Incidence of Atrial Fibrillation or Arrhythmias After Patent Foramen Ovale Closure.

Background: Patients with a patent foramen ovale (PFO) who undergo percutaneous PFO closure are at a greater risk of developing atrial fibrillation (AF) compared with patients whose PFOs are managed medically. Postclosure AF appears to be well tolerated if treated but may increase the risk for stroke. Postclosure AF is reported to occur in 3.7% to 7.4% of patients; however, incidence across devices remains uncertain. This study aims to evaluate the frequency of postclosure AF, atrial flutter, and arrhythmias in 6 PFO closure devices. Methods: Four hundred forty-five patients underwent percutaneous PFO closure with appropriate follow-up between 2001 and 2021. The procedure was performed using Abbott Amplatzer PFO, Amplatzer ASD, Amplatzer Cribriform, NMT CardioSEAL, Gore Helex, or Gore Cardioform devices. Incidence of AF, atrial flutter, and arrhythmias were assessed by electrocardiogram within 6 months from closure. Multivariate logistic regression evaluated potential predictors of postclosure AF or atrial flutter. Results: Postclosure AF or atrial flutter occurred in 30 patients (6.7%) within 6 months, and its incidence was significantly different across devices. Gore Cardioform had the greatest frequency of postclosure AF or atrial flutter events (16.8%) compared with other devices. The Gore Cardioform device, larger device sizes, and male sex were associated with greater risk of postclosure AF or atrial flutter. Conclusions: Postclosure AF or atrial flutter was more likely to occur in the Gore Cardioform device, in males, and in patients who underwent PFO closure with larger devices. Although it is more effective for complete closure, the Gore Cardioform device was shown to be an independent predictor of postclosure AF or atrial flutter.

Advanced hemodynamic and cluster analysis for identifying novel RV function subphenotypes in patients with pulmonary hypertension.

BACKGROUND: Quantifying right ventricular (RV) function is important to describe the pathophysiology of in pulmonary hypertension (PH). Current phenotyping strategies in PH rely on few invasive hemodynamic parameters to quantify RV dysfunction severity. The aim of this study was to identify novel RV phenotypes using unsupervised clustering methods on advanced hemodynamic features of RV function. METHODS: Participants were identified from the University of Arizona Pulmonary Hypertension Registry (n = 190). RV-pulmonary artery coupling (Ees/Ea), RV systolic (Ees), and diastolic function (Eed) were quantified from stored RV pressure waveforms. Consensus clustering analysis with bootstrapping was used to identify the optimal clustering method. Pearson correlation analysis was used to reduce collinearity between variables. RV cluster subphenotypes were characterized using clinical data and compared to pulmonary vascular resistance (PVR) quintiles. RESULTS: Five distinct RV clusters (C1-C5) with distinct RV subphenotypes were identified using k-medoids with a Pearson distance matrix. Clusters 1 and 2 both have low diastolic stiffness (Eed) and afterload (Ea) but RV-PA coupling (Ees/Ea) is decreased in C2. Intermediate cluster (C3) has a similar Ees/Ea as C2 but with higher PA pressure and afterload. Clusters C4 and C5 have increased Eed and Ea but C5 has a significant decrease in Ees/Ea. Cardiac output was high in C3 distinct from the other clusters. In the PVR quintiles, contractility increased and stroke volume decreased as a function of increased afterload. World Symposium PH classifications were distributed across clusters and PVR quintiles. CONCLUSIONS: RV-centric phenotyping offers an opportunity for a more precise-medicine-based management approach.

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension.

Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca2+ and Na+ influx in multiple types of cells. Little is known about the functional role of Piezo1 in the lung vasculature and its potential pathogenic role in pulmonary arterial hypertension (PAH). Pulmonary arterial endothelial cells (PAECs) are constantly under mechanic stretch and shear stress that are sufficient to activate Piezo channels. Here, we report that Piezo1 is significantly upregulated in PAECs from patients with idiopathic PAH and animals with experimental pulmonary hypertension (PH) compared with normal controls. Membrane stretch by decreasing extracellular osmotic pressure or by cyclic stretch (18% CS) increases Ca2+-dependent phosphorylation (p) of AKT and ERK, and subsequently upregulates expression of Notch ligands, Jagged1/2 (Jag-1 and Jag-2), and Delta like-4 (DLL4) in PAECs. siRNA-mediated downregulation of Piezo1 significantly inhibited the stretch-mediated pAKT increase and Jag-1 upregulation, whereas downregulation of AKT by siRNA markedly attenuated the stretch-mediated Jag-1 upregulation in human PAECs. Furthermore, the mRNA and protein expression level of Piezo1 in the isolated pulmonary artery, which mainly contains pulmonary arterial smooth muscle cells (PASMCs), from animals with severe PH was also significantly higher than that from control animals. Intraperitoneal injection of a Piezo1 channel blocker, GsMTx4, ameliorated experimental PH in mice. Taken together, our study suggests that membrane stretch-mediated Ca2+ influx through Piezo1 is an important trigger for pAKT-mediated upregulation of Jag-1 in PAECs. Upregulation of the mechanosensitive channel Piezo1 and the resultant increase in the Notch ligands (Jag-1/2 and DLL4) in PAECs may play a critical pathogenic role in the development of pulmonary vascular remodeling in PAH and PH.

Dynamic differential evolution schemes of WRKY transcription factors in domesticated and wild rice.

WRKY transcription factors play key roles in stress responses, growth, and development. We previously reported on the evolution of WRKYs from unicellular green algae to land plants. To address recent evolution events, we studied three domesticated and eight wild species in the genus Oryza, an ideal model due to its long history of domestication, economic importance, and central role as a model system. We have identified prevalence of Group III WRKYs despite differences in breeding of cultivated and wild species. Same groups of WRKY genes tend to cluster together, suggesting recent, multiple duplication events. Duplications followed by divergence may result in neofunctionalizations of co-expressed WRKY genes that finely tune the regulation of target genes in a same metabolic or response pathway. WRKY genes have undergone recent rearrangements to form novel genes. Group Ib WRKYs, unique to AA genome type Oryza species, are derived from Group III genes dated back to 6.76 million years ago. Gene tree reconciliation analysis with the species tree revealed details of duplication and loss events in the 11 genomes. Selection analysis on single copy orthologs reveals the highly conserved nature of the WRKY domain and clusters of fast evolving sites under strong positive selection pressure. Also, the numbers of single copy orthologs under positive or negative selection almost evenly split. Our results provide valuable insights into the preservation and diversification of an important gene family under strong selective pressure for biotechnological improvements of the world's most valued food crop.

MicroRNA-mediated downregulation of K+ channels in pulmonary arterial hypertension.

Downregulated expression of K+ channels and decreased K+ currents in pulmonary artery smooth muscle cells (PASMC) have been implicated in the development of sustained pulmonary vasoconstriction and vascular remodeling in patients with idiopathic pulmonary arterial hypertension (IPAH). However, it is unclear exactly how K+ channels are downregulated in IPAH-PASMC. MicroRNAs (miRNAs) are small non-coding RNAs that are capable of posttranscriptionally regulating gene expression by binding to the 3'-untranslated regions of their targeted mRNAs. Here, we report that specific miRNAs are responsible for the decreased K+ channel expression and function in IPAH-PASMC. We identified 3 miRNAs (miR-29b, miR-138, and miR-222) that were highly expressed in IPAH-PASMC in comparison to normal PASMC (>2.5-fold difference). Selectively upregulated miRNAs are correlated with the decreased expression and attenuated activity of K+ channels. Overexpression of miR-29b, miR-138, or miR-222 in normal PASMC significantly decreased whole cell K+ currents and downregulated voltage-gated K+ channel 1.5 (KV1.5/KCNA5) in normal PASMC. Inhibition of miR-29b in IPAH-PASMC completely recovered K+ channel function and KV1.5 expression, while miR-138 and miR-222 had a partial or no effect. Luciferase assays further revealed that KV1.5 is a direct target of miR-29b. Additionally, overexpression of miR-29b in normal PASMC decreased large-conductance Ca2+-activated K+ (BKCa) channel currents and downregulated BKCa channel ß1 subunit (BKCaß1 or KCNMB1) expression, while inhibition of miR-29b in IPAH-PASMC increased BKCa channel activity and BKCaß1 levels. These data indicate upregulated miR-29b contributes at least partially to the attenuated function and expression of KV and BKCa channels in PASMC from patients with IPAH.

Seeing it my way: living with childhood onset visual disability.

BACKGROUND: Although the significant impact of visual disability in childhood has been widely recognized, children's own perspectives of living with a visual impairment have not been considered. We report the experiences of visually impaired (VI) children and young people aged 10-15 years about growing up with impaired sight. METHODS: The participants were 32 VI children and young people, aged 10-15 years [visual acuity logarithm of minimum angle of resolution (LogMAR) worse than 0.51] recruited through National Health Service (NHS) paediatric ophthalmology and developmental vision clinics and 11 VI pupils aged 12-17 attending a specialist school for pupils with disabilities. Individual semi-structured interviews with participants captured their experiences of living with a visual impairment. A child-centred interview topic guide was developed from a literature review, observations at ophthalmology clinics, consultation with health and education professionals working with VI children and young people, and interviews and a focus group with VI pupils from the specialist school. Collaborative qualitative thematic analysis by three researchers identified emergent themes. NVivo software was used for coding the data. RESULTS: Analysis identified six themes concerning living with a visual impairment: (i) social relationships, participation and acceptance; (ii) independence and autonomy; (iii) psychological and emotional well-being; (iv) aspirations and concerns about the future; (v) functioning - home, school and leisure; and (vi) treatment of eye condition. Key issues included: the importance of family and peer support; balancing independence, support and safety; the emotional burden and adjustment of living with a disability; concerns about education and job prospects in the future; functional restrictions and limitations; and ongoing management of the eye condition. CONCLUSIONS: The findings offer insights into the complex realities of living with visual impairment. They provide the basis for development of patient-reported outcome measures. They can also serve to help enrich the understanding of health professionals working with VI children and young people, potentially enabling them to better support them.

Effectiveness of four hours of education in interpretation of radiographic studies.

Clinicians working with oropharyngeal swallowing disorders often use videofluoroscopy to define their patients' swallowing abnormalities. This study examined the effect of 4 hours of training in the identification of head and neck anatomy and oropharyngeal swallowing disorders viewed radiographically. Ninety clinicians participated in a 5-hour session which included 30-minute pre- and post-tests requiring identification of head and neck anatomy and oropharyngeal swallowing disorders and a 4-hour training period. Results showed significant improvement in identification of both radiographic anatomy and swallowing disorders. The change in pre- and post-test measures was negatively correlated with extent of prior experience in dysphagia. Similar studies are needed with clinicians or students inexperienced in dysphagia to define the number of hours of education needed in order for students to reach a desired accuracy level in their identifications.

Plasminogen activator inhibitor type-1 and interleukin-6 in haemolytic uraemic syndrome.

OBJECTIVE: Because haemolytic uraemic syndrome (HUS) is an important cause of renal dysfunction in children, the availability of prognostic markers of disease severity could assist in identifying those at risk of developing long-term sequelae. The aim of this study was to test the hypothesis that plasma levels of plasminogen activator inhibitor type-1 (PAI-1) and interleukin-6 (IL-6) in children at the time of diagnosis of HUS would predict renal function outcome in terms of glomerular filtration rate (GFR). METHODOLOGY: Fourteen children suffering from diarrhoeal HUS were studied. Plasma samples were assayed for PAI-1 and IL-6, and GFR was measured at intervals after discharge from hospital. Twelve months following their recovery from HUS, the children were allocated to one of two outcome groups depending on whether GFR was above (Good Outcome, n = 9), or below (Poor Outcome, n = 5) 80 mL/min per 1.73 m2. RESULTS: Elevated concentrations of PAI-1 were found in 4 of 5 Poor Outcome and 4 of 9 Good Outcome children. At the same time, increased concentrations of IL-6 were observed in 3 of 5 Poor Outcome and 3 of 9 Good Outcome children. Renal function continued to be compromised in four Poor Outcome children 36 months after diagnosis. CONCLUSIONS: Our data show that PAI-1 and IL-6 are elevated in the plasma of some children at the time of diagnosis of HUS, but that neither is a definitive prognostic marker of poor outcome 3 years later.

Molecular evidence for an African origin of the Hawaiian endemic Hesperomannia (Asteraceae).

Identification of the progenitors of plants endemic to oceanic islands often is complicated by extreme morphological divergence between island and continental taxa. This is especially true for the Hawaiian Islands, which are 3,900 km from any continental source. We examine the origin of Hesperomannia, a genus of three species endemic to Hawaii that always have been placed in the tribe Mutisieae of the sunflower family. Phylogenetic analyses of representatives from all tribes in this family using the chloroplast gene ndhF (where ndhF is the ND5 protein of chloroplast NADH dehydrogenase) indicate that Hesperomannia belongs to the tribe Vernonieae. Phylogenetic comparisons within the Vernonieae using sequences of both ndhF and the internal transcribed spacer regions of nuclear ribosomal DNA reveal that Hesperomannia is sister to African species of Vernonia. Long-distance dispersal northeastward from Africa to southeast Asia and across the many Pacific Ocean island chains is the most likely explanation for this unusual biogeographic connection. The 17- to 26-million-year divergence time between African Vernonia and Hesperomannia estimated by the DNA sequences predates the age of the eight existing Hawaiian Islands. These estimates are consistent with an hypothesis that the progenitor of Hesperomannia arrived at one of the low islands of the Hawaiian-Emperor chain between the late Oligocene and mid-Miocene when these islands were above sea level. Subsequent to its arrival the southeast Pacific island chains served as steppingstones for dispersal to the existing Hawaiian Islands.

Homograft root replacement for juvenile rheumatoid aortic valve incompetence.

We report a case of severe, crippling juvenile rheumatoid arthritis and aortic insufficiency in a young woman. Homograft replacement of the aortic root offered both long-term durability and the freedom from thromboembolism that her systemic illness required.

Severe meningococcal septicaemia associated with splenic rupture.

OBJECTIVE: To present the first report of ruptured spleen associated with meningococcal septicaemia. CLINICAL FEATURES: A 13-year-old girl presented with an acute abdomen and clinical signs of meningococcal septicaemia. Features of her illness placed her in a high mortality group. INTERVENTION AND OUTCOME: She required cardiovascular and respiratory support in the Intensive Care Unit. Failure to initially identify the organism led to percutaneous fine-needle aspiration of fluid in the lesser sac. A laparotomy revealed free intraperitoneal blood and a ruptured spleen. During the course of her illness she was given penicillin and methylprednisolone, and required haemodialysis. She made a complete recovery. CONCLUSION: Ruptured spleen does occur with severe meningococcaemia, and may complicate management.

Caval thrombolysis in neonates using low doses of recombinant human tissue-type plasminogen activator.

Four neonates suffered caval thrombosis secondary to indwelling central catheters. Dissolution of thrombus with recombinant tissue plasminogen activator (rt-PA) as a low-dose infusion (0.05 mg/kg/hr) directly into thrombus was successful in three patients. rt-PA was ceased after three days in the fourth patient because of catheter malposition. Thrombolysis was achieved between four and ten days. Rethrombosis occurred in one patient despite heparin prophylaxis. Plasminogen activator infusions were titrated to maintain fibrinogen levels above 100 mg/dl. One neonate suffered an intracranial haemorrhage. Regional rt-PA is an alternative to thrombectomy in critically ill neonates.

Prothrombinex-induced thrombosis and its management with regional plasminogen activator in hepatic failure.

Fulminant hepatic failure causes a bleeding diathesis as a result of impaired synthesis of hepatic clotting factors, thrombocytopenia, fibrinolysis and disseminated intravascular coagulation. Administration of clotting factor concentrates can cause thrombosis in patients with acute hepatic failure. Regional infusion of recombinant tissue-type plasminogen activator may be used to induce local thrombolysis. A case report of a five-year-old child is presented and the literature is reviewed.

The use of inotropic and afterload-reducing agents in neonates.

Vasodilators have demonstrated efficacy in neonates with depressed myocardial function. The magnitude of benefit depends on the preexisting hemodynamic state and concurrent treatment modalities. In patients with increased filling pressures, vasodilators increase cardiac output with negligible effect on MAP, with volume resuscitation to restore pretreatment filling pressures offering additional benefit. The rationale for use in neonatal respiratory disease remains less clear, with no vasoactive drug showing selective pulmonary vasodilatation. Benefit no doubt accrues from the improved coronary perfusion that occurs with reduction in filling pressures. In addition, reduced interventricular diastolic dependence and thereby improved ventricular compliance, as well as the afterload-reducing effect of decreased chamber size, may significantly reduce the effect of the lung disease on myocardial functioning.

The skeletonized internal mammary artery.

The internal mammary artery increasingly is being used to construct multiple distal anastomoses. By skeletonizing the pedicle, the artery is functionally lengthened and sequential anastomoses are easier to perform.

Arterial injuries below the knee: fifty-one patients with 82 injuries.

Clinical features of tibial and peroneal artery injuries are characterized in a review of 51 patients with 82 injured arteries. Injuries were penetrating in 34 (67%) patients and blunt in 17 (33%). Physical findings suggested arterial injuries in 42 (82%) patients, but nine had no signs of vascular trauma. Nineteen patients with no palpable distal pulses had average preoperative delays of nearly 5 hours, suggesting a lack of appreciation for the morbid potential of these injuries. Operations included ligations of single-vessel injuries and arterial reconstructions in the 21 (41%) patients with two or more injured vessels. Amputations were necessary in eight (16%) patients. Limb loss was more frequent with blunt trauma (23%), shotgun wounds (33%), initial absent pulses (32%), and three injured vessels (60%). The frequency of limb loss with these injuries emphasizes the importance of early diagnosis, expedient operation, and thorough revascularization.

Replacement of aromatic or heteroaromatic groups in nonsteroidal antiinflammatory agents with the ferrocene group.

Ferrocene analogues of the antiinflammatory agents tolmetin (1), fenbufen (2), flurbiprofen (3), and fenclofenac (4) were synthesized and tested for biological activity. The derivatives exhibited little or no antiarthritic or platelet antiaggregatory activity, indicating that the ferrocene moiety is a poor bioisostere for aromatic or heteroaromatic groups in nonsteroidal antiinflammatory agents.