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Background: Androgen insensitivity syndrome is an X-linked genetic disease characterized by resistance to the actions of androgen in an individual with 46, XY karyotype. It is one of the most common causes of Disorders of sex development (DSD). Clinical Description: A 10-year-7-month-old child, reared as female, was incidentally detected with minor virilization of external genitalia. She had achieved thelarche and adrenarche with a Prader Stage 2. Management and Outcome: Routine investigations showed normal hemogram and kidney and liver functions, as also normal values of serum electrolytes. Ultrasonogram showed the absence of Mullerian structures and the presence of prostate- and testis-like structures. Karyotyping showed 46, XY. There were grossly elevated levels of testosterone and dihydrotestosterone, as well as raised follicle-stimulating hormone and luteinizing hormone levels. Diagnostic laparoscopy showed inguinal testis-like structures and biopsy from the same confirmed testicular tissue. Parents were counseled regarding the prognosis, need for gonadectomy, and hormone replacement. Conclusion: Our case creates awareness regarding the importance of early identification of minor virilizing features in a child, so as to avoid late revelation of an underlying DSD leading to undue anxiety and psychological trauma to parents and child.

Objectives: Transcriptomic data demonstrated that fibroblasts are heterogeneous with functionally diverse subpopulations. Although fibroblasts are key effector cells of fibrotic diseases such as systemic sclerosis (SSc), they have not yet been characterised spatially at the cellular level. Here, we aimed to investigate fibroblast subpopulations using imaging mass cytometry (IMC) as a proteomic-based, spatially resolved omics approach., Methods: We applied IMC to deconvolute the heterogeneity of 49 969 cells including 6501 fibroblasts at the single-cell level, to analyse their spatial distribution and to characterise their cellular niches in skin sections of patients with SSc and controls in situ., Results: We identified 13 different subpopulations of fibroblasts in SSc and control skin, the proportion increases in five fibroblast subpopulations (myofibroblasts, FAP high , S1PR + , Thy1 + ;ADAM12 high ;PU.1 high and ADAM12 + ;GLI1 + fibroblasts) and decreases in three subpopulations (TFAM high , PI16 + ;FAP + and Thy1 + ;ADAM12 low fibroblasts). Several fibroblast subpopulations demonstrated spatial enrichment and altered cellular interactions in SSc. The proportion of S1PR + -fibroblast positively correlated with more extensive skin fibrosis, whereas high numbers of PI16 + ;FAP - -fibroblasts were associated with milder skin fibrosis. The frequency of aberrant cellular interaction between S1PR + and ADAM12 + ;GLI1 + -fibroblasts also positively associated with the extent of skin fibrosis in SSc., Conclusion: Using IMC, we demonstrated profound changes in composition and localisation of the majority of fibroblast subpopulations in SSc skin. These findings may provide a rationale for specific targeting of deregulated fibroblast subpopulations in SSc. Quantification of S1PR + -fibroblast and PI16 + ;FAP - -fibroblasts may offer potential for patient stratification according to severity of skin fibrosis., Competing Interests: Competing interests: A-HG received lecture fees from Boehringer Ingelheim and Abbvie. JHWD has consultancy relationships and/or has received research funding from AbbVie, Actelion, BMS, Celgene, Bayer Pharma, Boehringer Ingelheim, JB Therapeutics, Sanofi-Aventis, Novartis, UCB, GSK, Array Biopharma and Active Biotech in the area of potential treatments of SSc, is CEO of 4D Science and Scientific lead/Co-CEO of FibroCure. A-HG has received research founding from Boehringer Ingelheim. The project was supported by an unrestricted grant from the Hiller Foundation., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Background: Systemic sclerosis (SSc) is a connective tissue disease that can serve as a model to study vascular changes in response to inflammation, autoimmunity, and fibrotic remodeling. Although microvascular changes are the earliest histopathologic manifestation of SSc, the vascular pathophysiology remains poorly understood., Methods: We applied spatial proteomic approaches to deconvolute the heterogeneity of vascular cells at the single-cell level in situ and characterize cellular alterations of the vascular niches of patients with SSc. Skin biopsies of patients with SSc and control individuals were analyzed by imaging mass cytometry, yielding a total of 90 755 cells including 2987 endothelial cells and 4096 immune cells., Results: We identified 7 different subpopulations of blood vascular endothelial cells (VECs), 2 subpopulations of lymphatic endothelial cells, and 3 subpopulations of pericytes. A novel population of CD34 + ;αSMA + (α-smooth muscle actin);CD31 + VECs was more common in SSc, whereas endothelial precursor cells were decreased. Co-detection by indexing and tyramide signal amplification confirmed these findings. The microenvironment of CD34 + ;αSMA + ;CD31 + VECs was enriched for immune cells and myofibroblasts, and CD34 + ;αSMA + ;CD31 + VECs expressed markers of endothelial-to-mesenchymal transition. The density of CD34 + ;αSMA + ;CD31 + VECs was associated with clinical progression of fibrosis in SSc., Conclusions: Using spatial proteomics, we unraveled the heterogeneity of vascular cells in control individuals and patients with SSc. We identified CD34 + ;αSMA + ;CD31 + VECs as a novel endothelial cell population that is increased in patients with SSc, expresses markers for endothelial-to-mesenchymal transition, and is located in close proximity to immune cells and myofibroblasts. CD34 + ;αSMA + ;CD31 + VEC counts were associated with clinical outcomes of progressive fibrotic remodeling, thus providing a novel cellular correlate for the crosstalk of vasculopathy and fibrosis., Competing Interests: Disclosures Although no disclosures directly relate to the present study, J.H.W. Distler has consultancy relationships with AbbVie, Active Biotech, AnaMar, ARXX, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, Genentech, GSK, Inventiva, Janssen, Novartis, Pfizer, Roche, and UCB. JHWD has received research funding from AnaMar, Argenx, ARXX, BMS, Bayer Pharma, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, Galapagos, GSK, Inventiva, Kiniksa, Lassen, Sanofi-Aventis, RedX, and UCB. Moreover, J.H.W. Distler is a stock owner of 4D Science and a scientific leader of FibroCure.

Background: The brain and kidney have similar microvascular structure, which makes them susceptible to certain common pathophysiological processes. In this study, we examined several indicators of kidney injury/function associated with cognitive function in older diabetic patients in the hope of finding effective markers for detecting cognitive impairment (CI)., Methods: A total of 2209 older participants (aged ≥60 years) from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) were analyzed for the association between diabetes and CI using a multiple linear regression analysis model. Using the same approach, we also analyzed the relationship between indicators of kidney injury/function and cognitive function (Animal Fluency Test, Digit Symbol Substitution Test) in the diabetic population., Results: Diabetes was associated with CI. In age-adjusted model, older diabetics performed significantly poorer on tests of cognitive function compared to normoglycaemic individuals (1.145 points lower on the Animal Fluency Test ( P = 0.005) and 7.868 points reduced on the Digit Symbol Substitution Test ( P < 0.001)). In diabetics, we found elevated serum creatinine (SCr) (especially at SCr≥300uM) was associated with lower scores on cognitive function tests after strict adjustment for potential influences on cognitive function. While, albumin/creatinine ratio (ACR) was only associated with Digit Symbol Substitution score (DSS) not Animal Fluency score (AFS), and estimated glomerular filtration rate (eGFR) was only associated with CI (AFS and DSS) at the end-stage renal disease., Conclusion: SCr, as a sensitive indicator of kidney injury, was significantly associated with CI and can potentially be used as an effective marker for screening CI in older diabetics., 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 Xiao, Devakumar, Xu, Liu, Mo and Hong.)

Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

We examined the distribution of quantitative heel ultrasound (QUS) parameters in population samples of European men and looked at the influence of lifestyle factors on the occurrence of these parameters. Men aged between 40 and 79 years were recruited from eight European centers and invited to attend for an interviewer-assisted questionnaire, assessment of physical performance, and quantitative ultrasound (QUS) of the calcaneus (Hologic; Sahara). The relationships between QUS parameters and lifestyle variables were assessed using linear regression with adjustments for age, center, and weight. Three thousand two hundred fifty-eight men, mean age 60.0 years, were included in the analysis. A higher PASE score (upper vs. lower tertile) was associated with a higher BUA (beta coefficient = 2.44 dB/ Mhz), SOS (beta = 6.83 m/s), and QUI (beta = 3.87). Compared to those who were inactive, those who walked or cycled more than an hour per day had a higher BUA (beta = 3.71 dB/Mhz), SOS (beta = 6.97 m/s), and QUI (beta = 4.50). A longer time to walk 50 ft was linked with a lower BUA (beta = -0.62 dB/ Mhz), SOS (beta = -1.06 m/s), and QUI (beta = -0.69). Smoking was associated with a reduction in BUA, SOS, and QUI. There was a U-shaped association with frequency of alcohol consumption. Modification of lifestyle, including increasing physical activity and stopping smoking, may help optimize bone strength and reduce the risk of fracture in middle-aged and elderly European men.

Objective: Accelerated atherosclerosis and premature coronary heart disease (CHD) are recognized complications of systemic lupus erythematosus (SLE), but the exact etiology remains unclear and is likely to be multifactorial. We hypothesized that SLE patients with CHD have increased exposure to traditional risk factors as well as differing disease phenotype and therapy-related factors compared to SLE patients free of CHD. Our aim was to examine risk factors for development of clinical CHD in SLE in the clinical setting., Methods: In a UK-wide multicenter retrospective case-control study we recruited 53 SLE patients with verified clinical CHD (myocardial infarction or angina pectoris) and 96 SLE patients without clinical CHD. Controls were recruited from the same center as the case and matched by disease duration. Charts were reviewed up to time of event for cases, or the same "dummy-date" in controls., Results: SLE patients with clinical CHD were older at the time of event [mean (SD) 53 (10) vs 42 (10) yrs; p < 0.001], more likely to be male [11 (20%) vs 3 (7%); p < 0.001], and had more exposure to all classic CHD risk factors compared to SLE patients without clinical CHD. They were also more likely to have been treated with corticosteroids (OR 2.46; 95% CI 1.03, 5.88) and azathioprine (OR 2.33; 95% CI 1.16, 4.67) and to have evidence of damage on the pre-event SLICC damage index (SDI) (OR 2.20; 95% CI 1.09, 4.44). There was no difference between groups with regard to clinical organ involvement or autoantibody profile., Conclusion: Our study highlights the need for clinical vigilance to identify modifiable risk factors in the clinical setting and in particular with male patients. The pattern of organ involvement did not differ in SLE patients with CHD events. However, the higher pre-event SDI, azathioprine exposure, and pattern of damage items (disease-related rather than therapy-related) in cases suggests that a persistent active lupus phenotype contributes to CHD risk. In this regard, corticosteroids and azathioprine may not control disease well enough to prevent CHD. Clinical trials are needed to determine whether classic risk factor modification will have a role in primary prevention of CHD in SLE patients and whether new therapies that control disease activity can better reduce CHD risk.