Effect of treatment delivery schedule for early-stage non-small cell lung cancer patients treated with stereotactic ablative radiation therapy: a population-based analysis.

PURPOSE: The optimal stereotactic ablative body radiotherapy (SABR) delivery schedule in stage I non-small cell lung cancer (NSCLC) remains unclear. This population-based study investigated grade ≥ 2 toxicity rates, local failure (LF), and overall survival (OS) in patients treated with 48 Gy in 4 fractions scheduled every other day (QOD) versus daily with weekends (QDW) and consecutive daily without weekends (QD). MATERIALS AND METHODS: Between January 2019 and June 2022, treatment records using 48 Gy in 4 fractions were extracted from a provincial cancer registry and grouped by delivery as QOD, QDW, or QD. Toxicity events were recorded using CTCAE v5.0. The Kaplan-Meier method was used to compute OS while LF was calculated using cumulative incidence methods with death as a competing risk. Cox regression analyses and Fine-Gray modelling was used to assess for variables associated with OS and LF, respectively. RESULTS: Of 404 patients meeting study criteria, 190, 111, and 103 received QOD, QDW, and QD SABR, respectively. More patients receiving QDW SABR were medically inoperable and more patients receiving QD SABR had tumors abutting the chest wall. Median follow-up was 29.5 months (interquartile range [IQR] 19.2-38.4). Overall toxicity was low, with crude rates of acute and late grade ≥ 2 toxicity not being statistically different among the groups. No grade 4 or 5 toxicities were recorded. LF rates at 24 months were not different at 7.5% (95% confidence interval [CI] 3.7-11.3), 9.5% (95% CI 3.9-15.1), and 11.0% (95% CI 4.9-17.2) for the QOD, QDW, and QD groups, respectively (p = 0.60). QDW and QD schedules were not associated with LR. Similarly, no significant differences in median OS were found among the QOD, QDW, and QD groups at 47.5 months (95% CI 39.26-55,74), 52.7 (95% CI 34.7-70.7), and 49.0 months (95% CI 31.6-66.4), respectively. QDW and QD schedules were not associated with OS. CONCLUSIONS: This population-based study demonstrated no statistically significant differences in grade ≥ 2 toxicity rates, LF, and OS for stage I NSCLC patients treated with lung SABR using 48 Gy in 4 fractions delivered QOD, QDW, and QD. Patient convenience and optimization of resources may be considered when choosing a lung SABR treatment delivery schedule.

Effect of endothelin-1 on the blood pressure response to acute hypoxia and hyperoxia in healthy young men.

Endothelin-1 (ET-1) and its receptors are linked to increases in sensitivity of the chemoreceptors to hypoxic stress and the development of hypertension in preclinical models. We hypothesized ET receptor antagonism would lower resting blood pressure (BP) as well as the acute BP response to chemoreflex stress. Twenty-four men (31 ± 5 years, 26 ± 3 kg/m2) completed two study visits (control, bosentan). On each visit, BP was assessed under three conditions: (1) normoxia (FiO2 0.21), (2) chemoreflex excitation via hypoxia (FiO2 0.05-0.21), (3) chemoreflex inhibition via hyperoxia (FiO2 1.00). Bosentan increased plasma ET-1 (0.94 ± 0.90 to 1.27 ± 0.62 pg/mL, p = 0.004), supporting receptor blockade. Resting diastolic (73 ± 5 to 69 ± 7 mmHg, p = 0.007) and mean (93 ± 7 to 88 ± 7 mmHg, p = 0.005) BP were reduced following bosentan compared to control with no change in systolic BP (p = 0.507). The mean BP response to both acute hypoxia (-0.48 ± 0.38 to -0.25 ± 0.31 mmHg/%, p = 0.004) and hyperoxia (area under the curve -93 ± 108 to -27 ± 66 AU, p = 0.018) were attenuated following bosentan. Acute ET receptor inhibition attenuates the rise in BP during chemoreflex excitation as well as the fall in BP during chemoreflex inhibition in healthy young men. These data support a role for ET-1 in control of resting BP, possibly through a chemoreceptor-mediated mechanism.

Associations of Rest-Activity Rhythm Disturbances With Stroke Risk and Poststroke Adverse Outcomes.

BACKGROUND: Many disease processes are influenced by circadian clocks and display ~24-hour rhythms. Whether disruptions to these rhythms increase stroke risk is unclear. We evaluated the association between 24-hour rest-activity rhythms, stroke risk, and major poststroke adverse outcomes. METHODS AND RESULTS: We examined ~100 000 participants from the UK Biobank (aged 44-79 years; ~57% women) assessed with actigraphy (6-7 days) and 5-year median follow-up. We derived (1) most active 10-hour activity counts across the 24-hour cycle and the timing of its midpoint timing; (2) the least active 5-hour count and its midpoint; (3) relative amplitude; (4) interdaily stability; and (5) intradaily variability, for stability and fragmentation of the rhythm. Cox proportional hazard models were constructed for time to (1) incident stroke (n=1652) and (2) poststroke adverse outcomes (dementia, depression, disability, or death). Suppressed relative amplitude (lowest quartile [quartile 1] versus the top quartile [quartile 4]) was associated with stroke risk (hazard ratio [HR], 1.61 [95% CI, 1.35-1.92]; P<0.001) after adjusting for demographics. Later most active 10-hour activity count midpoint timing (14:00-15:26; HR, 1.26 [95% CI, 1.07-1.49]; P=0.007) also had higher stroke risk than earlier (12:17-13:10) participants. A fragmented rhythm (intradaily variability) was also associated with higher stroke risk (quartile 4 versus quartile 1; HR, 1.26 [95% CI, 1.06-1.49]; P=0.008). Suppressed relative amplitude was associated with risk for poststroke adverse outcomes (quartile 1 versus quartile 4; HR, 2.02 [95% CI, 1.46-2.48]; P<0.001). All associations were independent of age, sex, race, obesity, sleep disorders, cardiovascular diseases or risks, and other comorbidity burdens. CONCLUSIONS: Suppressed 24-hour rest-activity rhythm may be a risk factor for stroke and an early indicator of major poststroke adverse outcomes.

Interaction of simultaneous hypoxia and baroreflex loading on control of sympathetic action potential subpopulations.

Efferent muscle sympathetic nerve activity (MSNA) is under tonic baroreflex control. The arterial baroreflex exerts the strongest influence over medium-sized sympathetic action potential (AP) subpopulations in efferent MSNA recordings. Prior work from multiunit MSNA recordings has shown baroreflex loading selectively abolishes the sympathetic response to hypoxia. The purpose of the study was to examine baroreflex control over different-sized AP clusters and characterize the neural recruitment strategies of sympathetic AP subpopulations with baroreflex and combined baroreflex/chemoreflex (i.e., hypoxia) activation. We loaded the arterial baroreceptors [intravenous phenylephrine (PE)] alone and in combination with systemic hypoxia ([Formula: see text] 80%) in nine healthy young men. We extracted sympathetic APs using the wavelet-based methodology and quantified baroreflex gain for individual AP clusters. AP baroreflex threshold gain was measured as the slope of the linear relationship between AP probability versus diastolic blood pressure for 10 normalized clusters. Baroreflex loading with phenylephrine decreased MSNA and AP firing compared with baseline (all P < 0.05). However, the phenylephrine-mediated decrease in AP firing was lost with concurrent hypoxia (P = 0.384). Compared with baseline, baroreflex loading reduced medium-sized AP cluster baroreflex threshold slope (condition P = 0.005) and discharge probability (condition P < 0.0001); these reductions from baseline were maintained during simultaneous hypoxia (both P < 0.05). Present findings indicate a key modulatory role of the baroreceptors on medium-sized APs in blood pressure regulation that withstands competing signals from peripheral chemoreflex activation.NEW & NOTEWORTHY This study provides a novel understanding on baroreflex control of efferent sympathetic nervous system activity during competing stressors: baroreflex loading and peripheral chemoreflex activation. We show chemoreflex activation buffers baroreflex-mediated reductions in sympathetic nervous system activity. More importantly, baroreflex loading reduced baroreflex threshold gain of sympathetic action potential clusters and this reduction withstood chemoreflex activation. These data suggest the arterial baroreflex holds a primary regulatory role over medium-sized sympathetic neurons despite competing chemoreflex signals.

Access to oral health care services for children with disabilities: a mixed methods systematic review.

BACKGROUND: Children with disabilities experience poorer oral health and frequently have complex needs. The accessibility of oral health care services for children with disabilities is crucial for promoting oral health and overall well-being. This study aimed to systematically review the literature to identify the barriers and facilitators to oral health care services for children with disabilities, and to propose priority research areas for the planning and provision of dental services to meet their needs. METHODS: This was a mixed methods systematic review. Multiple databases searched included MEDLINE, Scopus, PsycINFO, EMBASE, and CINAHL. The search strategy included Medical Subject Heading (MeSH) terms related to children, disabilities, and access to oral health. Eligibility criteria focused on studies about children with disabilities, discussing the accessibility of oral health care. RESULTS: Using Levesque's framework for access identified barriers such as professional unwillingness, fear of the dentist, cost of treatment, and inadequate dental facilities. Facilitators of access offered insight into strategies for improving access to oral health care for children with disabilities. CONCLUSION: There is a positive benefit to using Levesque's framework of access or other established frameworks to carry out research on oral healthcare access, or implementations of dental public health interventions in order to identify gaps, enhance awareness and promote better oral health practices. The evidence suggests that including people with disabilities in co-developing service provision improves accessibility, alongside using tailored approaches and interventions which promote understanding of the importance of dental care and increases awareness for professionals, caregivers and children with disabilities. TRIAL REGISTRATION: Protocol has been registered online on the PROSPERO database with an ID CRD42023433172 on June 9, 2023.

When Are "Paraphernalia" Critical Medical Supplies?

Evidence of harm reduction interventions' morbidity and mortality benefits is abundant and of high quality, so there are good reasons for regional and national groups to advocate for more widespread distribution of legally regulated "drug paraphernalia," including needles, syringes, and fentanyl test strips. But lack of consistency among states' laws means that patients' interstate travel can subject them to being charged with possession of illegal items. This commentary on a case offers guidance to clinicians looking to help patients understand legal risks of interstate travel with supplies that are prescribed or recommended to reduce harms of their drug use and explores the ethical responsibilities of physicians in jurisdictions that legally prohibit these harm reduction interventions.

Central α2-adrenergic mechanisms regulate human sympathetic neuronal discharge strategies.

The present study investigated the impact of central α2-adrenergic mechanisms on sympathetic action potential (AP) discharge, recruitment and latency strategies. We used the microneurographic technique to record muscle sympathetic nerve activity and a continuous wavelet transform to investigate postganglionic sympathetic AP firing during a baseline condition and an infusion of a α2-adrenergic receptor agonist, dexmedetomidine (10 min loading infusion of 0.225 µg kg-1; maintenance infusion of 0.1-0.5 µg kg h-1) in eight healthy individuals (28 ± 7 years, five females). Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg, P < 0.001) but did not alter heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.748). Dexmedetomidine reduced sympathetic AP discharge (126 ± 73 to 27 ± 24 AP 100 beats-1, P = 0.003) most strongly for medium-sized APs (normalized cluster 2: 21 ± 10 to 5 ± 5 AP 100 beats-1; P < 0.001). Dexmedetomidine progressively de-recruited sympathetic APs beginning with the largest AP clusters (12 ± 3 to 7 ± 2 clusters, P = 0.002). Despite de-recruiting large AP clusters with shorter latencies, dexmedetomidine reduced AP latency across remaining clusters (1.18 ± 0.12 to 1.13 ± 0.13 s, P = 0.002). A subset of six participants performed a Valsalva manoeuvre (20 s, 40 mmHg) during baseline and the dexmedetomidine infusion. Compared to baseline, AP discharge (Δ 361 ± 292 to Δ 113 ± 155 AP 100 beats-1, P = 0.011) and AP cluster recruitment elicited by the Valsalva manoeuvre were lower during dexmedetomidine (Δ 2 ± 1 to Δ 0 ± 2 AP clusters, P = 0.041). The reduction in sympathetic AP latency elicited by the Valsalva manoeuvre was not affected by dexmedetomidine (Δ -0.09 ± 0.07 to Δ -0.07 ± 0.14 s, P = 0.606). Dexmedetomidine reduced baroreflex gain, most strongly for medium-sized APs (normalized cluster 2: -6.0 ± 5 to -1.6 ± 2 % mmHg-1; P = 0.008). These data suggest that α2-adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans. KEY POINTS: Sympathetic postganglionic neuronal subpopulations innervating the human circulation exhibit complex patterns of discharge, recruitment and latency. However, the central neural mechanisms governing sympathetic postganglionic discharge remain unclear. This microneurographic study investigated the impact of a dexmedetomidine infusion (α2-adrenergic receptor agonist) on muscle sympathetic postganglionic action potential (AP) discharge, recruitment and latency patterns. Dexmedetomidine infusion inhibited the recruitment of large and fast conducting sympathetic APs and attenuated the discharge of medium sized sympathetic APs that fired during resting conditions and the Valsalva manoeuvre. Dexmedetomidine infusion elicited shorter sympathetic AP latencies during resting conditions but did not affect the reductions in latency that occurred during the Valsalva manoeuvre. These data suggest that α2-adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans.

An Early Gestation Plasma Inflammasome in Rural Bangladeshi Women.

Circulating α1-acid glycoprotein (AGP) and C-reactive protein (CRP) are commonly measured to assess inflammation, but these biomarkers fail to reveal the complex molecular biology of inflammation. We mined the maternal plasma proteome to detect proteins that covary with AGP and CRP. In 435 gravida predominantly in <12-week gestation, we correlated the relative quantification of plasma proteins assessed via a multiplexed aptamer assay (SOMAScan®) with AGP and CRP, quantified by immunoassay. We defined a plasma inflammasome as protein correlates meeting a false discovery rate <0.05. We examined potential pathways using principal component analysis. A total of 147 and 879 of 6431 detected plasma proteins correlated with AGP and CRP, respectively, of which 61 overlapped with both biomarkers. Positive correlates included serum amyloid, complement, interferon-induced, and immunoregulatory proteins. Negative correlates were micronutrient and lipid transporters and pregnancy-related anabolic proteins. The principal components (PCs) of AGP were dominated by negatively correlated anabolic proteins associated with gestational homeostasis, angiogenesis, and neurogenesis. The PCs of CRP were more diverse in function, reflecting cell surface and adhesion, embryogenic, and intracellular and extra-hepatic tissue leakage proteins. The plasma proteome of AGP or CRP reveals wide proteomic variation associated with early gestational inflammation, suggesting mechanisms and pathways that merit future research.

A qualitative meta-synthesis of carers' perceptions of factors influencing preschool children's oral hygiene practices-A social practices perspective.

OBJECTIVES: This study comprises a synthesis of published qualitative studies from developed countries on the perspectives of carers regarding the oral hygiene toothbrushing practices of preschool children, through the lens of social practice theory. METHODS: A search of the following electronic databases was conducted for all available years: MEDLINE, EMBASE and Global Health using the Ovid platform; Dentistry & Oral Sciences Source (DOSS), Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Scopus. Included qualitative studies reported primary caregivers' perceptions of oral hygiene practices (focusing on toothbrushing) in preschool children (0-5 years old) in developed countries. A thematic synthesis of the qualitative findings was undertaken for the results of each study. RESULTS: Eleven articles were included in this meta-synthesis. The focus of this paper was toothbrushing practices. A conceptual map of toothbrushing as a social practice was developed. Key findings included practice elements (meanings, competences, and materials), spatial and temporal aspects, and barriers and facilitators to performance. CONCLUSIONS: The application of a social practice lens to published qualitative research on the oral hygiene of preschool children provided insights into the meanings and competences related to toothbrushing, as perceived by primary caregivers. However, it also revealed limited information on material, spatial and temporal aspects of toothbrushing practices, indicating the importance of considering social practice theory as a framework in future research to address this gap. Furthermore, exploring toothbrushing in connection with related social practices has the potential to increase understanding of factors influencing oral health in preschool children.

Dental caries and school readiness in 5-year-olds: A birth cohort data linkage study.

OBJECTIVE: To describe the association between dental caries and school readiness in 5-year-old children taking part in the Born in Bradford (BiB) birth cohort, UK. METHODS: The Early Years Foundation Stage Profile (EYFSP) assesses the school readiness of young children and is strongly predictive of future academic attainment. Children are recorded as 'emerging' (below expected), 'expected', or 'exceeding' in five key learning areas. The Oral Health Survey of 5-year-olds (OHS5) is undertaken biennially in England, assessing caries experience at a dentine threshold (d3mft). EYFSP and OHS5 were available for a proportion of children participating in BiB. Odds ratios and confidence intervals for caries experience were established, and odds ratios adjusted for significant sociodemographic variables. RESULTS: EYFSP and OHS5 data were available for 2.5% (n = 346) BiB participants. Nearly half (45.2%) had caries. A measure of socio-economic status, receiving free school meals, was the only demographic variable strongly related to caries experience (OR: 2.8, 95% CI: 1.6-4.9). After adjustment, children 'emerging' in EYFSP learning areas had 1.6- to 2.2-fold (95% CI: 1.0-3.8) higher odds of experiencing caries. Children 'exceeding' EYFSP learning areas had 2.3- to 4-fold (95% CI: 0.1-0.9) lower odds of caries experience. CONCLUSION: This is the first study to explore the association between caries experience and school readiness using a holistic assessment tool. The association was found across different learning areas and was comparable to and independent of socio-economic status. The findings indicate oral health-related absenteeism is not a causative factor. EYFSP shows potential to enhance the targeting of preventive interventions at a child, class or school level.

In vivo activities of heparan sulfate differentially modified by NDSTs during development.

Heparan sulfate proteoglycans (HSPGs) serve as co-receptors for growth factor signaling during development. It is well known that the level and patterns of sulfate groups of heparan sulfate (HS) chains, or HS fine structures, have a major impact on HSPG function. On the other hand, the physiological significance of other structural features of HS, including NS/NA domain organization, remains to be elucidated. A blueprint of the HS domain structures is mainly controlled by HS N-deacetylase/N-sulfotransferases (NDSTs). To analyze in vivo activities of differentially modified HS, we established two knock-in (KI) Drosophila strains with the insertion of mouse Ndst1 (mNdst1) or Ndst2 (mNdst2) in the locus of sulfateless (sfl), the only Drosophila NDST. In these KI lines, mNDSTs are expressed from the sfl locus, in the level and patterns identical to the endogenous sfl gene. Thus, phenotypes of Ndst1 KI and Ndst2KI animals reflect the ability of HS structures made by these enzymes to rescue sfl mutation. Remarkably, we found that mNdst1 completely rescued the loss of sfl. mNdst2 showed a limited rescue ability, despite a higher level of HS sulfation compared to HS in mNdst1 KI. Our study suggests that independent of sulfation levels, additional HS structural features controlled by NDSTs play key roles during tissue patterning.

Sleep and circadian biomarkers of postoperative delirium (SLEEP-POD): protocol for a prospective and observational cohort study.

INTRODUCTION: Surgical patients over 70 experience postoperative delirium (POD) complications in up to 50% of procedures. Sleep/circadian disruption has emerged as a potential risk factor for POD in epidemiological studies. This protocol presents a single-site, prospective observational study designed to examine the relationship between sleep/circadian regulation and POD and how this association could be moderated or mediated by Alzheimer's disease (AD) pathology and genetic risk for AD. METHODS AND ANALYSIS: Study staff members will screen for eligible patients (age ≥70) seeking joint replacement or spinal surgery at Massachusetts General Hospital (MGH). At the inclusion visit, patients will be asked a series of questionnaires related to sleep and cognition, conduct a four-lead ECG recording and be fitted for an actigraphy watch to wear for 7 days before surgery. Blood samples will be collected preoperatively and postoperatively and will be used to gather information about AD variant genes (APOE-ε4) and AD-related pathology (total and phosphorylated tau). Confusion Assessment Method-Scale and Montreal Cognitive Assessment will be completed twice daily for 3 days after surgery. Seven-day actigraphy assessments and Patient-Reported Outcomes Measurement Information System questionnaires will be performed 1, 3 and 12 months after surgery. Relevant patient clinical data will be monitored and recorded throughout the study. ETHICS AND DISSEMINATION: This study is approved by the IRB at MGH, Boston, and it is registered with the US National Institutes of Health on ClinicalTrials.gov (NCT06052397). Plans for dissemination include conference presentations at a variety of scientific institutions. Results from this study are intended to be published in peer-reviewed journals. Relevant updates will be made available on ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT06052397.

Ethnographic perspectives of mothers and professionals on including children with disabilities in oral health in the Kingdom of Saudi Arabia.

BACKGROUND: Children with disabilities generally face poorer oral health outcomes compared with their non-disabled peers due to a range of factors including inadequate oral hygiene, infrequent dental visits and systemic barriers in accessing care. AIM: This ethnographic study explored the perspectives of caregivers and professionals to identify the ways that children with disabilities are included in oral health. DESIGN: A purposive sample of 10 caregivers, all mothers with disabled children aged 9-15 years, five healthcare providers and five educators in Saudi Arabia, participated. Data collection used participant observation and semi-structured in-depth interviews. Data were analysed using reflexive thematic analysis. RESULTS: The findings suggest that mothers lacked a supportive environment to develop their skills and knowledge about oral health care, preventing them from including their children in oral health. Inaccessible services added to the exclusion of both mothers and children. Some dental professionals exhibited poor communication skills and discriminatory attitudes towards the children and problematising mothers. Educators tended to discuss disabled children in terms of inability, displaying a deficit approach to impairment. CONCLUSIONS: The evidence suggests the exclusion of mothers from oral health. This has an impact on how they enable their children. Recommendations include adopting a social model of disability in dental education and policies in Saudi Arabia to address inequalities. Provision of support, education and focusing on societal barriers moves towards inclusion rather than conceptualising disability as an individual problem.

'It's like being in a tunnel': Understanding the patient journey from tooth loss to life with removable dentures.

INTRODUCTION: The aim of this study was to conceptualise the key stages of the patient journey in the provision of a new denture and examine the factors leading to successful patient-related outcomes. METHODS: Two partially dentate patient samples were included: (i) Denture wearers - patients who had a denture fitted within the previous five years and (ii) New dentures - patients receiving treatment for a new or replacement denture. The methods involved direct targeted participant observations of the denture fitting process, debriefing interviews and a follow-up focus group exploring the patient journey. Data were analysed through the use of phenomenology and grounded theory. RESULTS: Interviews were completed with twenty participants of the denture-wearing sample (11 males and nine females, age range 22 to 86 years). Thirteen participants were included in the treatment journey sample in two primary care settings (six males and seven females, age range 55 to 101 years). Tooth loss and recovery was described as being in an 'emotional tunnel' resulting from 'bodyphonic processes' associated with tooth loss. 'Bodyphonia' subsequently became the context for 'taking control' and 'managing disclosure' when living with a removable denture. Different courses through this process can be readily observed, moderated by different variables (i.e., previous experience, working knowledge, a good fit, the treatment alliance, negotiated compromises and bounded responsibility). CONCLUSIONS: An'integrating framework' that seeks to describe the patient journey from the experience of tooth loss to recovery with a denture is proposed. This framework could be used to aid development of a clinical pathway to guide treatment options. CLINICAL SIGNIFICANCE: This paper conceptualises the patient journey. It stresses the importance of understanding the stages patients go through and highlights that for the dental team, the try-in stage is perhaps the best stage to give information about the denture and plans for continued care.

Flagellin-modulated inflammasome pathways characterize the human alveolar macrophage response to Burkholderia pseudomallei, a lung-tropic pathogen.

Melioidosis is an emerging tropical infection caused by inhalation, inoculation, or ingestion of the flagellated, facultatively intracellular pathogen Burkholderia pseudomallei. The melioidosis case fatality rate is often high, and pneumonia, the most common presentation, doubles the risk of death. The alveolar macrophage is a sentinel pulmonary host defense cell, but the human alveolar macrophage in B. pseudomallei infection has never been studied. The objective of this study was to investigate the host-pathogen interaction of B. pseudomallei infection with the human alveolar macrophage and to determine the role of flagellin in modulating inflammasome-mediated pathways. We found that B. pseudomallei infects primary human alveolar macrophages but is gradually restricted in the setting of concurrent cell death. Electron microscopy revealed cytosolic bacteria undergoing division, indicating that B. pseudomallei likely escapes the alveolar macrophage phagosome and may replicate in the cytosol, where it triggers immune responses. In paired human blood monocytes, uptake and intracellular restriction of B. pseudomallei are similar to those observed in alveolar macrophages, but cell death is reduced. The alveolar macrophage cytokine response to B. pseudomallei is characterized by marked interleukin (IL)-18 secretion compared to monocytes. Both cytotoxicity and IL-18 secretion in alveolar macrophages are partially flagellin dependent. However, the proportion of IL-18 release that is driven by flagellin is greater in alveolar macrophages than in monocytes. These findings suggest differential flagellin-mediated inflammasome pathway activation in the human alveolar macrophage response to B. pseudomallei infection and expand our understanding of intracellular pathogen recognition by this unique innate immune lung cell.

Setting the context for a complex dental intervention of role substitution in care homes: Initial process evaluation findings.

OBJECTIVES: SENIOR (uSing rolE-substitutioN In care homes to improve oRal health) is a randomised controlled trial designed to determine whether role substitution could improve oral health for this population. A parallel process evaluation was undertaken to understand context. This paper reports on the first phase of the process evaluation. BACKGROUND: The oral health and quality-of-life of older adults residing in care homes is poorer than those in the community. Oral health care provision is often unavailable and a concern and challenge for managers. The use of Dental Therapists and Dental Nurses rather than dentists could potentially meet these needs. MATERIALS AND METHODS: Semi-structured interviews were conducted with 21 key stakeholders who either worked or had experience of dependent care settings. Questions were theoretically informed by the: Promoting Action on Research Implementation in Health Services (PAHRIS) framework. The focus was on contextual factors that could influence adoption in practice and the pathway-to-impact. Interviews were fully transcribed and analysed thematically. RESULTS: Three themes (receptive context, culture, and leadership) and 11 codes were generated. Data show the complexity of the setting and contextual factors that may work as barriers and facilitators to intervention delivery. Managers are aware of the issues regarding oral health and seek to provide best care, but face many challenges including staff turnover, time pressures, competing needs, access to services, and financial constraints. Dental professionals recognise the need for improvement and view role substitution as a viable alternative to current practice. CONCLUSION: Although role substitution could potentially meet the needs of this population, an in-depth understanding of contextual factors appeared important in understanding intervention delivery and implementation.

Conventional and unconventional T-cell responses contribute to the prediction of clinical outcome and causative bacterial pathogen in sepsis patients.

Sepsis is characterized by a dysfunctional host response to infection culminating in life-threatening organ failure that requires complex patient management and rapid intervention. Timely diagnosis of the underlying cause of sepsis is crucial, and identifying those at risk of complications and death is imperative for triaging treatment and resource allocation. Here, we explored the potential of explainable machine learning models to predict mortality and causative pathogen in sepsis patients. By using a modelling pipeline employing multiple feature selection algorithms, we demonstrate the feasibility of identifying integrative patterns from clinical parameters, plasma biomarkers, and extensive phenotyping of blood immune cells. While no single variable had sufficient predictive power, models that combined five and more features showed a macro area under the curve (AUC) of 0.85 to predict 90-day mortality after sepsis diagnosis, and a macro AUC of 0.86 to discriminate between Gram-positive and Gram-negative bacterial infections. Parameters associated with the cellular immune response contributed the most to models predictive of 90-day mortality, most notably, the proportion of T cells among PBMCs, together with expression of CXCR3 by CD4+ T cells and CD25 by mucosal-associated invariant T (MAIT) cells. Frequencies of Vδ2+ γδ T cells had the most profound impact on the prediction of Gram-negative infections, alongside other T-cell-related variables and total neutrophil count. Overall, our findings highlight the added value of measuring the proportion and activation patterns of conventional and unconventional T cells in the blood of sepsis patients in combination with other immunological, biochemical, and clinical parameters.

Single vs. multiple fraction non-inferiority trial of stereotactic ablative radiotherapy for the comprehensive treatment of oligo-metastases/progression: SIMPLIFY-SABR-COMET.

BACKGROUND: Radiotherapy delivery regimens can vary between a single fraction (SF) and multiple fractions (MF) given daily for up to several weeks depending on the location of the cancer or metastases. With limited evidence comparing fractionation regimens for oligometastases, there is support to explore toxicity levels to nearby organs at risk as a primary outcome while using SF and MF stereotactic ablative radiotherapy (SABR) as well as explore differences in patient-reported quality of life and experience. METHODS: This study will randomize 598 patients in a 1:1 ratio between the standard arm (MF SABR) and the experimental arm (SF SABR). This trial is designed as two randomized controlled trials within one patient population for resource efficiency. The primary objective of the first randomization is to determine if SF SABR is non-inferior to MF SABR, with respect to healthcare provider (HCP)-reported grade 3-5 adverse events (AEs) that are related to SABR. Primary endpoint is toxicity while secondary endpoints include lesional control rate (LCR), and progression-free survival (PFS). The second randomization (BC Cancer sites only) will allocate participants to either complete quality of life (QoL) questionnaires only; or QoL questionnaires and a symptom-specific survey with symptom-guided HCP intervention. The primary objective of the second randomization is to determine if radiation-related symptom questionnaire-guided HCP intervention results in improved reported QoL as measured by the EuroQoL-5-dimensions-5levels (EQ-5D-5L) instrument. The primary endpoint is patient-reported QoL and secondary endpoints include: persistence/resolution of symptom reporting, QoL, intervention cost effectiveness, resource utilization, and overall survival. DISCUSSION: This study will compare SF and MF SABR in the treatment of oligometastases and oligoprogression to determine if there is non-inferior toxicity for SF SABR in selected participants with 1-5 oligometastatic lesions. This study will also compare patient-reported QoL between participants who receive radiation-related symptom-guided HCP intervention and those who complete questionnaires alone. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05784428. Date of Registration: 23 March 2023.

Using Standardised International Oral Health-Related Datasets in 6 Countries.

INTRODUCTION: Oral diseases affect a significant proportion of the world's population, yet international comparisons involving oral health outcomes have often been limited due to differences in the way country-level primary data are collected. In response to this, the World Dental Federation (FDI) Oral Health Observatory project was launched with the goal of collecting and producing standardised international data on oral health across countries. The aim of this descriptive cross-sectional study was to examine associations between self-reported general health and a range of factors (sociodemographics, oral health-related behaviours, oral impacts, clinical variables) using these standardised international datasets. METHODS: Dentists within FDI member National Dental Associations who chose to take part in the project were selected using a multistage sampling method. The number of dentists in each cluster was set according to the proportion of the national population living in the area, and 50 patients per dentist were systematically approached to take part. Patients and dentists completed 2 separate questionnaires on a mobile app. Ordinal logistic regression (conducted in December 2022) was used to analyse the linked patient and dentist data from 6 countries: China (n = 2242); Colombia (n = 1029); India (n = 999); Italy (n = 711); Japan (n = 1271); and Lebanon (n = 798). Self-reported general health was the dependent variable, with age, sex, education, self-reported oral health-related behaviours, self-reported oral impacts, and clinical variables acting as the independent variables. RESULTS: The results demonstrated a different pattern of associations in the different countries. Better self-reported general health was associated with degree-level education in all 6 countries and with reporting no oral impact and no sensitive teeth in 4 countries. Several country-specific patterns were also found, including the importance of tooth brushing in Colombia, periodontal health in Italy, and differing associations with sugary drinks consumption in India and Japan. CONCLUSIONS: These descriptive findings provide a basis for further research and, importantly, for advocacy in identifying patient oral health care needs according to both person-reported and clinical aspects. This can facilitate optimisation of service provision and potentially influence policy and investments.

Oral health experiences of people living with Parkinson's disease: a scoping review.

Background and aim Parkinson's disease is the fastest growing and second most common progressive neurodegenerative condition in the UK; poised to represent a major societal and health care challenge. The scoping review aims to provide an overview of the literature on the oral health (OH) experiences of people living with Parkinson's, identifying current research gaps and future priorities.Method Search strategies included three electronic databases, two grey literature databases, relevant organisations, specialist journals and hand searching of the reference lists. A data extraction tool was developed and piloted.Results A total of 121 items were included in the review. Four themes were identified: OH impact, education and training, service delivery and wider impacts of OH for people with Parkinson's (PwP). The majority of studies included were cross-sectional in design, describing the OH status of PwP.Conclusion The majority of research to date has focused on OH impact. Areas for future research include use of qualitative studies exploring the experiences, attitudes and priorities of PwP and their care partners. Inclusion of medical, dental and allied health care professionals, together with people with lived experience, is required to develop, implement and evaluate interventions to support OH.