Sexually dimorphic tissues are formed by cells that are regulated by sex hormones. While a number of systemic hormones and transcription factors are known to regulate proliferation and differentiation of osteoblasts and osteoclasts, the mechanisms that determine sexually dimorphic differences in bone regeneration are unclear. To explore how sex hormones regulate bone regeneration, we compared bone fracture repair between adult male and female mice. We found that skeletal stem cell (SSC) mediated regeneration in female mice is dependent on estrogen signaling but SSCs from male mice do not exhibit similar estrogen responsiveness. Mechanistically, we found that estrogen acts directly on the SSC lineage in mice and humans by up-regulating multiple skeletogenic pathways and is necessary for the stem cell’s ability to self- renew and differentiate. Our results also suggest a clinically applicable strategy to accelerate bone healing using localized estrogen hormone therapy.

Craniofacial surgery, since its inauguration, has been the culmination of collaborative efforts to solve complex congenital, dysplastic, oncological, and traumatic cranial bone defects. Now, 50 years on from the first craniofacial meeting, the collaborative efforts between surgeons, scientists, and bioengineers are further advancing craniofacial surgery with new discoveries in tissue regeneration. Recent advances in regenerative medicine and stem cell biology have transformed the authors' understanding of bone healing, the role of stem cells governing bone healing, and the effects of the niche environment and extracellular matrix on stem cell fate. This review aims at summarizing the advances within each of these fields.

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Background:The advent of medical alternatives to splenectomy, particularly the thrombopoietin receptor agonists (TPO‐RA) has seen reduction in its use for ITP. It is now generally reserved in the UK for patients who fail multiple lines of therapy.Aims:We aimed to evaluate practices around splenectomy in the UK and long term response rates using data from the UK ITP registry, a large national database of primary ITP cases set up in 2007.Methods:We analysed all splenectomy cases from the UK ITP registry entered to December 2018. Data was studied on demographics, response rates, relapse rates and influence on response to medical therapies. Statistical analysis was performed using STATA. To identify the influence of medical therapies, we divided patients into treatment time brackets: 1989–1998, 1999–2008 and 2009–2018. The following response criteria were used:Complete response (CR platelets>100 x 109/l),partial response (PR platelets>30 but <100x109/l or doubling from baseline),overall response (OR = PR+CR).Results:Of 3236 registered patients(ITP diagnosis date ranging 1951 – 2018), 321(9.92%)(62%F/38%M) had undergone splenectomy with a total of 4611patient‐years follow‐up(Median 13.2 years, IQR 6.68,23.6). Median age at splenectomy was 40 years(y)(IQR27.0, 55.5).86.2%(268 patients) were <65y old and 13.8%(43 patients) 65y or older.72 patients were excluded from subsequent analysis due to incomplete data(including patients who had splenectomy <1989).Number of patients undergoing splenectomy decreased over time:1989–1998 34.1%;1999–2008 14.8%;2009–2018 4.8%. Median time from ITP diagnosis to splenectomy was 1.46y(IQR 0,20.3) increasing from 1.51y(IQR0,9.23.) in 1989–1998 to 1.69y(IQR0.14,18.5) in 2009–2018. This was associated with an increase in median number of treatment modalities from 2(IQR1,3) in 1989–1998 to 3 (IQR1,7) in 2009–2018 and median number of treatment episodes from 1(IQR1,2) in 1989–1998 to 3 (IQR1,11) in 2009–2018 pre‐splenectomy. The most common treatment modalities pre‐splenectomy were prednisolone(92%),IV immunoglobulin(50%),Azathioprine(27%),Rituximab(21%),Dexamethasone(12%),Mycophenolate(10%) and Romiplostim(10%).CR/PR and OR rates post‐splenectomy were 63.1%/24.3%/87.4% at 1month and 52.2%/15.3%/67.5% at 6months.67.2% of patients who had OR to splenectomy at 1month still had OR at latest follow‐up(median follow‐up 10.5y,IQR4.37,14.4).OR in patients <65y old were 86.8% at 1month and 51.8% at 6months post‐splenectomy.OR in those 65y and older were 73.9% at 1month and 46.2% at 6months post‐splenectomy.Beyond 6 months there is a trend towards reducing response in >65y group, but currently further analysis is limited by missing data.Overall median duration of response(DOR) was 2.5y(IQR0.51,7.01).The median DOR fell over time from 7.35y(1989–1998) to 0.52y(2009–2018).Median DOR was 3.02y in <65y old(IQR0.60,7.70) and 0.76y in 65y or older(IQR0.17,4.2.93).In patients who relapsed post‐splenectomy, median time to treatment was 2.56y(IQR0.09,35.48).59patients(18.4%) had complications post splenectomy.42patients(13.1%) had infections of which 32cases(76.2%) were attributed to splenectomy.53patients(11.2%) had an arterial or venous thrombotic event post‐splenectomy. Of 4deaths(1.25%),1 was listed as being attributed to splenectomy.Summary/Conclusion:Splenectomy rates for ITP in the UK have fallen since 1989, associated with increased medical treatment. There appears to be a trend to reduced response rates and shortened remission duration when this is used later in the treatment pathway.