom but also appeared to deepen the students' understanding of the humanistic aspects of medicine and its many facets.

A prospective evaluation of breast thermography enhanced by a novel machine learning technique for screening breast abnormalities in a general population of women presenting to a secondary care hospital.

Objective: Artificial intelligence-enhanced breast thermography is being evaluated as an ancillary modality in the evaluation of breast disease. The objective of this study was to evaluate the clinical performance of Thermalytix, a CE-marked, AI-based thermal imaging test, with respect to conventional mammography. Methods: A prospective, comparative study performed between 15 December 2018 and 06 January 2020 evaluated the performance of Thermalytix in 459 women with both dense and nondense breast tissue. Both symptomatic and asymptomatic women, aged 30-80 years, presenting to the hospital underwent Thermalytix followed by 2-D mammography and appropriate confirmatory investigations to confirm malignancy. The radiologist interpreting the mammograms and the technician using the Thermalytix tool were blinded to the others' findings. The statistical analysis was performed by a third party. Results: A total of 687 women were recruited, of whom 459 fulfilled the inclusion criteria. Twenty-one malignancies were detected (21/459, 4.6%). The overall sensitivity of Thermalytix was 95.24% (95% CI, 76.18-99.88), and the specificity was 88.58% (95% CI, 85.23-91.41). In women with dense breasts (n = 168, 36.6%), the sensitivity was 100% (95% CI, 69.15-100), and the specificity was 81.65% (95% CI, 74.72-87.35). Among these 168 women, 37 women (22%) were reported as BI-RADS 0 on mammography; in this subset, the sensitivity of Thermalytix was 100% (95% CI, 69.15-100), and the specificity was 77.22% (95% CI, 69.88-83.50). Conclusion: Thermalytix showed acceptable sensitivity and specificity with respect to mammography in the overall patient population. Thermalytix outperformed mammography in women with dense breasts and those reported as BI-RADS 0.

Maternal Immune Cell and Cytokine Profiles to Predict Cardiovascular Risk Six Months after Preeclampsia.

Women who develop preeclampsia (PE) are at high risk for cardiovascular disease (CVD). Early identification of women with PE who may benefit the most from early cardiovascular risk screening and interventions remains challenging. Our objective was to assess whether cytokine and immune cell profiles after PE are helpful in distinguishing women at low and high CVD risk at 6-months postpartum. Individuals who developed PE were followed for immune cell phenotyping and plasma cytokine quantification at delivery, at 3-months, and at 6-months postpartum. Lifetime CVD risk was assessed at 6-months postpartum, and the immune cell and cytokine profiles were compared between risk groups at each time point. Among 31 participants, 18 (58.1%) exhibited high CVD-risk profiles at 6-months postpartum. The proportion of circulating NK-cells was significantly lower in high-risk participants at delivery (p = 0.04). At 3-months postpartum, high-risk participants exhibited a lower proportion of FoxP3+ regulatory T-cells (p = 0.01), a greater proportion of CD8+ T cells (p = 0.02) and a lower CD4+:CD8+ ratio (p = 0.02). There were no differences in immune cell populations at 6-months postpartum. There were no differences in plasma cytokines levels between risk groups at any time point. Subtle differences in immune cell profiles may help distinguish individuals at low and high CVD risk in the early postpartum period and warrants further investigation.

IFN-gamma expressed by T cells regulates the persistence of antigen presentation by limiting the survival of dendritic cells.

Ag presentation to T cells orchestrates the development of acquired immune response. Although it is considered that Ag presentation may persist at high levels during chronic infections, we have previously reported that in mice infected with bacillus Calmette-Guérin, Ag presentation gets drastically curtailed during the chronic stage of infection despite antigenic persistence. In this report we evaluated the mechanism of this curtailment. Ag presentation declined precipitously as the T cell response developed, and Ag presentation was not curtailed in mice that were deficient in CD8(+) T cells or MHC class II, suggesting that T cells regulate Ag presentation. Curtailment of Ag presentation was reduced in IFN-gamma-deficient mice, but not in mice with a deficiency/mutation in inducible NOS2, perforin, or Fas ligand. In hosts with no T cells (Rag1(-/-)), Ag presentation was not curtailed during the chronic stage of infection. However, adoptive transfer of wild-type, but not IFN-gamma(-/-), CD4(+) and CD8(+) T cells into Rag1-deficient hosts strongly curtailed Ag presentation. Increased persistence of Ag presentation in IFN-gamma-deficient hosts correlated to increased survival of dendritic cells, but not of macrophages, and was not due to increased stimulatory capacity of IFN-gamma-deficient dendritic cells. These results reveal a novel mechanism indicating how IFN-gamma prevents the persistence of Ag presentation, thereby preventing memory T cells from going into exhaustion.

Selectively reduced intracellular proliferation of Salmonella enterica serovar typhimurium within APCs limits antigen presentation and development of a rapid CD8 T cell response.

Ag presentation to CD8(+) T cells commences immediately after infection, which facilitates their rapid expansion and control of pathogen. This paradigm is not followed during infection with virulent Salmonella enterica serovar Typhimurium (ST), an intracellular bacterium that causes mortality in susceptible C57BL/6J mice within 7 days and a chronic infection in resistant mice (129 x 1SvJ). Infection of mice with OVA-expressing ST results in the development of a CD8(+) T cell response that is detectable only after the second week of infection despite the early detectable bacterial burden. The mechanism behind the delayed CD8(+) T cell activation was evaluated, and it was found that dendritic cells/macrophages or mice infected with ST-OVA failed to present Ag to OVA-specific CD8(+) T cells. Lack of early Ag presentation was not rescued when mice or dendritic cells/macrophages were infected with an attenuated aroA mutant of ST or with mutants having defective Salmonella pathogenicity island I/II genes. Although extracellular ST proliferated extensively, the replication of ST was highly muted once inside macrophages. This muted intracellular proliferation of ST resulted in the generation of poor levels of intracellular Ag and peptide-MHC complex on the surface of dendritic cells. Additional experiments revealed that ST did not actively inhibit Ag presentation, rather it inhibited the uptake of another intracellular pathogen, Listeria monocytogenes, thereby causing inhibition of Ag presentation against L. monocytogenes. Taken together, this study reveals a dichotomy in the proliferation of ST and indicates that selectively reduced intracellular proliferation of virulent pathogens may be an important mechanism of immune evasion.