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1.
BMC Musculoskelet Disord ; 25(1): 453, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38849773

ABSTRACT

BACKGROUND: Posttraumatic wrist osteoarthritis is an irreversible and often progressive condition. Many surgical treatments, used in (daily) practice, aim to relieve symptoms like pain and restore function. The aim of this systematic review is to assess the patient reported and functional outcomes of the most common surgical interventions in patients with posttraumatic wrist osteoarthritis. This overview can help clinicians select the best treatment and manage patient's expectations. METHODS: A literature search was performed in Pubmed, Embase and Cochrane for articles published between 1990 and November 2022 according to the PRISMA guidelines. The study protocol has been registered in the PROSPERO database (CRD42017080427). Studies that describe patient reported outcomes (pain and Disability of Arm, Shoulder and Hand (DASH) -score) and functional outcomes (range of motion (ROM) and grip strength) after surgical intervention with a minimal follow-up of 1 year were included. The identified surgical procedures included denervation, proximal row carpectomy, interpositional- and total arthroplasty, and midcarpal-, radiocarpal- and total arthrodesis. The pre-and postoperative outcomes were pooled and presented per salvage procedure. RESULTS: Data from 50 studies was included. Pain score improved after all surgeries except denervation. Flexion/extension decreased after radiocarpal arthrodesis, did not show significant changes after proximal row carpectomy, and improved for all other surgeries. DASH score improved after arthroplasty, proximal row carpectomy and midcarpal arthrodesis. Grip strength improved after interposition arthroplasty and partial arthrodesis. CONCLUSION: Evidence from this review did not support the indication for denervation in this particular patient population. In patients with SLAC/SNAC II, proximal row carpectomy might be favourable to a midcarpal arthrodesis solely based on better FE ROM of the radiocarpal joint after proximal row carpectomy. In terms of radiocarpal mobility, total wrist arthroplasty might be preferred to radiocarpal arthrodesis in patients with osteoarthritis after a distal radius fracture. More uniform measurements of outcomes would improve the understanding of the effect of surgical treatments of the posttraumatic osteoarthritic wrist.


Subject(s)
Osteoarthritis , Patient Reported Outcome Measures , Range of Motion, Articular , Salvage Therapy , Wrist Joint , Humans , Osteoarthritis/surgery , Wrist Joint/surgery , Wrist Joint/physiopathology , Salvage Therapy/methods , Arthrodesis/methods , Hand Strength , Treatment Outcome , Wrist Injuries/surgery , Wrist Injuries/physiopathology , Recovery of Function , Denervation/methods
2.
Nat Commun ; 15(1): 4751, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38834573

ABSTRACT

Intracellular potassium (K+) homeostasis is fundamental to cell viability. In addition to channels, K+ levels are maintained by various ion transporters. One major family is the proton-driven K+ efflux transporters, which in gram-negative bacteria is important for detoxification and in plants is critical for efficient photosynthesis and growth. Despite their importance, the structure and molecular basis for K+-selectivity is poorly understood. Here, we report ~3.1 Å resolution cryo-EM structures of the Escherichia coli glutathione (GSH)-gated K+ efflux transporter KefC in complex with AMP, AMP/GSH and an ion-binding variant. KefC forms a homodimer similar to the inward-facing conformation of Na+/H+ antiporter NapA. By structural assignment of a coordinated K+ ion, MD simulations, and SSM-based electrophysiology, we demonstrate how ion-binding in KefC is adapted for binding a dehydrated K+ ion. KefC harbors C-terminal regulator of K+ conductance (RCK) domains, as present in some bacterial K+-ion channels. The domain-swapped helices in the RCK domains bind AMP and GSH and they inhibit transport by directly interacting with the ion-transporter module. Taken together, we propose that KefC is activated by detachment of the RCK domains and that ion selectivity exploits the biophysical properties likewise adapted by K+-ion-channels.


Subject(s)
Cryoelectron Microscopy , Escherichia coli Proteins , Escherichia coli , Potassium , Escherichia coli/metabolism , Escherichia coli/genetics , Escherichia coli Proteins/metabolism , Escherichia coli Proteins/chemistry , Escherichia coli Proteins/genetics , Glutathione/metabolism , Molecular Dynamics Simulation , Potassium/metabolism , Potassium-Hydrogen Antiporters/metabolism , Potassium-Hydrogen Antiporters/chemistry , Potassium-Hydrogen Antiporters/genetics , Protein Domains
3.
Neth Heart J ; 32(7-8): 283-289, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38865067

ABSTRACT

INTRODUCTION: When electrical storm (ES) is amenable to neither antiarrhythmic drugs, nor deep sedation or catheter ablation, autonomic modulation may be considered. We report our experience with percutaneous left stellate ganglion block (PSGB) to temporarily suppress refractory ventricular arrhythmia (VA) in patients with structural heart disease. METHODS: A retrospective analysis was performed at our institution of patients with structural heart disease and an implantable cardioverter defibrillator (ICD) who had undergone PSGB for refractory VA between January 2018 and October 2021. The number of times antitachycardia pacing (ATP) was delivered and the number of ICD shocks/external cardioversions performed in the week before and after PSGB were evaluated. Charts were checked for potential complications. RESULTS: Twelve patients were identified who underwent a combined total of 15 PSGB and 5 surgical left cardiac sympathetic denervation procedures. Mean age was 73 ± 5.8 years and all patients were male. Nine of 12 (75%) had ischaemic cardiomyopathy, with the remainder having non-ischaemic dilated cardiomyopathy. Mean left ventricular ejection fraction was 35% (±â€¯12.2%). Eight of 12 (66.7%) patients were already being treated with both amiodarone and beta-blockers. The reduction in ATP did not reach statistical significance (p = 0.066); however, ICD shocks (p = 0.028) and ATP/shocks combined were significantly reduced (p = 0.04). At our follow-up electrophysiology meetings PSGB was deemed ineffective in 4 of 12 patients (33%). Temporary anisocoria was seen in 2 of 12 (17%) patients, and temporary hypotension and hoarseness were reported in a single patient. DISCUSSION: In this limited series, PSGB showed promise as a method for temporarily stabilising refractory VA and ES in a cohort of male patients with structural heart disease. The side effects observed were mild and temporary.

4.
J Immunother Cancer ; 12(4)2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38604812

ABSTRACT

BACKGROUND: Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies in the Western world. Contributing factors include a high frequency of late-stage diagnosis, the development of chemoresistance, and the evasion of host immune responses. Currently, debulking surgery and platinum-based chemotherapy are the treatment cornerstones, although recurrence is common. As the clinical efficacy of immune checkpoint blockade is low, new immunotherapeutic strategies are needed. Chimeric antigen receptor (CAR) T cell therapy empowers patients' own T cells to fight and eradicate cancer, and has been tested against various targets in OC. A promising candidate is the MUC16 ectodomain. This ectodomain remains on the cell surface after cleavage of cancer antigen 125 (CA125), the domain distal from the membrane, which is currently used as a serum biomarker for OC. CA125 itself has not been tested as a possible CAR target. In this study, we examined the suitability of the CA125 as a target for CAR T cell therapy. METHODS: We tested a series of antibodies raised against the CA125 extracellular repeat domain of MUC16 and adapted them to the CAR format. Comparisons between these candidates, and against an existing CAR targeting the MUC16 ectodomain, identified K101 as having high potency and specificity. The K101CAR was subjected to further biochemical and functional tests, including examination of the effect of soluble CA125 on its activity. Finally, we used cell lines and advanced orthotopic patient-derived xenograft (PDX) models to validate, in vivo, the efficiency of our K101CAR construct. RESULTS: We observed a high efficacy of K101CAR T cells against cell lines and patient-derived tumors, in vitro and in vivo. We also demonstrated that K101CAR functionality was not impaired by the soluble antigen. Finally, in direct comparisons, K101CAR, which targets the CA125 extracellular repeat domains, was shown to have similar efficacy to the previously validated 4H11CAR, which targets the MUC16 ectodomain. CONCLUSIONS: Our in vitro and in vivo results, including PDX studies, demonstrate that the CA125 domain of MUC16 represents an excellent target for treating MUC16-positive malignancies.


Subject(s)
CA-125 Antigen , Membrane Proteins , Female , Humans , CA-125 Antigen/metabolism , Ovarian Neoplasms/drug therapy
5.
J Hand Surg Eur Vol ; : 17531934241242678, 2024 Mar 27.
Article in English | MEDLINE | ID: mdl-38534125

ABSTRACT

The aims of this study were to retrospectively assess the occurrence of complications or need for secondary wrist procedures after the Sauvé-Kapandji procedure, and to prospectively assess patient-reported outcomes at long-term follow-up. All patients treated with the Sauvé-Kapandji procedure in our tertiary referral hospital between January 2008 and September 2021 were identified and contacted to complete the Quick Disabilities of the Arm, Shoulder, and Hand and the Patient-Rated Wrist/Hand Evaluation outcome measures. In total, 30 patients, with a median follow-up of 82 months, were included in this study. Complications occurred in 6 of 30 patients, which resulted in six secondary wrist procedures. Mean Quick Disabilities of the Arm, Shoulder, and Hand and Patient-Rated Wrist/Hand Evaluation scores were 30.1 and 33.6, respectively. We conclude that in respect of long-term outcomes, the Sauvé-Kapandji procedure can still be deemed to be a useful procedure, especially in patients with few other reconstructive options.Level of evidence: IV.

6.
Circ Genom Precis Med ; 16(4): 328-336, 2023 08.
Article in English | MEDLINE | ID: mdl-37199186

ABSTRACT

BACKGROUND: Genetic variants in TNNI3K (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between TNNI3K variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function. METHODS: We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including TNNI3K. We further performed burden testing of TNNI3K in the UK Biobank. For 2 novel TNNI3K variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays. RESULTS: We demonstrate enrichment of rare coding TNNI3K variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between TNNI3K missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation. CONCLUSIONS: Our findings demonstrate an increased burden of rare coding TNNI3K variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic TNNI3K variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.


Subject(s)
Cardiomyopathy, Dilated , Humans , Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Dilated/genetics , Retrospective Studies , Arrhythmias, Cardiac/genetics , Genetic Testing , Cardiac Conduction System Disease/genetics , Protein Serine-Threonine Kinases/genetics
7.
Clin Orthop Relat Res ; 481(1): 97-104, 2023 01 01.
Article in English | MEDLINE | ID: mdl-35833810

ABSTRACT

BACKGROUND: Conventional radiographs and clinical reassessment are considered guides in managing clinically suspected scaphoid fractures. This is a unique study as it assessed the value of conventional radiographs and clinical reassessment in a cohort of patients, all of whom underwent additional imaging, regardless of the outcome of conventional radiographs and clinical reassessment. QUESTIONS/PURPOSES: (1) What is the diagnostic performance of conventional radiographs in patients with a clinically suspected scaphoid fracture compared with high-resolution peripheral quantitative CT (HR-pQCT)? (2) What is the diagnostic performance of clinical reassessment in patients with a clinically suspected scaphoid fracture compared with HR-pQCT? (3) What is the diagnostic performance of conventional radiographs and clinical reassessment combined compared with HR-pQCT? METHODS: Between December 2017 and October 2018, 162 patients with a clinically suspected scaphoid fracture presented to the emergency department (ED). Forty-six patients were excluded and another 25 were not willing or able to participate, which resulted in 91 included patients. All patients underwent conventional radiography in the ED and clinical reassessment 7 to 14 days later, together with CT and HR-pQCT. The diagnostic performance characteristics and accuracy of conventional radiographs and clinical reassessment were compared with those of HR-pQCT for the diagnosis of fractures since this was proven to be superior to CT scaphoid fracture detection. The cohort included 45 men and 46 women with a median (IQR) age of 52 years (29 to 67). Twenty-four patients with a median age of 44 years (35 to 65) were diagnosed with a scaphoid fracture on HR-pQCT. RESULTS: When compared with HR-pQCT, conventional radiographs alone had a sensitivity of 67% (95% CI 45% to 84%), specificity of 85% (95% CI 74% to 93%), positive predictive value (PPV) of 62% (95% CI 46% to 75%), negative predictive value (NPV) of 88% (95% CI 80% to 93%), and a positive and negative likelihood ratio (LR) of 4.5 (95% CI 2.4 to 8.5) and 0.4 (95% CI 0.2 to 0.7), respectively. Compared with HR-pQCT, clinical reassessment alone resulted in a sensitivity of 58% (95% CI 37% to 78%), specificity of 42% (95% CI 30% to 54%), PPV of 26% (95% CI 19% to 35%), NPV of 74% (95% CI 62% to 83%), as well as a positive and negative LR of 1.0 (95% CI 0.7 to 1.5) and 1.0 (95% CI 0.6 to 1.7), respectively. Combining clinical examination with conventional radiography produced a sensitivity of 50% (95% CI 29% to 71%), specificity of 91% (95% CI 82% to 97%), PPV of 67% (95% CI 46% to 83%), NPV of 84% (95% CI 77% to 88%), as well as a positive and negative LR of 5.6 (95% CI 2.4 to 13.2) and 0.6 (95% CI 0.4 to 0.8), respectively. CONCLUSION: The accuracy of conventional radiographs (80% compared with HR-pQCT) and clinical reassessment (46% compared with HR-pQCT) indicate that the value of clinical reassessment is limited in diagnosing scaphoid fractures and cannot be considered directive in managing scaphoid fractures. The combination of conventional radiographs and clinical reassessment does not increase the accuracy of these diagnostic tests compared with the accuracy of conventional radiographs alone and is therefore also limited in diagnosing scaphoid fractures. LEVEL OF EVIDENCE: Level II, diagnostic study.


Subject(s)
Fractures, Bone , Hand Injuries , Scaphoid Bone , Wrist Injuries , Male , Humans , Female , Adult , Middle Aged , Fractures, Bone/diagnostic imaging , Scaphoid Bone/injuries , Wrist Injuries/diagnostic imaging , Radiography
8.
Nat Commun ; 13(1): 6383, 2022 10 26.
Article in English | MEDLINE | ID: mdl-36289233

ABSTRACT

The strict exchange of protons for sodium ions across cell membranes by Na+/H+ exchangers is a fundamental mechanism for cell homeostasis. At active pH, Na+/H+ exchange can be modelled as competition between H+ and Na+ to an ion-binding site, harbouring either one or two aspartic-acid residues. Nevertheless, extensive analysis on the model Na+/H+ antiporter NhaA from Escherichia coli, has shown that residues on the cytoplasmic surface, termed the pH sensor, shifts the pH at which NhaA becomes active. It was unclear how to incorporate the pH senor model into an alternating-access mechanism based on the NhaA structure at inactive pH 4. Here, we report the crystal structure of NhaA at active pH 6.5, and to an improved resolution of 2.2 Å. We show that at pH 6.5, residues in the pH sensor rearrange to form new salt-bridge interactions involving key histidine residues that widen the inward-facing cavity. What we now refer to as a pH gate, triggers a conformational change that enables water and Na+ to access the ion-binding site, as supported by molecular dynamics (MD) simulations. Our work highlights a unique, channel-like switch prior to substrate translocation in a secondary-active transporter.


Subject(s)
Escherichia coli Proteins , Escherichia coli Proteins/metabolism , Protons , Antiporters/metabolism , Histidine/metabolism , Hydrogen-Ion Concentration , Escherichia coli/metabolism , Sodium-Hydrogen Exchangers/metabolism , Ions/metabolism , Sodium/metabolism , Water/metabolism
9.
J Hand Surg Eur Vol ; 47(11): 1128-1133, 2022 12.
Article in English | MEDLINE | ID: mdl-36071642

ABSTRACT

Distal oblique bundle (DOB) reinforcement for treatment of post-traumatic bidirectional instability of the distal radioulnar joint (DRUJ) has previously been reported. The objective of the current study was to assess the incidence of symptomatic graft failure and the need for secondary wrist procedures at a longer follow-up in an updated patient cohort of 27 patients with 28 DOB reinforcement procedures. Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) and patient-rated wrist/hand evaluation (PRWHE) outcome measures were also evaluated. At median 82 months follow-up, pre- to postoperative QuickDASH score improved from a mean of 62 (SD 14) to 31 (SD 22) (p < 0.01) and PRWHE score from a mean of 67 (SD 17) to 34 (SD 23) (p < 0.01). Symptomatic graft failure with resultant painful DRUJ instability occurred in four out of 28 procedures, which was better than the published results of alternative surgical options for DRUJ instability. DOB reinforcement presents a relatively safe, effective and durable method for treatment of post-traumatic DRUJ instability.Level of evidence: III.


Subject(s)
Joint Instability , Triangular Fibrocartilage , Wrist Injuries , Humans , Wrist Joint/surgery , Joint Instability/etiology , Cohort Studies , Wrist Injuries/surgery , Triangular Fibrocartilage/surgery
10.
Article in English | MEDLINE | ID: mdl-36128030
13.
Front Cell Dev Biol ; 9: 784367, 2021.
Article in English | MEDLINE | ID: mdl-34912813

ABSTRACT

Eukaryotic cells are characterized by their exquisite compartmentalization resulting from a cornucopia of membrane-bound organelles. Each of these compartments hosts a flurry of biochemical reactions and supports biological functions such as genome storage, membrane protein and lipid biosynthesis/degradation and ATP synthesis, all essential to cellular life. Acting as hubs for the transfer of matter and signals between organelles and throughout the cell, membrane contacts sites (MCSs), sites of close apposition between membranes from different organelles, are essential to cellular homeostasis. One of the now well-acknowledged function of MCSs involves the non-vesicular trafficking of lipids; its characterization answered one long-standing question of eukaryotic cell biology revealing how some organelles receive and distribute their membrane lipids in absence of vesicular trafficking. The endoplasmic reticulum (ER) in synergy with the mitochondria, stands as the nexus for the biosynthesis and distribution of phospholipids (PLs) throughout the cell by contacting nearly all other organelle types. MCSs create and maintain lipid fluxes and gradients essential to the functional asymmetry and polarity of biological membranes throughout the cell. Membrane apposition is mediated by proteinaceous tethers some of which function as lipid transfer proteins (LTPs). We summarize here the current state of mechanistic knowledge of some of the major classes of LTPs and tethers based on the available atomic to near-atomic resolution structures of several "model" MCSs from yeast but also in Metazoans; we describe different models of lipid transfer at MCSs and analyze the determinants of their specificity and directionality. Each of these systems illustrate fundamental principles and mechanisms for the non-vesicular exchange of lipids between eukaryotic membrane-bound organelles essential to a wide range of cellular processes such as at PL biosynthesis and distribution, lipid storage, autophagy and organelle biogenesis.

14.
PLoS Comput Biol ; 17(12): e1009686, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34890397

ABSTRACT

[This corrects the article DOI: 10.1371/journal.pcbi.1008570.].

15.
J Biomech ; 128: 110726, 2021 11 09.
Article in English | MEDLINE | ID: mdl-34534791

ABSTRACT

Scaphoid fractures are difficult to diagnose with current imaging modalities. It is unknown whether the shape of the scaphoid bone, assessed by statistical shape modeling, can be used to differentiate between fractured and non-fractured bones. Therefore, the aim of this study was to investigate whether the presence of a scaphoid fracture is associated with shape modes of a statistical shape model (SSM). Forty-one high-resolution peripheral quantitative computed tomography (HR-pQCT) scans were available from patients with a clinically suspected scaphoid fracture of whom 15 patients had a scaphoid fracture. The scans showed no motion artefacts affecting bone shape. The scaphoid bones were semi-automatically contoured, and the contours were converted to triangular meshes. The meshes were registered, followed by principal component analysis to determine mean shape and shape modes describing shape variance. The first five out of the forty shape modes cumulatively explained 87.8% of the shape variance. Logistic regression analysis was used to study the association between shape modes and fracture presence. The regression models were used to classify the 41 scaphoid bones as fractured or non-fractured using a cut-off value that maximized the sum of sensitivity and specificity. The classification of the models was compared with fracture diagnosis on HR-pQCT. A regression model with four shape modes had an area under the ROC-curve of 72.3% and correctly classified 75.6% of the scaphoid bones (fractured: 60.0%, non-fractured: 84.6%). To conclude, fracture presence in patients with a clinically suspected scaphoid fracture appears to be associated with the shape of the scaphoid bone.


Subject(s)
Fractures, Bone , Scaphoid Bone , Fractures, Bone/diagnostic imaging , Humans , Models, Statistical , Scaphoid Bone/diagnostic imaging , Sensitivity and Specificity , Tomography, X-Ray Computed
16.
J Biol Chem ; 296: 100557, 2021.
Article in English | MEDLINE | ID: mdl-33744283

ABSTRACT

Biological membranes define the boundaries of cells and compartmentalize the chemical and physical processes required for life. Many biological processes are carried out by proteins embedded in or associated with such membranes. Determination of membrane protein (MP) structures at atomic or near-atomic resolution plays a vital role in elucidating their structural and functional impact in biology. This endeavor has determined 1198 unique MP structures as of early 2021. The value of these structures is expanded greatly by deposition of their three-dimensional (3D) coordinates into the Protein Data Bank (PDB) after the first atomic MP structure was elucidated in 1985. Since then, free access to MP structures facilitates broader and deeper understanding of MPs, which provides crucial new insights into their biological functions. Here we highlight the structural and functional biology of representative MPs and landmarks in the evolution of new technologies, with insights into key developments influenced by the PDB in magnifying their impact.


Subject(s)
Databases, Protein , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Databases, Protein/history , History, 20th Century , History, 21st Century , Protein Conformation , Structure-Activity Relationship
17.
J Am Heart Assoc ; 10(7): e018063, 2021 04 06.
Article in English | MEDLINE | ID: mdl-33787324

ABSTRACT

Background One third of primary prevention implantable cardioverter-defibrillator patients receive appropriate therapy, but all remain at risk of defibrillator complications. Information on these complications in contemporary cohorts is limited. This study assessed complications and their risk factors after defibrillator implantation in a Dutch nationwide prospective registry cohort and forecasts the potential reduction in complications under distinct scenarios of updated indication criteria. Methods and Results Complications in a prospective multicenter registry cohort of 1442 primary implantable cardioverter-defibrillator implant patients were classified as major or minor. The potential for reducing complications was derived from a newly developed prediction model of appropriate therapy to identify patients with a low probability of benefitting from the implantable cardioverter-defibrillator. During a follow-up of 2.2 years (interquartile range, 2.0-2.6 years), 228 complications occurred in 195 patients (13.6%), with 113 patients (7.8%) experiencing at least one major complication. Most common ones were lead related (n=93) and infection (n=18). Minor complications occurred in 6.8% of patients, with lead-related (n=47) and pocket-related (n=40) complications as the most prevailing ones. A surgical reintervention or additional hospitalization was required in 53% or 61% of complications, respectively. Complications were strongly associated with device type. Application of stricter implant indication results in a comparable proportional reduction of (major) complications. Conclusions One in 13 patients experiences at least one major implantable cardioverter-defibrillator-related complication, and many patients undergo a surgical reintervention. Complications are related to defibrillator implantations, and these should be discussed with the patient. Stricter implant indication criteria and careful selection of device type implanted may have significant clinical and financial benefits.


Subject(s)
Death, Sudden, Cardiac , Defibrillators, Implantable , Electric Countershock , Postoperative Complications , Prosthesis Implantation/adverse effects , Aged , Death, Sudden, Cardiac/epidemiology , Death, Sudden, Cardiac/prevention & control , Defibrillators, Implantable/adverse effects , Defibrillators, Implantable/classification , Defibrillators, Implantable/statistics & numerical data , Electric Countershock/adverse effects , Electric Countershock/instrumentation , Electric Countershock/methods , Equipment Failure Analysis/methods , Equipment Failure Analysis/statistics & numerical data , Female , Humans , Male , Needs Assessment , Netherlands/epidemiology , Patient Selection , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Registries/statistics & numerical data , Reoperation/statistics & numerical data , Risk Assessment , Risk Factors
18.
PLoS Comput Biol ; 17(2): e1008570, 2021 02.
Article in English | MEDLINE | ID: mdl-33626036

ABSTRACT

How does morphological complexity evolve? This study suggests that the likelihood of mutations increasing phenotypic complexity becomes smaller when the phenotype itself is complex. In addition, the complexity of the genotype-phenotype map (GPM) also increases with the phenotypic complexity. We show that complex GPMs and the above mutational asymmetry are inevitable consequences of how genes need to be wired in order to build complex and robust phenotypes during development. We randomly wired genes and cell behaviors into networks in EmbryoMaker. EmbryoMaker is a mathematical model of development that can simulate any gene network, all animal cell behaviors (division, adhesion, apoptosis, etc.), cell signaling, cell and tissues biophysics, and the regulation of those behaviors by gene products. Through EmbryoMaker we simulated how each random network regulates development and the resulting morphology (i.e. a specific distribution of cells and gene expression in 3D). This way we obtained a zoo of possible 3D morphologies. Real gene networks are not random, but a random search allows a relatively unbiased exploration of what is needed to develop complex robust morphologies. Compared to the networks leading to simple morphologies, the networks leading to complex morphologies have the following in common: 1) They are rarer; 2) They need to be finely tuned; 3) Mutations in them tend to decrease morphological complexity; 4) They are less robust to noise; and 5) They have more complex GPMs. These results imply that, when complexity evolves, it does so at a progressively decreasing rate over generations. This is because as morphological complexity increases, the likelihood of mutations increasing complexity decreases, morphologies become less robust to noise, and the GPM becomes more complex. We find some properties in common, but also some important differences, with non-developmental GPM models (e.g. RNA, protein and gene networks in single cells).


Subject(s)
Computer Simulation , Developmental Biology/methods , Gene Regulatory Networks , Software , Animals , Biological Evolution , Cell Adhesion , Epithelial Cells/metabolism , Gene Expression , Gene Expression Profiling , Gene Expression Regulation, Developmental , Genetic Association Studies , Genotype , Models, Genetic , Mutation , Phenotype , Signal Transduction/physiology
19.
Bone Joint J ; 102-B(12): 1697-1702, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33249894

ABSTRACT

AIMS: Fixation of scaphoid nonunion with a volar locking plate and cancellous bone grafting has been shown to be a successful technique in small series. Few mid- or long-term follow-up studies have been reported. The aim of this study was to report the mid-term radiological and functional outcome of plate fixation for scaphoid nonunion. METHODS: Patients with a scaphoid nonunion were prospectively enrolled and treated with open reduction using a volar approach, debridement of the nonunion, and fixation using a locking plate and cancellous bone grafting, from the ipsilateral iliac crest. Follow-up included examination, functional assessment using the patient-rated wrist/hand evaluation (PRWHE), and multiplanar reformation CT scans at three-month intervals until union was confirmed. RESULTS: A total of 49 patients with a mean age of 31 years (16 to 74) and a mean duration of nonunion of 3.6 years (0.4 to 16) were included. Postoperatively, the nonunion healed in 47 patients (96%) as shown on CT scans. The mean time to union was 4.2 months (3 to 12). Due to impingement of the plate on the volar rim of the radius and functional limitation, the hardware was removed in 18 patients. At a median follow-up of 38 months in 34 patients, the mean active range of motion (ROM) improved significantly from 89° to 124° (SD 44°; p = 0.003). The mean grip strength improved significantly from 52% to 79% (SD 28%; p < 0.001) of the contralateral side. The mean PRWHE score improved significantly from 66 to 17 points (SD 25; p < 0.001). CONCLUSION: Locking plate fixation supplemented with autologous cancellous bone grafting is a successful form of treatment for scaphoid nonunion. Functional outcomes improve with the passage of time, and mid-term results are excellent with a significant improvement in ROM, grip strength, and functional outcome as measured by the PRWHE. Cite this article: Bone Joint J 2020;102-B(12):1697-1702.


Subject(s)
Bone Transplantation , Fracture Fixation, Internal , Fractures, Ununited/surgery , Scaphoid Bone/injuries , Scaphoid Bone/surgery , Adolescent , Adult , Aged , Bone Plates , Debridement , Female , Fractures, Ununited/diagnostic imaging , Humans , Male , Middle Aged , Prospective Studies , Recovery of Function , Scaphoid Bone/diagnostic imaging , Tomography, X-Ray Computed , Treatment Outcome , Young Adult
20.
Eur Heart J Case Rep ; 4(FI1): 1-5, 2020 Oct.
Article in English | MEDLINE | ID: mdl-33089050

ABSTRACT

BACKGROUND: Early studies have led to the repositioning of a subgroup of antimalarial agents (e.g. chloroquine and hydroxychloroquine) as antiviral treatment in coronavirus disease 2019 (COVID-19) patients. These drugs are now being prescribed based on small non-controlled studies, but larger controlled studies have yet to demonstrate the positive effect of these drugs. In addition, these drugs are also known for their QT interval-prolonging effect associated with significant morbidity and mortality. CASE SUMMARY: We present a case of a 66-year-old female admitted to the intensive care unit with respiratory failure due to COVID-19. She was treated with chloroquine (QTc interval at baseline was 429 ms). Despite cessation of chloroquine, but after the start of erythromycin, she developed severe QTc interval prolongation (QTc interval 550 ms) and 'Torsade de Pointes'. Two weeks after cessation of all QTc interval-prolonging drugs, the QTc interval was restored. DISCUSSION: The elimination half-life of chloroquine ranges from days up to weeks. Even after discontinuation of chloroquine, ECG monitoring in COVID-19 patients is warranted. We recommend observation of the QT interval after cessation of chloroquine in cases where other potentially QT interval-prolonging drugs are introduced.

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