Cell type-specific inference of differential expression in spatial transcriptomics.

A central problem in spatial transcriptomics is detecting differentially expressed (DE) genes within cell types across tissue context. Challenges to learning DE include changing cell type composition across space and measurement pixels detecting transcripts from multiple cell types. Here, we introduce a statistical method, cell type-specific inference of differential expression (C-SIDE), that identifies cell type-specific DE in spatial transcriptomics, accounting for localization of other cell types. We model gene expression as an additive mixture across cell types of log-linear cell type-specific expression functions. C-SIDE's framework applies to many contexts: DE due to pathology, anatomical regions, cell-to-cell interactions and cellular microenvironment. Furthermore, C-SIDE enables statistical inference across multiple/replicates. Simulations and validation experiments on Slide-seq, MERFISH and Visium datasets demonstrate that C-SIDE accurately identifies DE with valid uncertainty quantification. Last, we apply C-SIDE to identify plaque-dependent immune activity in Alzheimer's disease and cellular interactions between tumor and immune cells. We distribute C-SIDE within the R package https://github.com/dmcable/spacexr .

Comparing the Fracture Profile of Osteosarcopenic Older Adults with Osteopenia/Osteoporosis Alone.

PURPOSE: To determine whether osteosarcopenia is associated with a greater likelihood of recurrent fractures, as well as type of fracture, than osteopenia/osteoporosis or sarcopenia alone. METHODS: Anthropometry (height/weight; scales and stadiometer), body composition (bone mineral density [BMD] and appendicular lean mass; dual-energy x-ray absorptiometry), grip strength (hydraulic dynamometer), and gait speed (4 m) were measured in an outpatient clinic. WHO definition for osteopenia/osteoporosis (BMD T-score below -1 SDs) while sarcopenia was defined by SDOC or EWGSOP2. Number and location of fractures within the past 5 years were self-reported and verified by medical records (unverified fractures excluded). Univariable and multivariable regressions were used to examine the association between the exposure and outcome while adjusting for confounders. RESULTS: 481 community-dwelling older adults (median age: 78, IQR: 72, 83; 75.9% women) were included. Prevalence of osteosarcopenia depended on the definition (SDOC: 179 (37.2%); EWGSOP2: 123 (25.6%)). In multivariable analysis adjusting for age, sex, alcohol, smoking, BMI, lowest BMD T-score, physical activity, and comorbidities, the likelihood of recurrent fractures (≥ 2 vs 0-1) was significantly higher in those with osteosarcopenia versus osteopenia/osteoporosis irrespective of the definition (SDOC: odds ratio [OR]: 1.63, 95% CI: 1.03, 2.59, p = 0.037; EWGSOP2: OR: 1.83, 95% CI: 1.12, 3.01, p = 0.016]. Associations with sarcopenia alone (SDOC: 10; EWGSOP2: 7) were not possible due to the extremely low prevalence of this condition in those with normal BMD. CONCLUSION: Our data suggest osteosarcopenia is associated with a greater likelihood of recurrent fractures versus osteopenia/osteoporosis alone. Further studies are needed to evaluate the relationship with sarcopenia alone.

Detection of functional haematopoietic stem cell niche using real-time imaging.

Haematopoietic stem cell (HSC) niches, although proposed decades ago, have only recently been identified as separate osteoblastic and vascular microenvironments. Their interrelationships and interactions with HSCs in vivo remain largely unknown. Here we report the use of a newly developed ex vivo real-time imaging technology and immunoassaying to trace the homing of purified green-fluorescent-protein-expressing (GFP(+)) HSCs. We found that transplanted HSCs tended to home to the endosteum (an inner bone surface) in irradiated mice, but were randomly distributed and unstable in non-irradiated mice. Moreover, GFP(+) HSCs were more frequently detected in the trabecular bone area compared with compact bone area, and this was validated by live imaging bioluminescence driven by the stem-cell-leukaemia (Scl) promoter-enhancer. HSCs home to bone marrow through the vascular system. We found that the endosteum is well vascularized and that vasculature is frequently localized near N-cadherin(+) pre-osteoblastic cells, a known niche component. By monitoring individual HSC behaviour using real-time imaging, we found that a portion of the homed HSCs underwent active division in the irradiated mice, coinciding with their expansion as measured by flow assay. Thus, in contrast to central marrow, the endosteum formed a special zone, which normally maintains HSCs but promotes their expansion in response to bone marrow damage.

Epidemiology of fractures in adults of African ancestry with diabetes mellitus: A systematic review and meta-analysis.

Diabetes mellitus (DM) is associated with increased fracture risk in White adults. However, the impact of DM on fractures in Black adults is unknown. This systematic review and meta-analysis investigated the association between DM and fractures in adults of African ancestry. MEDLINE, Scopus, CINAHL and Embase databases were searched from their inception up to November 2023 for all studies in the English language investigating the epidemiology of fractures (prevalence, incidence, or risk) in Black men and women (age ≥ 18 years) with type 1 or type 2 DM. Effect sizes for prevalence of previous fractures (%) and incident fracture risk (hazard ratio [HR]) were calculated using a random-effects model on Stata (version 18.0). There were 13 eligible studies, of which 12 were conducted in Black adults from the United States, while one was conducted in adults of West African ancestry from Trinidad and Tobago. We found no fracture data in Black adults with DM living in Africa. Five studies were included in a meta-analysis of incident fracture risk, reporting data from 2926 Black and 6531 White adults with DM. There was increased risk of fractures in Black adults with DM compared to non-DM (HR = 1.65; 95 % confidence interval [CI]: 1.14, 2.39). The risk of fractures was also higher in White adults with DM compared to non-DM (HR = 1.31; 95 % CI: 1.06, 1.61) among these studies. Five studies were included in a meta-analysis of fracture prevalence, of which three also reported fracture prevalence in White adults. There were 175 previous fractures among 993 Black adults with DM and 384 previous fractures among 1467 White adults with DM, with a pooled prevalence of 17.5 % (95 % CI: 15.4, 19.6) and 25.8 % (95 % CI: 4.8, 46.8), respectively. Our results indicate a high burden of fractures in Black adults with DM.