VSCode-Antimony: a source editor for building, analyzing, and translating antimony models.

MOTIVATION: Developing biochemical models in systems biology is a complex, knowledge-intensive activity. Some modelers (especially novices) benefit from model development tools with a graphical user interface. However, as with the development of complex software, text-based representations of models provide many benefits for advanced model development. At present, the tools for text-based model development are limited, typically just a textual editor that provides features such as copy, paste, find, and replace. Since these tools are not "model aware," they do not provide features for: (i) model building such as autocompletion of species names; (ii) model analysis such as hover messages that provide information about chemical species; and (iii) model translation to convert between model representations. We refer to these as BAT features. RESULTS: We present VSCode-Antimony, a tool for building, analyzing, and translating models written in the Antimony modeling language, a human readable representation of Systems Biology Markup Language (SBML) models. VSCode-Antimony is a source editor, a tool with language-aware features. For example, there is autocompletion of variable names to assist with model building, hover messages that aid in model analysis, and translation between XML and Antimony representations of SBML models. These features result from making VSCode-Antimony model-aware by incorporating several sophisticated capabilities: analysis of the Antimony grammar (e.g. to identify model symbols and their types); a query system for accessing knowledge sources for chemical species and reactions; and automatic conversion between different model representations (e.g. between Antimony and SBML). AVAILABILITY AND IMPLEMENTATION: VSCode-Antimony is available as an open source extension in the VSCode Marketplace https://marketplace.visualstudio.com/items?itemName=stevem.vscode-antimony. Source code can be found at https://github.com/sys-bio/vscode-antimony.

Food neophobia scores at 8 Years and associations with nutrition-related behaviors at home in early life: Findings from a New Zealand contemporary birth cohort.

Food neophobia (FN) reduces nutritional adequacy and variety which poses a significant concern for children's health and well-being We described the FN scores among 8-year-olds and examined its associations with nutrition-related behaviors at 45 months within the Growing Up in New Zealand cohort (n = 4621). FN was estimated using the Food Neophobia Scale (FNS). Mean FNS scores between variable categories were compared using t-tests for independent samples and ANOVA. Associations between FNS scores at 8 years and nutrition-related behaviors at 45-months were examined using multivariate linear regression. The mean (standard deviation) FN score was 46.2 (15.2) with statistically significant differences by sex (boys = 47.6 (15.7), girls = 43.8 (14.2), p=<0.001). For all children, in models adjusted by breastfeeding duration and sociodemographic characteristics: children who sometimes and never/almost never ate the same foods as their parents, scored, on average, 5.8 and 11 points higher in the FNS (versus those who did always/almost always); children who occasionally/never found mealtimes enjoyable scored on average 3.6 points lower in the FNS (versus mostly/quite often); children who always/almost always had the television on during mealtimes scored on average 2.7 higher in the FNS (versus never/almost never). In comparison to children who mostly/quite often had time to talk to others during mealtimes, those who never/occasionally did it scored on average higher points in the FNS overall (1.46 points higher) and within girls (1.73 points higher). These findings support the eating behavior statements in the National Children's Food and Nutrition Guidelines, which emphasize early exposure to food variety, limiting mealtime distractions, and acknowledge that parental role modeling shapes children's nutrition-related behaviors. Early adoption of preventative interventions for reducing FN in early and middle childhood are needed.

Incidental durotomy during tubular microdiscectomy does not preclude same-day discharge.

PURPOSE: One of the major advantages of a minimally invasive microdiscectomy is that when CSF leak occurs, there is minimal anatomic dead space for ongoing leakage following removal of the tubular retractor. However, there are no published reports that address the safety and long-term outcomes of same-day discharge for CSF leak after tubular microdiscectomy. METHODS: This is a retrospective compartive study of 30 patients with incidental durotomy during minimally invasive tubular microdiscectomy occurring between January 1, 2009 to August 31, 2023 at our institution. RESULTS: There were 16 patients (53%) admitted to hospital and 14 (47%) patients discharged home the same day following CSF leak. There were no differences in patient demographics between the two groups at baseline. Twenty-nine out of 30 (97%) of the patients had onlay duraplasty, and one (3%) patient was repaired using sutures through the tubular retractor. None were converted to an open approach. The hospitalized group was kept on bed rest overnight or for 24 h. The discharge group was kept on best rest for 2 h or mobilized immediately after surgery. No patients in either group required readmission or revision surgery for CSF leak. The average length of admission for the hospitalized group was 2.4 ± 4.0 days. CONCLUSION: Patients with CSF leak during minimally invasive tubular microdiscectomy can be safely discharged home the same day.

Assessing the robustness of negative vascular surgery randomized controlled trials using their reverse fragility index.

OBJECTIVE: The reverse fragility index (RFI) describes the number of event conversions needed to convert a statistically nonsignificant dichotomous outcome to a significant one. The objective of the present study was to assess the RFI of vascular surgery randomized controlled trials (RCTs) comparing endovascular vs open surgery for the treatment of abdominal aortic aneurysms (AAAs), carotid artery stenosis (CAS), and peripheral artery disease (PAD). METHODS: MEDLINE and Embase were searched for RCTs that had investigated AAAs, CAS, or PAD with statistically nonsignificant binary primary outcomes. The primary outcome for the present study was the median RFI. Calculation of the RFI was performed by creating two-by-two contingency tables and subtracting events from the group with fewer events and adding nonevents to the same group until a two-tailed Fisher exact test had produced a statistically significant result (P ≤ .05). RESULTS: Of 4187 reports, 49 studies reporting 103 different primary end points were included. The overall median RFI was 7 (interquartile range [IQR], 5-13). The specific RFIs for AAA, CAS, and PAD were 10 (IQR, 6-15.5), 6 (IQR, 5-9.5), and 7 (IQR, 5.5-10), respectively. Of the 103 end points, 42 (47%) had had a loss to follow-up greater than the RFI, of which 10 were AAA trials (24%), 23 were CAS trials (55%), and 9 were PAD trials (21%). The Pearson correlation demonstrated a significant positive relationship between a study's RFI and the impact factor of its publishing journal (r = 0.38; 95% confidence interval [CI], 0.20-0.54; P < .01), length of follow-up (r = 0.43; 95% CI, 0.26-0.58; P < .01), and sample size (r = 0.28; 95% CI, 0.09-0.45; P < .01). CONCLUSIONS: A small number of events (median, 7) was required to change the outcome of negative RCTs from statistically nonsignificant to significant, with 47% of the studies having missing data that could have reversed the finding of its primary outcome. Reporting of the RFI relative to the loss to follow-up could be of benefit in future trials and provide confidence regarding the robustness of the P value.

No Sex Differences in Mechanical Thrombectomy Time Metrics and Outcomes in Saskatchewan.

BACKGROUND AND PURPOSE: Numerous studies have shown longer pre-hospital and in-hospital workflow times and poorer outcomes in women after acute ischemic stroke (AIS) in general and after endovascular treatment (EVT) in particular. We investigated sex differences in acute stroke care of EVT patients over 5 years in a comprehensive Canadian provincial registry. METHODS: Clinical data of all AIS patients who underwent EVT between January 2017 and December 2022 in the province of Saskatchewan were captured in the Canadian OPTIMISE registry and supplemented with patient data from administrative data sources. Patient baseline characteristics, transport time metrics, and technical EVT outcomes between female and male EVT patients were compared. RESULTS: Three-hundred-three patients underwent EVT between 2017 and 2022: 144 (47.5%) women and 159 (52.5%) men. Women were significantly older (median age 77.5 [interquartile range: 66-85] vs.71 [59-78], p < 0.001), while men had more intracranial internal carotid artery occlusions (48/159 [30.2%] vs. 26/142 [18.3%], p = 0.03). Last-known-well to comprehensive stroke center (CSC)-arrival time (median 232 min [interquartile range 90-432] in women vs. 230 min [90-352] in men), CSC-arrival-to-reperfusion time (median 108 min [88-149] in women vs. 102 min [77-141] in men), reperfusion status (successful reperfusion 106/142 [74.7%] in women vs. 117/158 [74.1%] in men) as well as modified Rankin score at 90 days did not differ significantly. This held true after adjusting for baseline variables in multivariable analyses. CONCLUSION: While women undergoing EVT in the province of Saskatchewan were on average older than men, they were treated just as fast and achieved similar technical and clinical outcomes compared to men.

Molecular analysis of enthesopathy in a mouse model of hypophosphatemic rickets.

The bone tendon attachment site known as the enthesis comprises a transitional zone between bone and tendon, and plays an important role in enabling movement at this site. X-linked hypophosphatemia (XLH) is characterized by impaired activation of vitamin D, elevated serum FGF23 levels and low serum phosphate levels, which impair bone mineralization. Paradoxically, an important complication of XLH is mineralization of the enthesis (enthesopathy). Studies were undertaken to identify the cellular and molecular pathways important for normal post-natal enthesis maturation and to examine their role during the development of enthesopathy in mice with XLH (Hyp). The Achilles tendon entheses of Hyp mice demonstrate an expansion of hypertrophic-appearing chondrogenic cells by P14. Post-natally, cells in wild-type and Hyp entheses similarly descend from scleraxis- and Sox9-expressing progenitors; however, Hyp entheses exhibit an expansion of Sox9-expressing cells, and enhanced BMP and IHH signaling. These results support a role for enhanced BMP and IHH signaling in the development of enthesopathy in XLH.

Stemless anatomic total shoulder arthroplasty: a systematic review and meta-analysis.

BACKGROUND: Stemless anatomic total shoulder arthroplasty (TSA) is used in the treatment of osteoarthritis of the shoulder joint and other degenerative shoulder diseases. It has several proposed advantages over stemmed TSA including increased bone preservation, decreased operative time, and easier removal at revision. METHODS: A systematic search was conducted using MEDLINE, Embase, PubMed, and CENTRAL (Cochrane Central Register of Controlled Trials) to retrieve all relevant studies. RESULTS: The literature search yielded 1417 studies, of which 22 were included in this review, with 962 patients undergoing stemless TSA. Stemless TSA led to significant improvements in range of motion and functional scores in all included studies. Meta-analysis of comparative studies between stemless and stemmed TSA identified no significant differences in postoperative Constant scores (mean difference [MD], 1.26; 95% confidence interval [CI], -3.29 to 5.81 points; P = .59) or complication rates (odds ratio, 1.79; 95% CI, 0.71-4.54; P = .22). Stemless TSA resulted in a significantly shorter operative time compared with stemmed TSA (MD, -15.03 minutes; 95% CI, -23.79 to -6.26 minutes; P = .0008). Stemless TSA also resulted in significantly decreased intraoperative blood loss compared with stemmed TSA (MD, -96.95 mL; 95% CI, -148.53 to -45.36 mL; P = .0002). CONCLUSION: Stemless anatomic TSA resulted in similar functional outcomes and complication rates to stemmed TSA with decreased operative time and lower blood loss. Further research is required to investigate the long-term durability of the stemless implant.

c-Raf promotes angiogenesis during normal growth plate maturation.

Extracellular phosphate plays a key role in growth plate maturation by inducing Erk1/2 (Mapk3/1) phosphorylation, leading to hypertrophic chondrocyte apoptosis. The Raf kinases induce Mek1/2 (Map2k1/2) and Erk1/2 phosphorylation; however, a role for Raf kinases in endochondral bone formation has not been identified. Ablation of both A-Raf (Araf) and B-Raf (Braf) in chondrocytes does not alter growth plate maturation. Because c-Raf (Raf1) phosphorylation is increased by extracellular phosphate and c-Raf is the predominant isoform expressed in hypertrophic chondrocytes, chondrocyte-specific c-Raf knockout mice (c-Raf(f/f);ColII-Cre(+)) were generated to define a role for c-Raf in growth plate maturation. In vivo studies demonstrated that loss of c-Raf in chondrocytes leads to expansion of the hypertrophic layer of the growth plate, with decreased phospho-Erk1/2 immunoreactivity and impaired hypertrophic chondrocyte apoptosis. However, cultured hypertrophic chondrocytes from these mice did not exhibit impairment of phosphate-induced Erk1/2 phosphorylation. Studies performed to reconcile the discrepancy between the in vitro and in vivo hypertrophic chondrocyte phenotypes revealed normal chondrocyte differentiation in c-Raf(f/f);ColII-Cre(+) mice and lack of compensatory increase in the expression of A-Raf and B-Raf. However, VEGF (Vegfa) immunoreactivity in the hypertrophic chondrocytes of c-Raf(f/f);ColII-Cre(+) mice was significantly reduced, associated with increased ubiquitylation of VEGF protein. Thus, c-Raf plays an important role in growth plate maturation by regulating vascular invasion, which is crucial for replacement of terminally differentiated hypertrophic chondrocytes by bone.

Heterotopic ossification after total elbow arthroplasty: a systematic review.

BACKGROUND: Heterotopic ossification (HO) is a known complication that can arise after total elbow arthroplasty (TEA). In most cases, it is asymptomatic; however, in some patients, it can limit range of motion and lead to poor outcomes. The objective of this review was to assess and report the incidence, risk factors, prophylaxis, and management of HO after TEA. METHODS: A systematic search was conducted using MEDLINE, Embase, and PubMed to retrieve all relevant studies evaluating the occurrence of HO after TEA. The search was performed in duplicate, and a quality assessment of all included studies was performed. RESULTS: A total of 1907 studies were retrieved, of which 45 were included involving 2256 TEA patients. HO was radiographically present in 10% of patients and was symptomatic in 3%. Fewer than 1% of patients went on to undergo surgical excision of HO, with outcomes after surgery reported as good or excellent as assessed by range of motion and the Mayo Elbow Performance Score. HO appears more likely to develop in patients undergoing TEA because of ankylosis, primary osteoarthritis, and distal humeral fractures. Surgical intervention is more likely to be required in patients in whom HO develops after TEA performed for ankylosis and post-traumatic osteoarthritis. CONCLUSION: HO is an uncommon complication after TEA, with most patients in whom HO develops being asymptomatic and requiring no surgical management. Routine HO prophylaxis for TEA is not supported by the literature. The effectiveness of prophylaxis in high-risk patients is uncertain, and future studies are required to clarify its usefulness.

Raf Kinases Are Essential for Phosphate Induction of ERK1/2 Phosphorylation in Hypertrophic Chondrocytes and Normal Endochondral Bone Development.

Hypophosphatemia causes rickets by impairing hypertrophic chondrocyte apoptosis. Phosphate induction of MEK1/2-ERK1/2 phosphorylation in hypertrophic chondrocytes is required for phosphate-mediated apoptosis and growth plate maturation. MEK1/2 can be activated by numerous molecules including Raf isoforms. A- and B-Raf ablation in chondrocytes does not alter skeletal development, whereas ablation of C-Raf decreases hypertrophic chondrocyte apoptosis and impairs vascularization of the growth plate. However, ablation of C-Raf does not impair phosphate-induced ERK1/2 phosphorylation in vitro, but leads to rickets by decreasing VEGF protein stability. To determine whether Raf isoforms are required for phosphate-induced hypertrophic chondrocyte apoptosis, mice lacking all three Raf isoforms in chondrocytes were generated. Raf deletion caused neonatal death and a significant expansion of the hypertrophic chondrocyte layer of the growth plate, accompanied by decreased cleaved caspase-9. This was associated with decreased phospho-ERK1/2 immunoreactivity in the hypertrophic chondrocyte layer and impaired vascular invasion. These data further demonstrated that Raf kinases are required for phosphate-induced ERK1/2 phosphorylation in cultured hypertrophic chondrocytes and perform essential, but partially redundant roles in growth plate maturation.

Determinants of uptake of hepatitis B testing and healthcare access by migrant Chinese in the England: a qualitative study.

BACKGROUND: Global migration from hepatitis B endemic countries poses a significant public health challenge in receiving low-prevalence countries. In the UK, Chinese migrants are a high risk group for hepatitis B. However, they are an underserved population that infrequently accesses healthcare. This study sought to increase understanding of the determinants of hepatitis B testing and healthcare access among migrants of Chinese ethnicity living in England. METHODS: We sought to obtain and integrate insights from different key stakeholders in the system. We conducted six focus group discussions and 20 in-depth interviews with community members and patients identifying themselves as 'Chinese', and interviewed 21 clinicians and nine health service commissioners. Data were thematically analysed and findings were corroborated through two validation workshops. RESULTS: Three thematic categories emerged: knowledge and awareness, visibility of the disease, and health service issues. Low disease knowledge and awareness levels among community members contributed to erroneous personal risk perception and suboptimal engagement with services. Limited clinician knowledge led to missed opportunities to test and inaccurate assessments of infection risks in Chinese patients. There was little social discourse and considerable stigma linked to the disease among some sub-sections of the Chinese population. A lack of visibility of the issue and the population within the health system meant that these health needs were not prioritised by clinicians or commissioners. Service accessibility was also affected by the lack of language support. Greater use of community outreach, consultation aids, 'cultural competency' training, and locally adapted testing protocols may help. CONCLUSIONS: Hepatitis B among migrants of Chinese ethnicity in England can be characterised as an invisible disease in an invisible population. Multi-modal solutions are needed to tackle barriers within this population and the health system.

An Exploratory Study on Exemplary Practice of Nurse Consultants.

PURPOSE: To examine the exemplary practice of nurse consultants (NCs) and derive a model to illustrate the highest level of advanced nursing practice. DESIGN: A descriptive study was conducted to examine the practice and outcomes of seven NC roles in varied clinical specialties in Hong Kong. Exemplary practice was examined in relation to competencies for advanced practice nursing in Hong Kong and the United Kingdom. METHODS: Data about NC characteristics and their practices were collected using a structured questionnaire and analyzed using descriptive statistics. Health service documents and clinical notes were analyzed using the framework approach. FINDINGS: All NCs demonstrated the competence expected of an advanced practice nurse with impacts on patients, nursing profession, and the organization as identified in the advanced nursing practice framework in Hong Kong. NCs also performed at the highest level of practice delineated by Skills for Health in the United Kingdom. They were involved in diagnostic and therapeutic practice, and identified patient satisfaction and symptom management as key outcomes. CONCLUSIONS: This study provides new insight into levels of advanced practice and illustrates the exemplary work of NCs to demonstrate how they have developed and shaped services to bring about positive patient and organizational outcomes. Career laddering that places NCs at the highest level of advanced practice is important for making the best use of nursing expertise to achieve optimal patient and organizational outcomes. CLINICAL RELEVANCE: This study addresses a knowledge gap to enrich our current understanding of the impact of advanced practice nursing roles by linking NC role practices and competencies to key outcomes.

Long-Term (>24 Months) Duration of Symptoms Negatively Impacts Patient-Reported Outcomes Following Anterior Cervical Discectomy and Fusion for Cervical Radiculopathy.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To investigate the impact of long symptom duration (>24 mo) on patient self-reported outcomes for pain, function, and quality of life following anterior cervical discectomy and fusion (ACDF) for cervical radiculopathy. SUMMARY OF BACKGROUND DATA: ACDF is an effective treatment to relieve the symptoms of cervical radiculopathy. However, there is no consensus on whether prolonged preoperative length of symptoms negatively impacts postoperative outcomes. METHODS: This study included consecutive patients who underwent ACDF for cervical radiculopathy from May 1, 2012 to Dec 1, 2019 by a single surgeon. Patients were stratified by short (<24 mo) and long (>24 mo) duration of symptoms. Outcomes including visual analog scale (VAS) neck and arm, neck disability index (NDI), EuroQol-5D (EQ-5D), and overall state of health (EQ-VAS) were compared between cohort both for absolute values and percentage of patients achieving minimal clinically important difference. RESULTS: A total of 111 consecutive patients were included in our study, including 59 patients in the short symptom duration group and 52 patients in the long symptom duration group. The mean age of the patients was 51.4±9.4 and 41 (36.9%) were female. The baseline VAS neck and arm, NDI, EQ-5D, and EQ-VAS were similar between groups. Patients in both long and short symptom duration groups had clinical improvement following surgery. However, patients with short symptom duration had better VAS Neck and EQ-5D outcomes, and were more likely to meet minimal clinically important difference for NDI, EQ-5D, or any outcome. Multivariate analysis confirmed symptom duration <24 months as an independent predictor for better patient-reported outcomes. CONCLUSION: We appreciated better clinical outcomes in patients with shorter symptom duration who received ACDF for cervical radiculopathy. On the basis of this data, we advocate for prompt treatment of cervical radiculopathy to avoid the potential for long-term impairment. LEVEL OF EVIDENCE: Level 3.

Chronic Subdural Hematoma Drainage under Local versus General Anesthesia: Systematic Review and Meta-Analysis.

BACKGROUND: Chronic subdural hematoma (CSDH) is one of the most frequently encountered neurosurgical conditions. Although the mainstay treatment of chronic subdural hematoma has been burr-hole drainage, no consensus yet exists on the optimal anesthetic strategy between general anesthesia (GA) and local anesthesia (LA). This systematic review compares postoperative outcomes after CSDH evacuation under LA and GA. METHODS: A search was conducted in MEDLINE (1946 to November 2023), Embase (1974 to November 2023), and PubMed (up to November 2023). We followed the PRISMA guidelines to systematically screen studies. RESULTS: Our literature search identified 629 studies, out of which 12 were included. There were 1035 patients in the LA group and 699 patients in the GA group. Our meta-analysis found that the LA group had significantly shorter operative time (mean difference, -29.28 minutes; P < 0.0001), length of admission (mean difference, -1.58 days; 95% confidence interval [CI], -2.40 to -0.76 days; P = 0.0002), and postoperative complications rate (odds ratio [OR], 0.38; 95% CI, 0.25-0.59; P < 0.0001) compared with GA. There was no significant difference between the 2 groups in revision rate (OR, 0.77; 95% CI, 0.39-1.51; P = 0.45) and mortality (OR, 1.23; 95% CI, 0.63-2.43; P = 0.55). CONCLUSIONS: In this meta-analysis, LA shows benefits in shorter operative time, shorter admission length, and fewer postoperative complications. This finding makes LA a less invasive alternative to GA, especially in elderly patients.

The role of GDF5 in regulating enthesopathy development in the Hyp mouse model of XLH.

X-linked hypophosphatemia (XLH) is caused by mutations in PHEX, leading to rickets and osteomalacia. Adults affected with XLH develop a mineralization of the bone-tendon attachment site (enthesis), called enthesopathy, which causes significant pain and impaired movement. Entheses in mice with XLH (Hyp) have enhanced bone morphogenetic protein (BMP) and Indian hedgehog (IHH) signaling. Treatment of Hyp mice with the BMP signaling blocker palovarotene attenuated BMP/IHH signaling in Hyp entheses, thus indicating that BMP signaling plays a pathogenic role in enthesopathy development and that IHH signaling is activated by BMP signaling in entheses. It was previously shown that mRNA expression of growth/differentiation factor 5 (Gdf5) is enhanced in Hyp entheses at P14. Thus, to determine a role for GDF5 in enthesopathy development, Gdf5 was deleted globally in Hyp mice and conditionally in Scx + cells of Hyp mice. In both murine models, BMP/IHH signaling was similarly decreased in Hyp entheses, leading to decreased enthesopathy. BMP/IHH signaling remained unaffected in WT entheses with decreased Gdf5 expression. Moreover, deletion of Gdf5 in Hyp entheses starting at P30, after enthesopathy has developed, partially reversed enthesopathy. Taken together, these results demonstrate that while GDF5 is not essential for modulating BMP/IHH signaling in WT entheses, inappropriate GDF5 activity in Scx + cells contributes to XLH enthesopathy development. As such, inhibition of GDF5 signaling may be beneficial for the treatment of XLH enthesopathy.

X-linked hypophosphatemia (XLH) is a rare bone disorder that leads to short stature and poorly mineralized bones. As adults, patients with XLH often develop a mineralization of the bone-tendon attachment site, called enthesopathy, which results in significant pain. We previously showed that Achilles bone-tendon attachment sites (entheses) in mice with XLH (Hyp) have an enthesopathy characterized by increased bone morphogenetic protein (BMP) signaling. In the current studies, we show that treating Hyp mice with the BMP signaling inhibitor palovarotene prevents enthesopathy, demonstrating that the increased BMP signaling in Hyp entheses leads to enthesopathy development. We also reported that gene expression of Gdf5, which activates BMP signaling, is enhanced in Hyp entheses. Therefore, to determine if the enhanced Gdf5 expression leads to the increased BMP signaling seen Hyp entheses, Gdf5 was deleted from Hyp mice and also deleted specifically in the entheses of Hyp mice. In both mouse models, enthesopathy development was attenuated, demonstrating that the increased Gdf5 expression in Hyp entheses plays a role in enthesopathy development. These data indicate that blocking GDF5 and BMP signaling may prevent enthesopathy in patients with XLH.

NFATc1 Is Required for Vitamin D- and Phosphate-Mediated Regulation of Osteocyte Lacuno-Canalicular Remodeling.

Osteocytes are embedded in lacunae and connected by canaliculi (lacuno-canalicular network, LCN). Bones from mice with X-linked hypophosphatemia (Hyp), which have impaired production of 1,25 dihydroxyvitamin D (1,25D) and hypophosphatemia, have abnormal LCN structure that is improved by treatment with 1,25D or an anti-FGF23 targeting antibody, supporting roles for 1,25D and phosphate in regulating LCN remodeling. Bones from mice lacking the vitamin D receptor (VDR) in osteocytes (Vdrf/f;Dmp1Cre+) and mice lacking the sodium phosphate transporter 2a (Npt2aKO), which have low serum phosphate with high serum 1,25D, have impaired LCN organization, demonstrating that osteocyte-specific actions of 1,25D and hypophosphatemia regulate LCN remodeling. In osteoclasts, nuclear factor of activated T cells cytoplasmic 1 (NFATc1) is critical for stimulating bone resorption. Since osteocytes also resorb matrix, we hypothesize that NFATc1 plays a role in 1,25D and phosphate-mediated LCN remodeling. Consistent with this, 1,25D and phosphate suppress Nfatc1 mRNA expression in IDG-SW3 osteocytes, and knockdown of Nfatc1 expression in IDG-SW3 cells blocks 1,25D- and phosphate-mediated suppression of matrix resorption gene expression and 1,25D- and phosphate-mediated suppression of RANKL-induced acidification of the osteocyte microenvironment. To determine the role of NFATc1 in 1,25D- and phosphate-mediated LCN remodeling in vivo, histomorphometric analyses of tibiae from mice lacking osteocyte-specific Nfatc1 in Vdrf/f;Dmp1Cre+ and Npt2aKO mice were performed, demonstrating that bones from these mice have decreased lacunar size and expression of matrix resorption genes, and improved canalicular structure compared to Vdrf/f;Dmp1Cre+ and Npt2aKO control. This study demonstrates that NFATc1 is necessary for 1,25D- and phosphate-mediated regulation of LCN remodeling.

Development of an Aotearoa New Zealand adapted Mediterranean dietary pattern and Kai/food basket for the He Rourou Whai Painga randomised controlled trial.

Background: Following a Mediterranean diet (MedDiet) is associated with a lower risk of cardiovascular disease. He Rourou Whai Painga is a dietary intervention trial with behaviour change support that seeks to determine whether a MedDiet pattern can provide equivalent benefits in Aotearoa New Zealand (NZ), a country where cardiovascular disease is a leading cause of death. To do this, the MedDiet needs to be adapted in an acceptable way for NZ, with consideration of the Maori (indigenous) population. Methods: The MedDiet was defined using existing MedDiet scoring tools and adapted to the NZ context using local guidelines. The resulting NZ MedDiet pattern was used to develop a kai/food basket, including products from industry partners, for participants in He Rourou Whai Painga. Criteria set for the kai/food basket included providing up to 75% of energy requirements and falling within the Australia/NZ Acceptable Macronutrient Distribution Range to reduce risk of chronic disease. Maori researchers on the team provided support to ensure Matauranga Maori (Maori knowledge and values) was upheld through this process. Results: The NZ MedDiet pattern criteria was similar to the identified MedDiet scoring tools, with differences in recommendations for dairy, red meat, alcohol and olive oil. The resulting kai/food baskets were estimated to provide on average 73.5% of energy requirements for households, with 36% from fat, 8.6% from saturated fat, 17% protein, and 42% carbohydrate. Forty-two industry partners, including 3 Maori businesses, agreed to provide 22 types of food products towards the total. Conclusion: Small, feasible changes to the MedDiet can be made to align with the NZ guidelines and food environment. However, this eating pattern still differs from what the population, particularly Maori, are currently consuming. Continued partnership with Maori and additional behavioural support is important to facilitate adherence to this dietary pattern within He Rourou Whai Painga.Trial registration: https://www.anzctr.org.au/Default.aspx, identifier ACTRN12622000906752 and https://www.isrctn.com/, identifier ISRCTN89011056.

Bilateral occipital condyle fracture with an avulsion fracture of the foramen magnum: nonoperative care guided by a traction test. Illustrative case.

BACKGROUND: Bilateral occipital condyle fractures (OCFs) with involvement of the inferior clivus, otherwise known as "avulsion of the anterior foramen magnum," are an exceedingly rare injury with only a few published reports. OBSERVATIONS: A 24-year-old male presented with bilateral OCFs with involvement of the clivus after a motor vehicle accident. The patient had no neurological deficits and was successfully managed nonoperatively using a halo vest. The authors used a traction test to guide the duration of nonoperative care. The operative and nonoperative management of this rare injury is discussed with respect to other cases in the literature. LESSONS: External immobilization through a halo vest is an effective treatment option for bilateral OCFs with clivus involvement. The traction test can be used, along with computed tomography, to guide the duration of treatment.

Impaired 1,25-dihydroxyvitamin D3 action underlies enthesopathy development in the Hyp mouse model of X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is characterized by high serum fibroblast growth factor 23 (FGF23) levels, resulting in impaired 1,25-dihydroxyvitamin D3 (1,25D) production. Adults with XLH develop a painful mineralization of the tendon-bone attachment site (enthesis), called enthesopathy. Treatment of mice with XLH (Hyp) with 1,25D or an anti-FGF23 Ab, both of which increase 1,25D signaling, prevents enthesopathy. Therefore, we undertook studies to determine a role for impaired 1,25D action in enthesopathy development. Entheses from mice lacking vitamin D 1α-hydroxylase (Cyp27b1) (C-/-) had a similar enthesopathy to Hyp mice, whereas deletion of Fgf23 in Hyp mice prevented enthesopathy, and deletion of both Cyp27b1 and Fgf23 in mice resulted in enthesopathy, demonstrating that the impaired 1,25D action due to high FGF23 levels underlies XLH enthesopathy development. Like Hyp mice, enthesopathy in C-/- mice was observed by P14 and was prevented, but not reversed, with 1,25D therapy. Deletion of the vitamin D receptor in scleraxis-expressing cells resulted in enthesopathy, indicating that 1,25D acted directly on enthesis cells to regulate enthesopathy development. These results show that 1,25D signaling was necessary for normal postnatal enthesis maturation and played a role in XLH enthesopathy development. Optimizing 1,25D replacement in pediatric patients with XLH is necessary to prevent enthesopathy.

Impaired Growth Plate Maturation in XLH Is due to Both Excess FGF23 and Decreased 1,25-Dihydroxyvitamin D Signaling.

X-linked hypophosphatemia (XLH) is the most common form of hereditary hypophosphatemic rickets. The genetic basis for XLH is loss of function mutations in the phosphate-regulating endopeptidase X-linked (PHEX), which leads to increased circulating fibroblast growth factor 23 (FGF23). This increase in FGF23 impairs activation of vitamin D and attenuates renal phosphate reabsorption, leading to rickets. Previous studies have demonstrated that ablating FGF23 in the Hyp mouse model of XLH leads to hyperphosphatemia, high levels of 1,25-dihydroxyvitamin D, and is not associated with the development of rickets. Studies were undertaken to define a role for the increase in 1,25-dihydroxyvitamin D levels in the prevention of rickets in Hyp mice lacking FGF23. These mice were mated to mice lacking Cyp27b1, the enzyme responsible for activating vitamin D metabolites, to generate Hyp mice lacking both FGF23 and 1,25-dihydroxyvitamin D (FCH mice). Mice were fed a special diet to maintain normal mineral ion homeostasis. Despite normal mineral ions, Hyp mice lacking both FGF23 and Cyp27b1 developed rickets, characterized by an interrupted, expanded hypertrophic chondrocyte layer and impaired hypertrophic chondrocyte apoptosis. This phenotype was prevented when mice were treated with 1,25-dihydroxyvitamin D from day 2 until sacrifice on day 30. Interestingly, mice lacking FGF23 and Cyp27b1 without the PHEX mutation did not exhibit rickets. These findings define an essential PHEX-dependent, FGF23-independent role for 1,25-dihydroxyvitamin D in XLH and have important therapeutic implications for the treatment of this genetic disorder.