Bulk and Interfacial Behavior of Potato Protein-Based Microgels.

This study aims to understand the bulk and interfacial performance of potato protein microgels. Potato protein (PoP) was used to produce microgels of submicrometer diameter via a top-down approach of thermal cross-linking followed by high-shear homogenization of the bulk gel. Bulk "parent" gels were formed at protein concentrations [PoP] = 5-18 wt %, which subsequently varied in their bulk shear elastic modulus (G') by several orders of magnitude (1-100 kPa), G' increasing with increasing [PoP]. The PoP microgels (PoPM) formed from these parent gels had diameters varying between 100 and 300 nm (size increasing with increasing G' and [PoP]), as observed via dynamic light scattering and atomic force microscopy (AFM) of PoPM adsorbed onto silicon. Interfacial rheology (interfacial shear storage and loss moduli, Gi' and Gi″) and interfacial tension (γ) of adsorbed films of PoP (i.e., nonheated PoP) and PoPM (both at tetradecane-water interfaces) were also studied, as well as the bulk rheology of the PoPM dispersions. The results showed that PoPM dispersions (at 50 vol %) had significantly higher bulk viscosity and shear thinning properties compared to the nonmicrogelled PoP at the same overall [PoP], but the bulk rheological behavior was in sharp contrast to the interfacial rheological performance, where Gi' and Gi″ of PoP were higher than for any of the PoPM. This suggests that the deformability and size of the microgels were key in determining the interfacial rheology of the PoPM. These findings may be attributed to the limited capacity for "unfolding" and lateral interactions of the larger PoPM at the interface, which are presumed to be stiffer due to their production from the strongest PoP gels. Our study further confirmed that heating and cooling the adsorbed films of PoPM after their adsorption showed little change, highlighting that hydrogen bonding was limited between the microgel particles.

Sticky Science: Using Complex Coacervate Adhesives for Biomedical Applications.

Tissue adhesives are used for various medical applications, including wound closure, bleeding control, and bone healing. Currently available options often show weak adhesion or cause adverse effects. Recently, there has been an increasing interest in complex coacervates as medical adhesives. Complex coacervates are formed by mixing oppositely charged macromolecules that associate and undergo liquid-liquid phase separation, in which the dense bottom phase is the complex coacervate. Complex coacervates are strong and often biocompatible, and show strong underwater adhesion. The properties of the resulting materials are tunable by intrinsic factors such as polymer chemistry, molecular weight, charge density, and topology of the macromolecules, as well as extrinsic factors such as temperature, pH, and salt concentration. Therefore, complex coacervates are interesting new candidates for medical adhesives. In this review, it is described how complex coacervates form and how different factors influence their behavior. Next, an overview of recent studies on complex coacervates in the context of medical adhesives is presented. The application of complex coacervates as hemostatic or embolic agents, skin or bone repair adhesives, and soft tissue sealants is discussed. Lastly, additional possibilities for utilizing these materials in the future are discussed.

Human and hamster sera correlate well in identifying antigenic drift among SARS-CoV-2 variants, including JN.1.

Antigenic assessments of SARS-CoV-2 variants inform decisions to update COVID-19 vaccines. Primary infection sera are often used for assessments, but such sera are rare due to population immunity from SARS-CoV-2 infections and COVID-19 vaccinations. Here, we show that neutralization titers and breadth of matched human and hamster pre-Omicron variant primary infection sera correlate well and generate similar antigenic maps. The hamster antigenic map shows modest antigenic drift among XBB sub-lineage variants, with JN.1 and BA.4/BA.5 variants within the XBB cluster, but with fivefold to sixfold antigenic differences between these variants and XBB.1.5. Compared to sera following only ancestral or bivalent COVID-19 vaccinations, or with post-vaccination infections, XBB.1.5 booster sera had the broadest neutralization against XBB sub-lineage variants, although a fivefold titer difference was still observed between JN.1 and XBB.1.5 variants. These findings suggest that antibody coverage of antigenically divergent JN.1 could be improved with a matched vaccine antigen.IMPORTANCEUpdates to COVID-19 vaccine antigens depend on assessing how much vaccine antigens differ antigenically from newer SARS-CoV-2 variants. Human sera from single variant infections are ideal for discriminating antigenic differences among variants, but such primary infection sera are now rare due to high population immunity. It remains unclear whether sera from experimentally infected animals could substitute for human sera for antigenic assessments. This report shows that neutralization titers of variant-matched human and hamster primary infection sera correlate well and recognize variants similarly, indicating that hamster sera can be a proxy for human sera for antigenic assessments. We further show that human sera following an XBB.1.5 booster vaccine broadly neutralized XBB sub-lineage variants but titers were fivefold lower against the more recent JN.1 variant. These findings support updating the current COVID-19 vaccine variant composition and developing a framework for assessing antigenic differences in future variants using hamster primary infection sera.

Clinical effectiveness of DREAMS START (Dementia Related Manual for Sleep; Strategies for Relatives) versus usual care for people with dementia and their carers: a single-masked, phase 3, parallel-arm, superiority randomised controlled trial.

BACKGROUND: Sleep disturbances are common and distressing for people with dementia and their families. Non-pharmacological interventions should be first-line management, avoiding harmful pharmacological side-effects, but there is none with known effectiveness. We aimed to establish whether DREAMS START, a multicomponent intervention, reduced sleep disturbance in people with dementia living at home compared with usual care. METHODS: We conducted a phase 3, two-arm, multicentre, parallel-arm, superiority randomised controlled trial with masked outcome assessment, recruiting dyads of people with dementia and sleep disturbance and family carers from community settings. Randomisation to the DREAMS START intervention (plus usual treatment) or usual treatment was conducted at dyadic level, blocked, and stratified by site, with a web-based system assigning allocation. DREAMS START is a six-session, manualised intervention delivered face to face or remotely by non-clinically trained graduates over an approximately 3-month period. The primary outcome was sleep disturbance measured by the Sleep Disorders Inventory (SDI) at 8 months. Analyses were on the intention-to-treat population. This trial is registered with ISRCTN 13072268. FINDINGS: Between Feb 24, 2021, and March 5, 2023, 377 dyads were randomly assigned (1:1), 189 to usual treatment and 188 to intervention. The mean age of participants with dementia was 79·4 years (SD 9·0), and 206 (55%) were women. The mean SDI score at 8 months was lower in the intervention group compared with the usual treatment group (15·16 [SD 12·77], n=159, vs 20·34 [16·67], n=163]; adjusted difference in means -4·70 [95% CI -7·65 to -1·74], p=0·002). 17 (9%) people with dementia in the intervention group and 17 (9%) in the control group died during the trial; the deaths were unrelated to the intervention. INTERPRETATION: To our knowledge, DREAMS START is the first multicomponent intervention to improve the sleep of people living at home with dementia more than usual clinical care. It had sustained effectiveness beyond intervention delivery. The intervention's delivery by non-clinically trained graduates increases the potential for implementation within health services, adding to usual clinical care. FUNDING: National Institute for Health and Care Research Health Technology Assessment.

Comparison of patch testing Brazilian (Green) propolis and Chinese (poplar-type) propolis: Clinical epidemiological study using data from the Information Network of Departments of Dermatology (IVDK).

BACKGROUND: Propolis types differ regarding their chemical composition. OBJECTIVES: To compare patch test results based on Brazilian (Green) propolis with data based on Chinese (poplar-type) propolis, and to evaluate the specifications of raw materials used for the PT preparations. METHODS: In the Information Network of Departments of Dermatology (IVDK), 1290 consecutive patients were patch tested with Brazilian (Green) propolis (NH400, SmartPractice Europe). Patch test reactivity was compared with results obtained with Chinese (poplar-type) propolis (NA71, SmartPractice Europe) by calculating frequencies and corresponding 95% confidence intervals. Data on the specifications of raw materials used for NH400 and NA71 were obtained from the manufacturer. RESULTS: Positive reactions to NH400 were found in 303 (23.5%) patients with unclear clinical relevance in most cases. Patients reacting to NH400 were less often sensitised to fragrances and colophony, but more often to nickel sulphate and cobalt chloride than patients reacting to NA71. The NH400 batch used contained high levels of aerobic bacteria, and was not purified by ethanolic extraction. CONCLUSIONS: Pattern of concomitant reactivity along with raw material properties suggests that the high frequency of positive reactions to NH400 may primarily result from bacterial contamination or impurities in the PT preparation rather than from propolis constituents.

SARS-CoV-2 variant replacement constrains vaccine-specific viral diversification.

Coronavirus disease 2019 (COVID-19) vaccine breakthrough infections have been important for all circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant periods, but the contribution of vaccine-specific SARS-CoV-2 viral diversification to vaccine failure remains unclear. This study analyzed 595 SARS-CoV-2 sequences collected from the Military Health System beneficiaries between December 2020 and April 2022 to investigate the impact of vaccination on viral diversity. By comparing sequences based on the vaccination status of the participant, we found limited evidence indicating that vaccination was associated with increased viral diversity in the SARS-CoV-2 spike, and we show little to no evidence of a substantial sieve effect within major variants; rather, we show that rapid variant replacement constrained intragenotype COVID-19 vaccine strain immune escape. These data suggest that, during past and perhaps future periods of rapid SARS-CoV-2 variant replacement, vaccine-mediated effects were subsumed with other drivers of viral diversity due to the massive scale of infections and vaccinations that occurred in a short time frame. However, our results also highlight some limitations of using sieve analysis methods outside of placebo-controlled clinical trials.

Australia's recently established predators restore complexity to food webs simplified by extinction.

Since prehistory, humans have altered the composition of ecosystems by causing extinctions and introducing species. However, our understanding of how waves of species extinctions and introductions influence the structure and function of ecological networks through time remains piecemeal. Here, focusing on Australia, which has experienced many extinctions and introductions since the Late Pleistocene, we compared the functional trait composition of Late Pleistocene (130,00-115,000 years before present [ybp]), Holocene (11,700-3,000 ybp), and current Australian mammalian predator assemblages (≥70% vertebrate meat consumption; ≥1 kg adult body mass). We then constructed food webs for each period based on estimated prey body mass preferences. We found that introduced predators are functionally distinct from extinct Australian predators, but they rewire food webs toward a state that closely resembles the Late Pleistocene, prior to the megafauna extinctions. Both Late Pleistocene and current-day food webs consist of an apex predator and three smaller predators. This leads to food web networks with a similar total number of links, link densities, and compartmentalizations. However, this similarity depends on the presence of dingoes: in their absence, food webs become simplified and reminiscent of those following the Late Pleistocene extinctions. Our results suggest that recently established predators, even those implicated in species extinctions and declines, can restore complexity to food webs simplified by extinction.

Attention focused on memory: The episodic flanker effect with letters, words, colors, and pictures.

We report 10 experiments exploring the proposition that memory retrieval is perceptual attention turned inward. The experiments adapt the Eriksen and Eriksen perceptual flanker effect to a memory task in which subjects must decide whether a cued item in a probe display appeared in the same position in a memory list. Previous research with this episodic flanker task found distance and compatibility effects like those in the perceptual flanker task, suggesting that the same attentional spotlight is turned inward in memory retrieval. The previous experiments used lists of six consonants. The experiments reported here were designed to generalize the results to a broader range of conditions, from letters to words, colors, and pictures, and from set size 6 to set sizes of 4 and 5. Experiments 1-4 varied distance and set size with lists of four, five, or six letters, words, colors, and pictures, respectively. The distance effect was observed with all materials and all set sizes. Experiments 5-8 varied compatibility by presenting context items in the probe that were either the same as the memory list (and therefore compatible with "yes" responses and incompatible with "no" responses) or different from the memory list (and therefore incompatible with "yes" responses and compatible with "no" responses). We found compatibility effects with all materials and all set sizes. These results support the proposition that memory retrieval is attention turned inward. Turned inward or outward, attention is a general process that applies the same computations to different kinds of materials.

CT-guided infiltration of the ischiofemoral space in young patients with ischiofemoral impingement is an effective diagnostic tool.

OBJECTIVES: To present our technique of diagnostic CT-guided ischiofemoral space injection and report on pain response, complications, and associated imaging findings in young patients with ischiofemoral impingement (IFI). METHODS: Retrospective case series of patients with a clinical diagnosis of IFI that underwent CT-guided IFS injection with local anesthetic in a prone position with the feet in maximum internal rotation between 06/2019 and 04/2021. The response was evaluated using maximum subjective pain evaluation on a 0-10 visual analog scale (VAS) during a standardized pre- and postinterventional clinical examination. Patient charts and radiographic imaging data were reviewed to report associated imaging findings and subsequent surgeries. RESULTS: Eleven patients (13 hips, 9 females) with a median age of 31 years (interquartile range; IQR: 25-37 years) were included. Median baseline VAS was 7 points (IQR: 5-8) with a pain reduction of 5 points (IQR: 5-7 points, p = 0.001) after the injection. One patient reported transient ischial nerve paresthesia, otherwise, no complications occurred. Quadratus femoris muscle edema was present in 85% (11 of 13 hips). Excessively high femoral torsion (11/13 hips, 85%) and cam deformities (8/13 hips, 62%) were the most common osseous deformities. Eight of 13 hips (62%) underwent subsequent surgery for IFI. CONCLUSION: CT-guided diagnostic injection of the ischiofemoral space is safe and feasible. In young IFI patients, diagnostic IFS injections have the potential to improve the differential diagnosis of hip pain and to inform decision-making with regard to a possible benefit of joint-preserving hip surgery. CRITICAL RELEVANCE STATEMENT: In young patients with hip pain, diagnosis of IFI can be challenging due to concomitant pathologies. Furthermore, surgical treatment in these patients is controversial. In this context, CT-guided diagnostic infiltrations of the ischiofemoral space may facilitate not only the initial diagnosis of IFI, but could also improve surgical decision-making. KEY POINTS: CT-guided diagnostic injection of local anesthetic in the ischiofemoral space is safe. In young patients with IFI, it leads to subjective pain reduction. In young patients with concomitant osseous deformities, it may improve surgical decision-making.

Fibrinogen αC-region acts as a functional safety latch: implications for a fibrin biomechanical behaviour model.

Fibrin has unique biomechanical properties which are essential for its role as a scaffold for blood clots. Fibrin is highly extensible and demonstrates significant strain stiffening behaviour, which is essential for stress-distribution in the network. Yet the exact structures of fibrin at the sub-fibre level that contribute to its unique biomechanical characteristic are unknown. Here we show how truncations of the fibrinogen αC-region impact the biomechanical properties of fibrin fibres. Surprisingly, absence of the complete αC-region did not influence the low strain modulus of fibrin fibres but led to premature fibre rupture and decreased extensibility. Intermediate effects were observed with partial deletion of the αC-region, reflected by intermediate rupture stress and toughness. However, overall strain-stiffening behaviour remained even in absence of the αC-region, indicating that strain stiffening is not due to stress being transferred from the αC-region to the protofibril backbone. Upon stress-relaxation, decay constants and their relative contribution to the total relaxation remained similar at all strains, showing that a distinct relaxation process is present until fibre rupture. However, relative contribution of fast relaxation was maximal only in crosslinked fibres if the flexible αC-connector was present. These data show that the αC-region is not the main load-bearing structure within fibrin fibres and point to a critical role for the protofibril backbone instead. We present a revised structural model based on protofibril branching that fully explains the unique biomechanical behaviour of fibrin fibres, while the αC-region primarily acts as a safety latch at the highest of strains. STATEMENT OF SIGNIFICANCE: The findings presented in this paper reveal critically important details about how the molecular structure of fibrin contributes to its unique mechanical properties which are essential to fulfil its function as the scaffold of blood clots. In this work we used engineered proteins with alterations in an important but highly disordered area of the molecule called αC-region and we provide direct evidence for the first time for how the absence of either the globular αC-domain, or the complete αC-region impacts the mechanical behaviour of individual fibrin fibres. Using these results we developed a new structural model of protofibril organisation within fibrin fibres that fully explains their strain stiffening, relatively low modulus and their high, largely variable, extensibility.

David Taylor-Robinson: Medical Microbiologist and Research Pioneer of Sexually Transmitted Infections.

David Taylor-Robinson has been an inspiration to many investigators in the field of sexually transmitted infections (STIs) as, arguably, the father of modern mycoplasmology. Born in 1931, his career as a physician-scientist was initially in virology, researching chickenpox and the common cold, for both of which he made key discoveries at a time when little was known about these conditions. Soon, however, David's attention turned to bacteriology, developing a passionate interest in mycoplasmas and chlamydia. This gave rise to research collaborations all around the world in marginalized and regional communities, stretching from Tristan da Cunha and Antarctica to the South Pacific and sub-Saharan Africa. He was the discoverer of Mycoplasma genitalium, which today is a commonly diagnosed and increasingly antibiotic-resistant pathogen of the genitourinary tract and a significant cause of female infertility. His problem-solving mindset led to research on associations between mycoplasmas with rheumatological conditions and chlamydia with coronary artery plaque formation late into his working life. Throughout his distinguished career, David Taylor-Robinson, affectionately truncated to "DTR" to all who knew him professionally, has been a beloved mentor to hundreds of aspiring scientists, some of whom are now leaders in their field. His open-door policy meant that there was rarely a time when there was no visiting researcher from each of the six inhabited continents under his expert tutelage. A strong work ethic and drive for scientific excellence, allied to his unstinting kindness and jovial demeanor, has provided a source of inspiration to a wide diaspora of research colleagues over more than six decades. This is as much David's legacy to medical science as the undoubted public health impact of his own pioneering research on STIs.

Sex, Gender, and Stroke Recovery: Functional Limitations and Inpatient Care Needs in Canadian and European Survivors.

BACKGROUND: Stroke is a leading cause of long-term disability among survivors. Past literature already investigated the biological sex differences in stroke outcome, still limited work on gender differences is published. Therefore, the study aimed at investigating whether biological sex and sociocultural gender of survivors play a role as determinants of disability and quality of life among stroke survivors across Europe and Canada. METHODS: Data were gathered from the European Health Information Survey (EHIS, n=316,333) and Canadian Community Health Survey (CCHS, n=127,462) datasets. Main outcomes of interest were disability, assessed through evaluating the impairment of Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (iADL), and inpatient care needs, such as hospitalization or institutionalization. Multivariate logistic regression models were utilized to identify factors independently associated with outcomes. Federated analysis was conducted for cross-country comparisons. Data were adjusted for the country-specific Gender Inequality Index (GII), with higher score corresponding to more gender inequality towards femalesResults: Female survivors showed greater impairments in iADL (OR=1.73, 95% CI 1.53 - 1.96) and ADL (OR=1.25, 95% CI 1.09-1.44), without a corresponding increase in inpatient care needs. Socioeconomic factors such as marital status and income level were significant predictors of disability, with low income and being single/divorced associated with higher risks. The impact of sex was more pronounced in countries with higher GII, indicating the influence of gender inequality on stroke outcomes. INTERPRETATION: The findings highlight the significant impact of biological sex and gender-related social determinants on post-stroke disability, with female sex and unfavorable socioeconomic conditions being associated with worse outcomes.

Low Rate of AVN and Complications in Unstable SCFE With Epiphyseal-metaphyseal Discontinuity After Treatment With a Modified Dunn Procedure.

BACKGROUND: The risk of developing avascular necrosis (AVN) in the setting of an unstable slipped capital femoral epiphysis (SCFE) that is undergoing treatment with the modified Dunn procedure is not well understood. In addition, since the Loder classification of unstable is reportedly different than actual intraoperatively observed instability (that is, discontinuity between the femoral head epiphysis and proximal femoral metaphysis), the overall risk of developing AVN, as well as the potential complications of treatment of these patients with the modified Dunn procedure, are unknown. QUESTIONS/PURPOSES: To evaluate the modified Dunn procedure for the treatment of patients with epiphyseal-metaphyseal discontinuity, we asked: (1) What was the survivorship free from AVN at 10 years? (2) What was the survivorship free from subsequent surgery and/or complications at 10 years? (3) What were the clinical and patient-reported outcome scores? METHODS: In a retrospective analysis, we identified 159 patients (159 hips) treated with a modified Dunn procedure for SCFE between 1998 and 2020, of whom 97% (155 of 159) had documentation about intraoperatively observed epiphyseal-metaphyseal stability. Of those, 37% (58 of 155) of patients were documented to have intraoperatively observed epiphyseal-metaphyseal discontinuity and were considered eligible for inclusion, whereas 63% (97 of 155) had documented epiphyseal-metaphyseal stability and were excluded. No patients were lost to follow-up before the 2-year minimum. All patients were assessed for survival, but 7% (4 of 58) did not fill out our outcomes score questionnaire. This resulted in 93% (54 of 58) of patients who were available for outcome score assessment. Additionally, 50% (29 of 58) of patients had not been seen within the last 5 years; they are included, but we note that there is uncertainty about their status. The median (range) age at surgery was 13 years (10 to 16), and the sex ratio was 60% (35 of 58) male and 40% (23 of 58) female patients. Sixty-four percent (37 of 58) of patients were classified as acute-on-chronic, and 17% (10 of 58) of patients were classified as acute. Forty-seven percent (27 of 58) of patients presented with severe slips and 43% (25 of 58) of patients with moderate slips based on radiographic classification. All patients underwent surgical hip dislocation with the modified Dunn procedure to correct the slip deformity and provide stabilization. Complications and reoperations were assessed from a review of electronic medical records, and a Kaplan-Meier estimator was used to estimate survivorship free from complications and reoperations at 10 years. Clinical examination results and questionnaire responses were evaluated at minimum 2-year follow-up. RESULTS: Kaplan-Meier survivorship free from AVN was 93% (95% CI 87% to 100%) at 10 years. Survivorship free from any reoperation was 75% (95% CI 64% to 88%) at 10 years. In addition, survivorship free from complications, defined as development of AVN, reoperation, or a Sink Grade II complication or higher, was 57% (95% CI 45% to 73%) at 10 years. The median (range) Merle D'Aubigne Postel score was 18 (14 to 18) for the patients who did not develop AVN, and 12 (6 to 16) for the four patients who developed AVN (p < 0.001). The median modified Harris hip score was 100 (74 to 100) in the non-AVN cohort and 65 (37 to 82) in the AVN cohort (p = 0.001). Median HOOS total score was 95 (50 to 100) in the non-AVN cohort and 53 (40 to 82) in the AVN cohort (p = 0.002). CONCLUSION: Although the modified Dunn procedure is technically challenging, this study shows that in experienced hands, patients with who have demonstrated epiphyseal-metaphyseal discontinuity can be treated with a low risk of AVN and subsequent surgery. Referral of these patients to specialists who have substantial expertise in this procedure is recommended to improve patient outcomes. Prospective, long-term observational studies will help us identify these high-risk patients preoperatively and determine the long-term success of this procedure. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Highlights from the 11th BRONCHITIS International Symposium -"Heterogeneity of lung disease in a changing environment" Groningen, The Netherlands, 2024.

This meeting report provides an overview of the highlights of the BRONCHITIS XI international symposium, held in June 2024 in Groningen, The Netherlands. The theme of this year's symposium was "Heterogeneity of lung disease in a changing environment", and the symposium contained five different sessions focused on i) Heterogeneity of Chronic Lung Disease, ii) Environmental Changes with Impact on Lung Disease, iii) The Aging Lung, iv) Bronchitis and v) Innovative Therapy. The highlights from each of these sessions will be discussed separately, providing an overview of latest studies, new data and enthralling discussions.

Oxidative Stress and Cataract Formation: Evaluating the Efficacy of Antioxidant Therapies.

This comprehensive review investigates the pivotal role of reactive oxygen species (ROS) in cataract formation and evaluates the potential of antioxidant therapies in mitigating this ocular condition. By elucidating the mechanisms of oxidative stress, the article examines how ROS contribute to the deterioration of lens proteins and lipids, leading to the characteristic aggregation, cross-linking, and light scattering observed in cataracts. The review provides a thorough assessment of various antioxidant strategies aimed at preventing and managing cataracts, such as dietary antioxidants (i.e., vitamins C and E, lutein, and zeaxanthin), as well as pharmacological agents with antioxidative properties. Furthermore, the article explores innovative therapeutic approaches, including gene therapy and nanotechnology-based delivery systems, designed to bolster antioxidant defenses in ocular tissues. Concluding with a critical analysis of current research, the review offers evidence-based recommendations for optimizing antioxidant therapies. The current literature on the use of antioxidant therapies to prevent cataract formation is sparse. There is a lack of evidence-based conclusions; further clinical studies are needed to endorse the use of antioxidant strategies in patients to prevent cataractogenesis. However, personalized treatment plans considering individual patient factors and disease stages can be applied. This article serves as a valuable resource, providing insights into the potential of antioxidants to alleviate the burden of cataracts.

Effects of Azithromycin on Blood Inflammatory Gene Expression and Cytokine Production in Sarcoidosis.

INTRODUCTION: In sarcoidosis granulomas, monocyte-derived macrophages are activated by pro-inflammatory cytokines including TNF and IL-6. Current drug treatment for sarcoidosis aims to suppress inflammation but disabling side effects can ensue. The macrolide azithromycin may be anti-inflammatory. We aimed to determine whether treatment with azithromycin affects blood inflammatory gene expression and monocyte functions in sarcoidosis. METHODS: Blood samples were collected from patients with chronic pulmonary sarcoidosis enrolled in a single arm, open label clinical trial who received oral azithromycin 250 mg once daily for 3 months. Whole blood inflammatory gene expression with or without LPS stimulation was measured using a 770-mRNA panel. Phenotypic analysis and cytokine production were conducted by flow cytometry and ELISA after 24h stimulation with growth factors and TLR ligands. mTOR activity was assessed by measuring phosphorylated S6RP. RESULTS: Differential gene expression analysis indicated a state of heightened myeloid cell activation in sarcoidosis. Compared with controls, sarcoidosis patients showed increased LPS responses for several cytokines and chemokines. Treatment with azithromycin had minimal effect on blood gene expression overall, but supervised clustering analysis identified several chemokine genes that were upregulated. At the protein level, azithromycin treatment increased LPS-stimulated TNF and unstimulated IL-8 production. No other cytokines showed significant changes following azithromycin. Blood neutrophil counts fell during azithromycin treatment whereas mononuclear cells remained stable. Azithromycin had no detectable effects on mTOR activity or activation markers. CONCLUSION: Blood myeloid cells are activated in sarcoidosis, but azithromycin therapy did not suppress inflammatory gene expression or cytokine production in blood. TRIAL REGISTRATION: EudraCT 2019-000580-24 (17 May 2019).

Effects of High Dose Bolus Cholecalciferol on Free Vitamin D Metabolites, Bone Turnover Markers and Physical Function.

High dose bolus cholecalciferol supplementation has been associated with falls and fracture, and this does not appear to be due to hypercalcaemia. The primary aim of this study was to determine the change in free vitamin D and metabolites after high dose bolus supplementation. This was a single centre, double-blinded, randomised, controlled trial of three different oral bolus doses of vitamin D3 (50,000 IU, 150,000 IU, and 500,000 IU) in otherwise healthy, vitamin D deficient (total 25-hydroxylated vitamin 25(OH)D < 30 nmol/L) postmenopausal women. Thirty-three women were randomized to one of the three treatment groups. Twenty-seven vitamin D sufficient (25(OH)D > 50 nmol/L) postmenopausal women were recruited as a concurrent control group. Participants attended five study visits over three months. We measured total 25(OH)D3 and free 25(OH)D, total and free 1,25(OH)2D, parathyroid hormone, fibroblast-growth factor-23, serum calcium, ionised calcium, urinary calcium excretion, and bone turnover markers (procollagen I N-propeptide (PINP), serum C-telopeptides of type I collagen (CTX-I) and Osteocalcin (OC)). We assessed muscle strength and function with grip strength and a short physical performance battery. Postural blood pressure and aldosterone:renin ratio (ARR) was also measured. Total 25(OH)D3 and free 25(OH)D increased in response to dose, and there were proportionate increases in total and free metabolites. Treatment did not affect serum calcium, postural blood pressure, ARR, or physical function. Bone turnover markers increased transiently one week after administration of 500,000 IU. High dose bolus cholecalciferol supplementation does not cause disproportionate increases in free vitamin D or metabolites. We did not identify any effect on blood pressure regulation or physical function that would explain increased falls after high dose treatment. A transient increase in bone turnover markers one week after a 500,000 IU bolus suggests that very high doses can have acute effects on bone metabolism, but the clinical significance of this transient increase is uncertain.

Nurse-delivered sleep restriction therapy to improve insomnia disorder in primary care: the HABIT RCT.

Background: Insomnia is a prevalent and distressing sleep disorder. Multicomponent cognitive-behavioural therapy is the recommended first-line treatment, but access remains extremely limited, particularly in primary care where insomnia is managed. One principal component of cognitive-behavioural therapy is a behavioural treatment called sleep restriction therapy, which could potentially be delivered as a brief single-component intervention by generalists in primary care. Objectives: The primary objective of the Health-professional Administered Brief Insomnia Therapy trial was to establish whether nurse-delivered sleep restriction therapy in primary care improves insomnia relative to sleep hygiene. Secondary objectives were to establish whether nurse-delivered sleep restriction therapy was cost-effective, and to undertake a process evaluation to understand intervention delivery, fidelity and acceptability. Design: Pragmatic, multicentre, individually randomised, parallel-group, superiority trial with embedded process evaluation. Setting: National Health Service general practice in three regions of England. Participants: Adults aged ≥ 18 years with insomnia disorder were randomised using a validated web-based randomisation programme. Interventions: Participants in the intervention group were offered a brief four-session nurse-delivered behavioural treatment involving two in-person sessions and two by phone. Participants were supported to follow a prescribed sleep schedule with the aim of restricting and standardising time in bed. Participants were also provided with a sleep hygiene leaflet. The control group received the same sleep hygiene leaflet by e-mail or post. There was no restriction on usual care. Main outcome measures: Outcomes were assessed at 3, 6 and 12 months. Participants were included in the primary analysis if they contributed at least one post-randomisation outcome. The primary end point was self-reported insomnia severity with the Insomnia Severity Index at 6 months. Secondary outcomes were health-related and sleep-related quality of life, depressive symptoms, work productivity and activity impairment, self-reported and actigraphy-defined sleep, and hypnotic medication use. Cost-effectiveness was evaluated using the incremental cost per quality-adjusted life-year. For the process evaluation, semistructured interviews were carried out with participants, nurses and practice managers or general practitioners. Due to the nature of the intervention, both participants and nurses were aware of group allocation. Results: We recruited 642 participants (n = 321 for sleep restriction therapy; n = 321 for sleep hygiene) between 29 August 2018 and 23 March 2020. Five hundred and eighty participants (90.3%) provided data at a minimum of one follow-up time point; 257 (80.1%) participants in the sleep restriction therapy arm and 291 (90.7%) participants in the sleep hygiene arm provided primary outcome data at 6 months. The estimated adjusted mean difference on the Insomnia Severity Index was -3.05 (95% confidence interval -3.83 to -2.28; p < 0.001, Cohen's d = -0.74), indicating that participants in the sleep restriction therapy arm [mean (standard deviation) Insomnia Severity Index = 10.9 (5.5)] reported lower insomnia severity compared to sleep hygiene [mean (standard deviation) Insomnia Severity Index = 13.9 (5.2)]. Large treatment effects were also found at 3 (d = -0.95) and 12 months (d = -0.72). Superiority of sleep restriction therapy over sleep hygiene was evident at 3, 6 and 12 months for self-reported sleep, mental health-related quality of life, depressive symptoms, work productivity impairment and sleep-related quality of life. Eight participants in each group experienced serious adverse events but none were judged to be related to the intervention. The incremental cost per quality-adjusted life-year gained was £2075.71, giving a 95.3% probability that the intervention is cost-effective at a cost-effectiveness threshold of £20,000. The process evaluation found that sleep restriction therapy was acceptable to both nurses and patients, and delivered with high fidelity. Limitations: While we recruited a clinical sample, 97% were of white ethnic background and 50% had a university degree, which may limit generalisability to the insomnia population in England. Conclusions: Brief nurse-delivered sleep restriction therapy in primary care is clinically effective for insomnia disorder, safe, and likely to be cost-effective. Future work: Future work should examine the place of sleep restriction therapy in the insomnia treatment pathway, assess generalisability across diverse primary care patients with insomnia, and consider additional methods to enhance patient engagement with treatment. Trial registration: This trial is registered as ISRCTN42499563. Funding: The award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/84/01) and is published in full in Health Technology Assessment; Vol. 28, No. 36. See the NIHR Funding and Awards website for further award information.

Insomnia refers to problems with falling asleep or staying asleep, which affects 10% of the adult population. The recommended treatment for insomnia is a psychological treatment called cognitive­behavioural therapy. Research shows this to be a very effective and long-lasting treatment, but there are not enough trained therapists to support the large number of poor sleepers in the United Kingdom. We have developed a brief version of cognitive­behavioural therapy, called sleep restriction therapy, which involves supporting the patient to follow a new sleep­wake pattern. We carried out this study to see if sleep restriction therapy, given by nurses working in general practice, can improve insomnia and quality of life. We searched general practice records and invited people with insomnia to take part. Six hundred and forty-two participants were assigned, by chance, to either sleep restriction therapy or a comparison treatment, called sleep hygiene. Sleep restriction therapy involved meeting with a nurse on four occasions and following a prescribed sleep schedule. Sleep hygiene involved receiving a leaflet of sleep 'do's and dont's'. Those receiving sleep restriction therapy were also provided with the same sleep hygiene leaflet so that the difference between the two groups was whether or not they received nurse treatment. We measured sleep, quality of life, daytime functioning and use of sleep medication through questionnaires, before and after treatment. We calculated the cost to deliver the treatment, as well as the cost of other National Health Service treatments that participants accessed during the study. We also interviewed participants and nurses to understand their views of the treatment. We found that participants in the sleep restriction therapy group experienced greater reduction in their insomnia symptoms compared to sleep hygiene. They also experienced improved sleep, mental health, quality of life and work productivity. The two groups did not differ in their use of prescribed sleep medication. Our results suggest that the treatment is likely to represent good value for money for the National Health Service. Both nurses and participants considered the treatment to be acceptable and beneficial, and they suggested some potential refinements. The study shows that nurse-delivered sleep restriction therapy is likely to be a clinically effective approach to the treatment of insomnia, and good value for money for the National Health Service.

Individual and neighborhood-level social and deprivation factors impact kidney health in the GLOMMS-CORE study.

Prospective cohort studies of kidney equity are limited by a focus on advanced rather than early disease and selective recruitment. Whole population studies frequently rely on area-level measures of deprivation as opposed to individual measures of social disadvantage. Here, we linked kidney health and individual census records in the North of Scotland (Grampian area), 2011-2021 (GLOMMS-CORE) and identified incident kidney presentations at thresholds of estimated glomerular filtration rate (eGFR) under 60 (mild/early), under 45 (moderate), under 30 ml/min/1.73m2 (advanced), and acute kidney disease (AKD). Household and neighborhood socioeconomic measures, living circumstances, and long-term mortality were compared. Case-mix adjusted multivariable logistic regression (living circumstances), and Cox models (mortality) incorporating an interaction between the household and the neighborhood were used. Among census respondents, there were 48546, 29081, 16116, 28097 incident presentations of each respective eGFR cohort and AKD. Classifications of socioeconomic position by household and neighborhood were related but complex, and frequently did not match. Compared to households of professionals, people with early kidney disease in unskilled or unemployed households had increased mortality (adjusted hazard ratios: 95% confidence intervals) of (1.26: 1.19-1.32) and (1.77: 1.60-1.96), respectively with adjustment for neighborhood indices making little difference. Those within either a deprived household or deprived neighborhood experienced greater mortality, but those within both had the poorest outcomes. Unskilled and unemployed households frequently reported being limited by illness, adverse mental health, living alone, basic accommodation, lack of car ownership, language difficulties, and visual and hearing impairments. Thus, impacts of deprivation on kidney health are spread throughout society-complex, serious, and not confined to those living in deprived neighborhoods.

Opportunities for Enhanced Public Health Surveillance via Molecular Detection and Sequencing of Diverse Respiratory Viruses From Self-collected SARS-CoV-2 Antigen Test Swabs.

We sequenced and genotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, adenovirus, and respiratory syncytial virus, among other pathogens, from residual anterior nasal swabs self-collected for rapid SARS-CoV-2 antigen testing at the US Naval Academy. This is a key proof-of-concept for an acute respiratory infection surveillance approach, which could leverage prevalent SARS-CoV-2 antigen self-testing.