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Background Suicidality is highly prevalent in autistic people without co-occurring intellectual disabilities, and high autistic traits are found in adults who have attempted suicide. However, prevalence rates for both autistic and possibly autistic people have not been synthesised meta-analytically. Aims To (1) calculate pooled prevalence estimates of suicidality in autistic people and possibly autistic people without co-occurring intellectual disability; (2) evaluate the influence of participant and study level characteristics on heterogeneity; and (3) determine the quality of evidence. Methods Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed. PsycINFO, Embase, MEDLINE and Web of Science were systematically searched from 1992 to January 25, 2022. Empirical quantitative studies reporting prevalence of suicidal ideation, suicide plans, or suicide attempts and behaviours were considered for inclusion. Random effects models were used to estimate pooled prevalence of each suicidality outcome with 95% confidence intervals. Heterogeneity was explored using sensitivity and moderator analyses. Results Data from 48,186 autistic and possibly autistic participants in 36 primary studies were meta-analysed. Pooled prevalence of suicidal ideation was 34.2% (95% CI 27.9–40.5), suicide plans 21.9% (13.4–30.4), and suicidal attempts and behaviours 24.3% (18.9–29.6). High levels of heterogeneity ( I 2  > 75) were observed in all three analyses. Estimates did not differ between autistic or possibly autistic samples. Geographical location ( p  = 0.005), transgender or gender non-conforming samples ( p  < 0.001) and type of report ( p  < 0.001) significantly moderated suicidal ideation, whereas age group ( p  = 0.001) and measure of suicidality ( p  = 0.001) significantly moderated suicide plans. There was a significant association between the proportion of male participants and prevalence of suicide plans, with a decrease in the proportion of males for every unit change of suicide plan prevalence ( p  = 0.013). No variables were found to moderate estimates of suicide attempts and behaviours. Conclusions The results confirm suicidality is highly prevalent in both autistic and possibly autistic people without co-occurring intellectual disability and highlights potential moderators. Possibly autistic individuals require more attention in clinical and research considerations going forward to further understand and prevent suicide in both groups.

ObjectivesTo explore the acceptability and perceived motivations and barriers of using nicotine replacement therapy (NRT) to reduce the number of daily cigarettes smoked in pregnancy, rather than for stopping completely.DesignTelephone, semi-structured interviews, audio-recorded and transcribed verbatim. Transcripts were analysed using an inductive thematic analysis.ParticipantsEighteen pregnant women in the UK, who were smoking or had recently stopped smoking, were recruited.ResultsHalf of interviewees reported having used NRT to reduce smoking during their current pregnancy, and there was overwhelming support for the UK National Health Service to recognise this as a potentially useful way to use these products. The cost and stigma associated with purchasing NRT products when pregnant were seen as barriers to using NRT in this way. The early offer of NRT for reduction along with a tailored, structured approach to support was seen as important.ConclusionsUsing NRT to help women, who are unable to stop smoking, to reduce their smoking may be acceptable to pregnant women. This study found women were already using NRT alongside ad hoc strategies to reduce their smoking. Further research evaluating structured smoking reduction support, alongside concurrent NRT use is needed.

Many countries recommend Nicotine Replacement Therapy (NRT) for smoking cessation in pregnancy. Preclinical studies of nicotine exposure to pregnant mammals could indicate how nicotine may adversely affect the developing fetus. As a first step towards summarising this literature, we undertook a systematic scoping review to determine the number and nature of offspring outcomes studied. We searched MEDLINE and EMBASE databases for papers reporting empirical data on offspring outcomes following nicotine exposure to pregnant non-human mammals. We excluded studies that investigated exposure to only smoking, e-cigarettes, nicotine vaccines, or studies with no 'nicotine only' group. We developed a draft taxonomy and using this, described and quantified outcomes reported. We identified 476 studies, which reported 729 offspring outcomes. The draft taxonomy classified outcomes as being measured in i) whole animals, ii) body systems and iii) 'other'. Body system outcomes were further categorised as being functional changes, or changes at macroscopic or cellular levels. The most frequently used outcomes were those detecting changes in the brain (n = 265), physical parameters measured in whole animals (n = 122) and any respiratory system changes (n = 97). This scoping review quantifies the nature and frequency of outcomes used in preclinical studies investigating the potential impacts of nicotine administration in pregnancy on offspring. Systematic reviews of studies investigating outcomes involving animal brains, respiratory system, or 'whole animal' outcomes may have greatest potential for further advancing knowledge regarding impacts of gestational nicotine exposure on offspring. Protocol for this review can be found on Open Science Framework (https://osf.io/ptmzc/).

Diligent side-by-side comparisons of how different methodologies affect growth efficiency and quality of intestinal colonoids have not been performed leaving a gap in our current knowledge. Here, we summarize our efforts to optimize culture conditions for improved growth and functional differentiation of mouse and human colon organoids. Mouse and human colon organoids were grown in four different media. Media-dependent long-term growth was measured by quantifying surviving organoids imaging and a cell viability readout over five passages. The impact of diverse media on differentiation was assessed by quantifying the number of epithelial cell types using markers for enterocytes, stem cells, Goblet cells, and enteroendocrine cells by qPCR and histology upon removal of growth factors. In contrast to Wnt3a-conditioned media, media supplemented with recombinant Wnt3a alone did not support long-term survival of human or mouse colon organoids. Mechanistically, this observation can be attributed to the fact that recombinant Wnt3a did not support stem cell survival or proliferation as demonstrated by decreased LGR5 and Ki67 expression. When monitoring expression of markers for epithelial cell types, the highest level of organoid differentiation was observed after combined removal of Wnt3a, Noggin, and R-spondin from Wnta3a-conditioned media cultures. Our study defined Wnt3a-containing conditioned media as optimal for growth and survival of human and mouse organoids. Furthermore, we established that the combined removal of Wnt3a, Noggin, and R-spondin results in optimal differentiation. This study provides a step forward in optimizing conditions for intestinal organoid growth to improve standardization and reproducibility of this model platform.

A painful, chronic condition, Rheumatoid Arthritis, is marked by bone erosion and soft tissue swelling at the joint. As treatments are investigated in pre-clinical models, characterizing disease progression is integral to assessing treatment efficacy. Here, in vivo and ex vivo micro-computed tomography (µCT) are used in parallel with traditional caliper score measurement to quantify physiological changes in the tarsal region in a murine, collagen-induced arthritis model. In vivo imaging methods, which are validated here through comparison to ex vivo and caliper methods, afford longitudinal analysis of both bone and soft tissue through a single image acquisition. This method removes the subjectivity of swelling quantification which is inherently associated with traditional caliper measurements. Histopathology offers an additional assessment of bone erosion and inflammation by providing a microscopic characterization of disease activity. In comparison to untreated animals, daily prednisolone (glucocorticoid) treatment is shown to restore bone volume, as reflected through in vivo and ex vivo µCT images, as well as histopathology. Prednisolone-associated reduction in inflammation is shown through in vivo µCT soft tissue volume measurements, paw caliper measurements, and histopathology. The findings reported here provide a comprehensive validation of in vivo µCT with a sensitivity that enables characterization of pre-clinical disease assessment in response to treatment in a murine, collagen-induced arthritis model.

Alterations to post-translational crosslinking modifications in the extracellular matrix (ECM) are known to drive the pathogenesis of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Thus, the methodology for measuring crosslinking dynamics is valuable for understanding disease progression. The existing crosslinking analysis sample preparation and liquid chromatography tandem mass spectrometry (LC-MS/MS) methods are typically labor-intensive and time-consuming which limits throughput. We, therefore, developed a rapid approach minimizing specialized equipment and hands-on time. The LC-MS/MS sample analysis time was reduced to two minutes per sample. We then improved the analytical integrity of the method by developing a novel surrogate matrix approach for the dihydroxylysinonorleucine (DHLNL) crosslink. By modifying sample preparation, we prepared a tissue-based surrogate matrix with undetectable levels of endogenous DHLNL, providing a strategy for quantifying this crosslink with a more relevant standard matrix. We then applied this rapid methodology to evaluating crosslinking in lung fibrosis. We showed an increase in DHLNL in human IPF lung relative to healthy donors, as well as in a fibrotic mouse model. Finally, we demonstrated that this increase in DHLNL could be mitigated with an anti-fibrotic compound, suggesting that this assay has potential for evaluating pharmaceutical compound efficacy.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by repetitive alveolar injuries with excessive deposition of extracellular matrix (ECM) proteins. A crucial need in understanding IPF pathogenesis is identifying cell types associated with histopathological regions, particularly local fibrosis centers known as fibroblast foci. To address this, we integrated published spatial transcriptomics and single-cell RNA sequencing (scRNA-seq) transcriptomics and adopted the Query method and the Overlap method to determine cell type enrichments in histopathological regions. Distinct fibroblast cell types are highly associated with fibroblast foci, and transitional alveolar type 2 and aberrant KRT5-/KRT17+ (KRT: keratin) epithelial cells are associated with morphologically normal alveoli in human IPF lungs. Furthermore, we employed laser capture microdissection-directed mass spectrometry to profile proteins. By comparing with another published similar dataset, common differentially expressed proteins and enriched pathways related to ECM structure organization and collagen processing were identified in fibroblast foci. Importantly, cell type enrichment results from innovative spatial proteomics and scRNA-seq data integration accord with those from spatial transcriptomics and scRNA-seq data integration, supporting the capability and versatility of the entire approach. In summary, we integrated spatial multi-omics with scRNA-seq data to identify disease-associated cell types and potential targets for novel therapies in IPF intervention. The approach can be further applied to other disease areas characterized by spatial heterogeneity.

In this work, the impact of physicochemical modifications on pharmacokinetics and in vivo targeting of a small molecule fibroblast activation protein inhibitor (FAPI) imaging ligand in a murine model of rheumatoid arthritis was evaluated. While similar ligands have been well-reported in oncology for molecular imaging and radiotherapy, there are limited reports of FAPI derivatives in targeted applications in immunology. As inflammation may increase both specific and non-specific delivery of targeted agents in general, we sought to identify the optimal targeted molecular imaging probe characteristics for efficient cell surface engagement. A series of FAPI derivatives were synthesized and their physicochemical properties modified via conjugation of fluorescent dyes and/or an albumin-binding small molecule. The impact of these modifications on cell surface binding affinity was assessed using an overexpressing cell line. Additionally, a thorough mechanistic characterization of fibroblast activation protein (FAP) cell surface internalization was evaluated in both overexpressing and endogenously expressing cells. Lastly, the pharmacokinetics and in vivo uptake in inflamed arthritic paws were characterized via near-infrared (NIR) imaging. All targeted molecular imaging agents tested maintained strong nanomolar binding affinity to cell surface FAP independent of chemical modification. The murine fibroblast-like synoviocytes expressed lower absolute cell-surface FAP compared to a transfected line, and the net internalization half-life measured for the transfected cells via flow cytometry was 7.2 h. The unmodified FAPI ligand exhibited the poorest in vivo targeting, likely resulting from its large apparent volume of distribution (62.7 ml) and rapid systemic clearance ( t 1 /2  = 0.5 h). Conjugation of a charged, hydrophilic AF647 fluorophore decreased systemic clearance ( t 1 /2  = 2.1 h) and demonstrated a 2-fold improvement in blocking FAPI-800CW engagement of FAP in vivo when compared to blocking of FAPI-800CW with FAPI with up to 2.8-fold improvements noted for the equivalent albumin binding construct comparison.

Understanding the heterogeneity of Rheumatoid Arthritis (RA) and identifying therapeutic targets remain challenging using traditional bulk transcriptomics alone, as it lacks the spatial and protein-level resolution needed to fully capture disease and tissue complexities. In this study, we applied Laser Capture Microdissection (LCM) coupled with mass spectrometry-based proteomics to analyze histopathological niches of the RA synovium, enabling the identification of protein expression profiles of the diseased synovial lining and sublining microenvironments compared to their healthy counterparts. In this respect, key pathogenetic RA proteins like membrane proteins (TYROBP, AOC3, SLC16A3, TCIRG1, and NCEH1), and extracellular matrix (ECM) proteins (PLOD2, OGN, and LUM) showed different expression patterns in diseased synovium compartments. To enhance our understanding of cellular dynamics within the dissected regions, we further integrated the proteomic dataset with single-cell RNA sequencing (scRNA-seq), and deduced cell type enrichment, including T cells, fibroblasts, NK cells, myeloid cells, B cells, and synovial endothelial cells. By combining high-resolution spatial proteomics and transcriptomic analyses, we provide novel insights into the molecular mechanisms driving RA, and highlight potential protein targets for therapeutic intervention. This integrative approach offers a more comprehensive view of RA synovial pathology, and mitigates the limitations of traditional bulk transcriptomics in target discovery.

CT sagittal plane showing a 3.2 cm lesion in the anterior mediastinum with areas of focal calcification (A) and positron emission tomography/CT demonstrating significant metabolic activity (maximum standardised uptake value of 13.7) in this mass (B). Haemolysis liberates cholesterol from the cell membranes of degenerating erythrocytes to form crystals, which stimulate a foreign body type giant cell reaction, leading to chronic inflammation and granuloma formation.1 An alternative pathogenesis involving inflammation in a benign cystic tumour has also been proposed.2 Cholesterol granulomas, occurring most frequently in the petrous apex of the temporal bone adjacent to the middle ear, are associated with chronic infections and if left untreated, may cause bony erosion and cranial nerve injury. [...]cholesterol granuloma is an extremely rare cause of an anterior mediastinal mass that may masquerade as a more sinister pathology or be found incidentally during cardiac surgery.