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Rheumatoid arthritis (RA) is a debilitating autoimmune disease that includes exacerbations with gradual disability. Diagnosis within the first 12 weeks of disease onset is vital for optimal treatment outcomes. Magnetic Resonance Imaging (MRI) and Ultrasonography (US) are often employed to diagnose early-stage hand and wrist RA. However, there is a lack of consensus on the standardized imaging method for early clinical detection. As such, we aim to examine the diagnostic accuracy of MRI and US in detecting three commonest signs in early RA; bone erosions, synovitis and tenosynovitis in the metacarpophalangeal, proximal interphalangeal and wrist joints. Biological risks, operator dependency levels, inherent artefacts and imaging costs will also be discussed. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) methodology, systematic literature search from databases: PubMed-MEDLINE, Cochrane Library and ScienceDirect resulted in 122 articles, of which 43 included studies were critically evaluated. A total of 489 patients with RA were included in our study. The pooled sensitivity of MRI in detecting bone erosions, synovitis and tenosynovitis were 68%-80.7%, 77.8%, and 24%-60% respectively while pooled specificities were 96%-99.4%, 49,7% and 73%-88%. Conversely, the pooled sensitivity of US in detecting bone erosions, synovitis and tenosynovitis were 27%-75%, 50%-95.2%, and 15%-52% respectively while pooled specificities were 46%-98%, 49%-100%, and 83-99%. Multiplanar and multisequence of MR imaging provides significantly higher reliability in detecting bone erosions and tenosynovitis, with a comparable diagnostic accuracy for synovitis in early RA. Whilst biological and hazardous effects are comparable in both modalities, higher cost of MRI in developing countries may render US as a viable option for early RA detection. [ABSTRACT FROM AUTHOR]

Breast cancer is the leading cause of death amongst women in Singapore. Wire-guided localisation (WGL) is a conventional yet effective technique to provide intraoperative guidance for excision of impalpable breast lesions. However, it is associated with scheduling inflexibility and distal wire displacement. Magnetic seed localisation (MSL) is a recently established alternative to WGL that eliminates the aforementioned drawbacks. This study aims to compare and assess the efficacy and implications of both methods in providing intra-operative guidance. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols, a systematic literature search was performed on the following databases: PubMed-MEDLINE, Cochrane Library, CINAHL and ScienceDirect. A total of 57 articles were included and critically evaluated. 427 and 328 subjects with various breast densities underwent WGL and MSL respectively. All seeds were detectable transcutaneously at all depths. Placement accuracy, lesion retrieval and re-excision rate, along with reported adverse events were not significantly different between both techniques (p >0.05). However, higher pain levels were reported for WGL during movement and rest (p <0.001). Targeting, tissue excision time and skin incision to tumor extraction time did not differ statistically between both groups (p >0.05). Surgical complexity and efficacy of GWL and MSL are comparable in facilitating lesion excision with acceptable cosmetic outcomes. MSL enables seed embedment in lesions for days prior to tumour excision, which could increase capacity for new patient referrals albeit its higher cost to GWL. MSL is also associated with higher patient comfort and easier access for targeted axillary node dissection. [ABSTRACT FROM AUTHOR]

The project was intended to bring all NHGD DXA machines a state of cross-calibration to allow patients to have follow up scans done at different scanners and still have comparable DXA results. DXA machines are measurement instruments which are high internal accuracy but poor external precision when compared against other DXA machines. Cross-calibration between DXA machines are performed to ensure that DXA results obtained from different DXA machines can be compared for comparison study, while allowing flexibility for patients with increased access to wider range of DXA machines without compromising on their DXA results within primary healthcare. The Cross-Calibration exercise was performed according to the guidelines in ISCD Official position 2019 for cross-calibration of DXA scanner of same make and model for 20 days. The NHGD identified "Gold Spine Phantom" was transported in a shockproof case by appointed courier service between the DXA machines during the exercise period. The DXA values obtained during the period were recorded and mean DXA was calculated. Subsequently, Quality Control (QC) plots were reviewed monthly for monitoring after the cross-calibration exercise. The percentage difference of all new DXA scanners to index scanner in NHGD is 0.01%, 0.19% and 0.11% respectively, within 0.5% difference. The QC Plots are stable within limits (0.12%, 0.05%, 0.18% and 0.13% respectively). All 4 unit of NHGD DXA machines were observed to be within cross-calibrated limit, indicating results obtained on the DXA scanners can be used interchangeably, allowing comparing of DXA results within the acceptable limit. This allows flexibility and accessibility of DXA scanners to the community at risk of osteoporosis. This study may provide an insight and could potentially be an initiator for the cross-calibration exercise among multiple DXA facilities within cluster or nationwide. [ABSTRACT FROM AUTHOR]

It has been postulated that rare coding variants (RVs; MAF < 0.01) contribute to the "missing" heritability of complex traits. We developed a framework, the Rare variant heritability (RARity) estimator, to assess RV heritability (h 2 RV ) without assuming a particular genetic architecture. We applied RARity to 31 complex traits in the UK Biobank (n = 167,348) and showed that gene-level RV aggregation suffers from 79% (95% CI: 68-93%) loss of h 2 RV . Using unaggregated variants, 27 traits had h 2 RV  > 5%, with height having the highest h 2 RV at 21.9% (95% CI: 19.0-24.8%). The total heritability, including common and rare variants, recovered pedigree-based estimates for 11 traits. RARity can estimate gene-level h 2 RV , enabling the assessment of gene-level characteristics and revealing 11, previously unreported, gene-phenotype relationships. Finally, we demonstrated that in silico pathogenicity prediction (variant-level) and gene-level annotations do not generally enrich for RVs that over-contribute to complex trait variance, and thus, innovative methods are needed to predict RV functionality., (© 2024. The Author(s).)

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries., (© 2022. The Author(s).)

Uromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin's complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.

Background and Objectives: Low buffy coat mitochondrial DNA copy number (mtDNA-CN) is associated with incident risk of stroke and poststroke mortality; however, its prognostic utility has not been extensively explored. Our goal was to investigate whether low buffy coat mtDNA-CN is a marker and causal determinant of poststroke outcomes using epidemiologic and genetic studies., Methods: First, we performed association testing between baseline buffy coat mtDNA-CN measurements and 1-month poststroke outcomes in 3,498 cases of acute, first stroke from 25 countries from the international, multicenter case-control study Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World (INTERSTROKE). Then, we performed 2-sample mendelian randomization analyses to evaluate potential causative effects of low mtDNA-CN on 3-month modified Rankin Scale (mRS) score. Genetic variants associated with mtDNA-CN levels were derived from the UK Biobank study (N = 383,476), and corresponding effects on 3-month mRS score were ascertained from the Genetics of Ischemic Stroke Functional Outcome (GISCOME; N = 6,021) study., Results: A 1-SD lower mtDNA-CN at baseline was associated with stroke severity (baseline mRS score: odds ratio [OR] 1.27, 95% confidence interval [CI] 1.19-1.36; p = 4.7 × 10 -12 ). Independently of baseline stroke severity, lower mtDNA-CN was associated with increased odds of greater 1-month disability (ordinal mRS score: OR 1.16, 95% CI 1.08-1.24; p = 4.4 × 10 -5 ), poor functional outcome status (mRS score 3-6 vs 0-2: OR 1.21, 95% CI 1.08-1.34; p = 6.9 × 10 -4 ), and mortality (OR 1.35, 95% CI 1.14-1.59; p = 3.9 × 10 -4 ). Subgroup analyses demonstrated consistent effects across stroke type, sex, age, country income level, and education level. In addition, mtDNA-CN significantly improved reclassification of poor functional outcome status (net reclassification index [NRI] score 0.16, 95% CI 0.08-0.23; p = 3.6 × 10 -5 ) and mortality (NRI score 0.31, 95% CI 0.19-0.43; p = 1.7 × 10 -7 ) beyond known prognosticators. With the use of independent datasets, mendelian randomization revealed that a 1-SD decrease in genetically determined mtDNA-CN was associated with increased odds of greater 3-month disability quantified by ordinal mRS score (OR 2.35, 95% CI 1.13-4.90; p = 0.02) and poor functional outcome status (OR 2.68, 95% CI 1.05-6.86; p = 0.04)., Discussion: Buffy coat mtDNA-CN is a novel and robust marker of poststroke prognosis that may also be a causal determinant of poststroke outcomes., Classification of Evidence: This study provides Class II evidence that low buffy coat mtDNA-CN (>1 SD) was associated with worse baseline severity and 1-month outcomes in patients with ischemic or hemorrhagic stroke., (© 2021 American Academy of Neurology.)

Introduction: The effect of the treating surgeon's subspecialty training on the outcomes of managing displaced supracondylar humerus fractures in the pediatric cohort remains under debate. The objective of this study was to examine patient outcomes and treatment variables for these injuries based on the surgeon subspecialty training., Methods: A retrospective study of children who had undergone primary closed reduction and percutaneous fixation for displaced supracondylar humerus fractures was done from January 2012 through May 2019. The following four groups with differing orthopaedic subspecialty training were evaluated: (1) pediatric fellowship trained (2) trauma fellowship trained, (3) sports medicine fellowship trained, and (4) all others. Outcomes examined included time to surgery, surgical time, fluoroscopy usage, postoperative follow-up protocols, radiographic measurements of alignment, and complications between surgeon groups., Results: Two hundred thirty-one cases were included (mean age 6 ± 2 years). Pediatric fellowship-trained surgeons took patients to surgery in a more delayed fashion (>12 hours, P = 0.02). Surgical time and fluoroscopy usage were significantly shorter for pediatric fellowship-trained surgeons (P < 0.001). No statistical difference was noted in pin configuration constructs between the groups. Pediatric fellowship-trained surgeons, on average, saw patients two times postoperatively within a year with most patients being within 30 days. Complications were not statistically different between the groups., Conclusions: Pediatric fellowship-trained orthopaedic surgeons provide more efficient care on a more delayed basis for displaced supracondylar humerus fractures than other subspecialty-trained orthopaedic surgeons. However, if barriers exist that limit the practicality or availability of these specialists, nonpediatric fellowship-trained surgeons achieve similar and satisfactory outcomes., Level of Evidence: Level III retrospective cohort study., (Copyright © 2021 by the American Academy of Orthopaedic Surgeons.)

Background: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF., Methods: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events., Results: We identified 13 novel genome-wide significant ( P≤2.5×10 -8 ) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk., Conclusions: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.