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The nuclear factor I/X (NFIX) gene encodes a ubiquitously expressed transcription factor whose mutations lead to two allelic disorders characterized by developmental, skeletal, and neural abnormalities, namely, Malan syndrome (MAL) and Marshall–Smith syndrome (MSS). NFIX mutations associated with MAL mainly cluster in exon 2 and are cleared by nonsense‐mediated decay (NMD) leading to NFIX haploinsufficiency, whereas NFIX mutations associated with MSS are clustered in exons 6–10 and escape NMD and result in the production of dominant‐negative mutant NFIX proteins. Thus, different NFIX mutations have distinct consequences on NFIX expression. To elucidate the in vivo effects of MSS‐associated NFIX exon 7 mutations, we used CRISPR‐Cas9 to generate mouse models with exon 7 deletions that comprised: a frameshift deletion of two nucleotides (Nfix Del2); in‐frame deletion of 24 nucleotides (Nfix Del24); and deletion of 140 nucleotides (Nfix Del140). Nfix+/Del2, Nfix+/Del24, Nfix+/Del140, NfixDel24/Del24, and NfixDel140/Del140 mice were viable, normal, and fertile, with no skeletal abnormalities, but NfixDel2/Del2 mice had significantly reduced viability (p < 0.002) and died at 2–3 weeks of age. Nfix Del2 was not cleared by NMD, and NfixDel2/Del2 mice, when compared to Nfix+/+ and Nfix+/Del2 mice, had: growth retardation; short stature with kyphosis; reduced skull length; marked porosity of the vertebrae with decreased vertebral and femoral bone mineral content; and reduced caudal vertebrae height and femur length. Plasma biochemistry analysis revealed NfixDel2/Del2 mice to have increased total alkaline phosphatase activity but decreased C‐terminal telopeptide and procollagen‐type‐1‐N‐terminal propeptide concentrations compared to Nfix+/+ and Nfix+/Del2 mice. NfixDel2/Del2 mice were also found to have enlarged cerebral cortices and ventricular areas but smaller dentate gyrus compared to Nfix+/+ mice. Thus, NfixDel2/Del2 mice provide a model for studying the in vivo effects of NFIX mutants that escape NMD and result in developmental abnormalities of the skeletal and neural tissues that are associated with MSS. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. A mouse model for Marshall–Smith syndrome.

IntroductionBiologic drugs are effective treatments in IBD, the use of therapeutic drug monitoring (TDM) is rapidly becoming part of routine clinical practice. The American Gastroenterology Association (AGA) and the Australian Gastroenterology Association have recently published guidance recommending the use of therapeutic drug monitoring in clinical practice. Recommendations on the minimum trough level for Infliximab differ between these two guidelines. The AGA recommends a level >5 µg/ml, whilst the Australian guidance suggests >3 µg/ml. To date there are no published recommendations from ECCO or BSG. In patients with active disease and sub-therapeutic trough levels we shorten the dose interval from 8 to 4 weeks.AimTo review the clinical and cost implications of introducing these guidelines into clinical practice at a large district general hospitalMethodsWe maintain a prospective IBD database and have used TDM routinely since2014. Data on the use of TDM from 2016 to 2017 were reviewed. Age, Sex, disease type, and disease activity were reviewed. Results of drug levels in the active disease and remission group were compared and the cost implications of intensifying drug treatment to achieve recommended trough levels calculated. The costs were calculated for escalating all patients below recommended levels to dosing every 4 weeks.ResultsBiosimilar Infliximab (Remsima) trough level data was available for 167 patients. Mean age=42, Range 18–81. 133 (80%) had Crohn’s disease and 34 (20%) UC. 118 had inactive disease at the time of TDM, whilst 49 had active disease. Of those with inactive disease 78/118 (66%) had an Infliximab TL <3 µg/L and 104/118 (88%) had a level <5 µg/L. In patients with active disease 33/49 (67%) had a TL <3 µg/ml and 40/49 (82%) a level <5 µg/mL. Across both groups antibodies were present in 72 (43%). The annual cost for maintaining all 167 patients on biosimilar infliximab (5 mg/kg) was calculated at £521,040, (assuming a standard dose of 5 mg/kg). If all patients with a TL <3 had treatment intensified the total annual drug cost would be £9 25 080 (+77%). If all patients<5 µg/ml were intensified the annual cost rises to £1,045,200 (+100%). If only those patients with active disease and <3 µg/mL were escalated the annual cost rises to £6 41 160 (+23%) and £6 66 640 (+28%) if those <5 µg/mL were escalated.ConclusionsIn our cohort of 167, 62% (n=104) of patients had a TL below the recently published recommended guidelines (5 µg/ml) yet were in a clinical remission. Therefore following these guidelines would lead to a significant increase in drug spend which may not translate into improved clinical outcomes; since in this cohort only 24% with sub-therapeutic levels had active disease. Escalating only those with active disease may represent a more acceptable financial solution but too will lead to an increase in drug spend.

Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1 , and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease. Osteoarthritis is a chronic, heritable disease with no available treatment. Here, the authors show that a validated, rapid-throughput joint phenotyping pipeline detects osteoarthritis in the mouse knee following surgical provocation, in aging and after single gene deletion or point mutation.

BackgroundThiopurines are widely used for maintenance of remission in Crohn's disease (CD). Published data report >50% of patients stop thiopurines due to therapeutic failure, hepatitis or side effects. In this situation, many UK clinicians start biologics in CD patients. This has significant cost implications. An alternative strategy is low dose thiopurine and allopurinol (LDTA) co-therapy. We report the annual cost savings from adopting this strategy at our centre.MethodsPatients with CD treated with LDTA in preference to biological therapy were identified using a prospective local inflammatory bowel disease database. The annual drug cost of treatment with LDTA compared with biologic therapy was calculated. Cost of attending the day unit for an infusion was not included.Results26 patients with CD who failed standard dose thiopurine and were treated with LDTA were identified over a 12-month period and followed up for 1 year. 12 patients failed LDTA and progressed to biological therapy. The remaining 14 patients entered sustained clinical remission on LDTA. The cost savings achieved using the LDTA strategy in this group of patients was £146 413 per year with an average saving of £10 458 per patient per year.ConclusionsThis study has identified a significant annual cost savings with this treatment strategy through the prevention of escalation to biologics. These cost savings are likely to be even more significant in the long term since a significant proportion of patients treated with biological therapy require dose escalation. We believe adopting this strategy more widely could lead to significant healthcare savings.

In the version of this article initially published, in Fig. 5a, the data in the right column of ‘DAAM2 gRNA1’ were incorrectly plotted as circles indicating ‘untreated’ rather than as squares indicating ‘treated’. The error has been corrected in the HTML and PDF versions of the article.

According to the document, members of the community are concerned about \"job opportunities for local residents, contract opportunities for local businesses, well-defined objectives for affordability, sustainability, and diversity and assistance for current homeowners in distressed housing.\"

According to Clark, the caller pointed out that the ordinance against firearms in parks conflicted with Ohio's current gun laws.

While current research on this topic is not conclusive, many neuroscientists believe that dreams are a way that new information is consolidated into long-term memory in the hippocampus.

According to Oberlin Board of Education President Ken Stanley, up to 50 percent and no less than 39 percent of a teacher's evaluation will come from their students' scores on these examinations.