The juxtaposition of the natural and the medical perspectives in noisy breathing at the end of life.

BACKGROUND: Noisy breathing is common at the end of life. Management of noisy breathing aims to reduce the noise via repositioning the person, suctioning the person's airways and using antimuscarinic drugs. Dying people are generally thought not to be distressed by noisy breathing at the end of life, but the noise may distress others. There is doubt on whether antimuscarinic drugs are any more effective than a placebo for noisy breathing. However, antimuscarinics are still commonly administered to people at the end of life. AIM: To illuminate reasons behind decision making and noisy breathing at the end of life. METHODS: Semi-structured interviews and 'self-recorded brief accounts' with healthcare professionals. FINDINGS: Noisy breathing at the end of life is viewed as both a natural and a medical phenomenon. However, while most participants in the interviews thought that antimuscarinics were uneffective, the prescription and administration of antimuscarinics were embedded within professional culture. CONCLUSION: Managing noisy breathing is a complex issue that incorporates natural and medical viewpoints and has a long-standing culture of practice. Research should aim to determine best practice and reduce a person's distress at the end of life.

Specific human cytomegalovirus signature detected in NK cell metabolic changes post vaccination.

Effective vaccines for human immunodeficiency virus-1 (HIV-1) and hepatitis C virus (HCV) remain a significant challenge for these infectious diseases. Given that the innate immune response is key to controlling the scale and nature of developing adaptive immune responses, targeting natural killer (NK) cells that can promote a T-helper type 1 (Th1)-type immune response through the production of interferon-γ (IFNγ) remains an untapped strategic target for improved vaccination approaches. Here, we investigate metabolic and functional responses of NK cells to simian adenovirus prime and MVA boost vaccination in a cohort of healthy volunteers receiving a dual HCV-HIV-1 vaccine. Early and late timepoints demonstrated metabolic changes that contributed to the sustained proliferation of all NK cells. However, a strong impact of human cytomegalovirus (HCMV) on some metabolic and functional responses in NK cells was observed in HCMV seropositive participants. These changes were not restricted to molecularly defined adaptive NK cells; indeed, canonical NK cells that produced most IFNγ in response to vaccination were equally impacted in individuals with latent HCMV. In summary, NK cells undergo metabolic changes in response to vaccination, and understanding these in the context of HCMV is an important step towards rational vaccine design against a range of human viral pathogens.

Spiritual distress: symptoms, quality of life and hospital utilisation in home-based palliative care.

OBJECTIVES: The purpose of this study was to use a spiritual screening question to quantify the prevalence of spiritual distress (SD) in a large cohort of seriously ill patients at admission to home-based palliative care (HBPC) and to examine the associations between SD with symptom burden, quality of life and hospital-based utilisation up to 6 months after admission to HBPC. METHODS: Data for this cohort study (n=658) were drawn from a pragmatic comparative-effectiveness trial testing two models of HBPC. At admission to HBPC, SD was measured using a global question (0-10-point scale: none=0; mild=1-4; moderate-to-severe=5+); symptoms and quality of life were measured with the Edmonton Symptom Assessment Scale (ESAS) and PROMIS-10. Hospital utilisation was captured using electronic records and claims. Median regression and proportional hazard competing risk models assessed the association between SD with symptoms and quality of life, and hospital utilisation, respectively. RESULTS: Nearly half of the patients/proxies reported some level of SD. Increasing SD was significantly associated with higher symptom burden (increase of 7-14 points on ESAS) and worse mental well-being (decrease of 2.7 to 4.6 points on PROMIS-10-mental) in adjusted models. Compared with patients/proxies who reported no SD, those with at least some level of SD were not at increased risk for hospital-based utilisation over a median follow-up period of 2 months. CONCLUSION: While SD is cross-sectionally associated with worse symptoms and mental well-being, it did not predict downstream hospital-based utilisation. Our results highlight the importance of assessing for and managing SD in patients with serious illness.

Immune-Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B-Infected Cells.

BACKGROUND AND AIMS: Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBV-specific immune responses, and treatment regimens that require lifelong adherence to suppress the virus. Immune mobilizing monoclonal T Cell receptors against virus (ImmTAV) molecules represent a therapeutic strategy combining an affinity-enhanced T Cell receptor with an anti-CD3 T Cell-activating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virus-derived peptides presented by human leukocyte antigen (HLA). APPROACH AND RESULTS: ImmTAV molecules specific for HLA-A*02:01-restricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAV-Env to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imaging-based killing assays. Elimination of infected cells was further quantified using a modified fluorescent hybridization of viral RNA assay. Here, we demonstrate that picomolar concentrations of ImmTAV-Env can redirect T cells from healthy and HBV-infected donors toward hepatocellular carcinoma (HCC) cells containing integrated HBV DNA resulting in cytokine release, which could be suppressed by the addition of a corticosteroid in vitro. Importantly, ImmTAV-Env redirection of T cells induced cytolysis of antigen-positive HCC cells and cells infected with HBV in vitro, causing a reduction of hepatitis B e antigen and specific loss of cells expressing viral RNA. CONCLUSIONS: The ImmTAV platform has the potential to enable the elimination of infected cells by redirecting endogenous non-HBV-specific T cells, bypassing exhausted HBV-specific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials.

Linking isotope analysis and paleopathology: An andean perspective.

This paper reviews the significant advances in isotopic investigations in Andean South America and directs scholars to explore new theoretical and analytical directions, specifically the applicability of isotope data to paleopathology. Excellent preservation and large skeletal collections of human remains make the Central Andes ideal for biogeochemical reconstructions and advancements in isotopic methods. Our aims are twofold: first, we present a meta-analysis of stable and radiogenic isotope research in the Central Andes since 1985, and highlight those that combine analyses of isotope ratios and pathological conditions. Second, we discuss useful directions for incorporating stable isotope analysis more explicitly in studies of paleopathology in the Andes more in the future. Principle research foci have described dietary variation and regional population mobility since the 1980s, where early methodological explorations identified significant trends in isotopic variation. For the years 1980-2017, we identified 96 scholarly publications through a meta-data analysis of major peer-reviewed journals, book chapters, and conference proceedings. These demonstrate specific trends in topical and methodological preferences across the Andean region and a shift from 10 publications pre-1997 to 67 in the last 10 years. However, combined isotope and paleopathology studies in this region remain sparse; given the ecological, geological, and cultural complexity of the Central Andes, analyses of pathological conditions in different regions would significantly benefit from the information on diet, mobility, and local ecology that isotope ratios provide. Isotope analysis requires destruction of archaeological tissues, and interpreting isotope data can be complex, but it can also provide unique insights into the pathogenesis of multifactorial conditions and assist differential diagnosis. Therefore, we also discuss research designs for pairing isotopic and paleopathological variables that will allow researchers to better capture disease ecologies in archaeological samples and their variation across different regions, within related sites, and within individual lifespans.

MHC class II invariant chain-adjuvanted viral vectored vaccines enhances T cell responses in humans.

Strategies to enhance the induction of high magnitude T cell responses through vaccination are urgently needed. Major histocompatibility complex (MHC) class II-associated invariant chain (Ii) plays a critical role in antigen presentation, forming MHC class II peptide complexes for the generation of CD4+ T cell responses. Preclinical studies evaluating the fusion of Ii to antigens encoded in vector delivery systems have shown that this strategy may enhance T cell immune responses to the encoded antigen. We now assess this strategy in humans, using chimpanzee adenovirus 3 and modified vaccinia Ankara vectors encoding human Ii fused to the nonstructural (NS) antigens of hepatitis C virus (HCV) in a heterologous prime/boost regimen. Vaccination was well tolerated and enhanced the peak magnitude, breadth, and proliferative capacity of anti-HCV T cell responses compared to non-Ii vaccines in humans. Very high frequencies of HCV-specific T cells were elicited in humans. Polyfunctional HCV-specific CD8+ and CD4+ responses were induced with up to 30% of CD3+CD8+ cells targeting single HCV epitopes; these were mostly effector memory cells with a high proportion expressing T cell activation and cytolytic markers. No volunteers developed anti-Ii T cell or antibody responses. Using a mouse model and in vitro experiments, we show that Ii fused to NS increases HCV immune responses through enhanced ubiquitination and proteasomal degradation. This strategy could be used to develop more potent HCV vaccines that may contribute to the HCV elimination targets and paves the way for developing class II Ii vaccines against cancer and other infections.

Characterizing Hepatitis C Virus-Specific CD4+ T Cells Following Viral-Vectored Vaccination, Directly Acting Antivirals, and Spontaneous Viral Cure.

BACKGROUND AND AIMS: Induction of functional helper CD4+ T cells is the hallmark of a protective immune response against hepatitis C virus (HCV), associated with spontaneous viral clearance. Heterologous prime/boost viral vectored vaccination has demonstrated induction of broad and polyfunctional HCV-specific CD8+ T cells in healthy volunteers; however, much less is known about CD4+ T-cell subsets following vaccination. APPROACH AND RESULTS: We analyzed HCV-specific CD4+ T-cell populations using major histocompatibility complex class II tetramers in volunteers undergoing HCV vaccination with recombinant HCV adenoviral/modified vaccinia Ankara viral vectors. Peptide-specific T-cell responses were tracked over time, and functional (proliferation and cytokine secretion) and phenotypic (cell surface and intranuclear) markers were assessed using flow cytometry. These were compared to CD4+ responses in 10 human leukocyte antigen-matched persons with HCV spontaneous resolution and 21 chronically infected patients treated with directly acting antiviral (DAA) therapy. Vaccination induced tetramer-positive CD4+ T cells that were highest 1-4 weeks after boosting (mean, 0.06%). Similar frequencies were obtained for those tracked following spontaneous resolution of disease (mean, 0.04%). In addition, the cell-surface phenotype (CD28, CD127) memory subset markers and intranuclear transcription factors, as well as functional capacity of peptide-specific CD4+ T-cell responses characterized after vaccination, are comparable to those following spontaneous viral resolution. In contrast, helper responses in chronic infection were infrequently detected and poorly functional and did not consistently recover following HCV cure. CONCLUSIONS: Helper CD4+ T-cell phenotype and function following HCV viral vectored vaccination resembles "protective memory" that is observed following spontaneous clearance of HCV. DAA cure does not promote resurrection of exhausted CD4+ T-cell memory in chronic infection.

An audit of the use of hydroxychloroquine in rheumatology clinics.

OBJECTIVE: The aim was to audit the use, indications, complications and patient information regarding HCQ treatment in rheumatology clinics in a tertiary referral centre. METHODS: During a 9-month period, we identified all patients prescribed HCQ and attending rheumatology clinics in one hospital. We established: (i) the indication for HCQ; (ii) the prevalence of HCQ overdosing based on absolute body weight (ABW); (iii) documentation of warning of risk of retinal toxicity; (iv) systemic and ocular co-morbidities; (v) ocular symptoms during treatment; and (vi) reasons for stopping HCQ. RESULTS: We identified 427 patients (104 male and 323 female). The cumulative dose of HCQ was lower in RA (median 365 g; range 6-1752 g) compared with SLE (450 g; 66-1788 g) (P = 0.105). The median duration of HCQ therapy was 4 years (range 0.1-13 years); 28% of patients with RA and 29% with SLE continued HCQ beyond 5 years. After adjusting for ABW and renal function, 10% (31/312) had been prescribed doses exceeding recommendations. Formal documentation of counselling on ocular complications was found in only one-third of patients. Three cases of HCQ retinopathy were identified (all of whom had RA). CONCLUSION: HCQ therapy is being used for >5 years in 29% of patients with rheumatic diseases, with higher than recommended doses in ∼10% of patients. We recommend more rigorous scrutiny of the use of HCQ to reduce the risk of retinopathy.

A Novel Vaccine Strategy Employing Serologically Different Chimpanzee Adenoviral Vectors for the Prevention of HIV-1 and HCV Coinfection.

Background: Nearly 3 million people worldwide are coinfected with HIV and HCV. Affordable strategies for prevention are needed. We developed a novel vaccination regimen involving replication-defective and serologically distinct chimpanzee adenovirus (ChAd3, ChAd63) vector priming followed by modified vaccinia Ankara (MVA) boosts, for simultaneous delivery of HCV non-structural (NSmut) and HIV-1 conserved (HIVconsv) region immunogens. Methods: We conducted a phase I trial in which 33 healthy volunteers were sequentially enrolled and vaccinated via the intramuscular route as follows: 9 received ChAd3-NSmut [2.5 × 1010 vp] and MVA-NSmut [2 × 108 pfu] at weeks 0 and 8, respectively; 8 received ChAdV63.HIVconsv [5 × 1010 vp] and MVA.HIVconsv [2 × 108 pfu] at the same interval; 16 were co-primed with ChAd3-NSmut [2.5 × 1010 vp] and ChAdV63.HIVconsv [5 × 1010 vp] followed at week 8 by MVA-NSmut and MVA.HIVconsv [both 1 × 108 pfu]. Immunogenicity was assessed using peptide pools in ex vivo ELISpot and intracellular cytokine assays. Vaccine-induced whole blood transcriptome changes were assessed by microarray analysis. Results: All vaccines were well tolerated and no vaccine-related serious adverse events occurred. Co-administration of the prime-boost vaccine regimens induced high magnitude and broad T cell responses that were similar to those observed following immunization with either regimen alone. Median (interquartile range, IQR) peak responses to NSmut were 3,480 (2,728-4,464) and 3,405 (2,307-7,804) spot-forming cells (SFC)/106 PBMC for single and combined HCV vaccinations, respectively (p = 0.8). Median (IQR) peak responses to HIVconsv were 1,305 (1,095-4,967) and 1,005 (169-2,482) SFC/106 PBMC for single and combined HIV-1 vaccinations, respectively (p = 0.5). Responses were maintained above baseline to 34 weeks post-vaccination. Intracellular cytokine analysis indicated that the responding populations comprised polyfunctional CD4+ and CD8+ T cells. Canonical pathway analysis showed that in the single and combined vaccination groups, pathways associated with antiviral and innate immune responses were enriched for upregulated interferon-stimulated genes 24 h after priming and boosting vaccinations. Conclusions: Serologically distinct adenoviral vectors encoding HCV and HIV-1 immunogens can be safely co-administered without reducing the immunogenicity of either vaccine. This provides a novel strategy for targeting these viruses simultaneously and for other pathogens that affect the same populations. Clinical trial registration: https://clinicaltrials.gov, identifier: NCT02362217.

Analysis of nutritional disease in prehistory: The search for scurvy in antiquity and today.

In this paper, we discuss the issues surrounding the study of scurvy, or vitamin C deficiency, in paleopathology, and highlight the work of Donald Ortner in advancing this area of research. This micronutrient deficiency impacts collagen formation and results in damage to a variety of bodily tissues. While clinical manifestations are observed routinely, the lack of specific signatures on bone makes paleopathological diagnosis difficult. Rapid growth in infants, children, and subadults provides abundant remodeled tissue and an increase in vascularization that makes identification possible in younger segments of the population. However, diagnosis of scurvy in adults remains problematic, given that diagnostic lesions are strikingly similar to those associated with rickets, osteomalacia, and other conditions. We argue that this confounding factor underscores the need for a broader anthropological approach to scurvy research that expands beyond differential diagnosis to include more accurate reconstruction of diets and available resources, greater consideration of the possibility - even likelihood - of multiple nutrient deficiencies simultaneously affecting an individual, and the patterning of these deficiencies along lines of status, sex, and age.

Beyond the Paleolithic prescription: incorporating diversity and flexibility in the study of human diet evolution.

Evolutionary paradigms of human health and nutrition center on the evolutionary discordance or "mismatch" model in which human bodies, reflecting adaptations established in the Paleolithic era, are ill-suited to modern industrialized diets, resulting in rapidly increasing rates of chronic metabolic disease. Though this model remains useful, its utility in explaining the evolution of human dietary tendencies is limited. The assumption that human diets are mismatched to the evolved biology of humans implies that the human diet is instinctual or genetically determined and rooted in the Paleolithic era. This review looks at current research indicating that human eating habits are learned primarily through behavioral, social, and physiological mechanisms that start in utero and extend throughout the life course. Adaptations that appear to be strongly genetic likely reflect Neolithic, rather than Paleolithic, adaptations and are significantly influenced by human niche-constructing behavior. Several examples are used to conclude that incorporating a broader understanding of both the evolved mechanisms by which humans learn and imprint eating habits and the reciprocal effects of those habits on physiology would provide useful tools for structuring more lasting nutrition interventions.

The variable roads to sacrifice: Isotopic investigations of human remains from Chotuna-Huaca de los Sacrificios, Lambayeque, Peru.

This study investigates two key variables-residential context and subsistence-among sacrificial victims dating to the Late Horizon (A.D. 1450-1532) in the Huaca de los Sacrificios at the Chotuna-Chornancap Archaeological Complex in north coastal Peru. We investigate whether aspects of sacrifice in this distant coastal province mirrored that found in Inca heartland contexts such as the capacocha, or remained more typical of coastal sacrificial traditions. Stable carbon, nitrogen, and oxygen isotope values were characterized in bone carbonate, bone collagen, and hair keratin to estimate geographic residence during the decade before death and diet in the decade, versus months, before death. Bone δ18 Ocarbonate values have a mean (±SD) of 26.8 ± 1.1%, bone δ13 Ccarbonate values -6.7 ± 1.7%, and bone δ(13) Ccollagen values 11.8 ± 1.3%; bone δ15 Ncollagen values have a mean of 11.5 ± 1.3%. Combined hair δ13 Ckeratin values have a mean of -12.8 ± 1.6%, and hair δ15 Nkeratin values 10.8 ± 1.3%. In contrast to contemporaneous coastal and highland contexts, we are unable to identify immigrants among the sacrificed individuals or changes in diet that indicate provisioning with a standardized diet leading up to death. Instead, results suggest that victims were local to the area, but consumed moderately variable diets consistent with local subsistence patterns. These findings suggest a distinct pattern of human sacrifice in the Late Horizon and underscore the regional and temporal variation in sacrificial practices in the central Andes.

Diet, residential origin, and pathology at Machu Picchu, Peru.

Pathological conditions in human skeletal remains provide a wealth of information about archaeological populations, but many are limited in their interpretive significance by their nonspecific etiologies. This study analyzes three common pathological conditions known to manifest in infancy and childhood in the skeletal population from Machu Picchu, Peru (N = 74) with published carbon, nitrogen, oxygen, strontium, and lead isotopic data (Turner et al.: J Archaeol Sci 36 (2009) 317-332; Turner et al.: Chungara: Revista de Antropología Chilena 42 (2010) 515-524) to distinguish early-life diet from residential origins as significantly associated with pathologies among the site's inhabitants. Analyses of variance indicate highly significant variation between enamel δ(18)O values, which serve as a rough proxy of local environment, and both cribra orbitalia (CO) and porotic hyperostosis (PH), generally understood to be markers of anemia. Results tentatively suggest that individuals manifesting these lesions may have lived closer to the arid coasts; however, no significant variation was found in parameters of diet (enamel δ(13) C(carbonate), dentin δ(13) C(collagen), dentin δ(15)N) by either CO or PH, suggesting that the primary factors causing anemia may have been more significantly related to residential origin rather than diet. Linear enamel hypoplasia (LEH) frequency significantly varied by both dietary and residential parameters, supporting models of LEH formation from a synergy of dietary and environmental factors. These results support previous research on the etiology of PH in the Andes; they also represent a useful approach to refining site-specific interpretations of pathological conditions in archaeological populations, and exploring etiological variation between populations.

Evolutionary, historical and political economic perspectives on health and disease.

The origin and rise of social inequalities that are a feature of the post-Neolithic society play a major role in the pattern of disease in prehistoric and contemporary populations. We use the concept of epidemiological transition to understand changing ecological relationships between humans, pathogens and other disease insults. With the Paleolithic period as a baseline, we begin with ecological and social relationships that minimized the impact of infectious disease. Paleolithic populations would have retained many of the pathogens that they shared with their primate ancestors and would have been exposed to zoonoses that they picked up as they adapted to a foraging existence. The sparse mobile populations would have precluded the existence of endemic infectious disease. About 10,000 years ago, the shift to an agricultural subsistence economy created the first epidemiological transition, marked by the emergence of infections, a pattern that has continued to the present. Beginning about a century ago, some populations have undergone a second epidemiological transition in which public health measures, improved nutrition and medicine resulted in declines in infectious disease and a rise in non-infectious, chronic and degenerative diseases. Human populations are entering the third epidemiological transition in which there is a reemergence of infectious diseases previously thought to be under control, and the emergence of novel diseases. Many of the emerging and reemerging pathogens are antibiotic resistant and some are multi-antibiotic resistant. Inequality continues to widen within and between societies, accelerating the spread of emerging and reemerging diseases.