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Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Background: Children and young adults needing surgery for a primary malignant bone tumour around the knee face a difficult, life changing decision. This study describes the level of shared decision making (SDM) experienced and preferred by these patients, parents and physicians in surgical consultations, and its relation to experienced decisional conflict and decisional regret. Methods: Multicentre, cross-sectional cohort study. All patients who underwent surgery for a primary bone tumour around the knee in the Dutch designated orthopaedic oncological centres between 2012 and 2015, and their parents, were invited to complete the SDM-patient-Questionnaire (SDM-Q-9), Decisional Conflict Scale (DCS), Decisional Regret Scale (DRS) and Control Preferences Scale (CPS). Physicians completed the SDM- physician-Questionnaire (SDM-Q-Doc) and CPS. Results: Twenty-four patients >16 years with twenty-two parents, and ten parents of patients between 5 and 16 years old, completed the questionnaires. Patients’ median SDM-Q-9 score was 60 (8.9–97.8), parents’ 77.8 (8.9–100) and physicians’ 82.2 (66.7–97.8). The SDM-Q-9 scores of patients (rs=−0.753, p

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

In the midst of the current opioid crisis, it has become critically important to properly manage opioid-prescribing patterns for the treatment of postoperative pain. There is currently a scarcity of literature specifying prescription and consumption patterns following orthopedic surgery and specifically foot and ankle surgery. Clinical guidelines for postoperative pain management are deficient.

This paper investigates the formation of spatial locative relativization in three African varieties of Portuguese. While research on relative constructions in Portuguese has deserved considerable attention in the literature, it tends to focus on the European and Brazilian varieties, with locative relativization being only marginally addressed. Using data extracted from spoken corpora of contemporary, urban varieties of Angolan, Mozambican, and Santomean Portuguese, we aim to discuss whether there is a correlation between syntactic and semantic variables and the selection of the two main locative relative morphemes, onde ‘where’ and que ‘that’. Overall, the three varieties at stake behave similarly with respect to the analyzed syntactic variables and follow the tendency found in Portuguese varieties toward the use of pied-piping and P-chopping as the dominant relativization mechanisms, independent of the syntactic relation between the antecedent and the relative clause. Semantically, we identified some fine-grained differences between the three varieties, with Santomean Portuguese generally being the outlier or one of the outliers. Crucially, definiteness of the head noun stands out as the one variable that plays a major role in the selection of the relative morpheme: [−definite] head nouns show a proportionally higher preference for que in both AP and STP, which is particularly visible with bare nouns in the latter. This motivates the hypothesis that less specified head nouns show a preference for the un(der)specified relative morpheme que. We further show that the role of language contact is at best very limited.

Background Cystic fibrosis (CF) is a rare hereditary disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Recent therapies enable effective restoration of CFTR function of the most common F508del CFTR mutation. This shifts the unmet clinical need towards people with rare CFTR mutations such as nonsense mutations, of which G542X and W1282X are most prevalent. CFTR function measurements in patient-derived cell-based assays played a critical role in preclinical drug development for CF and may play an important role to identify new drugs for people with rare CFTR mutations. Methods Here, we miniaturised the previously described forskolin-induced swelling (FIS) assay in intestinal organoids from a 96-well to a 384-well plate screening format. Using this novel assay, we tested CFTR increasing potential of a 1400-compound Food and Drug Administration (FDA)-approved drug library in organoids from donors with W1282X/W1282X CFTR nonsense mutations. Results The 384-well FIS assay demonstrated uniformity and robustness based on coefficient of variation and Z’-factor calculations. In the primary screen, CFTR induction was limited overall, yet interestingly, the top five compound combinations that increased CFTR function all contained at least one statin. In the secondary screen, we indeed verified that four out of the five statins (mevastatin, lovastatin, simvastatin and fluvastatin) increased CFTR function when combined with CFTR modulators. Statin-induced CFTR rescue was concentration-dependent and W1282X-specific. Conclusions Future studies should focus on elucidating genotype specificity and mode-of-action of statins in more detail. This study exemplifies proof of principle of large-scale compound screening in a functional assay using patient-derived organoids.

Despite various proposed measurement techniques for assessing syndesmosis integrity, a standardized protocol is lacking, and the existing literature reports inconsistent findings regarding normal and abnormal relationships between the fibula and tibia at the distal level. Therefore, this study aims to present an overview of two- (2D) and three-dimensional (3D) measurement methods utilized to evaluate syndesmosis integrity. A topical literature review was conducted, including studies employing 2D or 3D measurement techniques to quantify distal tibiofibular syndesmosis alignment on computed tomography (CT) or weight-bearing CT (WBCT) scans. A total of 49 eligible articles were included in this review. While most interclass correlation (ICC) values indicate favorable reliability, certain measurements involving multiple steps exhibited lower ICC values, potentially due to the learning curve associated with their implementation. Inconclusive results were obtained regarding the influence of age, sex, and height on syndesmotic measurements. No significant difference was observed between bilateral ankles, permitting the use of the opposite side as an internal control for comparison. There is a notable range of normal and pathological values, as evidenced by the standard deviation associated with each measurement. This review highlights the absence of a consensus on syndesmotic measurements for assessing integrity despite numerous CT scan studies. The diverse measurement techniques, complexity, and inconclusive findings present challenges in distinguishing between normal and pathological values in routine clinical practice. Promising advancements in novel 3D techniques offer potential for automated measurements and reduction of observer inaccuracies, but further validation is needed.

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Abstract Early detection of congenital disorders by newborn screening (NBS) programs is essential to prevent or limit disease manifestation in affected neonates. These programs balance between the detection of the highest number of true cases and the lowest number of false‐positives. In this case report, we describe four unrelated cases with a false‐positive NBS result for very‐long‐chain acyl‐CoA dehydrogenase deficiency (VLCADD). Three neonates presented with decreased but not deficient VLCAD enzyme activity and two of them carried a single heterozygous ACADVL c.1844G>A mutation. Initial biochemical investigations after positive NBS referral in these infants revealed acylcarnitine and organic acid profiles resembling those seen in multiple acyl‐CoA dehydrogenase deficiency (MADD). Genetic analysis did not reveal any pathogenic mutations in the genes encoding the electron transfer flavoprotein (ETF alpha and beta subunits) nor in ETF dehydrogenase. Subsequent further diagnostics revealed decreased levels of riboflavin in the newborns and oral riboflavin administration normalized the MADD‐like biochemical profiles. During pregnancy, the mothers followed a vegan, vegetarian or lactose‐free diet which probably caused alimentary riboflavin deficiency in the neonates. This report demonstrates that a secondary (alimentary) maternal riboflavin deficiency in combination with reduced VLCAD activity in the newborns can result in an abnormal VLCADD/MADD acylcarnitine profile and can cause false‐positive NBS. We hypothesize that maternal riboflavin deficiency contributed to the false‐positive VLCADD neonatal screening results.

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

Category: Ankle; Arthroscopy Introduction/Purpose: Syndesmotic instability, when subtle, can be challenging to diagnose-and often requires visualization of the syndesmosis during applied stress. Portable ultrasonography is increasingly used to evaluate ankle instability at the point of care. This study aims to evaluate 1) whether portable ultrasonography (P-US) can diagnose syndesmotic instability in the sagittal plane, and 2) how P-US measurements compare to arthroscopic evaluation. Methods: Eight fresh, above-knee cadaveric specimen were used. The syndesmosis was evaluated with P-US and arthroscopy in the intact state, and thereafter with progressive sectioning of, 1) anterior-inferior tibiofibular ligament (AITFL), 2) interosseous ligament (IOL), and 3) posterior-inferior tibiofibular ligament (PITFL). Sagittal plane translation was simulated with 100N of anterior to posterior (A to P) and posterior to anterior (P to A) directed force using a bone hook. Separately, a 50N manual force was applied to the fibular tip and measured with P-US to simulate a fibular 'shuck test' performed in the clinical setting. Results: When all three syndesmotic ligaments were transected, there was a significant increase in fibular motion in the sagittal plane when evaluated using portable ultrasonography with application of 50N of manual pressure and when applying a 100N hook test when measuring total sagittal plane motion (p=

Category: Ankle Introduction/Purpose: Portable ultrasonography (P-US) is increasingly used to diagnose syndesmotic instability. The aim of this study was to evaluate syndesmotic instability by measuring the distal tibiofibular clear space (TFCS) in a cadaveric model using P- US with progressive stages of syndesmotic ligamentous transection. Methods: Ten fresh lower leg cadaveric specimens amputated above the proximal tibiofibular joint were used. Using P-US, the TFCS was evaluated in the intact stage and after progressive sectioning of the 1) anterior-inferior tibiofibular ligament (AITFL), 2) interosseous ligament (IOL), and 3) posterior-inferior tibiofibular ligament (PITFL). The TFCS was measured in both the unstressed (0 Nm) state and with 4.5 Nm, 6.0 Nm, 7.5 Nm, and 9.0 Nm of external rotation stress at each stage of ligamentous transection stage using both P-US and fluoroscopy. Results: When assessed with P-US, partial syndesmotic injury encompassing the AITFL and IOL resulted in significant TFCS widening at 4.5 Nm of external rotation torque when compared to intact state with a TFCS-opening of 2.6 +- 2 mm, p = 0.01. In contrast, no significant differences in TFCS were detected using fluoroscopy. Only a moderate correlation was found between P- US and fluoroscopy. Conclusion: P-US is much more sensitive than fluoroscopy in diagnosing syndesmotic instability during external rotation stress examination. Extrapolated to the clinical setting, 4.5 Nm of force can be used when comparing to the stressed, uninjured side, and may be better tolerated by patients than higher torque values. When using P-US, a TFCS-opening of 2.6 mm is likely to correlate with syndesmotic instability. While absolute threshold values may vary between individuals, the ready availability of the contralateral, uninjured side overcomes this constraint.

Category: Ankle; Sports; Trauma Introduction/Purpose: While the lateral hook test (LHT) has been widely used to arthroscopically evaluate syndesmotic instability in the coronal plane, it is unclear whether the angulation of the applied force has any impact on the degree of instability. The aim of this study was to determine if changing the direction of the force applied while performing the LHT impacts the amount of coronal diastasis observed in purely ligamentous syndesmotic injuries. Methods: In 10 cadaveric specimens, arthroscopic evaluation of the distal tibiofibular joint in the coronal plane was performed. Anterior and posterior third coronal plane diastasis were assessed in the intact state and repeated after sequential transection of the, 1) anterior inferior tibiofibular ligament (AITFL), 2) the interosseous ligament (IOL) and the 3) posterior inferior tibiofibular ligament (PITFL). In all scenarios, the lateral hook test (LHT) was performed under 100N of laterally directed force. Additionally, LHT was also performed under 1) anterior inclination of 15 degrees and 2) posterior inclination of 15 degrees in the intact and AITFL+IOL deficient state. One-way ANOVA with post hoc Tukey HSD was used to test for significant differences in coronal plane measurements between each stage of ligament transection, and to determine the effect of different directions of force application on coronal space measurements in the intact and AITFL+IOL transected states. Results: Compared to the intact state, the distal tibiofibular joint remained stable after transection of AITFL under laterally directed force with no angulation. However, after additional transection of the IOL, the syndesmosis became unstable in the coronal plane (p = 0.029 and 0.025 for anterior and posterior third diastasis, respectively). This instability worsened further with subsequent transection of the PITFL (p =

Category: Ankle; Trauma Introduction/Purpose: Despite the fact that stress fluoroscopy is the most common method of quantifying lateral ankle instability, ultrasound evaluation has grown in popularity as a way to assess ankle stability at the point of care due to its simplicity, accuracy, low cost, and lack of exposure. The aim of this study is to introduce a new method for evaluating lateral ankle instability using ultrasound. Methods: A 37-year-old man with history of lateral ankle ligament injury underwent ultrasound and fluoroscopic evaluation. The anterior drawer distance (ADD) was quantified under anterior drawer stress. During ADD measurement, the patient sat with the knee extended and the heel on the examination table or chair, and the examiner performed the anterior drawer test (Image 1a). The amount of talar movement was measured as an ADD using an ultrasound probe placed on the posteromedial side of the ankle (Image 1b). A lateral clear space (LCS) was also measured under varus stress using ultrasound from the tip of the lateral malleolar to the lateral process of the talus. The aforementioned measurements were repeated under stress fluoroscopy and compared with ultrasound findings. Results: On ultrasound evaluation, the ADD was 7.1 mm and the LCS was 17.1 mm. Furthermore, the stress fluoroscopic evaluation yielded a similar result, with an ADD of 8.7 mm and an LCS of 17.5 mm. Conclusion: Our findings suggest that this new method of evaluation of lateral ankle instability under dynamic ultrasound appears to be a highly accurate and useful alternative for assessing lateral ankle stability at the point of care in a radiation-free, non- invasive, and low-cost manner.

In research on African varieties of Portuguese, especially Angolan and Mozambican Portuguese, it is often referred that Goal arguments of verbs of movement show a tendency to be headed by locative preposition em ‘in’, contrasting with the use of a ‘to’ and para ‘to, toward’ in European Portuguese. Language contact is generally considered the primary factor with respect to the use of the noncanonical pattern. Using spoken corpora of the urban varieties of Angolan, Mozambican and Santomean Portuguese, this paper develops a case-study of Goal arguments that occur with two frequently used verbs of inherently directed motion, ir ‘to go’ and chegar ‘to arrive’, to assess the contact-induced hypothesis and to explore alternative, semantic-based hypotheses. Overall, a cross-comparison of the varieties at stake and their main contact languages shows that the role of language contact is limited at best. A semantic analysis of em, on the other hand, shows promising results, since the occurrence of this preposition is favored by NPs that denote an entity with well-defined boundaries and is sensitive to the lexical semantics of the verbs, i.e., whether the verb describes a durative or non-durative change of place, and to the type of eventuality described by the predication.

In this paper we compare dative ditransitive structures in nativized and nativizing urban varieties of Portuguese spoken in Angola, Mozambique, and São Tomé and Príncipe, using a corpus-based approach. It is shown that the expression of the Recipient exhibits considerable variation within and across these varieties, as well as at intraspeaker level. Despite the use of non-canonical patterns, namely prepositional structures with em and para and double object constructions, the canonical European Portuguese pattern with Case marker a is predominant in our data. Moreover, the pronominalized counterparts of these different realizations show much less variation and strong convergence toward dative clitic lhe(s). To account for the data, we propose a Larsonian VP-shell in which Recipients as extended DPs occur internally to a K(ase) projection whose functional head can be spelled out as a, em or para. Recipients in double object constructions, on the other hand, are treated as plain DPs which may pronominalize as dative clitics or, less commonly, as strong pronouns. Overall, our hypothesis weakens the role of language contact, which has often been assumed as a critical factor in the literature, but still allows for (individual) grammars that show evidence of being substrate-induced.

Category: Ankle; Arthroscopy; Basic Sciences/Biologics Introduction/Purpose: The lateral hook test is considered the gold standard for the diagnosis of coronal plane syndesmotic instability during arthroscopy. The amount of distal tibiofibular space is directly related to the amount of lateral directed applied force. This study aims to determine the optimal amount of forced needed during a lateral hook test to evaluate syndesmotic instability in the coronal plane. The secondary aim was to determine the amount of displacement variation that occurs when the lateral force is angled anteriorly or posteriorly. Methods: Ten fresh-frozen above-knee amputated cadaveric specimens underwent arthroscopic evaluation of the distal tibiofibular joint. The assessment was done first with all syndesmotic and ankle ligaments intact and subsequently with transection of the anterior inferior tibiofibular ligament (AITFL) and the interosseous ligament (IOL). In all scenarios, a lateral hook test was performed under increasing force from 0N to 120N of direct force, with increments of 20N. The lateral hook test was performed in: 1) the neutral position (no angulation), 2) anterior inclination of 15 degrees, and 3) posterior inclination of 15 degrees under the aforementioned force. Anterior and posterior coronal plane distal tibiofibular space were arthroscopically measured. Descriptive statistics were employed to determine the force and the most sensitive method to pull during arthroscopic evaluation to detect syndesmotic instability. Results: Among the specimens, after transection of AITFL and IOL, the anterior and posterior coronal plane space increased with increment in force until 60N and then displayed no change in these measurements despite the increase in force. In the intact state, there was an increase in syndesmosis coronal space with increase in force. Of the three methods of force application, the posteriorly directed force has the largest absolute value for the anterior and posterior coronal space, suggesting it is the most sensitive in distinguishing between stable and unstable syndesmotic injury. Conclusion: Arthroscopic coronal plane evaluation under 60N of direct force is best suited to distinguish stable from an unstable syndesmosis. Syndesmosis anterior and posterior coronal plane space measurement demonstrate the largest absolute difference when subjected to posteriorly directed force, suggesting that this new method of assessment has the highest potential for diagnosing even subtle syndesmotic instability, along with a lower propensity for error.

Introduction: Guidelines are designed to encompass the needs of the majority of patients with a particular condition. The American Heart Association (AHA) in conjunction with the American College of Cardiology (ACC) and the American College of Emergency Physicians (ACEP) developed risk stratification guidelines to aid physicians with accurate and efficient diagnosis and management of patients with acute coronary syndrome (ACS). While useful in a primary care setting, in the unique environment of an emergency department (ED), the feasibility of incorporating guidelines into clinical workflow remains in question. We aim to compare emergency physicians’ (EP) clinical risk stratification ability to AHA/ACC/ACEP guidelines for ACS, and assessed each for accuracy in predicting ACS.Methods: We conducted a prospective observational cohort study in an urban teaching hospital ED. All patients presenting to the ED with chest pain who were evaluated for ACS had two risk stratification scores assigned: one by the treating physician based on clinical evaluation and the other by the AHA/ACC/ACEP guideline aforementioned. The patient’s ACS risk stratification classified by the EP was compared to AHA/ACC/ACEP guidelines. Patients were contacted at 30 days following the index ED visit to determine all cause mortality, unscheduled hospital/ED revisits, and objective cardiac testing performed.Results: We enrolled 641 patients presenting for evaluation by 21 different EPs. There was a difference between the physician’s clinical assessment used in the ED, and the AHA/ACC/ACEP task force guidelines. EPs were more likely to assess patients as low risk (40%), while AHA/ACC/ACEP guidelines were more likely to classify patients as intermediate (45%) or high (45%) risk. Of the 119 (19%) patients deemed high risk by EP evaluation, 38 (32%) were diagnosed with ACS. AHA/ACC/ACEP guidelines classified only 57 (9%) patients low risk with 56 (98%) of those patients diagnosed with no ACS.Conclusion: In the ED, physicians are more efficient at correctly placing patients with underlying ACS into a high-risk category. A small percentage of patients were considered low risk when applying AHA/ACC/ACEP guidelines, which demonstrates how clinical insight is often required to make an efficient assessment of cardiac risk and established criteria may be overly conservative when applied to an acute care population.

We discuss the emergence of the cross-linguistically marked discontinuous/final negation pattern in the four Gulf of Guinea Creoles by taking into account the different linguistic strata and their structural profiles that contributed to the formation of the protolanguage, in particular southern Nigerian and western Bantu languages. While the phonetic source of the final negation marker (fa/f/wa~va) in the creoles remains unclear, we argue that its syntax and functions, which also include emphasis, show a strong parallel with utterance-final markers in the contributing African languages. Although the trigger of these patterns should be sought in the earliest African contribution from Nigeria, their entrenchment and full grammaticalization can be attributed to heavy secondary contact with languages of the Kongo Bantu cluster.