Citations

Abstract Aims Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. Methods and results Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II–III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II–III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II–III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. Conclusion The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II–III loop. This represents a ‘mutation hotspot’ in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

Significance Statement Because renal function often remains stable in the early stages of autosomal dominant polycystic kidney disease (ADPKD), total kidney volume (TKV) is the most important biomarker of disease severity and progression. The authors developed and validated a fully automated method of simultaneously measuring TKV and total liver volume (TLV) as well as their growth rates from magnetic resonance images. Their findings indicate that the method’s performance is equivalent to the gold standard of manual tracing while requiring a fraction of the time and skill. This approach may address the unmet need for rapid and reliable assessment of TKV and TLV, allowing identification of patients with rapidly progressing ADPKD for emerging drug treatments and serving as a reliable alternative for assessment of disease progression in clinical trials. Background The formation and growth of cysts in kidneys, and often liver, in autosomal dominant polycystic kidney disease (ADPKD) cause progressive increases in total kidney volume (TKV) and liver volume (TLV). Laborious and time-consuming manual tracing of kidneys and liver is the current gold standard. We developed a fully automated segmentation method for TKV and TLV measurement that uses a deep learning network optimized to perform semantic segmentation of kidneys and liver. Methods We used 80% of a set of 440 abdominal magnetic resonance images (T2-weighted HASTE coronal sequences) from patients with ADPKD to train the network and the remaining 20% for validation. Both kidneys and liver were also segmented manually. To evaluate the method’s performance, we used an additional test set of images from 100 patients, 45 of whom were also involved in longitudinal analyses. Results TKV and TLV measured by the automated approach correlated highly with manually traced TKV and TLV (intraclass correlation coefficients, 0.998 and 0.996, respectively), with low bias and high precision (<0.1%±2.7% for TKV and −1.6%±3.1% for TLV); this was comparable with inter-reader variability of manual tracing (<0.1%±3.5% for TKV and −1.5%±4.8% for TLV). For longitudinal analysis, bias and precision were <0.1%±3.2% for TKV and 1.4%±2.9% for TLV growth. Conclusions These findings demonstrate a fully automated segmentation method that measures TKV, TLV, and changes in these parameters as accurately as manual tracing. This technique may facilitate future studies in which automated and reproducible TKV and TLV measurements are needed to assess disease severity, disease progression, and treatment response.

ABSTRACTAimThis study aimed to assess the relationship between admission Calcium‐phosphate (CaP) and in‐hospital mortality in hospitalized patients.MethodsAll adult hospitalized patients who had both admission serum calcium and phosphate levels available between years 2009 and 2013 were enrolled. Admission CaP was categorized based on its distribution into six groups (<21, 21–<27, 27–<33, 33 39, 39–<45 and ≥45 mg2/dL2). Multivariate logistic regression was used to assess the association between admission CaP and in‐hospital mortality, using the CaP of 27–<33 mg2/dL2 as the reference group.ResultsAbut 14 772 patients were included in the analysis. The association between CaP and in‐hospital mortality was U‐shaped with the lowest in‐hospital mortality in CaP of 27–<33 mg2/dL2. After adjusting for potential confounders, both CaP <21 and ≥39 mg2/dL2 were associated with higher in‐hospital mortality. Subgroup analysis demonstrated that the highest in‐hospital mortality risk in both chronic kidney disease (CKD) and non‐CKD patients occurred when CaP ≥ 45 mg2/dL2.ConclusionCaP levels on admission were associated with in‐hospital mortality. Highest mortality risk was observed in hospitalized patients with admission CaP of ≥45 mg2/dL2 in both CKD and non‐CKD patients.

Background: The medial ulnar collateral ligament (UCL) insertion of the elbow has been shown to extend distally beyond the sublime tubercle. The contribution to valgus stability of the distal aspect of the footprint is unknown. Purpose/Hypothesis: The purpose of this study was to determine the contribution of each part of the UCL footprint to the elbow valgus stability provided by the UCL. It was hypothesized that the distal two-thirds of the ulnar UCL footprint would not contribute significantly to valgus stability provided by the UCL. Study Design: Descriptive laboratory study. Methods: Fifteen cadaveric arms were dissected to the capsuloligamentous elbow structures and potted. A servohydraulic load frame was used to place 5 N·m of valgus stress on the intact elbow at 30°, 60°, 90°, and 120° of flexion. The UCL insertional footprint was measured and divided into thirds (proximal, middle, and distal). One-third of the UCL footprint was elevated off the bone (leaving the ligament in continuity), and the elbow was retested at the same degrees of flexion. This was repeated until the entire UCL footprint on the ulna was sectioned. Each elbow was randomized for how the UCL would be sectioned (sectioning the proximal, then middle, and then distal third or sectioning the distal, then middle, and then proximal third). Ulnohumeral joint gapping (millimeters) was recorded with a 3-dimensional motion capture system using physical and virtual markers. Two-group comparisons were made between each sectioned status versus the intact condition for each flexion angle. Results: When the UCL was sectioned from distal to proximal, none of the ligaments failed prior to complete sectioning. When the UCL was sectioned from proximal to distal, 3 of the 6 ligaments failed after sectioning of the proximal third, while 2 more failed after the proximal and middle thirds were sectioned. Of the specimens with the distal third of the ligament sectioned first, no significant differences were found between intact, distal third cut, and distal plus middle thirds cut at all flexion angles. Conclusion: The middle and distal thirds of the insertional footprint of the UCL on the ulna did not significantly contribute to gap resistance at 5 N·m of valgus load. The proximal third of the footprint is the primary resistor of valgus load. Clinical Relevance: This cadaveric biomechanical study demonstrated that the middle and distal thirds of the native UCL insertion onto the ulna did not significantly contribute to valgus resistance at the elbow. When a UCL reconstruction is performed, the proximal third of the UCL insertion may be the most clinically important portion of the ligament to reconstruct.

This article discusses the requirements of a formal specification for the annotation of temporal information in clinical narratives. We discuss the implementation and extension of ISO-TimeML for annotating a corpus of clinical notes, known as the THYME corpus. To reflect the information task and the heavily inference-based reasoning demands in the domain, a new annotation guideline has been developed, “the THYME Guidelines to ISO-TimeML (THYME-TimeML)”. To clarify what relations merit annotation, we distinguish between linguistically-derived and inferentially-derived temporal orderings in the text. We also apply a top performing TempEval 2013 system against this new resource to measure the difficulty of adapting systems to the clinical domain. The corpus is available to the community and has been proposed for use in a SemEval 2015 task.