Implementing a cirrhosis order set in a tertiary healthcare system: a theory-informed formative evaluation.

BACKGROUND: Standardized order sets are a means of increasing adherence to clinical practice guidelines and improving the quality of patient care. Implementation of novel quality improvement initiatives like order sets can be challenging. Before the COVID-19 pandemic, we conducted a formative evaluation to understand healthcare providers' perspectives on implementing clinical changes and the individual, collective and organizational contextual factors that might impact implementation at eight hospital sites in Alberta, Canada. METHODS: We utilized concepts from the Consolidated Framework for Implementation Research (CFIR) and Normalisation Process Theory (NPT) to understand the context, past implementation experiences, and perceptions of the cirrhosis order set. Eight focus groups were held with healthcare professionals caring for patients with cirrhosis. Data were coded deductively using relevant constructs of NPT and CFIR. A total of 54 healthcare professionals, including physicians, nurses, nurse practitioners, social workers and pharmacists and a physiotherapist, participated in the focus groups. RESULTS: Key findings revealed that participants recognized the value of the cirrhosis order set and its potential to improve the quality of care. Participants highlighted potential implementation challenges, including multiple competing quality improvement initiatives, feelings of burnout, lack of communication between healthcare provider groups, and a lack of dedicated resources to support implementation. CONCLUSIONS: Implementing a complex improvement initiative across clinician groups and acute care sites presents challenges. This work yielded insights into the significant influence of past implementation of similar interventions and highlighted the importance of communication between clinician groups and resources to support implementation. However, by using multiple theoretical lenses to illuminate what and how contextual and social processes will influence uptake, we can better anticipate challenges during the implementation process.

Knight Shift and Leading Superconducting Instability from Spin Fluctuations in Sr_{2}RuO_{4}.

Recent nuclear magnetic resonance studies [A. Pustogow et al., Nature 574, 72 (2019)] have challenged the prevalent chiral triplet pairing scenario proposed for Sr_{2}RuO_{4}. To provide guidance from microscopic theory as to which other pair states might be compatible with the new data, we perform a detailed theoretical study of spin fluctuation mediated pairing for this compound. We map out the phase diagram as a function of spin-orbit coupling, interaction parameters, and band structure properties over physically reasonable ranges, comparing when possible with photoemission and inelastic neutron scattering data information. We find that even-parity pseudospin singlet solutions dominate large regions of the phase diagram, but in certain regimes spin-orbit coupling favors a near-nodal odd-parity triplet superconducting state, which is either helical or chiral depending on the proximity of the γ band to the van Hove points. A surprising near degeneracy of the nodal s^{'} and d_{x^{2}-y^{2}} wave solutions leads to the possibility of a near-nodal time-reversal symmetry broken s^{'}+id_{x^{2}-y^{2}} pair state. Predictions for the temperature dependence of the Knight shift for fields in and out of plane are presented for all states.

Personalizing obesity assessment and care planning in primary care: patient experience and outcomes in everyday life and health.

Obesity is a complex, chronic disease, frequently associated with multiple comorbidities. Its management is hampered by a lack of translation of evidence on chronicity and pathophysiology into clinical practice. Also, it is not well understood how to support effective provider-patient communication that adequately addresses patients' personal root causes and barriers and helps them feel capable to take action for their health. This study examined interpersonal processes during clinical consultations, their impacts, and outcomes with the aim to develop an approach to personalized obesity assessment and care planning. We used a qualitative, explorative design with 20 participants with obesity, sampling for maximum variation, to examine video-recorded consultations, patient interviews at three time points, provider interviews and patient journals. Analysis was grounded in a dialogic interactional perspective and found eight key processes that supported patients in making changes to improve health: compassion and listening; making sense of root causes and contextual factors in the patient's story; recognizing strengths; reframing misconceptions about obesity; focusing on whole-person health; action planning; fostering reflection and experimenting. Patient outcomes include activation, improved physical and psychological health. The proposed approach fosters emphatic care relationships and sensible care plans that support patients in making manageable changes to improve health.

A Low Concentration of Tacrolimus/Semifluorinated Alkane (SFA) Eyedrop Suppresses Intraocular Inflammation in Experimental Models of Uveitis.

PURPOSE: Corticosteroids remain the mainstay therapy for uveitis, a major cause of blindness in the working age population. However, a substantial number of patients cannot benefit from the therapy due to steroids resistance or intolerance. Tacrolimus has been used to treat refractory uveitis through systemic administration. The aim of this study was to evaluate the therapeutic potential of 0.03% tacrolimus eyedrop in mouse models of uveitis. METHODS: 0.03% tacrolimus in perfluorobutylpentane (F4H5) (0.03% Tacrolimus/SFA) was formulated using a previously published protocol. Tacrolimus suspended in PBS (0.03% Tacrolimus/PBS) was used as a control. In addition, 0.1% dexamethasone (0.1% DXM) was used as a standard therapy control. Endotoxin-induced uveitis (EIU) and experimental autoimmune uveoretinitis (EAU) were induced in adult C57BL/6 mice using protocols described previously. Mice were treated with eyedrops three times/day immediately after EIU induction for 48 h or from day 14 to day 25 post-immunization (for EAU). Clinical and histological examinations were conducted at the end of the experiment. Pharmacokinetics study was conducted in mice with and without EIU. At different times after eyedrop treatment, ocular tissues were collected for tacrolimus measurement. RESULTS: The 0.03% Tacrolimus/SFA eyedrop treatment reduced the clinical scores and histological scores of intraocular inflammation in both EIU and EAU to the levels similar to 0.1% DXM eyedrop treatment. The 0.03% Tacrolimus/PBS did not show any suppressive effect in EIU and EAU. Pharmacokinetic studies showed that 15 min after topical administration of 0.03% Tacrolimus/SFA, low levels of tacrolimus were detected in the retina (48 ng/g tissue) and vitreous (2.5 ng/ml) in normal mouse eyes, and the levels were significantly higher in EIU eyes (102 ng/g tissue in the retina and 24 ng/ml in the vitreous). Tacrolimus remained detectable in intraocular tissues of EIU eyes 6 h after topical administration (68 ng/g retinal tissue, 10 ng/ml vitreous). Only background levels of tacrolimus were detected in the retina (2-8 ng/g tissue) after 0.03% Tacrolimus/PBS eyedrop administration. CONCLUSION: 0.03% Tacrolimus/SFA eyedrop can penetrate ocular barrier and reach intraocular tissue at therapeutic levels in mouse eyes, particularly under inflammatory conditions. 0.03% Tacrolimus/SFA eyedrop may have therapeutic potentials for inflammatory eye diseases including uveitis.

Challenges in interdisciplinary weight management in primary care: lessons learned from the 5As Team study.

Increasingly, research is directed at advancing methods to address obesity management in primary care. In this paper we describe the role of interdisciplinary collaboration, or lack thereof, in patient weight management within 12 teams in a large primary care network in Alberta, Canada. Qualitative data for the present analysis were derived from the 5As Team (5AsT) trial, a mixed-method randomized control trial of a 6-month participatory, team-based educational intervention aimed at improving the quality and quantity of obesity management encounters in primary care practice. Participants (n = 29) included in this analysis are healthcare providers supporting chronic disease management in 12 family practice clinics randomized to the intervention arm of the 5AsT trial including mental healthcare workers (n = 7), registered dietitians (n = 7), registered nurses or nurse practitioners (n = 15). Participants were part of a 6-month intervention consisting of 12 biweekly learning sessions aimed at increasing provider knowledge and confidence in addressing patient weight management. Qualitative methods included interviews, structured field notes and logs. Four common themes of importance in the ability of healthcare providers to address weight with patients within an interdisciplinary care team emerged, (i) Availability; (ii) Referrals; (iii) Role perception and (iv) Messaging. However, we find that what was key to our participants was not that these issues be uniformly agreed upon by all team members, but rather that communication and clinic relationships support their continued negotiation. Our study shows that firm clinic relationships and deliberate communication strategies are the foundation of interdisciplinary care in weight management. Furthermore, there is a clear need for shared messaging concerning obesity and its treatment between members of interdisciplinary teams.

Missing an opportunity: the embedded nature of weight management in primary care.

The 5As Team study was designed to create, implement and evaluate a flexible intervention to improve the quality and quantity of weight management visits in primary care. The objective of this portion of the study was to explore how primary care providers incorporate weight management in their practice. 5AsT is a randomized controlled trial (RCT) on the implementation of a 6-month 5 As Team (5AsT) intervention designed to operationalize the 5As of obesity management in primary care. Data for the qualitative portion of the study presented here included semi-structured interviews with 29 multidisciplinary team providers and field notes of intervention sessions. Thematic analysis was undertaken. A key pattern that emerged from the data was that healthcare providers usually do not address obesity as a primary focus for a visit. Rather, obesity is embedded in a wide range of primary care encounters for other conditions. Implications were it can take extra time to discuss weight, it can be inappropriate to bring up weight as a topic, and treating risk factors and root causes of obesity have indirect benefits to patient weight management. Our findings have implications for obesity treatment approaches and tools that assume a discreet weight management visit. The embedded nature of obesity management in primary care can be harnessed to leverage multiple opportunities for asking and assessing root causes of obesity, and working longitudinally towards individual health goals.

5As Team obesity intervention in primary care: development and evaluation of shared decision-making weight management tools.

Despite several clinical practice guidelines, there remains a considerable gap in prevention and management of obesity in primary care. To address the need for changing provider behaviour, a randomized controlled trial with convergent mixed method evaluation, the 5As Team (5AsT) study, was conducted. As part of the 5AsT intervention, the 5AsT tool kit was developed. This paper describes the development process and evaluation of these tools. Tools were co-developed by the multidisciplinary research team and the 5AsT, which included registered nurses/nurse practitioners (n = 15), mental health workers (n = 7) and registered dieticians (n = 7), who were previously randomized to the 5AsT intervention group at a primary care network in Edmonton, Alberta, Canada. The 5AsT tool development occurred through a practice/implementation-oriented, need-based, iterative process during learning collaborative sessions of the 5AsT intervention. Feedback during tool development was received through field notes and final provider evaluation was carried out through anonymous questionnaires. Twelve tools were co-developed with 5AsT. All tools were evaluated as either 'most useful' or 'moderately useful' in primary care practice by the 5AsT. Four key findings during 5AsT tool development were the need for: tools that were adaptive, tools to facilitate interdisciplinary practice, tools to help patients understand realistic expectations for weight loss and shared decision-making tools for goal setting and relapse prevention. The 5AsT tools are primary care tools which extend the utility of the 5As of obesity management framework in clinical practice.

Genetic variants in DNA repair genes as potential predictive markers for oxaliplatin chemotherapy in colorectal cancer.

Oxaliplatin-based chemotherapy exerts its effects through generating DNA damage. Hence, genetic variants in DNA repair pathways could modulate treatment response. We used a prospective cohort of 623 colorectal cancer patients with stage II-IV disease treated with adjuvant/palliative chemotherapy to comprehensively investigate 1727 genetic variants in the DNA repair pathways as potential predictive markers for oxaliplatin treatment. Single nucleotide polymorphisms (SNP) associations with overall survival and recurrence-free survival were assessed using a Cox regression model. Pathway analysis was performed using the gamma method. Patients carrying variant alleles of rs3783819 (MNAT1) and rs1043953 (XPC) experienced a longer overall survival after treatment with oxaliplatin than patients who did not carry the variant allele, while the opposite association was found in patients who were not treated with oxaliplatin (false discovery rate-adjusted P-values for heterogeneity 0.0047 and 0.0237, respectively). The nucleotide excision repair (NER) pathway was found to be most likely associated with overall survival in patients who received oxaliplatin (P-value=0.002). Our data show that genetic variants in the NER pathway are potentially predictive of treatment response to oxaliplatin.

Inhibition of cardiac Kv1.5 and Kv4.3 potassium channels by the class Ia anti-arrhythmic ajmaline: mode of action.

Ajmaline is a class Ia anti-arrhythmic compound that is widely used for the diagnosis of Brugada syndrome and the acute treatment of atrial or ventricular tachycardia. For ajmaline, inhibitory effects on a variety of cardiac K(+) channels have been observed, including cardiac Kv1 and Kv4 channels. However, the exact pharmacological properties of channel blockade have not yet been addressed adequately. Using two different expression systems, we analysed pharmacological effects of ajmaline on the potassium channels Kv1.5 and Kv4.3 underlying cardiac I Kur and I to current, respectively. When expressed in a mammalian cell line, we find that ajmaline inhibits Kv1.5 and Kv4.3 with an IC50 of 1.70 and 2.66 µM, respectively. Pharmacological properties were further analysed using the Xenopus expression system. We find that ajmaline is an open channel inhibitor of cardiac Kv1.5 and Kv4.3 channels. Whereas ajmaline results in a mild leftward shift of Kv1.5 activation curve, no significant effect on Kv4.3 channel activation could be observed. Ajmaline did not significantly affect channel inactivation kinetics. Onset of block was fast. For Kv4.3 channels, no significant effect on recovery from inactivation or channel deactivation could be observed. Furthermore, there was no use-dependence of block. Taken together, we show that ajmaline inhibits cardiac Kv1.5 and Kv4.3 channels at therapeutic concentrations. These data add to the current understanding of the electrophysiological basis of anti-arrhythmic action of ajmaline.

Central role of PKCα in isoenzyme-selective regulation of cardiac transient outward current Ito and Kv4.3 channels.

The transient outward current I(to) is an important determinant of the early repolarization phase. I(to) and its molecular basis Kv4.3 are regulated by adrenergic pathways including protein kinase C. However, the exact regulatory mechanisms have not been analyzed yet. We here analyzed isoenzyme specific regulation of Kv4.3 and I(to) by PKC. Kv4.3 channels were expressed in Xenopus oocytes and currents were measured with double electrode voltage clamp technique. Patch clamp experiments were performed in isolated rat cardiomyocytes. Unspecific PKC stimulation with PMA resulted in a reduction of Kv4.3 current. Similar effects could be observed after activation of conventional PKC isoforms by TMX. Both effects were reversible by pharmacological inhibition of the conventional PKC isoenzymes (Gö6976). In contrast, activation of the novel PKC isoforms (ingenol) did not significantly affect Kv4.3 current. Whereas TMX-induced PKC activation was not attenuated inhibition of PKCß, inhibition of PKCα with HBDDE prevented inhibitory effects of both PMA and TMX. Accordingly, stimulatory effects of PMA and TMX could be mimicked by the α-isoenzyme selective PKC activator iripallidal. Further evidence for the central role of PKCα was provided with the use of siRNAs. We found that PKCα siRNA but not PKCß siRNA abolished the TMX induced effect. In isolated rat cardiomyocytes, PMA dependent I(to) reduction could be completely abolished by pharmacologic inhibition of PKCα. In summary we show that PKCα plays a central role in protein kinase C dependent regulation of Kv4.3 current and native I(to). These results add to the current understanding of isoenzyme selective ion channel regulation by protein kinases.

IVIVR in oral absorption for fenofibrate immediate release tablets using dissolution and dissolution permeation methods.

In a previous study it has been demonstrated that a dissolution/permeation (D/P) system can discriminate between different immediate release fenofibrate formulations. The fractions permeated were correlated with fenofibrate's in vivo exposure in rats following p.o. administration. In the present study more detailed investigations are presented using data from six fenofibrate tablets tested in vivo in humans. In these pharmacokinetic studies no significant differences between formulations in AUC but in Cmax were found. Differences between the Cmax values were not explained by the dissolution characteristics of the tablets but were rationalized on the basis of micellar entrapment and diminished mobility of the active ingredient by surfactants in the formulations. This was demonstrated by a permeation system using dialysis membranes. Thus a permeation step in addition to dissolution measurement may significantly improve the establishment of an IVIV relationship.

IVIVR in oral absorption for fenofibrate immediate release tablets using dissolution and dissolution permeation methods.

In a previous study it has been demonstrated that a dissolution/permeation (D/P) system can discriminate between different immediate release fenofibrate formulations. The fractions permeated were correlated with fenofibrate's in vivo exposure in rats following p.o. administration. In the present study more detailed investigations are presented using data from six fenofibrate tablets tested in vivo in humans. In these pharmacokinetic studies no significant differences between formulations in AUC but in Cmax were found. Differences between the Cmax values were not explained by the dissolution characteristics of the tablets but were rationalized on the basis of micellar entrapment and diminished mobility of the active ingredient by surfactants in the formulations. This was demonstrated by a permeation system using dialysis membranes. Thus a permeation step in addition to dissolution measurement may significantly improve the establishment of an IVIV relationship.

Malignant Melanoma-a Genetic Overview / Melanoma maligno: una visión de conjunto sobre la genética

Malignant melanoma, a potentially lethal skin neoplasm, is characterized by a complex and heterogeneous etiology. Both incidences and deaths associated with melanoma are increasing in Caucasian populations. While exposure to ultraviolet radiation through sun-exposure is the major risk factor; the host factors including skin type and number of moles are critical in predisposition. The CDKN2A is a high penetrance melanoma susceptibility gene as carriers of the mutations are predisposed to the disease within familial settings. The gene is also somatically altered to varying degrees in sporadic melanoma. The CD K4 gene due to occurrence of activation mutations in a few families worldwide represents another melanoma susceptibility locus. The variants within the melanocortin receptor 1 (MC1R) gene, which encodes a melanocyte specific surface receptor with a key role in pigmentation, are associated with high risk phenotypes and increased risk of melanoma. Melanoma tumors are characterized by activation of the RAS- RAF -MEK -ERK pathway through either autocrine growth factor stimulation or oncogenic mutations in the B-RAF or N-RAS genes. Somatic mutations in the B-RAF gene are complemented by those in the N-RAS gene and represent the major genetic alterations. The mutations in the B-RAF gene in melanoma due to occurrence in melanocytic nevi represent early events that additionally require loss of cell cycle inhibitors like CDKN2A for melanoma progression and development. The sequence of events points to the cooperative collaboration between different genetic pathways in tumor development that can be and are being used as targets for developing specific therapeutic agents (AU)

El melanoma maligno, una neoplasia cutánea potencialmente mortal, se caracteriza por una etiología compleja y heterogénea. Tanto la incidencia como las muertes asociadas al melanoma están aumentando en la población caucásica. Aunque la exposición a la radiación ultravioleta a través de la exposición solar es el principal factor de riesgo, los factores que dependen del huésped, como el fototipo y el número de nevus, son críticos en la predisposición. El CD KN2A es un gen de susceptiblidad para el melanoma de alta penetrancia, ya que los portadores de mutaciones están predispuestos a la enfermedad en el entorno familiar. El gen también está alterado somáticamente, en grados variables, en el melanoma esporádico. El gen CDK4, debido a la activación de mutaciones en algunas familias a nivel mundial, representa otro locus de susceptibilidad para el melanoma. Las variaciones dentro del gen del receptor de la melanocortina 1, que codifica un receptor de superficie específico de los melanocitos con un papel clave en la pigmentación, están asociadas con fenotipos de alto riesgo y un riesgo aumentado de melanoma. Los tumores de melanoma se caracterizan por la activación de la vía RAS- RAF -MEK -ERK a través de la estimulación por factor de crecimiento autocrino o por mutaciones oncógenas en los genes B- RAF o N-RAS. Las mutaciones somáticas en el gen B- RAF se complementan por aquellas en el gen N-RAS y representan las principales alteraciones genéticas. Las mutaciones en el gen B- RAF en el melanoma, que tienen lugar en los nevus melanocíticos, representan eventos iniciales que requieren, además, la pérdida de inhibidores del ciclo celular como CDKN2A para la progresión y el desarrollo del melanoma. La secuencia de eventos apunta hacia una colaboración entre las diferentes vías genéticas en el desarrollo tumoral, que pueden y están siendo empleadas como dianas para desarrollar agentes terapéuticos específicos (AU)

Malignant melanoma--a genetic overview.

Malignant melanoma, a potentially lethal skin neoplasm, is characterized by a complex and heterogeneous etiology. Both incidences and deaths associated with melanoma are increasing in Caucasian populations. While exposure to ultraviolet radiation through sun-exposure is the major risk factor; the host factors including skin type and number of moles are critical in predisposition. The CDKN2A is a high penetrance melanoma susceptibility gene as carriers of the mutations are predisposed to the disease within familial settings. The gene is also somatically altered to varying degrees in sporadic melanoma. The CDK4 gene due to occurrence of activation mutations in a few families worldwide represents another melanoma susceptibility locus. The variants within the melanocortin receptor 1 (MC1R) gene, which encodes a melanocyte specific surface receptor with a key role in pigmentation, are associated with high risk phenotypes and increased risk of melanoma. Melanoma tumors are characterized by activation of the RAS-RAF-MEK-ERK pathway through either autocrine growth factor stimulation or oncogenic mutations in the B-RAF or N-RAS genes. Somatic mutations in the B-RAF gene are complemented by those in the N-RAS gene and represent the major genetic alterations. The mutations in the B-RAF gene in melanoma due to occurrence in melanocytic nevi represent early events that additionally require loss of cell cycle inhibitors like CDKN2A for melanoma progression and development. The sequence of events points to the cooperative collaboration between different genetic pathways in tumor development that can be and are being used as targets for developing specific therapeutic agents.

Lymphocyte development from hematopoietic stem cells.

The recent application of new techniques, such as multi-color cell sorting and the production of transgenic and gene-knockout mice, has contributed to a better understanding of lymphocyte development from hematopoietic stem cells. Now that we can purify progenitors at different maturational stages during lymphocyte development, the challenge is to understand the processes that govern each developmental stage transition.

The natural killer T-cell ligand alpha-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice.

Diabetes in non-obese diabetic (NOD) mice is mediated by pathogenic T-helper type 1 (Th1) cells that arise because of a deficiency in regulatory or suppressor T cells. V alpha 14-J alpha 15 natural killer T (NKT) cells recognize lipid antigens presented by the major histocompatibility complex class I-like protein CD1d (refs. 3,4). We have previously shown that in vivo activation of V alpha 14 NKT cells by alpha-galactosylceramide (alpha-GalCer) and CD1d potentiates Th2-mediated adaptive immune responses. Here we show that alpha-GalCer prevents development of diabetes in wild-type but not CD1d-deficient NOD mice. Disease prevention correlated with the ability of alpha-GalCer to suppress interferon-gamma but not interleukin-4 production by NKT cells, to increase serum immunoglobulin E levels, and to promote the generation of islet autoantigen-specific Th2 cells. Because alpha-GalCer recognition by NKT cells is conserved among mice and humans, these findings indicate that alpha-GalCer might be useful for therapeutic intervention in human diseases characterized by Th1-mediated pathology such as Type 1 diabetes.

Genomic organization of the human endogenous retrovirus HERV-K(HML-2.HOM) (ERVK6) on chromosome 7.

Recently, we reported an almost intact human endogenous retrovirus (HERV-K(HML-2.HOM); HGMW-approved symbol ERVK6) located on human chromosome 7, with open reading frames for all retroviral genes and a mutation only within the reverse transcriptase. We further characterized the genomic organization of this endogenous retrovirus by subcloning and sequencing of the proviral insert contained within a chromosome 7-specific cosmid clone and found HERV-K(HML-2.HOM) to be organized as a tandem repeat. Examination of various human DNA samples for this specific proviral repeat suggests a relatively ubiquitous distribution of the HERV-K(HML-2.HOM) tandem structure. However, we identified two human samples having only a single provirus at this locus. In addition, we investigated the presence of HERV-K(HML-2.HOM) alleles having an intact YXDD motif within the reverse transcriptase domain by sequencing the corresponding polymerase gene from various human DNA samples. We identified a HERV-K(HML-2.HOM) polymerase with an intact YXDD motif in two samples, thus potentially coding for an active reverse transcriptase. Our results show for the first time an endogenous retrovirus tandem repeat in human populations and suggest the existence of alleles harboring an intact human endogenous retrovirus including an intact polymerase gene.

Patent foramen ovale closure in patients with transient ischemia attack/stroke.

Paradoxical embolism through a patent foramen ovale (PFO) has been recognized as a potential cause of transient ischemia attack (TIA) and stroke especially in younger patients. The therapeutic options are medical treatment (antiaggregation or anticoagulation) with an annual recurrence rate of 3% to 4% for stroke or TIA, surgical PFO closure, or catheter closure. Randomized studies are ongoing; however, the results will not be available soon. Since August 1994, we have attempted catheter closure of a PFO in 281 patients (age 17 to 79 years, mean 46.8 +/- 13.2) with paradoxical embolism. Of these, 184 patients had at least one embolic stroke, 112 patients at least one TIA, and 15 patients at least one peripheral embolism. The diameter of the PFO, measured with a balloon catheter, ranged from 3 mm to 24 mm with a mean of 10 +/- 3.5 mm. Implantation of the occluder was technically successful in all patients (two attempts in four patients). Seven different devices were used: 26 Sideris buttoned, 11 ASDOS, 19 Angel Wings, 98 PFO-Star, 37 Cardioseal-Starflex, 57 Amplatzer and, 33 Helex devices. One patient suffered from septicemia and subsequently died. In 2 patients, device embolization occurred during or after the procedure (1 Sideris, 1 PFO-Star; catheter retrieval successful). Thirty-seven patients had other minor complications without long-term sequelae: atrial fibrillation within the first weeks after implantation in five patients, asymptomatic thrombus on the device at routine transesophageal echocardiogram (TEE) in 7 patients (1 Angel Wings, 1 ASDOS, 1 CardioSeal, 4 PFO-Star), and device frame fracture in 25 patients (2 Sideris, 4 ASDOS, 1 Angel Wings, 1 CardioSeal, 17 PFO-Star). No complications occurred with the newer devices (Amplatzer and Helex). A residual shunt after 6 months was found in 5.5% of the patients who had completed their 6-month TEE follow-up. In two patients, a second occluder was implanted because of a residual shunt. During a follow-up period of 1 month to 71 months (mean 12 +/- 16 months, 268 patient years), a recurrence of an embolic event (seven TIA, two stroke) occurred in eight patients. None of these occurred with the newer devices (Amplatzer, Helex). Freedom from recurrence of the combined end point of TIA, ischemic stroke, and peripheral embolism was 95.7% (95% CI: 89.0%-98.4%) at 1 year and 94.1% (95% CI: 80.1-98.4%) at 3 years. Catheter PFO closure is a technically simple procedure. With the newer devices and increasing experience, the success rate has improved and the complication rate has decreased. The advantage of the procedure is that closing the defect means a causal treatment. However, catheter closure of PFO despite a very low morbidity has inherent potential risks like any other interventional procedure. Furthermore, selection of patients who definitely have PFO as the cause of their cerebral event has not been defined. For these reasons, further studies are warranted.

Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines.

The primary role of cytokines in haemato-lymphopoiesis is thought to be the regulation of cell growth and survival. But the instructive action of cytokines in haematopoiesis has not been well addressed. Here we show that a clonogenic common lymphoid progenitor, a bone marrow-resident cell that gives rise exclusively to lymphocytes (T, B and natural killer cells), can be redirected to the myeloid lineage by stimulation through exogenously expressed interleukin (IL)-2 and GM-CSF (granulocyte/macrophage colony-stimulating factor) receptors. Analysis of mutants of the beta-chain of the IL-2 receptor revealed that the granulocyte- and monocyte-differentiation signals are triggered by different cytoplasmic domains, showing that the signalling pathway(s) responsible for these unique developmental outcomes are separable. Finally, we show that the endogenous myelomonocytic cytokine receptors for GM-CSF and macrophage colony-stimulating factor (M-CSF) are expressed at low to moderate levels on the more primitive haematopoietic stem cells, are absent on common lymphoid progenitors, and are upregulated after myeloid lineage induction by IL-2. We conclude that cytokine signalling can regulate cell-fate decisions and propose that a critical step in lymphoid commitment is downregulation of cytokine receptors that drive myeloid cell development.