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The complement system is a complex network of proteins that plays a crucial role in the innate immune response. One important component of this system is the C5a-C5aR1 complex, which is critical in the recruitment and activation of immune cells. In-depth investigation of the activation mechanism as well as biased signaling of the C5a-C5aR1 system will facilitate the elucidation of C5a-mediated pathophysiology. In this study, we determined the structure of C5a-C5aR1-Gi complex at a high resolution of 3 Å using cryo-electron microscopy (Cryo-EM). Our results revealed the binding site of C5a, which consists of a polar recognition region on the extracellular side and an amphipathic pocket within the transmembrane domain. Furthermore, we found that C5a binding induces conformational changes of C5aR1, which subsequently leads to the activation of G protein signaling pathways. Notably, a key residue (M265) located on transmembrane helix 6 (TM6) was identified to play a crucial role in regulating the recruitment of β-arrestin driven by C5a. This study provides more information about the structure and function of the human C5a-C5aR1 complex, which is essential for the proper functioning of the complement system. The findings of this study can also provide a foundation for the design of new pharmaceuticals targeting this receptor with bias or specificity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Available platforms for local excision (LE) of early rectal cancer are rigid or flexible [trans‑anal minimally invasive surgery (TAMIS)]. We systematically searched the literature to compare outcomes between platforms., Methods: PRISMA-compliant search of PubMed and Scopus databases until September 2022 was undertaken in this random-effect meta-analysis. Statistical heterogeneity was assessed using I 2 statistic. Studies comparing TAMIS versus rigid platforms for LE for early rectal cancer were included. Main outcome measures were intraoperative and short-term postoperative outcomes and specimen quality., Results: 7 studies were published between 2015 and 2022, including 931 patients (423 females); 402 underwent TAMIS and 529 underwent LE with rigid platforms. Techniques were similar for operative time (WMD 11.1, 95%CI - 2.6 to 25, p = 0.11), percentage of defect closure (OR 0.7, 95%CI 0.06-8.22, p = 0.78), and peritoneal violation (OR 0.41, 95%CI 0.12-1.43, p = 0.16). Rigid platforms had higher rates of short-term complications (19.1% vs 14.2, OR 1.6, 95%CI 1.07-2.4, p = 0.02), although no significant differences were seen for major complications (OR 1.41, 95%CI 0.61-3.23, p = 0.41). Patients in the rigid platforms group were 3-times more likely to be re-admitted within 30 days compared to the TAMIS group (OR 3.1, 95%CI 1.07-9.4, p = 0.03). Rates of positive resection margins (rigid platforms: 7.6% vs TAMIS: 9.34%, OR 0.81, 95%CI 0.42-1.55, p = 0.53) and specimen fragmentation (rigid platforms: 3.3% vs TAMIS: 4.4%, OR 0.74, 95%CI 0.33-1.64, p = 0.46) were similar between the groups. Salvage surgery was required in 5.5% of rigid platform patients and 6.2% of TAMIS patients (OR 0.8, 95%CI 0.4-1.8, p = 0.7)., Conclusion: TAMIS or rigid platforms for LE seem to have similar operative outcomes and specimen quality. The TAMIS group demonstrated lower readmission and overall complication rates but did not significantly differ for major complications. The choice of platform should be based on availability, cost, and surgeon's preference., (© 2024. The Author(s).)

HCN channels are important for regulating heart rhythm and nerve activity and have been studied as potential drug targets for treating depression, arrhythmia, nerve pain, and epilepsy. Despite possessing unique pharmacological properties, HCN channels share common characteristics in that they are activated by hyperpolarization and modulated by cAMP and other membrane lipids. However, the mechanisms of how these ligands bind and modulate HCN channels are unclear. In this study, we solved structures of full-length human HCN3 using cryo-EM and captured two different states, including a state without any ligand bound and a state with cAMP bound. Our structures reveal the novel binding sites for cholesteryl hemisuccinate in apo state and show how cholesteryl hemisuccinate and cAMP binding cause conformational changes in different states. These findings explain how these small modulators are sensed in mammals at the molecular level. The results of our study could help to design more potent and specific compounds to influence HCN channel activity and offer new therapeutic possibilities for diseases that lack effective treatment., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Limb-salvage surgery involving the utilization of endoprosthetic replacements is commonly employed following segmental bone resection for primary and secondary bone tumors. This study aimed to evaluate whether a fully porous bridging collar promotes early osseous integration in endoprosthetic replacements., Methods: We undertook a retrospective review of all lower-limb endoprostheses utilizing a fully porous endosteal bridging collar design. We matched this cohort with a conventional extra-osteal non-porous fully hydroxyapatite-coated grooved collar cohort according to surgical indication, implant type, resection length, age, and follow-up time. At 6, 12, and 24 months post-implantation, radiographs were assessed for the number of cortices with or without osseointegration on orthogonal radiographs. Each radiograph was scored on a scale of -4 to + 4 for the number of cortices bridging the ongrowth between the bone and the collar of the prosthesis. Implant survival was estimated using the Kaplan-Meier method, and the mean number of osseointegrated cortices at each time point between the collar designs was compared using a paired t-test., Results: Ninety patients were retrospectively identified and analyzed. After exclusion, 40 patients with porous bridging collars matched with 40 patients with conventional extra-osteal non-porous collars were included in the study (n = 80). The mean age was 63.4 years (range 16-91 years); there were 37 males and 43 females. The groups showed no difference in implant survival (P = 0.54). The mean number of cortices with radiographic ongrowth for the porous bridging collar and non-porous collar groups was 2.1 and 0.3, respectively, at 6-month (P < 0.0001), 2.4 and 0.5, respectively, at 12-month (P = 0.044), and 3.2 and -0.2, respectively, at 24-month (P = 0.18) radiological follow-up., Conclusion: These findings indicate that fully porous bridging collars increased the number of cortices, with evidence of bone ongrowth between 6 and 24 months post-implantation. By contrast, extra-osteal collars exhibited reduced evidence of ongrowth between 6 and 24 months post-implantation. In the medium term, the use of a fully porous bridging collar may translate to a reduced incidence of aseptic loosening., (© 2024. The Author(s).)

Background: Oral diseases affect close to 3.5 billion people worldwide and there has been a call by the World Health Organization (WHO) to integrate oral health into the Universal Health Coverage (UHC) agenda., Objectives: To collate and synthesise information regarding the status of integration of oral health into the health systems covered by UHC across the 11 countries in the South East Asian Regional Office., Methods: Drawing on the framework of the six building blocks of health systems as devised by WHO, we compared the public dental care coverage models, with a focus on outpatient dental care in these countries. We gathered this information from publicly available resources, databases and peer-reviewed publications to populate the template guided by the WHO Health System Building Blocks., Results: We found a poor access to oral health care, lopsided distribution of manpower, rickety health information systems, and private sector domination and inadequate or absent financing mechanisms for outpatient procedures. The private sector was dominant in all countries except Thailand and Srilanka. Financing was absent in most countries and deficient in Thailand and Indonesia. Dental workforce was deficient in most countries except India, Srilanka, and Thailand. Health information systems were weak with no dental items under price control. Better UHC indicators did not guarantee a lower oral disease burden., Conclusions: Our review highlighted the close connection between service quality and human resources, governance, and finance. There is a need to establish standardised dental treatment guidelines that are uniformly adopted across countries, integrate oral health into national health and development programs, push for functional oral health research through collecting robust surveillance, economic, and social impact data and the development of cost-effective strategies tailored to each country's unique needs., (© 2024 The Authors. The International Journal of Health Planning and Management published by John Wiley & Sons Ltd.)

Objectives: This study compared adults with type 2 diabetes (T2DM) and those without diabetes (ND) from East London in terms of sociodemographic characteristics, oral health behaviors, dietary practices, and alcohol and tobacco-related habits., Materials and Methods: A total of 182 participants (n = 91 for each group) were recruited and requested to complete the validated questionnaire with 33 items., Results: Results showed that the mean ± SD age was 61 ± 11.7 in the T2DM, while 51 ± 11.2 in the ND group. The mean ± SD age at T2DM diagnosis was 43 ± 10. There was a significant gender difference, with more males in the T2DM group (67.7%) and more females in the ND group (64.8%). Asian-British (38.4%) were significantly high in the T2DM group when compared to other ethnicities. 92.3% of T2DM participants were significantly more likely to use medications in comparison to the ND group (29.7%). The T2DM participants' personal statements on general health were fair (34%) and good (46.2%) when compared with the ND group (15.4% and 59.3%, respectively). The majority of T2DM and ND participants (98%) lacked dental insurance. In the T2DM group, 31.8% were receiving benefits, and 39.5% were retired, while 46% of the ND group were full-time employees. Tooth brushing twice a day was slightly less common in T2DM (68%) when compared to the ND group (78%). Nearly half of the participants in both groups failed to carry out interdental cleaning (T2DM = 52%; ND = 47%), and 38.5% of the T2DM group used mouthwash occasionally, while 30% of the ND group had it twice daily. There was a weak association between chewing paan and annual income in ND participants (r = .90, p = .49). There were significant differences in the presence of removable prostheses, juice, and sweetened juice consumptions between the two groups (p < .05)., Conclusion: Within the confines of this study, being male, Asian British, retired due to disability, polypharmacy, and the presence of removable prostheses were all significant factors for T2DM., (© 2024 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

Head and neck cancer (HNC) refers to malignancies found in mucosal surfaces anywhere from the paranasal sinuses to the larynx, including the various glands and cavities. Between the years 2016 and 2018, there were about 3900 new cases every year in women and 8600 in men, making it the thirteenth most common cancer in women and fourth most common in men. The aim of our study was to evaluate the amount and type of teaching United Kingdom (UK) medical students receive on HNC, and to assess their current knowledge of these cancers. An online survey distributed via university representatives was responded to by 311 final year medical students from 25 medical schools across the UK. Regarding HNC teaching, 72 students (23.2%) reported receiving no teaching at their medical school. Of the 239 who reported receiving teaching, 169 (54.3%) received it in the format of a non-interactive, large group lecture. A total of 271 respondents (87.1%) believed that medical students at their university would benefit from more teaching on HNC. Based on our sample, there appears to be an overall dissatisfaction and lack of confidence surrounding HNC in the undergraduate curriculum. With its increasing prevalence in the UK, it is vital that red-flag symptoms and referral criteria are understood by the future medical workforce., (Copyright © 2023 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Stable microbial colonization of the skin depends on tight control by the host immune system. The lipid-dependent yeast Malassezia typically colonizes skin as a harmless commensal and is subject to host type 17 immunosurveillance, but this fungus has also been associated with diverse skin pathologies in both humans and animals. Using a murine model of Malassezia exposure, we show that Vγ4+ dermal γδ T cells expand rapidly and are the major source of IL-17A mediating fungal control in colonized skin. A pool of memory-like Malassezia-responsive Vγ4+ T cells persisted in the skin, were enriched in draining lymph nodes even after fungal clearance, and were protective upon fungal re-exposure up to several weeks later. Induction of γδT17 immunity depended on IL-23 and IL-1 family cytokine signalling, whereas Toll-like and C-type lectin receptors were dispensable. Furthermore, Vγ4+ T cells from Malassezia-exposed hosts were able to respond directly and selectively to Malassezia-derived ligands, independently of antigen-presenting host cells. The fungal moieties detected were shared across diverse species of the Malassezia genus, but not conserved in other Basidiomycota or Ascomycota. These data provide novel mechanistic insight into the induction and maintenance of type 17 immunosurveillance of skin commensal colonization that has significant implications for cutaneous health., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: NEM has received consultancy fees and funding for research from ImCheck Therapeutics SAS, as well as funding for research from TC BioPharm., (Copyright: © 2024 Ruchti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

SARS-CoV-2 and its variants continue to threaten public health. Nanobodies that block the attachment of the RBD to host cell angiotensin-converting enzyme 2 (ACE2) represent promising drug candidates. In this study, we reported the identification and structural biological characterization of a nanobody from a RBD-immunized alpaca. The nanobody, termed as 2S-1-19, shows outstanding neutralizing activity against both pseudotyped and authentic SARS-CoV-2 viruses. The crystal structure of 2S-1-19 bound to SARS-CoV-2 RBD reveals an epitope that overlaps with the binding site for ACE2. We also showed that 2S-1-19 reserves promising, though compromised, neutralizing activity against the Delta variant and that the trivalent form of 2S-1-19 remarkably increases its neutralizing capacity. Despite this, neither the monomeric or trimeric 2S-1-19 could neutralize the Omicron BA.1.1 variant, possibility due to the E484A and Q493K mutations found within this virus variant. These data provide insights into immune evasion caused by SARS-CoV-2 variants., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aging results from the accumulation of molecular damage that impairs normal biochemical processes. We previously reported that age-linked damage to amino acid sequence NGR (Asn-Gly-Arg) results in "gain-of-function" conformational switching to isoDGR (isoAsp-Gly-Arg). This integrin-binding motif activates leukocytes and promotes chronic inflammation, which are characteristic features of age-linked cardiovascular disorders. We now report that anti-isoDGR immunotherapy mitigates lifespan reduction of Pcmt1 -/- mouse. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1 -/- and naturally aged WT animals, which could also be induced via injection of isoDGR-modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti-isoDGR mAb (1 mg/kg) was sufficient to significantly reduce isoDGR-protein levels in body tissues, decreased pro-inflammatory cytokine concentrations in blood plasma, improved cognition/coordination metrics, and extended the average lifespan of Pcmt1 -/- mice. Mechanistically, isoDGR-mAb mediated immune clearance of damaged isoDGR-proteins via antibody-dependent cellular phagocytosis (ADCP). These results indicate that immunotherapy targeting age-linked protein damage may represent an effective intervention strategy in a range of human degenerative disorders., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Serotonin is a neurotransmitter regulating numerous physiological processes also modulated by drugs, for example, schizophrenia, depression, migraine, and obesity. However, these drugs typically have adverse effects caused by promiscuous binding across 12 serotonin and more than 20 homologous receptors. Recently, structures of the entire serotonin receptor family uncovered molecular ligand recognition. Here, we present a map of 19 'selectivity hotspots', that is, nonconserved binding site residues governing selectivity via favorable target interactions or repulsive 'off-target' contacts. Furthermore, we review functional rationale from observed ligand-binding affinities and mutagenesis effects. Unifying knowledge underlying specific probes and drugs is critical toward the functional characterization of different receptors and alleviation of adverse effects., Competing Interests: Declaration of interests D.E.G. has a part-time employment at Kvantify. A.A.J. is co-founder and co-owner of the company Lophora ApS., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Adrenal insufficiency is a life-threatening condition resulting from the inability to produce adrenal hormones in a dose- and time-dependent manner. Establishing a cell-based therapy would provide a physiologically responsive approach for the treatment of this condition. We report the generation of large numbers of human-induced steroidogenic cells (hiSCs) from human pluripotent stem cells (hPSCs). Directed differentiation of hPSCs into hiSCs recapitulates the initial stages of human adrenal development. Following expression of steroidogenic factor 1, activation of protein kinase A signaling drives a steroidogenic gene expression profile most comparable to human fetal adrenal cells, and leads to dynamic secretion of steroid hormones, in vitro. Moreover, expression of the adrenocorticotrophic hormone (ACTH) receptor/co-receptor (MC2R/MRAP) results in dose-dependent ACTH responsiveness. This protocol recapitulates adrenal insufficiency resulting from loss-of-function mutations in AAAS, which cause the enigmatic triple A syndrome. Our differentiation protocol generates sufficient numbers of hiSCs for cell-based therapy and offers a platform to study disorders causing adrenal insufficiency., Competing Interests: Declaration of interests G.R.B. and S.R.B. have filed the patent application WO2023/083839 A1., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The Brief Psychiatric Rating Scale (BPRS) is a useful tool for measuring the severity of psychopathological symptoms among patients with psychosis. Many studies, predominantly in Western countries, have investigated its factor structure. This study has the following aims: (a) to further explore the factor structure of the BPRS-Expanded version (BPRS-E, 24 items) among outpatients with psychotic disorders in Southeast European countries; (b) to confirm the identified model; and (c) to investigate the goodness-of-fit of the three competing BPRS-E factor models derived from previous studies. The exploratory factor analysis (EFA) produced a solution with 21 items grouped into five factors, thus supporting the existence of a fifth factor, i.e., Disorganization. A follow-up confirmatory factor analysis (CFA) revealed a 19-item model (with two items removed) that fit the data well. In addition, the stability of two out of three competing factor models was confirmed. Finally, the BPRS-E model with 5 factors developed in this cross-national study was found to include a greater number of items compared to competing models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bajraktarov, Blazhevska Stoilkovska, Russo, Repišti, Maric, Dzubur Kulenovic, Arënliu, Stevovic, Novotni, Ribic, Konjufca, Ristic, Novotni and Jovanovic.)

Background: The Oral Health Observatory (OHO), launched in 2014 by FDI World Dental Federation, aims to provide a coordinated approach to international oral health data collection. A feasibility project involving 12 countries tested the implementation of the methodology and data collection tools and assessed data quality from 6 countries., Methods: National dental associations (NDAs) recruited dentists following a standardised sampling method. Dentists and patients completed paired questionnaires (N = 7907) about patients' demographics, dental attendance, oral health-related behaviours, oral impacts, and clinical measures using a mobile app. In addition, participating dentists (n = 93) completed an evaluation survey, and NDAs completed a survey and participated in workshops to assess implementation feasibility., Results: Feasibility data are presented from the 12 participating countries. In addition, the 6 countries most advanced with data collection as of July 2020 (China, Colombia, India, Italy, Japan, and Lebanon) were included in the assessment of data quality and qualitative evaluation of implementation feasibility. All NDAs in these 6 countries reported interest in collecting standardised, international data for policy and communication activities and to understand service use and needs. Eighty-two percent of dentists (n = 76) reported a patient response rate of between 80% and 100%. More than 70% (n = 71) of dentists were either satisfied or very satisfied with the patient recruitment and data collection methods. There were variations in patient oral health and behaviours across countries, such as self-reporting twice-daily brushing which ranged from 45% in India to 83% in Colombia., Conclusions: OHO provides a feasible model for collecting international standardised data in dental practices. Reducing time implications, ensuring mobile app reliability, and allowing practitioners to access patient-reported outcomes to inform practice may enhance implementation., Competing Interests: Conflict of interest Steve Mason is employed by Haleon (formally known as  GSK Consumer Healthcare). He reports no other conflicts of interest regarding the work under consideration for publication or relevant financial activities outside the submitted work. Sean Taylor, Sarah R. Baker, Tom Broomhead, Rachael England, Michael Sereny, Georgios Tsakos, and David M. Williams report no conflicts of interest regarding the work under consideration for publication, no relevant financial activities outside the submitted work, and no patents or copyrights., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This study aims to formulate experimental vinylpolysiloxane (VPS) impression materials and compare their elastic recovery and strain-in-compressions with three commercial VPS materials (Aquasil, Elite, and Extrude). Five experimental materials (Exp), two hydrophobic (Exp-I and II) and three hydrophilic (Exp-III, IV and V) were developed. Exp 1 contained vinyl-terminated poly-dimethyl siloxane and a conventional cross-linking agent (poly methylhydrosiloxane), while Exp- II contained a novel cross-linking agent that is tetra-functional dimethyl-silyl-ortho-silicate (TFDMSOS). Exp III-V (hydrophilic materials) were formulated by incorporating different concentrations of non-ionic surfactant (Rhodasurf CET-2) into Exp II formulation. Measurement of elastic recovery and strain-in-compression for commercial and experimental materials were performed according to ISO4823 standard using the calibrated mechanical testing machine (Tinius Olsen). One-way analysis of variance (one-way ANOVA) and Tukey's post-hoc (HSD) test were used for statistical analysis and a p -value of ≤ 0.05 was considered significant. Exp-I has statistically similar values to commercial VPS. The Exp-II showed the highest elastic recovery, while % elastic recovery was reduced with the addition of the non-ionic surfactant (Rhodasurf CET-2). The % reduction was directly related to the concentration of Rhodasurf CET-2. In addition, Exp II had significantly higher strain-in-compression values compared to Exp-I and commercial materials. These values were further increased with the addition of a non-ionic surfactant (Rhodasurf CET-2) was added (Exp-III, IV and V)., Competing Interests: The authors declare there are no competing interests., (©2023 Ud Din et al.)

Background: CLUSTER is a UK consortium focussed on precision medicine research in JIA/JIA-Uveitis. As part of this programme, a large-scale JIA data resource was created by harmonizing and pooling existing real-world studies. Here we present challenges and progress towards creation of this unique large JIA dataset., Methods: Four real-world studies contributed data; two clinical datasets of JIA patients starting first-line methotrexate (MTX) or tumour necrosis factor inhibitors (TNFi) were created. Variables were selected based on a previously developed core dataset, and encrypted NHS numbers were used to identify children contributing similar data across multiple studies., Results: Of 7013 records (from 5435 individuals), 2882 (1304 individuals) represented the same child across studies. The final datasets contain 2899 (MTX) and 2401 (TNFi) unique patients; 1018 are in both datasets. Missingness ranged from 10 to 60% and was not improved through harmonisation., Conclusions: Combining data across studies has achieved dataset sizes rarely seen in JIA, invaluable to progressing research. Losing variable specificity and missingness, and their impact on future analyses requires further consideration., (© 2023. The Author(s).)

There is an accelerated demand for non-surgical facial aesthetics (NSFA) encompassing the use of botulinum toxin and dermal fillers. Healthcare professionals may either treat NSFA-related complications in the public sector or practise in the private sector. Currently, there is no standardised undergraduate teaching in the UK to educate healthcare professionals on NSFA. The aim of our study was to compare medical and dental undergraduate students' perceptions and awareness of NSFA, and to understand its role if implemented in each curriculum in the UK. An online questionnaire was devised and distributed via social media platforms to medical and dental students across the UK. Student responses were anonymised and collated as quantitative data, and subsequently analysed. Of the 146 respondents, 89% had no previous teaching on NSFA. Ninety-three per cent of medics and 75% of dentists agreed or strongly agreed that non-surgical aestheticians require dental or medical knowledge to deliver NSFA, and 66% of medics and 75% of dentists agreed or strongly agreed that NSFA should be incorporated into the undergraduate curriculum. Only 7% of medics and 8% of dentists were aware of the steps required to practise NSFA. Incoming doctors and dentists are showing interest in the field yet have no formal teaching in the area. Requiring healthcare professionals to have some baseline understanding of NSFA and its associated complications means that implementing formal education on the subject in the medical and dental curricula is an important consideration., (Copyright © 2023 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Maxillofacial surgery placement of fixatures (Leonard Buttons, LB) at close proximity to surgical incisions provides a potential reservoir as a secondary local factor to advanced periodontal disease, with bacterial formation around failed fixatures implicating plaque. To address infection rates, we aimed to surface coat LB and Titanium (Ti) discs using a novel form of chlorhexidine (CHX), CHX-CaCl 2 and 0.2% CHX digluconate mouthwash as a comparison. CHX-CaCl 2 coated, double-coated and mouthwash coated LB and Ti discs were transferred to 1 mL artificial saliva (AS) at specified time points, and UV-Visible spectroscopy (254 nm) was used to measure CHX release. The zone of inhibition (ZOI) was measured using collected aliquots against bacterial strains. Specimens were characterized using Energy Dispersive X-ray Spectroscopy (EDS), X-ray Diffraction (XRD) and Scanning Electron Microscopy (SEM). SEM displayed copious dendritic crystals on LB/ Ti disc surfaces. Drug release from double-coated CHX-CaCl 2 was 14 days (Ti discs) and 6 days (LB) above MIC, compared to the comparison group (20 min). The ZOI for the CHX-CaCl 2 coated groups was significantly different within groups ( p < 0.05). CHX-CaCl 2 surface crystallization is a new drug technology for controlled and sustained CHX release; its antibacterial effectiveness makes this drug an ideal adjunct following clinical and surgical procedures to maintain oral hygiene and prevent surgical site infections.

Aim: This study aimed to assess success, recurrence, and overall complication rates among different surgical procedures for stomal prolapse., Methods: This study was a PRISMA-compliant systematic review. PubMed, Scopus, and Google Scholar were searched until March 2022. Studies that assessed surgical treatments of stomal prolapse in adults were included. The primary outcome was recurrence of stomal prolapse and the secondary outcome was 30-day complications. A random-effect meta-analysis was used to estimate the weighted mean rates of recurrence., Results: Six studies published (111 patients; 103 males) were included. 52 (46.8%) patients had end colostomies, 35 (31.5%) had loop colostomies. Seven procedures were assessed and included local stoma reconstruction (40%), stapled local repair (27%), modified Altemeier technique (10%), mesh strip repair (9%), stoma relocation (6%) redo laparotomy repair (5%), and colectomy and end ileostomy (3%). The weighted mean recurrence rate after local stoma reconstruction was 37.2% (95% CI: -1.8 to 76.3), higher than that after the stapled local repair technique (14.9%; 95% CI: 1.7-28.2). The crude recurrence rate of the modified Altemeier technique was 20%, and of stoma relocation was 66.6%. No recurrence was detected after the mesh strip technique (n = 10). The median follow-up ranged between 7 months and 2.5 years., Conclusion: Several surgical techniques are available to treat stomal prolapse. Local stoma reconstruction may be associated with high rates of recurrence while the stapled local repair and modified Altemeier procedure has relatively low recurrence. Further larger studies are needed to compare the efficacy of these techniques., (© 2023 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Background: Plantar Heel Pain (PHP) is a common disorder with many treatment pathways and is not self-limiting, hence prognostic information concerning recovery or recalcitrance is needed to guide practice. In this systematic review, we investigate which prognostic factors are associated with favourable or unfavourable PHP outcomes., Methods: MEDLINE, Web of Science, EMBASE, Scopus and PubMed electronic bibliographic databases were searched for studies evaluating baseline patient characteristics associated with outcomes in prospective longitudinal cohorts or after specific interventions. Cohort, clinical prediction rule derivation and single arms of randomised controlled trials were included. Risk of bias was evaluated with method-specific tools and evidence certainty with GRADE., Results: The review included five studies which evaluated 98 variables in 811 participants. Prognostic factors could be categorised as demographics, pain, physical and activity-related. Three factors including sex and bilateral symptoms (HR: 0.49[0.30-0.80], 0.33[0.15-0.72], respectively) were associated with a poor outcome in a single cohort study. The remaining four studies reported twenty factors associated with a favourable outcome following shockwave therapy, anti-pronation taping and orthoses. Heel spur (AUC = 0.88[0.82-0.93]), ankle plantar-flexor strength (Likelihood ratio (LR): 2.17[1.20-3.95]) and response to taping (LR = 2.17[1.19-3.90]) were the strongest factors predicting medium-term improvement. Overall, the study quality was low. A gap map analysis revealed an absence of research that included psychosocial factors., Conclusions: A limited number of biomedical factors predict favourable or unfavourable PHP outcomes. High quality, adequately powered, prospective studies are required to better understand PHP recovery and should evaluate the prognostic value of a wide range of variables, including psychosocial factors., (© 2023. Crown.)

Background: Considerable evidence links dietary salt intake with the development of hypertension, left ventricular hypertrophy, and increased risk of stroke and coronary heart disease. Despite extensive epidemiological and basic science interrogation of the relationship between high salt (HS) intake and blood pressure, it remains unclear how HS impacts endothelial cell (EC) and vascular structure in vivo. This study aims to elucidate HS-induced vascular pathology using a differential systemic decellularization in vivo approach., Methods: We performed systematic molecular characterization of the endothelial glycocalyx and EC proteomes in mice with HS (8%) diet-induced hypertension versus healthy control animals. Isolation of eGC and EC compartments was achieved using differential systemic decellularization in vivo methodology. Altered protein expression in hypertensive compared to normal mice was characterized by liquid chromatography tandem mass spectrometry. Proteomic results were validated using functional assays, microscopic imaging, and histopathologic evaluation., Results: Proteomic analysis revealed a significant downregulation of eGC and associated proteins in HS diet-induced hypertensive mice (among 1696 proteins identified in this group, 723 were markedly decreased in abundance, while only 168 were increased in abundance. Bioinformatic analysis indicated substantial derangement of the eGC layer, which was subsequently confirmed by fluorescent and electron microscopy assessment of vessel damage ex vivo. In the EC fraction, HS-induced hypertension significantly altered protein mediators of contractility, metabolism, mechanotransduction, renal function, and the coagulation cascade. In particular, we observed dysregulation of integrin subunits α2, α2b, and α5, which was associated with arterial wall inflammation and substantial infiltration of CD68+ monocyte-macrophages. Consequently, HS-induced hypertensive mice also displayed reduced vascular integrity of multiple organs including lungs, kidneys, and heart., Conclusions: These findings provide novel molecular insight into HS-induced structural changes in eGC and EC composition that may increase cardiovascular risk and potentially guide the development of new diagnostics and therapeutic interventions.

Objective: Examine how rotator cuff (RC) tendinopathy differed from other shoulder problems (OSP) by measuring a variety of self-reported bio-psycho-social factors, and establish which explain severity., Methods: A validated online survey battery was used to collect self-reported biopsychosocial variables in an international population. Diagnostic group and severity were the dependent variables. Multiple logistic and linear regression analyses were utilised to generate explanatory models for group differences and severity after group comparison and univariate regression analysis., Results: 82 people with RC tendinopathy (50 female, 42.8 ± 13.9 years) and 54 with OSP (33 female, 40.2 ± 14.1 years) were recruited. Both groups had comparable severity results (Shoulder Pain and Disability Index = 37.3 ± 24.5 vs. 33.7 ± 22.5). Seven factors individually differentiated RC tendinopathy from OSP. The multivariable model included 4 factors: activity effect on pain (OR(95%CI) = 2.24(1.02-4.90)), previous injury in the shoulder (OR(95% CI) = 0.30(0.13-0.69)), activity level (moderate OR(95% CI) = 3.97(1.29-12.18), high OR(95% CI) = 3.66(1.41-9.48)) and self-efficacy (OR(95%CI) = 1.12(1.02-1.22)) demonstrating acceptable accuracy. The second multivariable model for RC tendinopathy severity included one demographic, three psychological and two biomedical variables (β(range) = 0.19-0.38) and explained 68% of the variance., Conclusion: Self-reported bio-psycho-social variables may be beneficial for further detailed clinical assessment as they partially distinguish RC tendinopathy from OSP, even when the groups have comparable overall pain and functional problems. Moreover, these variables were shown to be substantially associated with RC tendinopathy severity variance, implying that the clinical evaluation might be improved, perhaps by pre-consultation online data collection. The models should be validated in the future and considered alongside data from physical and imaging examinations., (© 2022 The Authors. Musculoskeletal Care published by John Wiley & Sons Ltd.)

Objectives: To estimate Achilles tendon forces and their relationship with self-reported pain in runners with Achilles tendinopathy (AT) during common rehabilitation exercises., Design: Cross-sectional., Setting: Laboratory., Participants: 24 recreational male runners (45.92 (8.24) years old; 78.20 (8.01) kg; 177.17 (6.69) cm) with symptomatic AT., Main Outcome Measures: Kinematic and kinetic data were collected to estimate Achilles tendon forces during 12 commonly prescribed exercises. Achilles tendon forces were estimated from biomechanical data and normalised to the participant's bodyweight. The secondary aim was to investigate the relationship between Achilles tendon forces and pain during these exercises., Results: Two exercise clusters were identified based on Achilles tendon forces. Cluster1 included various exercises including double heel raises, single heel raises, and walking (range: 1.10-2.76 BWs). Cluster2 included running, jumping and hopping exercises (range: 5.13-6.35 BWs). Correlation between tendon forces and pain was at best low for each exercise (range: -0.43 - 0.20). Higher force exercises lead to more tendon load for a given amount of pain (R 2  = 0.7505; y = 0.2367x + 0.6191)., Conclusion: This study proposes a hierarchical exercise progression based on Achilles tendon forces to guide treatment of runners with AT. Achilles tendon forces and pain are not correlated in runners with AT., Competing Interests: Declaration of competing interest Dr Morrissey was part funded by the NIHR/HEE Senior Clinical Lecturer scheme. This report presents independent research part-funded by the National Institute for Health Research (NIHR)CAT SCL-2013-04-003. The funders played no role in the design, conduct, or reporting of this study. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We describe the case of a woman in her 60s with mitral stenosis, rate-controlled atrial fibrillation and a history of childhood rheumatic fever. She successfully underwent elective percutaneous transvenous mitral commissurotomy (PTMC), also described as balloon mitral valvuloplasty, for severe, symptomatic mitral stenosis. This was completed via right femoral vein access, trans-septal puncture and commissural separation guided by real-time three-dimensional (3D) transoesophageal echocardiography under general anaesthesia.Balloon mitral valvuloplasty is being completed more frequently in the UK due to the population having a higher incidence of mitral valve disease as a result of migration and as a palliative measure in those considered too high risk for mitral valve replacement cardiothoracic surgery.Rheumatic mitral stenosis is known to be a disease prevalent in countries of low and middle income and with increased migration to the UK, resulting in an increased prevalence of rheumatic mitral valve disease in the UK. It is estimated that within the UK, one in seven persons are migrants, and as such, we believe it is important to pay attention to diseases which affect the evolving population of the UK.Technological advancements, including availability and use of 3D transoesophageal cardiac ultrasound/echocardiography, have made PTMC much safer and more effective than previously. Additionally, the multidisciplinary team approach to PTMC is very important to its success. The procedure was completed successfully, with no complications., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Maturation of bones in the hand-wrist region varies among individuals of the same age and among world groups. Although some studies from Africa report differences to other ethnic groups, the lack of detailed bone-specific maturity data prevents meaningful comparisons., Aim: The aim of this study was to describe bone-specific maturity for developing hand-wrist bones in individuals in Khartoum, Sudan., Subjects and Methods: The sample was selected from healthy patients attending a dental hospital in Khartoum with known age and ancestry (males = 280, females = 330; aged between 3 and 25 years). Bones were assessed from radiographs of the left hand and wrist after the Greulich and Pyle Atlas (1959). Median ages of attainment for bone stages were calculated using probit analysis for each stage in males and females separately., Results: Maturity data for stages of the phalanges, metacarpals, carpals and radius and ulna in males and females are presented. Median ages in females were earlier compared to males for all stages. These results are largely earlier than previously published findings or where these could be calculated., Conclusion: These results of individual maturity stages of phalanges, metacarpals, carpals and the distal epiphyses of the radius and ulna are useful to assess maturity in growing individuals from Sudan.

With increased technological sophistication and rapidly reducing costs, currently, a huge amount of personal and populationlevel human genomic data and information is generated globally. There is an urgent need for an adequately curated and annotated human genome variant database for successful and large-scale application and translation in biomedical research, medical (healthcare) applications, socio-economic benefits and many other applications. The bulk of the available genomic data is generated from peoples of European descent. The genome data, particularly the human genome variant data is skewed with minimal content from other populations, particularly the minority or diverse populations. It has further contributed to global health inequality, which is visible in inefficiency, lack of effectiveness and disparity in clinical diagnosis, and precision-personalized medicine and preventive healthcare. Inevitably, this gap is widened with ensuing socio-economic implications. This problem is now faced by medical practitioners and healthcare providers in India, South Asia and other low and middle-income countries (LMICs). The current review provides views and critical appraisal of the current status of genomic research, clinical utility and genome variant databases in India and South Asia. A few observations and recommendations are made to ensure harmonization that requires further structured audit and appraisal by the indigenous populations' consortium. Emphasis is made on the urgent need for statutory regulation of genome data generation, storage, and retrieval systems in research and diagnostic genomic laboratories.

The protein cargo of extracellular vesicles (EVs) determines their impact on recipient cell types and the downstream effects on biological function. Environmental cues can modify EV loading with proteins derived from the plasma membrane via endocytosis, obtained from the preexisting cytosolic pool via active sorting, or packaging with newly synthesized proteins drawn from trans-golgi networks. Given the major impact these pathways exert on EV content and functional potential, it is important to study how defined stimuli influence protein sorting into these vesicles for dispersal. To this end, pSILAC-based approaches can be used to pulse/trace the origins of EV protein content and thereby provide valuable insight into vesicle biology and likely effects on intercellular communication in diverse settings., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

The COVID-19 pandemic has necessitated adaptation of cancer patient care. Oncology patients who contract COVID-19 have poor outcomes. Telemedicine clinics (teleclinics) have been introduced for cancer patients to reduce the risk of horizontal transmission at St. Bartholomew's Hospital and The Royal Free Hospital in London. Teleclinics have become routine in many specialities; however, inclusion in oncology care was not standard prior to the pandemic. A mixed-methods survey was designed and delivered to cancer patients (n = 106) at St. Bartholomew's Hospital and The Royal Free Hospital who had transitioned to teleclinics in March 2020. The survey explored patients' perceptions of this format. In total, 96 (90.5%) patients consented to take part, across a range of tumour types. Overall, respondents reacted favourably to the format of the teleclinics, with 90.6% of respondents (87/96) stating they would utilise teleclinics beyond the pandemic. Additionally, a survey was distributed to clinicians delivering these teleclinics (n = 16) to explore previous training in, perceptions of, and lessons learned from the introduction of telemedicine. Results suggest patients are accepting of teleclinic use for most clinical purposes. Teleclinic implementation affords benefits to cancer patient care both during and after COVID-19, but there is an urgent need for telemedicine education in oncology specialty training., (© 2021. American Association for Cancer Education.)

Background: In India, due to a lack of population-level financial risk protection mechanisms, the expenditure on healthcare is primarily out-of-pocket in nature. Through Drug Price Control Orders (DPCOs), the Indian Government attempts to keep medicine prices under check. The aim of this study was to measure the potential impact of DPCO 2013 on the utilization of antibiotics under price regulation in India using large nationally representative pharmaceutical sales data., Methods: We used interrupted time series analysis, a quasi-experimental research design to estimate the impact of DPCO 2013 on the utilization of antibiotics in the private sector in India. Indian pharmaceutical sales data set, PharmaTrac from a market research company-All Indian Origin Chemists and Distributors Limited-was used for the study. The data are collected from a panel of around 18,000 stockists across 23 different regions of the country. The primary outcome measure is the percentage change (increase or decrease) in the sales volume of the antibiotics under DPCO 2013, measured in standard units (SUs)., Results: Our estimates suggest that post-intervention (after notification of DPCO 2013) there was an immediate reduction (level change) in the sales of antibiotics under DPCO 2013 by 3.7% (P > 0.05), followed by a sustained decline (trend change) of 0.3% (P > 0.05) as compared to the pre-intervention trend at the molecule level, but both changes were statistically insignificant. However, in terms of 'average monthly market share,' the DPCO 2013 notification resulted in a sharp reduction of 579% (P < 0.05) (level change) followed by a sustained increase of 9.5% (P > 0.05) (trend change) in the 'market share of antibiotics under DPCO' as compared to pre-intervention trend., Conclusions: The impact of DPCO 2013 in terms of the overall increase in the utilization of antibiotics under price regulation was limited but there was a switch from non-price controlled antibiotics to price regulated antibiotics (notified under DPCO 2013). We argue that policies on price control need to be complemented with continuous monitoring of market behavior to have a measurable and long-term impact., (© 2022. The Author(s).)

Background: Anticholinergic medications are drugs that block cholinergic transmission, either as their primary therapeutic action or as a secondary effect. Patients with dementia may be particularly sensitive to the central effects of anticholinergic drugs. Anticholinergics also antagonise the effects of the main dementia treatment, cholinesterase inhibitors. Our study aimed to investigate anticholinergic prescribing for dementia patients in UK acute hospitals before and after admission., Methods: We included 352 patients with dementia from 17 UK hospital sites in 2019. They were all inpatients on surgical, medical or Care of the Elderly wards. Information about each patient's medications were collected using a standardised form, and the anticholinergic drug burden of each patient was calculated with an evidence-based online calculator. Wilcoxon's rank test was used to look at the correlation between two subgroups upon admission and discharge., Results: On admission to hospital, 37.8% of patients had an anticholinergic burden score ≥ 1 and 5.68% ≥3. On discharge, 43.2% of patients with an anticholinergic burden score ≥ 1 and 9.1% ≥3. The increase in scores was statistically significant (p = 0.001). Psychotropics were the most common group of anticholinergic medications prescribed at discharge. Of those patients taking cholinesterase inhibitors, 44.9% were also prescribed anticholinergic medications., Conclusions: Our cross-sectional, multicentre study found that people with dementia are commonly prescribed anticholinergic medications, even if concurrently taking cholinesterase inhibitors, and are significantly more likely to be discharged from hospital with a higher anticholinergic burden than on admission., (© 2022. The Author(s).)

Introduction: The objective of this cross-sectional study was to investigate the oral health-related quality of life (OHQoL) amongst refugees at emergency dental clinics in settlements in Northern Greece., Methods: A self-reported survey was undertaken in 7 settlements. The American Dental Association questionnaire on oral health (OH) was adapted and distributed to adults attending a mobile dental clinic between July and August 2017. Data were collected on sociodemographics, length of stay in settlement, utilisation of dental service, and OHQoL. Statistical analysis included descriptive analysis and Chi-square tests of associations., Results: Of 156 participants, the majority were male (73%), were aged 18 to 34 (59%), and had education up to high school (48%). Most of the participants rated OH as fair or poor (76%) and had spent more than 6 months in the settlements (45%). A majority of the participants (85%) had no access to dental care without the mobile clinic. Negative impact on OHQoL was significantly (P < .05) related to settlement location and time spent, smoking status, frequency of cleaning teeth and use of fluoridated toothpaste, perceived OH, and time since last dental visit. Those who spent less than 1 month in the settlement reported a higher negative OHQoL impact related to chewing, anxiety, smiling, daily activity, and sleeping (range, 48%-73%) compared to those who had spent more than 6 months (range, 17%-41%) (P < .05)., Conclusions: To the best of our knowledge, this is the first cross-sectional study assessing the OHQoL of refugees seeking emergency dental care in settlements in Greece. There is evidence that the refugees who were new arrivals to the settlements when provided with access to dental care reported a negative impact on their OHQoL. There is an urgent need for further research to understand the OH needs of refugees in Europe in order to design and deliver targeted and effective interventions., Competing Interests: Conflict of interest None disclosed., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this research is to generate new evidence on the economic consequences of multimorbidity on households in terms of out-of-pocket (OOP) expenditures and their implications for catastrophic OOP expenditure., Methods: We analyzed Social Consumption Health data from National Sample Survey Organization (NSSO) 75th round conducted in the year 2017-2018 in India. The sample included 1,13,823 households (64,552 rural and 49,271 urban) through a multistage stratified random sampling process. Prevalence of multimorbidity and related OOP expenditure were estimated. Using Coarsened Exact Matching (CEM) we estimated the mean OOP expenditure for individuals reporting multimorbidity and single morbidity for each episode of outpatient visits and hospital admission. We also estimated implications in terms of catastrophic OOP expenditure for households., Results: Results suggest that outpatient OOP expenditure is invariably lower in the presence of multimorbidity as compared with single conditions of the selected Non-Communicable Diseases(NCDs) (overall, INR 720 [USD 11.3] for multimorbidity vs. INR 880 [USD 14.8] for single). In the case of hospitalization, the OOP expenditures were mostly higher for the same NCD conditions in the presence of multimorbidity as compared with single conditions, except for cancers and cardiovascular diseases. For cancers and cardiovascular, OOP expenditures in the presence of multimorbidity were lower by 39% and 14% respectively). Furthermore, around 46.7% (46.674-46.676) households reported incurring catastrophic spending (10% threshold) because of any NCD in the standalone disease scenario which rose to 63.3% (63.359-63.361) under the multimorbidity scenario. The catastrophic implications of cancer among individual diseases was the highest., Conclusions: Multimorbidity leads to high and catastrophic OOP payments by households and treatment of high expenditure diseases like cancers and cardiovascular are under-financed by households in the presence of competing multimorbidity conditions. Multimorbidity should be considered as an integrated treatment strategy under the existing financial risk protection measures (Ayushman Bharat) to reduce the burden of household OOP expenditure at the country level., (© 2022. The Author(s).)

Inducible T cell co-stimulator (ICOS), an immune checkpoint protein expressed on activated T cells and its unique ligand, ICOSL, which is expressed on antigen-presenting cells and non-hematopoietic cells, have been extensively investigated in the immune response. Recent findings showed that a soluble recombinant form of ICOS (ICOS-Fc) can act as an innovative immunomodulatory drug as both antagonist of ICOS and agonist of ICOSL, modulating cytokine release and cell migration to inflamed tissues. Although the ICOS-ICOSL pathway has been poorly investigated in the septic context, a few studies have reported that septic patients have reduced ICOS expression in whole blood and increased serum levels of osteopontin (OPN), that is another ligand of ICOSL. Thus, we investigated the pathological role of the ICOS-ICOSL axis in the context of sepsis and the potential protective effects of its immunomodulation by administering ICOS-Fc in a murine model of sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in five-month-old male wild-type (WT) C57BL/6, ICOS -/- , ICOSL -/- and OPN -/- mice. One hour after the surgical procedure, either CLP or Sham (control) mice were randomly assigned to receive once ICOS-Fc, F119S ICOS-Fc, a mutated form uncapable to bind ICOSL, or vehicle intravenously. Organs and plasma were collected 24 h after surgery for analyses. When compared to Sham mice, WT mice that underwent CLP developed within 24 h a higher clinical severity score, a reduced body temperature, an increase in plasma cytokines (TNF-α, IL-1β, IL-6, IFN-γ and IL-10), liver injury (AST and ALT) and kidney (creatinine and urea) dysfunction. Administration of ICOS-Fc to WT CLP mice reduced all of these abnormalities caused by sepsis. Similar beneficial effects were not seen in CLP-mice treated with F119S ICOS-Fc. Treatment of CLP-mice with ICOS-Fc also attenuated the sepsis-induced local activation of FAK, P38 MAPK and NLRP3 inflammasome. ICOS-Fc seemed to act at both sides of the ICOS-ICOSL interaction, as the protective effect was lost in septic knockout mice for the ICOS or ICOSL genes, whereas it was maintained in OPN knockout mice. Collectively, our data show the beneficial effects of pharmacological modulation of the ICOS-ICOSL pathway in counteracting the sepsis-induced inflammation and organ dysfunction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alves, Stoppa, Aimaretti, Monge, Mastrocola, Porchietto, Einaudi, Collotta, Bertocchi, Boggio, Gigliotti, Clemente, Aragno, Fernandes, Cifani, Thiemermann, Dianzani, Dianzani and Collino.)

Background: DIALOG+ is an evidence-based, generic, cost-saving and easily deliverable psychosocial intervention, adaptable to clinicians' personal manner of interaction with patients. It was implemented in mental health services in five low- and middle-income countries in South-Eastern Europe during a 12-month randomised-controlled trial (IMPULSE) to improve the effectiveness of out-patient treatment for people with psychotic disorders., Aims: To investigate barriers and facilitators to the perceived sustainability of DIALOG+ that has been successfully implemented as a part of the IMPULSE project., Method: Three months after the IMPULSE trial's end, perceived sustainability of the DIALOG+ intervention was assessed via a short survey of clinicians and patients who took part in the trial. Quantitative data collected from the survey were analysed using descriptive statistics; content analysis assessed qualitative survey data. The views and experiences of key informants (patients, clinicians and healthcare policy influencers) regarding the sustainability and scale-up of DIALOG+ were further explored through semi-structured interviews. These data were explored using framework analysis., Results: Clinicians mostly appreciated the comprehensiveness of DIALOG+, and patients described DIALOG+ meetings as empowering and motivating. The barrier most commonly identified by key informants was availability of financial resources; the most important facilitators were the clinically relevant structure and comprehensiveness of the DIALOG+ intervention., Conclusions: Participants showed a willingness to sustain the implementation of DIALOG+. It is important to maintain collaboration with healthcare policy influencers to improve implementation of DIALOG+ across different levels of healthcare systems and ensure availability of resources for implementing psychosocial interventions such as DIALOG+.

Objective: The aim of this study was toidentify dose-related systemic effects of inhaled glucocorticoids (GCs) on the global metabolome., Design and Methods: Metabolomics/lipidomic analysis from plasma was obtained from 54 subjects receiving weekly escalating doses (µg/day) of fluticasone furoate (FF; 25, 100, 200, 400 and 800), fluticasone propionate (FP; 50, 200, 500, 1000 and 2000), budesonide (BUD; 100, 400, 800, 1600 and 3200) or placebo. Samples (pre- and post-dose) were analysed using ultrahigh-performance liquid chromatography-tandem mass spectroscopy and liquid chromatography-mass spectrometry. Ions were matched to library standards for identification and quantification. Statistical analysis involved repeated measures ANOVA, cross-over model, random forest and principal component analysis using log-transformed data., Results: Quantifiable metabolites (1971) had few significant changes (% increases/decreases; P < 0.05) vs placebo: FF 1.34 (0.42/0.92), FP 1.95 (0.41/1.54) and BUD 2.05 (0.60/1.45). Therapeutic doses had fewer changes: FF 0.96 (0.36/0.61), FP 1.66 (0.44/1.22) and BUD 1.45 (0.56/0.90). At highest/supratherapeutic doses, changes were qualitatively similar: reduced adrenal steroids, particularly glucuronide metabolites of cortisol and cortisone and pregnenolone metabolite DHEA-S; increased amino acids and glycolytic intermediates; decreased fatty acid β-oxidation and branched-chain amino acids. Notable qualitative differences were lowered dopamine metabolites (BUD) and secondary bile acid profiles (BUD/FF), suggesting CNS and gut microbiome effects., Conclusions: Dose-dependent metabolomic changes occurred with inhaled GCs but were seen predominately at highest/supratherapeutic doses, supporting the safety of low and mid therapeutic doses. At comparable therapeutic doses (FF 100, FP 500 and BUD 800 µg/day), FF had the least effect on the most sensitive markers (adrenal steroids) vs BUD and FP.

Bromocriptine is approved as a diabetes therapy, yet its therapeutic mechanisms remain unclear. Though bromocriptine's actions have been mainly attributed to the stimulation of brain dopamine D 2 receptors (D2R), bromocriptine also targets the pancreas. Here, we employ bromocriptine as a tool to elucidate the roles of catecholamine signaling in regulating pancreatic hormone secretion. In β-cells, bromocriptine acts on D2R and α 2A -adrenergic receptor (α 2A -AR) to reduce glucose-stimulated insulin secretion (GSIS). Moreover, in α-cells, bromocriptine acts via D2R to reduce glucagon secretion. α 2A -AR activation by bromocriptine recruits an ensemble of G proteins with no β-arrestin2 recruitment. In contrast, D2R recruits G proteins and β-arrestin2 upon bromocriptine stimulation, demonstrating receptor-specific signaling. Docking studies reveal distinct bromocriptine binding to α 2A -AR versus D2R, providing a structural basis for bromocriptine's dual actions on β-cell α 2A -AR and D2R. Together, joint dopaminergic and adrenergic receptor actions on α-cell and β-cell hormone release provide a new therapeutic mechanism to improve dysglycemia., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Rationale: Sampling of dentine for stable carbon (δ 13 C) and nitrogen (δ 15 N) isotope ratios in the direction of tooth growth allows the study of temporal changes to the diet and physiological stress of an individual during tooth formation. Current methods of sampling permanent teeth using 1 mm increments provide temporal resolution of 6-9 months at best depending on the tooth chosen. Although this gives sufficient sample sizes for reliable analysis by mass spectrometry, sectioning the dentine across the incremental structures results in a rolling average of the isotope ratios. A novel method of incremental dentine collagen sampling has been developed to decrease the collagen increment size to 0.35 mm along the incremental structures, thus reducing averaging and improving the temporal resolution of short-term changes within the δ 13 C and δ 15 N values., Methods: This study presents data for a MicroMill-assisted sampling method that allows for sampling at 0.35 mm width × 1 mm depth increments following the incremental growth pattern of dentine. A NewWave MicroMill was used to sample the demineralised dentine section of modern donated human third molars from Sudan and compared to data from the same teeth using the 1 mm incremental sectioning method 2 established by Beaumont et al. RESULTS: The δ 13 C and δ 15 N isotopic data showed an increased temporal resolution, with each increment providing data for 2-4 months of dentine formation., Conclusions: The data show the potential of this method for studying dietary reconstruction, nutritional stress, and physiological change with greater temporal resolution potentially to seasonal level and with less attenuation of the δ 13 C and δ 15 N values than was previously possible from human dentine., (© 2022 The Authors. Rapid Communications in Mass Spectrometry published by John Wiley & Sons Ltd.)

G protein-coupled receptors (GPCRs) are the largest class of membrane proteins and the most common and extensively studied pharmacological target. Numerous studies over the last decade have confirmed that GPCRs do not only exist and function in their monomeric form but in fact, have the ability to form dimers or higher order oligomers with other GPCRs, as well as other classes of receptors. GPCR oligomers have become increasingly attractive to investigate as they have the ability to modulate the pharmacological responses of the receptors which in turn, could have important functional roles in diseases, such as cancer and several neurological & neuropsychiatric disorders. Despite the growing evidence in the field of GPCR oligomerisation, the lack of structural information, as well as targeting the 'undruggable' protein-protein interactions (PPIs) involved in these complexes, has presented difficulties. Outside the field of GPCRs, targeting PPIs has been widely studied, with a variety of techniques being investigated; from small-molecule inhibitors to disrupting peptides. In this review, we will demonstrate several physiologically relevant GPCR dimers and discuss an array of strategies and techniques that can be employed when targeting these complexes, as well as provide ideas for future development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Farooq, Howell and McCormick.)