Destabilisation of T cell-dependent humoral immunity in sepsis.

Sepsis is a heterogeneous condition defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For some, sepsis presents as a predominantly suppressive disorder, whilst others experience a pro-inflammatory condition which can culminate in a 'cytokine storm'. Frequently, patients experience signs of concurrent hyper-inflammation and immunosuppression, underpinning the difficulty in directing effective treatment. Although intensive care unit mortality rates have improved in recent years, one-third of discharged patients die within the following year. Half of post-sepsis deaths are due to exacerbation of pre-existing conditions, whilst half are due to complications arising from a deteriorated immune system. It has been suggested that the intense and dysregulated response to infection may induce irreversible metabolic reprogramming in immune cells. As a critical arm of immune protection in vertebrates, alterations to the adaptive immune system can have devastating repercussions. Indeed, a marked depletion of lymphocytes is observed in sepsis, correlating with increased rates of mortality. Such sepsis-induced lymphopenia has profound consequences on how T cells respond to infection but equally on the humoral immune response that is both elicited by B cells and supported by distinct CD4+ T follicular helper (TFH) cell subsets. The immunosuppressive state is further exacerbated by functional impairments to the remaining lymphocyte population, including the presence of cells expressing dysfunctional or exhausted phenotypes. This review will specifically focus on how sepsis destabilises the adaptive immune system, with a closer examination on how B cells and CD4+ TFH cells are affected by sepsis and the corresponding impact on humoral immunity.

Alternative pathway dysregulation in tissues drives sustained complement activation and predicts outcome across the disease course in COVID-19.

Complement, a critical defence against pathogens, has been implicated as a driver of pathology in COVID-19. Complement activation products are detected in plasma and tissues and complement blockade is considered for therapy. To delineate roles of complement in immunopathogenesis, we undertook the largest comprehensive study of complement in COVID-19 to date, comprehensive profiling of 16 complement biomarkers, including key components, regulators and activation products, in 966 plasma samples from 682 hospitalized COVID-19 patients collected across the hospitalization period as part of the UK ISARIC4C (International Acute Respiratory and Emerging Infection Consortium) study. Unsupervised clustering of complement biomarkers mapped to disease severity and supervised machine learning identified marker sets in early samples that predicted peak severity. Compared to healthy controls, complement proteins and activation products (Ba, iC3b, terminal complement complex) were significantly altered in COVID-19 admission samples in all severity groups. Elevated alternative pathway activation markers (Ba and iC3b) and decreased alternative pathway regulator (properdin) in admission samples were associated with more severe disease and risk of death. Levels of most complement biomarkers were reduced in severe disease, consistent with consumption and tissue deposition. Latent class mixed modelling and cumulative incidence analysis identified the trajectory of increase of Ba to be a strong predictor of peak COVID-19 disease severity and death. The data demonstrate that early-onset, uncontrolled activation of complement, driven by sustained and progressive amplification through the alternative pathway amplification loop is a ubiquitous feature of COVID-19, further exacerbated in severe disease. These findings provide novel insights into COVID-19 immunopathogenesis and inform strategies for therapeutic intervention.

The salutogenic gaze: Theorising the practitioner role in complementary and alternative medicine consultations.

Research on why people use complementary and alternative medicine (CAM) shows clients value the CAM consultation, where they feel listened to and empowered to control their own health. Such 'empowerment' through CAM use is often theorised as reflecting wider neoliberal imperatives of self-responsibility. CAM users' perspectives are well studied, but there has been little sociological analysis of interactions within the CAM consultation. Specifically, it is unclear how user empowerment/self-knowledge relates to the CAM practitioner's power and expert knowledge. We address this using audio-recorded consultations and interviews with CAM practitioners to explore knowledge use in client-practitioner interactions and its meaning for practitioners. Based on our analysis and drawing on Foucault (1973), The Birth of the Clinic: an archaeology of medical perception and Antonovsky (1979), Health, Stress and Coping, we theorise the operation of power/knowledge in the CAM practitioner-client dyad by introducing the concept of the 'salutogenic gaze'. This gaze operates in the CAM consultation with disciplining and productive effects that are oriented towards health promotion. Practitioners listen to and value clients' stories, but their gaze also incorporates surveillance and normalisation, aided by technologies that may or may not be shared with clients. Because the salutogenic gaze is ultimately transferred from practitioner to client, it empowers CAM users while simultaneously reinforcing the practitioner's power as a health expert.

Complement dysregulation and Alzheimer's disease in Down syndrome.

INTRODUCTION: Down syndrome (DS) is associated with immune dysregulation and a high risk of early onset Alzheimer's disease (AD). Complement is a key part of innate immunity and driver of pathological inflammation, including neuroinflammation in AD. Complement dysregulation has been reported in DS; however, the pattern of dysregulation and its relationship to AD risk is unclear. METHODS: Plasma levels of 14 complement biomarkers were measured in 71 adults with DS and 46 controls to identify DS-associated dysregulation; impact of apolipoprotein E (APOE) ε4 genotype, single nucleotide polymorphisms (SNPs) in CLU and CR1, and dementia on complement biomarkers was assessed. RESULTS: Plasma levels of complement activation products (TCC, iC3b), proteins (C1q, C3, C9), and regulators (C1 inhibitor, factor H, FHR4, clusterin) were significantly elevated in DS versus controls while FI and sCR1 were significantly lower. In DS with AD (n = 13), C3 and FI were significantly decreased compared to non-AD DS (n = 58). Neither APOE genotype nor CLU SNPs impacted complement levels, while rs6656401 in CR1 significantly impacted plasma sCR1 levels. CONCLUSIONS: Complement is dysregulated in DS, likely reflecting the generalized immune dysregulation state; measurement may help identify inflammatory events in individuals with DS. Complement biomarkers differed in DS with and without AD and may aid diagnosis and/or prediction. HIGHLIGHTS: Complement is significantly dysregulated in plasma of people with DS who show changes in levels of multiple complement proteins compared to controls. People with DS and dementia show evidence of additional complement dysregulation with significantly lower levels of C3 and factor I compared to those without dementia. rs6656401 in CR1 was associated with significantly elevated sCR1 plasma levels in DS.

Whole blood-based measurement of SARS-CoV-2-specific T cells reveals asymptomatic infection and vaccine immunogenicity in healthy subjects and patients with solid-organ cancers.

Accurate assessment of SARS-CoV-2 immunity is critical in evaluating vaccine efficacy and devising public health policies. Whilst the exact nature of effective immunity remains incompletely defined, SARS-CoV-2-specific T-cell responses are a critical feature that will likely form a key correlate of protection against COVID-19. Here, we developed and optimized a high-throughput whole blood-based assay to determine the T-cell response associated with prior SARS-CoV-2 infection and/or vaccination amongst 231 healthy donors and 68 cancer patients. Following overnight in vitro stimulation with SARS-CoV-2-specific peptides, blood plasma samples were analysed for TH 1-type cytokines. Highly significant differential IFN-γ+ /IL-2+ SARS-CoV-2-specific T-cell responses were seen amongst previously infected COVID-19-positive healthy donors in comparison with unknown / naïve individuals (p < 0·0001). IFN-γ production was more effective at identifying asymptomatic donors, demonstrating higher sensitivity (96·0% vs. 83·3%) but lower specificity (84·4% vs. 92·5%) than measurement of IL-2. A single COVID-19 vaccine dose induced IFN-γ and/or IL-2 SARS-CoV-2-specific T-cell responses in 116 of 128 (90·6%) healthy donors, reducing significantly to 27 of 56 (48·2%) when measured in cancer patients (p < 0·0001). A second dose was sufficient to boost T-cell responses in the majority (90·6%) of cancer patients, albeit IFN-γ+ responses were still significantly lower overall than those induced in healthy donors (p = 0·034). Three-month post-vaccination T-cell responses also declined at a faster rate in cancer patients. Overall, this cost-effective standardizable test ensures accurate and comparable assessments of SARS-CoV-2-specific T-cell responses amenable to widespread population immunity testing, and identifies individuals at greater need of booster vaccinations.

Community perspectives of barriers indigenous women face in accessing maternal health care services in the Chittagong Hill Tracts, Bangladesh.

OBJECTIVES: Bangladesh has achieved notable success in improving maternal health by increasing women's access to good quality and low-cost maternal health care (MHC) services. However, the health system of Bangladesh has earned criticism for not ensuring equitable MHC access for all women, particularly for Indigenous women in the Chittagong Hill Tracts (CHT). Little is known about Indigenous communities' perspectives on these inequalities in MHC service access in the CHT. Therefore, this study aimed to explore Indigenous communities' perspectives on challenges and opportunities for improving MHC service access in the CHT. DESIGN: This qualitative descriptive study was conducted in two sub-districts of Khagrachhari between September 2017 and February 2018. Eight Indigenous key informants from three Indigenous communities (Chakma, Marma and Tripura) were recruited via snowballing and purposive techniques and participated in face-to-face, semi-structured interviews. Key informants comprised community leaders and health care providers. Data were analysed thematically using Nvivo12 software. RESULTS: Findings suggest that distance, poor availability of resources and infrastructure, lack of community engagement in the design of health interventions, Indigenous cultural beliefs, misconceptions about MHC services, and maltreatment from health care providers were the key barriers to accessing MHC services; all are interconnected. Indigenous women faced humiliation and maltreatment from MHC staff. Failure to provide a culturally-safe environment suggests a lack of cultural competency among health staff, including Indigenous staff. CONCLUSION: Findings suggest that cultural competency training for all health care providers is needed to improve cultural appropriateness and accessibility of services. Refresher training and undisrupted supply of basic MHC services for front-line care providers will benefit the entire community and will likely be cost-effective for the government. Designing health programmes through extensive community consultation is essential.

Lessons from the development and delivery of a rural suicide prevention program.

AIMS: Suicide prevention remains a priority in rural and remote Australia, where suicide rates continue to be higher than those in urban communities. This commentary describes the Good SPACE suicide prevention program, and the lessons learned from delivering this program over a 14-year period. CONTEXT: The Good SPACE program has been operating in rural New South Wales since 2007. The program focuses on educating rural community members to recognise the signs of suicide vulnerability, and how to take appropriate action if they encounter someone considering suicide. APPROACH: Communities are selected to receive Good SPACE training in consultation with key stakeholder organisations, or by request from communities. Across the life of the program, key challenges in its administration have included short-term funding arrangements and staff turnover. Strengths have included the ability to adapt content to meet the needs of rural communities (eg from an initial focus on helping farmers during periods of drought, to a broader focus on all rural residents and a wider range of adversities). As the program moves forward, emphasis will be placed on harder-to-reach populations, including males and those with lower mental health literacy. CONCLUSION: The Good SPACE program has ongoing funding to adapt its content and continue administration through the Rural Adversity Mental Health Program (https://www.ramhp.com.au/). The lessons learned throughout the life of the program might be of use to other organisations aiming to provide community-based education programs in rural and remote communities.

The role of the peer support worker in increasing rural mental health help-seeking.

OBJECTIVE: Mental health peer support workers draw on lived experience to provide benefit to people experiencing mental distress. People living in rural areas are less likely than their urban counterparts to seek professional help for psychological distress. The aim of this study was to explore the perceived value of rural peer support workers as facilitators to rural mental health help-seeking. DESIGN: Data were gathered through a cross-sectional survey distributed by a social media boosted post. SETTING: A total of 349 "small" rural towns in New South Wales as defined by the Modified Monash Model classification system as MMM5. PARTICIPANTS: A total of 765 adult, rural residents completed the survey. MAIN OUTCOME MEASURE(S): Participants were asked to select, from a list of potential facilitators, those which they felt would make mental health help-seeking easier or harder. RESULTS: Study participants felt that a help provider with lived experience of mental illness or distress would make mental health help-seeking easier. Similarly, rural life experience in a help provider was thought to facilitate help-seeking. Participants also believed that flexible and informal meeting settings would make it easier to seek help for mental distress. CONCLUSIONS: Engaging rural mental health peer support workers in a flexible/informal setting, as a complement to conventional health service provision, may increase rural help-seeking for mental distress. Increased mental health help-seeking is likely to have a positive impact on instances of serious mental illness.

Connecting with social and emotional well-being in rural Australia: An evaluation of 'We-Yarn', an Aboriginal gatekeeper suicide prevention workshop.

OBJECTIVE: This evaluation considered the potential of We-Yarn, a suicide prevention gatekeeper training workshop, to contribute to Aboriginal suicide prevention in rural New South Wales. DESIGN: A mixed methods approach included surveys, in-depth interviews and workshop observations. SETTING: Aboriginal suicide prevention training in rural New South Wales, Australia. PARTICIPANTS: Attendees at We-Yarn training. INTERVENTION: We-Yarn provided culturally safe suicide prevention skills training for Aboriginal people and for those who work with Aboriginal communities and persons in rural New South Wales. Training workshops were delivered across multiple locations for 6 hours in one day. Workshops were facilitated by two facilitators with lived and professional experience; one Aboriginal and one non-Aboriginal facilitator. We-Yarn content was developed by staff from the Centre for Rural and Remote Mental Health, and in consultation with Aboriginal Elders and representatives of Aboriginal Medical Services to ensure relevance and cultural appropriateness. MAIN OUTCOME MEASURES: Pre and post-workshop surveys captured capacity and participants' confidence in identifying and responding to a person at risk of suicide. Interviews explored participants' experiences of workshops, implementation of learning, and attitudes regarding social and emotional wellbeing and suicide. Observations detailed the workshop environment, participants' engagement, and participants' responses to facilitators and content. RESULTS: We-Yarn was considered culturally appropriate. Participants responded to facilitators' lived experiences. Participants reported significant improvements in understanding the links between cultural strengths, social and emotional wellbeing and suicide prevention. However, health professionals with existing knowledge wanted a stronger focus on clinical training. CONCLUSION: We-Yarn promoted discussion of suicide prevention within a holistic health framework, building on participants' pre-existing knowledge about social and emotional wellbeing. Importantly, skilful facilitators with lived experience were vital to the success of the workshops. Consideration should be given to attracting people with low suicide prevention knowledge to the workshops, developing tailored workshops for health professionals and ensuring prolonged engagement with communities. Multifaceted and long term responses in addition to this type of training are important.

Medicines management in children and young people: pharmacokinetics, drug calculations and off-label drug use.

Medicines management in children and young people presents specific challenges because children differ from adults in their response to medicines. The way in which medicines work inside the human body, or pharmacokinetics, varies according to age and stage of development. Accurate drug calculations for a child rely on the careful consideration of a series of factors, such as weight and height, pharmacokinetics and drug characteristics. This article focuses on three fundamental aspects: pharmacokinetics, drug calculations, and unlicensed and off-label drug use.

Real-world utility of overnight oximetry for the screening of obstructive sleep apnea in children.

BACKGROUND: Obstructive sleep apnea (OSA) is a common problem in children and can result in developmental and cognitive complications if untreated. The gold-standard tool for diagnosis is polysomnography (PSG); however, it is an expensive and time-consuming test to undertake. Overnight oximetry has been suggested as a faster and cheaper initial test in comparison to PSG as it can be performed at home using limited, reusable equipment. AIM: This retrospective case control study aims to evaluate the effectiveness of a home oximetry service (implemented in response to extended waiting times for routine PSG) in reducing the time between patient referral and treatment. METHODS: Patients undergoing diagnostic sleep evaluation for suspected OSA who utilized the Queensland Children's Hospital screening home oximetry service in the first year since its inception in 2021 (n = 163) were compared to a historical group of patients who underwent PSG in 2018 (n = 311). Parameters compared between the two groups included time from sleep physician review to sleep test, ENT review, and definitive treatment in the form of adenotonsillectomy surgery (or CPAP initiation for those who had already undergone surgery). RESULTS: The time from sleep physician review and request of the sleep-related study to ENT surgical treatment was significantly reduced (187 days for the HITH oximetry group vs 359 days for the comparable PSG group; p-value <0.05), and time from sleep study request to the report of results was significantly lower for patients in the oximetry group compared to those in the PSG group (11 days vs 105 days; p-value <0.05). CONCLUSION: These results suggest that for children referred to a tertiary sleep center for possible obstructive sleep disordered breathing, a home oximetry service can be effective in assisting sleep evaluation and reducing the time to OSA treatment.

Parental positive affect and negative affect in same- and different-sex parent families: no associations with parental gender and caregiving role.

Positive and negative parental affect influence developing parent-child attachment relationships, especially during infancy as well as children's social-emotional, academic, and behavioral functioning later in life. Increasingly, because both mothers and fathers can play central caregiving roles, the parenting qualities of both parents demand consideration. Therefore, this study investigated whether parental gender and caregiving role were associated with mothers' and fathers' positive affect and negative affect during interactions with their 4-month-old firstborn infant, while determining whether parenting stress, infant temperament, having a singleton/twin, and living in the Netherlands, France, or the United Kingdom were related to parental positive affect and negative affect. In all, 135 different-sex, same-sex male, and same-sex female couples (113 fathers and 157 mothers, comprising 147 primary, and 123 secondary caregivers) who conceived through artificial reproductive techniques were studied. The couples were videorecorded at home while in feeding, cleaning, and playing contexts to assess the levels of positive and negative parental affect. In addition, the couples completed questionnaires about their caregiving role, parenting stress, and the infants' temperament. Mixed linear models indicated that the levels of positive and negative parental affect toward the infant in all contexts were not related to parental gender, caregiving role, the interaction between parental gender and caregiving role, parenting stress, infant temperament, or singleton/twin status. However, the target parental behaviors were related to the country of origin, suggesting differences among Dutch, French, and British parents. Overall, we found no evidence that gender or caregiving roles were associated with the levels of positive and negative affect shown by the parents.

Selective and faithful imitation at 12 and 15 months.

Research on imitation in infancy has primarily focused on what and when infants imitate. More recently, however, the question why infants imitate has received renewed attention, partly motivated by the finding that infants sometimes selectively imitate the actions of others and sometimes faithfully imitate, or overimitate, the actions of others. The present study evaluates the hypothesis that this varying imitative behavior is related to infants' social traits. To do so, we assessed faithful and selective imitation longitudinally at 12 and 15 months, and extraversion at 15 months. At both ages, selective imitation was dependent on the causal structure of the act. From 12 to 15 months, selective imitation decreased while faithful imitation increased. Furthermore, infants high in extraversion were more faithful imitators than infants low in extraversion. These results demonstrate that the onset of faithful imitation is earlier than previously thought, but later than the onset of selective imitation. The observed relation between extraversion and faithful imitation supports the hypothesis that faithful imitation is driven by the social motivations of the infant. We call this relation the King Louie Effect: like the orangutan King Louie in The Jungle Book, infants imitate faithfully due to a growing interest in the interpersonal nature of interactions.

Infants show stability of goal-directed imitation.

Previous studies have reported that infants selectively reproduce observed actions and have argued that this selectivity reflects understanding of intentions and goals, or goal-directed imitation. We reasoned that if selective imitation of goal-directed actions reflects understanding of intentions, infants should demonstrate stability across perceptually and causally dissimilar imitation tasks. To this end, we employed a longitudinal within-participants design to compare the performance of 37 infants on two imitation tasks, with one administered at 13 months and one administered at 14 months. Infants who selectively imitated goal-directed actions in an object-cued task at 13 months also selectively imitated goal-directed actions in a vocal-cued task at 14 months. We conclude that goal-directed imitation reflects a general ability to interpret behavior in terms of mental states.

Authentication of saffron using 60 MHz 1H NMR spectroscopy.

60 MHz proton NMR spectroscopy was used to analyse extracts from saffron spice and a range of potential adulterants and mixtures. Using a simple extraction procedure, good quality spectra were obtained which contain peaks from the characteristic metabolites picrocrocin and crocins, fatty acids and kaempferol. The spectra of samples from trusted suppliers were used to train one-class classification models by SIMCA, nearest neighbour and isolation forest methods. Applying these to spectra of saffron samples purchased from the online marketplace, it was found that 7 out of 33 samples were highly anomalous. From comparison with the spectra of known mixtures and confirmatory spectral analysis using 600 MHz NMR, it is probable that these contain considerable amounts of undisclosed foreign matter.

Defining avoidable healthcare-associated harm in prisons: A mixed-method development study.

BACKGROUND: Reducing avoidable healthcare-associated harm is a global health priority. Progress in evaluating the burden and aetiology of avoidable harm in prisons is limited compared with other healthcare sectors. To address this gap, this study aimed to develop a definition of avoidable harm to facilitate future epidemiological studies in prisons. METHODS: Using a sequential mixed methods study design we first characterised and reached consensus on the types and avoidability of patient harm in prison healthcare involving analysis of 151 serious prison incidents reported to the Strategic Executive Information System (StEIS) followed by in-depth nominal group (NG) discussions with four former service users and four prison professionals. Findings of the NG discussions and StEIS analysis were then synthesised and discussed among the research team and study oversight groups to develop an operational definition of avoidable harm in prison healthcare which was subsequently tested and validated using prison patient safety incident report data derived from the National Reporting and Learning System (NRLS). RESULTS: Analysis of StEIS incident reports and NG discussions identified important factors influencing avoidable harm which reflected the unique prison setting, including health care delivery issues and constraints associated with the secure environment which limited access to care. These findings informed the development of a new working two-tier definition of avoidable harm using appropriate and timely intervention, which included an additional assessment of harm avoidability taking into the account the prison regime and environment. The definition was compatible with the NRLS incident report narratives and illustrated how the prison environment may influence identification of avoidable harm and judgements of avoidability. CONCLUSIONS: We have developed a working definition of avoidable harm in prison health care that enables consideration of caveats associated with prison environments and systems. Our definition enables future studies of the safety of prison healthcare to standardise outcome measurement.