Use of Hand Therapy After Distal Radius Fracture: A National Perspective.

PURPOSE: To assess whether certain distal radius fracture (DRF) patients, such as opioid users or complex regional pain syndrome (CRPS) patients, receive more hand therapy. METHODS: Using the IBM MarketScan Research Databases from January 1, 2012, to December 31, 2016, we identified a cohort of DRF patients and created 4 subgroups of interest: frequent follow-up patients, persistent opioid users, prior opioid users, and patients with CRPS. We measured rates and demographic characteristics associated with therapy use in our populations of interest. RESULTS: In this cohort of 87,313 patients, 21% received hand therapy after primary DRF treatment. Patients with CRPS had a higher rate of therapy than non-CRPS patients (44% vs 21%, respectively). Frequent follow-up patients used more therapy than those with less follow-up (30% vs 17%, respectively). Persistent opioid users demonstrated slightly increased therapy use compared to the remaining population (25% vs 22%, respectively). Prior opioid users underwent less therapy than patients without prior opioid use (19% vs 22%, respectively). Female sex, residing in the Northeast, being on a preferred provider organization plan, and having more intense surgical treatments were associated with increased therapy use. CONCLUSIONS: This study showed variations in therapy use after DRF in subpopulations of interest. Patients with CRPS, persistent opioid use, and frequent follow-ups had higher rates of therapy. Patients with prior opioid use had lower rates of therapy. CLINICAL RELEVANCE: Therapy is more common in patients with DRF with CRPS, persistent opioid use, or more follow-up visits.

Prominin-1 Promotes Biliary Fibrosis Associated With Biliary Atresia.

In patients with biliary atresia (BA), the extent of intrahepatic biliary fibrosis negatively correlates with successful surgical bypass of the congenital cholangiopathy as well as subsequent transplant-free survival. We recently linked the expansion of a population of prominin-1 (Prom1)-expressing hepatic progenitor cells to biliary fibrogenesis. Herein, we hypothesized that Prom1-expressing progenitor cells play a role in BA-associated fibrosis. Rhesus rotavirus (RRV)-mediated experimental BA was induced in newborn mice homozygous for the transgene Prom1cre-ert2-nlacz , which was knocked in to the Prom1 gene locus, thus creating functional Prom1 knockout (KO) mice, and their wildtype (WT) littermates. Clinical data and tissue samples from BA infants from the Childhood Liver Disease Research Consortium were analyzed. Extrahepatic biliary obliteration was present in both WT and KO mice; there was no difference in serum total bilirubin (TBili) levels. The intrahepatic periportal expansion of the PROM1pos cell population, typically observed in RRV-induced BA, was absent in KO mice. RRV-treated KO mice demonstrated significantly fewer cytokeratin-19 (CK19)-positive ductular reactions (P = 0.0004) and significantly less periportal collagen deposition (P = 0.0001) compared with WT. RRV-treated KO mice expressed significantly less integrin-ß6, which encodes a key biliary-specific subunit of a transforming growth factor (TGF) ß activator (P = 0.0004). Infants with successful biliary drainage (Tbili ≤1.5 mg/dL within 3 months postoperatively), which is highly predictive of increased transplant-free survival, expressed significantly less hepatic PROM1, CK19, and COLLAGEN-1α compared with those with TBili >1.5 (P < 0.05). Conclusion: Prom1 plays an important role in biliary fibrogenesis, in part through integrin-mediated TGF pathway activation.

Cell-Cell Interactions Enhance Cartilage Zonal Development in 3D Gradient Hydrogels.

Cartilage tissue is characterized by zonal organization with gradual transitions of biochemical and mechanical cues from superficial to deep zones. We previously reported that 3D gradient hydrogels made of polyethylene glycol and chondroitin sulfate can induce zonal-specific responses of chondrocytes, resulting in zonal cartilage formation that mimics native tissues. While the role of cell-matrix interactions has been studied extensively, how cell-cell interactions across different zones influence cartilage zonal development remains unknown. The goal of this study is to harness gradient hydrogels as a tool to elucidate the role of cell-cell interactions in driving cartilage zonal development. When encapsulated in intact gradient hydrogels, chondrocytes exhibited strong zonal-specific responses that mimic native cartilage zonal organization. However, the separate culture of each zone of gradient hydrogels resulted in a significant decrease in cell proliferation and cartilage matrix deposition across all zones, while the trend of zonal dependence remains. Unexpectedly, mixing the coculture of all five zones of hydrogels in the same culture well largely abolished the zonal differences, with all zones behaving similarly to the softest zone. These results suggest that paracrine signal exchange among cells in different zones is essential in driving cartilage zonal development, and a spatial organization of zones is required for proper tissue zonal development. Intact, separate, or coculture groups resulted in distinct gene expression patterns in mechanosensing and cartilage-specific markers, suggesting that cell-cell interactions can also modulate mechanosensing. We further showed that 7 days of priming in intact gradient culture was sufficient to instruct the cells to complete the zonal development, and the separate or mixed coculture after 7 days of intact culture had minimal effects on cartilage formation. This study highlights the important role of cell-cell interactions in driving cartilage zonal development and validates gradient hydrogels as a useful tool to elucidate the role of cell-matrix and cell-cell interactions in driving zonal development during tissue morphogenesis and regeneration.

Impact of Adding Carpal Tunnel Release or Trigger Finger Release to Carpometacarpal Arthroplasty on Postoperative Complications.

BACKGROUND: This study assessed whether adding trigger finger or carpal tunnel release at the time of thumb carpometacarpal (CMC) arthroplasty would increase postoperative opioid use, readmissions, complications, or development of complex regional pain syndrome (CRPS). METHODS: Using the IBM MarketScan Research Databases from 2012 through 2016, the authors identified two CMC arthroplasty groups. The CMC-only group only had a CMC arthroplasty on the day of operation; the multiple-procedures group had a CMC arthroplasty and concurrent carpal tunnel or trigger finger release. Between the two groups, the authors compared persistent opioid use, 30-day readmissions, 30-day complications, and diagnosis of CRPS. RESULTS: The CMC-only group consisted of 18,010 patients; the multiple-procedures group consisted of 4064 patients. The patients in the multiple-procedures group received a CMC arthroplasty and a carpal tunnel release (74%), a trigger finger release (20%), or both (6%). CMC-only patients had lower rates of persistent opioid use compared with patients who underwent multiple procedures (16% versus 18%). Readmission rates were also lower for CMC-only patients (3% versus 4%). CMC-only patients had decreased odds of persistent opioid use (OR, 0.85; 95% CI, 0.75 to 0.97; P = 0.013) and readmissions (OR, 0.80; 95% CI, 0.67 to 0.96; P = 0.016). The most common reason for readmission was pain (16%). CONCLUSIONS: Adding another procedure to a CMC arthroplasty slightly increases the odds of adverse outcomes such as persistent opioid use and readmission. Patients and providers should weigh the efficiency of performing these procedures concurrently against the risk of performing multiple procedures at once. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

A cross-sectional analysis of trends in dermatology practice size in the United States from 2012 to 2020.

Physicians are trending towards practice consolidation nationally; however, changes in dermatology practice size remain to be assessed. The objective of this study was to analyze trends in dermatology practice size from 2012 to 2020 using a large-scale Medicare physician database. We performed a retrospective cross-sectional analysis using 2012 and 2020 data obtained from the Physician Compare Database. Responses from dermatologists were analyzed for trends in practice size, with a sub-analysis to examine differences among different regions, gender, and years of experience. The proportion of dermatologists in solo practice decreased from 26.1% in 2012 to 15.6% in 2020 (p < 0.001). Dermatologists were 40% less likely to be practicing in solo practice and 36% more likely to be in a practice with 10 or more members in 2020 (p < 0.001). These findings were consistent among all regions and genders examined. Additionally, in 2020, dermatologists with 30 or more years in practice were 7.5 times more likely to be in solo practice compared to dermatologists with 0-9 years in practice (p < 0.001). There is a trend of dermatologists working for larger practices, which is consistent with a larger nationwide trend of expanding physician practices. This shift in practice settings should be closely monitored to analyze the effect on healthcare efficiency, cost, and delivery.

Partnering with a senior living community to optimise teledermatology via full body skin screening during the COVID-19 pandemic: A pilot programme.

Background: Elderly patients in senior communities faced high barriers to care during the COVID-19 pandemic, including increased vulnerability to COVID-19, long quarantines for clinic visits, and difficulties with telemedicine adoption. Objective: To pilot a new model of dermatologic care to overcome barriers for senior living communities during the COVID-19 pandemic and assess patient satisfaction. Methods: From 16 November 2020 to 9 July 2021, this quality improvement programme combined in-residence full body imaging with real-time outlier lesion identification and virtual teledermatology. Residents from the Sequoias Portola Valley Senior Living Retirement Community (Portola Valley, California) voluntarily enroled in the Stanford Skin Scan Programme. Non-physician clinical staff with a recent negative COVID-19 test travelled on-site to obtain in-residence full body photographs using a mobile app-based system on an iPad called SkinIO that leverages deep learning to analyse patient images and suggest suspicious, outlier lesions for dermoscopic photos. A single dermatologist reviewed photographs with the patient and provided recommendations via a video visit. Objective measures included follow-up course and number of skin cancers detected. Subjective findings were obtained through patient experience surveys. Results: Twenty-seven individuals participated, three skin cancers were identified, with 11 individuals scheduled for a follow up in-person visit and four individuals starting home treatment. Overall, 88% of patients were satisfied with the Skin Scan programme, with 77% likely to recommend the programme to others. 92% of patients agreed that the Skin Scan photographs were representative of their skin. In the context of the COVID-19 pandemic, 100% of patients felt the process was safer or comparable to an in-person visit. Despite overall appreciation for the programme, 31% of patients reported that they would prefer to see dermatologist in-person after the pandemic. Conclusions: This programme offers a framework for how a hybrid skin scan programme may provide high utility for individuals with barriers to accessing in-person clinics.

Gradient hydrogels for screening stiffness effects on patient-derived glioblastoma xenograft cellfates in 3D.

Brain cancer is a devastating disease given its extreme invasiveness and intricate location. Glioblastoma multiforme (GBM) is one of the most common forms of brain cancer, and cancer progression is often correlated with significantly altered tissue stiffness. To elucidate the effect of matrix stiffness on GBM cell fates, previous research is largely limited to 2D studies using immortalized cell lines, which has limited physiological relevance. The objective of the study is to develop gradient hydrogels with brain-mimicking stiffness range as a 3Din vitro GBM model for screening of the effects of matrix stiffness on GBM. To increase the physiological relevance, patient-derived tumor xenograft (PDTX) GBM cells were used. Our gradient platform allows formation of cell-containing hydrogels with stiffness ranging from 40 Pa to 1,300 Pa within a few minutes. By focusing on a brain-mimicking stiffness range, this gradient hydrogel platform is designed for investigating brain cancer. Increasing stiffness led to decreased GBM proliferation and less spreading, which is accompanied by downregulation of matrix-metalloproteinases (MMPs). Using temozolomide (TMZ) as a model drug, we demonstrate that increasing stiffness led to higher drug resistance by PDTX GBM cells in 3D, suggesting matrix stiffness can directly modulate how GBM cells respond to drug treatment. While the current study focuses on stiffness gradient, the setup may also be adapted for screening other cancer niche cues such as how biochemical ligand gradient modulates brain cancer progression and drug responses using reduced materials and time.

Biochemical and Mechanical Gradients Synergize To Enhance Cartilage Zonal Organization in 3D.

Articular cartilage is characterized by zonal organizations containing dual gradients of biochemical cues and mechanical cues. However, how biochemical gradient interacts with the mechanical gradient to drive the cartilage zonal development remains largely unknown. Here, we report the development of a dual-gradient hydrogel platform as a 3D niche to elucidate the relative contributions of biochemical and mechanical niche gradients in modulating zonal-specific chondrocyte responses and cartilage zonal organization. Chondroitin sulfate (CS), a major constituent of cartilage extracellular matrix, was chosen as the biochemical cue. Poly(ethylene glycol), a bioinert polymer, was used to create the stiffness gradient. Dual-gradient hydrogels upregulated cartilage marker expressions and increased chondrocyte proliferation and collagen deposition in a zonal-dependent manner. Hydrogels with CS gradient alone exhibited poor mechanical strength and degraded prematurely after 1 week of culture. While CS gradient alone did not support long-term culture, adding CS gradient to mechanical-gradient hydrogels substantially enhanced cell proliferation, glycosaminoglycan production, and collagen deposition compared to mechanical-gradient hydrogels alone. These results suggest that biochemical and mechanical gradient cues synergize to enhance cartilage zonal organization by chondrocytes in 3D. Together, our results validate the potential of dual-gradient hydrogels as a 3D cell niche for cartilage regeneration with zonal organization and may be used to recreate other tissue interfaces.

Mimicking Cartilage Tissue Zonal Organization by Engineering Tissue-Scale Gradient Hydrogels as 3D Cell Niche.

Zonal organization plays an important role in cartilage structure and function, whereas most tissue-engineering strategies developed to date have only allowed the regeneration of cartilage with homogeneous biochemical and mechanical cues. To better restore tissue structure and function, there is a strong need to engineer materials with biomimetic gradient niche cues that recapitulate native tissue organization. To address this critical unmet need, in this study, we report a method for rapid formation of tissue-scale gradient hydrogels as a three-dimensional (3D) cell niche with tunable biochemical and physical properties. When encapsulated in stiffness gradient hydrogels, both chondrocytes and mesenchymal stem cells demonstrated zone-specific response and extracellular deposition that mimics zonal organization of articular cartilage. Blocking cell mechanosensing using blebbistatin abolished the zonal response of chondrocytes in 3D hydrogels with a stiffness gradient. Such tissue-scale gradient hydrogels can provide a 3D artificial cell niche to enable tissue engineering of various tissue types with zonal organizations or tissue interfaces.

Neurofibromatosis Type 1 and Risk of Skin Cancer.

This cohort study examines the odds of developing basal cell carcinoma, squamous cell carcinoma, or melanoma among insured adults with neurofibromatosis type 1.

Elastin-like protein-hyaluronic acid (ELP-HA) hydrogels with decoupled mechanical and biochemical cues for cartilage regeneration.

Hyaluronic acid (HA) is a major component of cartilage extracellular matrix and is an attractive material for use as 3D injectable matrices for cartilage regeneration. While previous studies have shown the promise of HA-based hydrogels to support cell-based cartilage formation, varying HA concentration generally led to simultaneous changes in both biochemical cues and stiffness. How cells respond to the change of biochemical content of HA remains largely unknown. Here we report an adaptable elastin-like protein-hyaluronic acid (ELP-HA) hydrogel platform using dynamic covalent chemistry, which allows variation of HA concentration without affecting matrix stiffness. ELP-HA hydrogels were created through dynamic hydrazone bonds via the reaction between hydrazine-modified ELP (ELP-HYD) and aldehyde-modified HA (HA-ALD). By tuning the stoichiometric ratio of aldehyde groups to hydrazine groups while maintaining ELP-HYD concentration constant, hydrogels with variable HA concentration (1.5%, 3%, or 5%) (w/v) were fabricated with comparable stiffness. To evaluate the effects of HA concentration on cell-based cartilage regeneration, chondrocytes were encapsulated within ELP-HA hydrogels with varying HA concentration. Increasing HA concentration led to a dose-dependent increase in cartilage-marker gene expression and enhanced sGAG deposition while minimizing undesirable fibrocartilage phenotype. The use of adaptable protein hydrogels formed via dynamic covalent chemistry may be broadly applicable as 3D scaffolds with decoupled niche properties to guide other desirable cell fates and tissue repair.