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Background Oral anticoagulants (OACs) are high-risk medications often used in older people with complex medication regimens. This study was the first to assess the association between overall regimen complexity and bleeding in people with atrial fibrillation (AF) initiating OACs. Methods Patients diagnosed with AF who initiated an OAC (warfarin, dabigatran, rivaroxaban, apixaban) between 2010 and 2016 were identified from the Hong Kong Clinical Database and Reporting System. Each patient’s Medication Regimen Complexity Index (MRCI) score was computed. Baseline characteristics were balanced using inverse probability of treatment weighting. People were followed until a first hospitalization for bleeding (intracranial hemorrhage, gastrointestinal bleeding, or other bleeding) and censored at discontinuation of the index OAC, death, or end of the follow-up period, whichever occurred first. Cox regression was used to estimate hazard ratios (HR) between MRCI quartiles and bleeding during initiation and all follow-up. Results There were 19 292 OAC initiators (n = 9 092 warfarin, n = 10 200 direct oral anticoagulants) with a mean (standard deviation) age at initiation of 73.9 (11.0) years. More complex medication regimens were associated with an increased risk of bleeding (MRCI > 14.0–22.00: aHR 1.17, 95% confidence interval [CI] 0.93–1.49; MRCI > 22.0–32.5: aHR 1.32, 95%CI 1.06–1.66; MRCI > 32.5: aHR 1.45, 95%CI 1.13–1.87, compared to MRCI ≤ 14). No significant association between MRCI and bleeding risk was observed during the initial 30, 60, or 90 days of treatment. Conclusion In this cohort study of people with AF initiating an OAC, a more complex medication regimen was associated with higher bleeding risk over periods longer than 90 days. Further prospective studies are needed to assess whether MRCI should be considered in OAC prescribing.

BackgroundPolypharmacy among older people represents a global challenge due to its association with adverse drug events. The reported prevalence of polypharmacy varies widely across countries, and is particularly high in Asian countries. However, there is no multinational study using standardised measurements exploring variations in prescribing trends.ObjectiveTo compare polypharmacy trends in older people in Asia, Australia and the United Kingdom.DesignMultinational, retrospective, time-trend, observational study using a common study protocol.SettingOutpatient and community settings.SubjectsAll individuals aged ≥ 65 years between 2013 and 2016.MethodsWe defined polypharmacy as the concomitant use of ≥5 medications for ≥45 days per year. We estimated the annual prevalence of polypharmacy and calculated average annual percentage change (AAPC) to assess the time trends.ResultsA total of 1.62 million individuals were included in this study. The highest prevalence of polypharmacy was observed in Hong Kong (46.4%), followed by Taiwan (38.8%), South Korea (32.0%), the United Kingdom (23.5%) and Australia (20.1%) in 2016. For the time trend, the Asian region showed a steady increase, particularly in Hong Kong and South Korea (AAPC: Hong Kong, 2.7%; South Korea, 1.8%; Taiwan, 1.0%). However, Australia and the United Kingdom showed a decreasing trend (Australia, −4.9%; the United Kingdom, −1.1%).ConclusionsPolypharmacy prevalence in older people was higher in Hong Kong, Taiwan and South Korea, with an increasing trend over time, compared with Australia and the United Kingdom. Our findings underline the necessity to monitor polypharmacy among older people in Asia by conducting government-level interventions and introducing medicine-optimisation strategies.

Spike-timing-dependent plasticity (STDP) is a candidate mechanism for information storage in the brain, but the whole-cell recordings required for the experimental induction of STDP are typically limited to one hour. This mismatch of time scales is a long-standing weakness in synaptic theories of memory. Here we use spectrally separated optogenetic stimulation to fire precisely timed action potentials (spikes) in CA3 and CA1 pyramidal cells. Twenty minutes after optogenetic induction of STDP (oSTDP), we observed timing-dependent depression (tLTD) and timing-dependent potentiation (tLTP), depending on the sequence of spiking. As oSTDP does not require electrodes, we could also assess the strength of these paired connections three days later. At this late time point, late tLTP was observed for both causal (CA3 before CA1) and anti-causal (CA1 before CA3) timing, but not for asynchronous activity patterns (Δt = 50 ms). Blocking activity after induction of oSTDP prevented stable potentiation. Our results confirm that neurons wire together if they fire together, but suggest that synaptic depression after anti-causal activation (tLTD) is a transient phenomenon.HighlightsOptogenetic induction of spike-timing-dependent plasticity at Schaffer collateral synapsesCausal pairing induces potentiation whereas anti-causal pairing induces depression during patch-clamp recordings.Three days after optogenetic induction, the consequence of STDP is potentiation (tLTP) irrespective of spiking order.Late tLTP requires ongoing activity in the days following oSTDP.Graphical Abstract

(Public) health economic evaluations face significant problems regarding the standardization and comparability of their methods. In addition, at least a quarter of the total direct cost impact of healthcare interventions affects other economic sectors. International methods and tools are lacking for the rigorous and comparable assessment of the costs and outcomes of (public) health care from a societal perspective. The H2020 PECUNIA project (grant No 779292) brought together ten partners from six countries (AT/DE/ES/HU/NL/UK) between 2018 and 2021 aiming to improve the comparability and feasibility of multi-sectoral, multi-national health economic evaluations in Europe. A multi-step, mixed methods approach was used following a new harmonized costing concept to develop new methods and tools for the standardised identification, definition, measurement and valuation of costs in multiple sectors (health care, social care, (criminal) justice, education, employment and productivity, and patient, family and informal care), and for the broader, harmonised, supra-national assessment of outcomes using selected mental disorders as illustrative examples. This presentation will summarise the relevant advances in costing methods, give an overview of the developed tools that are now publicly available (www.pecunia-project.eu/tools), and discuss the lessons learned regarding how far it is possible to harmonize costing evidence with standardised tools in Europe, and what the necessary future research directions may be.

Summary Capping protein regulator and myosin 1 linker 2 (CARMIL2) deficiency is characterized by impaired T cell activation, which is attributed to defective CD28-mediated co-signaling. Herein, we aimed to analyze the effect of exogenous interleukin (IL)-2 on in-vitro T cell activation and proliferation in a family with CARMIL2 deficiency. This study included four children (one male and three females; aged 2·5–10 years at presentation). The patients presented with inflammatory bowel disease and recurrent viral infections. Genetic analysis revealed a novel homozygous 25-base pairs deletion in CARMIL2. Immunoblotting demonstrated the absence of CARMIL2 protein in all four patients and confirmed the diagnosis of CARMIL2 deficiency. T cells were activated in-vitro with the addition of IL-2 in different concentrations. CD25 and interferon (IFN)-γ levels were measured after 48 h and 5 days of activation. CD25 surface expression on activated CD8+ and CD4+ T cells was significantly diminished in all patients compared to healthy controls. Additionally, CD8+ T cells from all patients demonstrated significantly reduced IFN-γ production. When cells derived from CARMIL2-deficient patients were treated with IL-2, CD25 and IFN-γ production increased in a dose-dependent manner. T cell proliferation, as measured by Cell Trace Violet, was impaired in one patient and it was also rescued with IL-2. In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients. Thus, IL-2 should be further studied as a potential therapeutic modality for these patients.

Our aim with this review is to provide practical advice and management support for nurses and other healthcare practitioners in managing fluid retention in adults with right heart failure (RHF) due to pulmonary arterial hypertension (PAH). Vigilant management of RHF is important for maintaining patient quality of life, as fluid overload can lead to abdominal bloating (ascites) and peripheral oedema, which also has a major impact on patients’ morbidity and mortality. Patients with RHF should be assessed regularly for signs of fluid retention. If fluid overload develops, it is important to determine whether it is caused by the progression of PAH, a side effect of PAH-specific treatment, or another drug or comorbid condition, as this affects both the prognosis and the management strategy. Right heart failure can be treated with both pharmacological and non-pharmacological interventions to reduce fluid retention; including altering fluid and salt intake, weight monitoring, and use of diuretics. All patients on diuretics should be regularly monitored for renal dysfunction and electrolyte imbalance and given advice on how to manage the side effects associated with diuretic use. Fluid retention is often assessed and treated in clinical practice by specialist nurses, who act as a key patient contact providing advice and information on symptom management. This review provides an overview of the challenges related to fluid retention, including strategies to help patients manage symptoms and side effects of treatment.

Background Intensive therapy is often required to reach glycated haemoglobin targets in people with Type 2 Diabetes (T2D), however, aggressive treatment in people >80 years, frail individuals and people with dementia may be harmful. We aimed to determine whether these factors predict the intensity of anti-hyperglycaemic therapies prescribed for older hospitalised patients with T2D. Methods A cohort study was completed using discharge prescribing data from Melbourne’s Eastern Health hospital network. We identified 3,067 patients, aged 65-99 years, with T2D, at least one diabetes related complication and an index discharge between 2012 and 2016. Multinomial Logistic Regression was used to estimate adjusted Odds Ratios (ORs) with 95% confidence intervals (CI) for being prescribed insulin-only (IO), non-insulin anti-hyperglycaemics only (NIO) or a combination of those two (CT) compared to no anti-hyperglycaemics (NA). Results At discharge, 23% of patients were prescribed NA, 19% IO, 39% NIO and 20% CT. People aged >80 were less likely than those aged 65-80 to be discharged with IO (OR = 0.53; 95%CI [0.42-0.68]) or CT (OR = 0.37; 95%CI [0.30-0.47]), compared to NA. Frailty was negatively associated with being prescribed IO (OR 0.64; 95%CI [0.43-0.94]) or NIO (OR 0.64; 95%CI [0.46-0.89], compared to NA. People with dementia were less likely to be discharged with CT (OR 0.56; 95%CI [0.34-0.92]) compared to NA. Conclusions Prescribers recognise advancing age, frailty and dementia as factors which necessitate less intensive T2D treatment in hospitalised older adults. Key messages Frailty, independent of chronological age, is associated with receiving less intensive T2D therapy in older hospitalised patients.

Funding Acknowledgements Type of funding sources: None. Aims Controversial results have been published regarding the influence of pulmonary vein (PV) anatomical variations on outcomes after pulmonary vein isolation (PVI). However, no data is available on the impact of PV orientation on the long-term success rates of point-by-point PVI. We sought to determine the impact of PV anatomy and orientation on atrial fibrillation (AF)-free survival in patients undergoing PVI using the radiofrequency point-by-point technique. Methods and results We retrospectively included 448 patients who underwent initial point-by-point radiofrequency ablation for AF at our department. Left atrial CT-angiography (CTA) was performed before each procedure. PV anatomical variations, ostial parameters (area, effective diameter and eccentricity), orientation and their associations with 24-month AF-free survival were analyzed. PV anatomical variations and ostial parameters were not predictive for AF-free survival (all p > 0.05). Univariate analysis showed that female sex (p = 0.025) was associated with higher rates of AF recurrence, ventral-caudal (p = 0.002), dorsal-cranial (p = 0.034) and dorsal-caudal (p = 0.042) orientation of the right superior PV (RSPV), on the other hand, showed an association with lower rates of AF recurrence, as compared to the reference ventral-cranial orientation. On multivariate analysis, both female sex [odds ratio(OR) 1.83, 95% CI 1.15-2.93, p = 0.011] and ventral-caudal RSPV orientation, compared with ventral-cranial orientation, proved to be independent predictors of 24-month AF recurrence (OR 0.37, 95% CI 0.19-0.71, p = 0.003). Conclusion Female sex and ventral-caudal RSPV orientation have an impact on long-term arrhythmia-free survival. Assessment of PV orientation may be a useful tool in predicting AF-free survival and may contribute to a more personalized management of AF.

Introduction Flibanserin, a treatment for acquired, generalized hypoactive sexual desire disorder (HSDD), is approved in the US for use in certain premenopausal women and in Canada for use in both premenopausal and naturally postmenopausal women ≤60 years of age. Improvement in symptoms following initiation of flibanserin may take several weeks to emerge and it is important to set realistic expectations of treatment onset. Objective The primary objective of this analysis was to evaluate the onset of flibanserin's treatment effect in naturally postmenopausal women with HSDD across the 6 subdomains of the FSFI. Methods A post-hoc analysis was conducted using FSFI data from a randomized, controlled, double-blind trial of flibanserin in naturally postmenopausal women with HSDD that included 895 postmenopausal women (flibanserin, n=432; placebo, n=463) who had at least one on-treatment efficacy assessment. The FSFI is a validated, 19-item self-report questionnaire comprising 6 subdomains of sexual functioning: desire, arousal, lubrication, orgasm, satisfaction, and pain. Each subdomain has a maximum score of 6 and higher scores indicate better sexual functioning. For each subdomain, change from baseline at each assessment visit (4, 8, 16, and 24 weeks) was calculated as the least squares mean difference. Comparisons between flibanserin and placebo groups were performed using analysis of covariance. Results Postmenopausal patients treated with flibanserin had significantly greater sexual desire and arousal scores than those treated with placebo at Week 4 and at every assessment timepoint thereafter (see figure). By Week 8, patients in the flibanserin group had significantly higher scores for all FSFI subdomains compared to the placebo group. This treatment effect was maintained at Week 24 for all subdomains except for pain. Conclusions Results from this post-hoc analysis indicates that postmenopausal women treated with flibanserin experienced improved sexual function compared to those treated with placebo with regard to sexual desire, arousal, lubrication, orgasm and satisfaction. This improvement was maintained over the entire course of treatment. These findings are consistent with those from a previous FSFI post-hoc analysis of clinical trial data from premenopausal women and suggest that flibanserin treatment of postmenopausal women was associated with improvement of multiple aspects of sexual function in addition to sexual desire. Disclosure Yes, this is sponsored by industry/sponsor: Sprout Pharmaceuticals, Inc. Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Sprout Pharmaceuticals, Inc.

Background: Frailty predicts mortality in residential aged care, but the relationship with hospitalization is inconsistent. The purpose of this study was to investigate and compare whether frailty is associated with hospitalization and mortality among residents of aged care services.Methods: A prospective cohort study of 383 residents aged 65 years and older was conducted in six Australian residential aged care services. Frailty was assessed using the FRAIL-NH scale and a 66-item frailty index.Results: Overall, 125 residents were hospitalized on 192 occasions and 85 died over the 12-month follow-up. Over this period, less than 3% of the nonfrail/vulnerable residents but more than 20% of the most frail residents died at the facility without hospitalization. Using the FRAIL-NH, residents with mild/moderate frailty had higher numbers of hospitalizations (adjusted incidence rate ratio 1.57, 95% confidence interval [CI] 1.11-2.20) and hospital days (incidence rate ratio 1.48, 95% CI 1.32-1.66) than nonfrail residents. Residents who were most frail had lower numbers of hospitalizations (incidence rate ratio 0.65, 95% CI 0.42-0.99) and hospital days (incidence rate ratio 0.39, 95% CI 0.33-0.46) than nonfrail residents. Similar patterns of associations with number of hospital days were observed for the frailty index. Most frail residents had a higher risk of death than nonfrail residents (for FRAIL-NH, adjusted hazard ratio 2.96, 95% CI 1.50-5.83; for frailty index, hazard ratio 5.28, 95% CI 2.05-13.59).Conclusions: Residents with mild/moderate frailty had higher risk of hospitalization and death than nonfrail residents. Residents who were most frail had higher risk of death but lower risk of hospitalization than nonfrail residents. Refereed/Peer-reviewed

Background Lifestyle and dietary advice typically precedes or accompanies the prescription of statin medications. However, evidence for adherence to this advice is sparse. The objective was to compare saturated fat intake, exercise, alcohol consumption and smoking between statin users and non-users in Australia. Methods Data were analysed for 4614 participants aged ≥37 years in the Australian Diabetes, Obesity and Lifestyle study in 2011–2012. Statin use, smoking status and physical activity were self-reported. Saturated fat and alcohol intake were measured via a food frequency questionnaire. Multinomial logistic regression was used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between statin use and the four lifestyle factors. All models were adjusted for age, sex, education, number of general practitioner visits, body mass index, hypertension, diabetes and prior cardiovascular diseases. Results In total 1108 (24%) participants used a statin. Statin users were 29% less likely to be within the highest quartile versus the lowest quartile of daily saturated fat intake compared to non-users (OR 0.71, 95% CI 0.54–0.94). There were no statistically significant associations between statin use and smoking, physical activity or alcohol consumption. Conclusions Smoking status, alcohol consumption and exercise level did not differ between users and non-users of statins. However, statin users were less likely to consume high levels of saturated fat than non-users. We found no evidence that people took statins to compensate for a poor diet or lifestyle.

Clinical observations and similarities to addiction suggest heightened reward sensitivity to food in patients with bulimic-type eating (BTE) disorders. Therefore, we investigated the expectation and receipt of food reward compared with monetary reward in patients with BTE. Fifty-six patients with BTE (27 patients with binge eating disorder and 29 with bulimia nervosa) and 55 matched healthy control participants underwent event-related functional magnetic resonance imaging while performing both food and monetary incentive delay tasks. BTE patients exhibited reduced brain activation in the posterior cingulate cortex during the expectation of food and increased activity in the medial orbitofrontal cortex, anterior medial prefrontal cortex and posterior cingulate cortex during the receipt of food reward. These findings were relevant to food because we found no significant group differences related to monetary reward. In the patients, higher brain activity in the medial orbitofrontal cortex during the receipt of food reward was related to higher levels of trait food craving and external eating. BTE patients exhibited increased hedonic processing during the receipt of food reward. These findings corroborate the notion that an altered responsiveness of the reward network to food stimuli is associated with BTE.

A human cortex-derived neural stem cell (NSC) line modified to express insulin-like growth factor-I (IGF-I), HK532-IGF-I, is characterized in this report. The cell line is under study as a cellular therapy for Alzheimer’s disease (AD). HK532-IGF-I cells preferentially differentiated into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produced increased vascular endothelial growth factor levels; and displayed an increased neuroprotective capacity in vitro. HK532-IGF-I cells survived peri-hippocampal transplantation in a murine AD model and exhibited long-term persistence in targeted brain areas., Alzheimer’s disease (AD) is the most prevalent age-related neurodegenerative disorder and a leading cause of dementia. Current treatment fails to modify underlying disease pathologies and very little progress has been made to develop effective drug treatments. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional single-target approaches. In amyotrophic lateral sclerosis, we have shown that transplanted spinal neural stem cells (NSCs) integrate into the spinal cord, form synapses with the host, improve inflammation, and reduce disease-associated pathologies. Our current goal is to develop a similar “best in class” cellular therapy for AD. Here, we characterize a novel human cortex-derived NSC line modified to express insulin-like growth factor-I (IGF-I), HK532-IGF-I. Because IGF-I promotes neurogenesis and synaptogenesis in vivo, this enhanced NSC line offers additional environmental enrichment, enhanced neuroprotection, and a multifaceted approach to treating complex AD pathologies. We show that autocrine IGF-I production does not impact the cell secretome or normal cellular functions, including proliferation, migration, or maintenance of progenitor status. However, HK532-IGF-I cells preferentially differentiate into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro. We also demonstrate that HK532-IGF-I cells survive peri-hippocampal transplantation in a murine AD model and exhibit long-term persistence in targeted brain areas. In conclusion, we believe that harnessing the benefits of cellular and IGF-I therapies together will provide the optimal therapeutic benefit to patients, and our findings support further preclinical development of HK532-IGF-I cells into a disease-modifying intervention for AD. Significance There is no cure for Alzheimer’s disease (AD) and no means of prevention. Current drug treatments temporarily slow dementia symptoms but ultimately fail to alter disease course. Given the prevalence of AD and an increasingly aging population, alternative therapeutic strategies are necessary. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional, single-target drug discovery approaches. This study describes a novel enhanced human stem cell line that produces increased amounts of growth factors beneficial to the disease environment. Findings support further development into a potentially safe and clinically translatable cellular therapy for patients with AD.

Food is an innate reward stimulus related to energy homeostasis and survival, whereas money is considered a more general reward stimulus that gains a rewarding value through learning experiences. Although the underlying neural processing for both modalities of reward has been investigated independently from one another, a more detailed investigation of neural similarities and/or differences between food and monetary reward is still missing. Here, we investigated the neural processing of food compared with monetary-related rewards in 27 healthy, normal-weight women using functional magnetic resonance imaging. We developed a task distinguishing between the anticipation and the receipt of either abstract food or monetary reward. Both tasks activated the ventral striatum during the expectation of a reward. Compared with money, greater food-related activations were observed in prefrontal, parietal and central midline structures during the anticipation and lateral orbitofrontal cortex (lOFC) during the receipt of food reward. Furthermore, during the receipt of food reward, brain activation in the secondary taste cortex was positively related to the body mass index. These results indicate that food-dependent activations encompass to a greater extent brain regions involved in self-control and self-reflection during the anticipation and phylogenetically older parts of the lOFC during the receipt of reward.

Background. Use of psychotropic and sedative drugs has been associated with impaired muscle strength. Muscle weakness predicts important outcomes for older people including functional disability and mortality. The objective of this study was to investigate if the use of drugs with sedative properties is associated with poorer muscle strength. Methods. Seven-hundred community-dwelling participants, aged 75 years and older, enrolled in the population-based Geriatric Multidisciplinary Strategy for the Good Care of the Elderly (GeMS) study in 2004 were included in the present analyses. Data on demographics, diagnostics, and drug use were collected during standardized interviews, conducted by trained nurses and verified through medical records. Physiotherapists conducted objective tests of handgrip strength, knee extension strength, and the five repeated chair stands test. Sedative load was calculated using a previously published model for each participant. Results. Twenty-one percent of the participants (n = 147) had a sedative load of 1–2 and 8% (n = 58) had a sedative load 3 or more. After adjusting for covariates, participants with sedative load more than 0 had poorer performance on grip strength (p = .009), knee extension strength (p = .02), and five chair stands (p = .003) than nonusers of drugs with sedative properties. Increasing sedative load was associated with poorer grip strength. Conclusions. Use of drugs with sedative properties was associated with impaired muscle strength. Although we adjusted for diagnoses affecting physical function, the possibility of confounding by indication cannot be entirely excluded. Given that muscle strength is predictive of functional disability and mortality, further attention should be directed toward conducting regular reviews of drug therapy and reducing use of sedative drugs. Refereed/Peer-reviewed

Amyotrophic lateral sclerosis (ALS) is a lethal disease involving the loss of motor neurons. Although the mechanisms responsible for motor neuron degeneration in ALS remain elusive, the development of stem cell-based therapies for the treatment of ALS has gained widespread support. Here, we review the types of stem cells being considered for therapeutic applications in ALS, and emphasize recent preclinical advances that provide supportive rationale for clinical translation. We also discuss early trials from around the world translating cellular therapies to ALS patients, and offer important considerations for future clinical trial design. Although clinical translation is still in its infancy, and additional insight into the mechanisms underlying therapeutic efficacy and the establishment of long-term safety are required, these studies represent an important first step towards the development of effective cellular therapies for the treatment of ALS.

One of every two older Americans is at risk for malnutrition. Despite a cadre of evidence-based programs (EBP) available to older adults nationwide, few specifically focus on nutrition and malnutrition prevention. Because EBP have defined implementation parameters and cannot be substantially altered, pairing brief interventions to EBP (as a session zero) is a promising strategy to introduce additional content and build relevant skills. In the context of Stepping Up Your Nutrition (SUYN), a 2.5-hour workshop to reduce malnutrition risk, the purpose of this session is to describe an innovative method of joining a brief intervention with two EBP (i.e., Stepping On and Chronic Disease Self-Management Program) to increase positive nutrition behavior among older adults and enhance EBP workshop attendance. As part of this ongoing project, a total of 42 SUYN facilitators have been trained with the capacity to deliver workshops in 11 counties. All SUYN participants complete a validated nutrition risk self-assessment and grip strength test prior to EBP enrollment. Assessments are collected again after the EBP concludes. Pilot phase data indicates nearly 1/3 of participants were at risk for malnutrition and unaware that malnutrition increased fall-related risk and complicated management of chronic conditions. Linking a brief malnutrition prevention intervention to EBP can bolster basic nutrition skills among older adults to assist them gain stronger benefits from EBP. This session will describe the evaluation instruments and protocols developed to assess fidelity and determine the effectiveness of SUYN. Outcomes related to malnutrition prevention, awareness, and action will also be presented.

Right atrial (RA) dilatation may be important for patients' outcome in pulmonary arterial hypertension (PAH). The aim of this study was to examine the longitudinal RA and right ventricular (RV) remodelling in PAH patients using real-time three-dimensional echocardiography (3DE) and their relation to clinical outcome. Methods and results Sixty-two consecutive PAH patients were studied and compared with a control group of 30 healthy volunteers. RA and RV sphericity indices were measured with 3DE. RV ejection fraction (RVEF), RA volume (RAvol), and the quan- tification of jet area of tricuspid regurgitation (TR) were measured. Two observers were used for reproducibility as- sessment. The geometrical change of RA and RV was assessed in relation to clinical outcome, as defined by the increase of functional class or admission to the hospital due to right heart failure. Over 1 year of follow-up, there was significant increase of RA sphericity index (0.85+ 0.16 vs. 1.2+ 0.24, P , 0.01), RV dilatation (RV sphericity index 0.71+ 0.07 vs. 0.98+ 0.04, P , 0.01), as well as deterioration of RV systolic function (RVEF 33+ 8.2 vs. 28+ 7.6%, P , 0.01). Twenty-three patients (37%) had a clinical deterioration within 1 year. An increase of RA sphericity index .0.24 predicted clinical deterioration with a sensitivity of 96% and a specificity of 90% (area under the curve (AUC) 0.97). RV sphericity index was less sensitive (70%) and specific (62%) in predicting clinical deterioration (AUC 0.649). The deterioration in RVEF had a sensitivity of 91.1% and a specificity of 35.3% (AUC 0.479) in predicting clinical deterioration. The dilatation of RA .14 mL over 1 year had high sensitivity at 82.6% but low specificity at 30.8% in predicting clinical deterioration. Conclusion PAH leads to RA and RV dilatation and functional deterioration which are linked to an adverse clinical outcome. 3DE measurement of RA sphericity index may be a suitable index in predicting clinical deterioration of PAH patients.

Summary The immunological hallmark of Omenn syndrome (OS) is the expansion and activation of an oligoclonal population of autoreactive T cells. These cells should be controlled rapidly by immunosuppressive agents, such as cyclosporin A (CsA), to avoid tissue infiltration and to improve the general outcome of the patients. Here we studied the clinical and the immune response to CsA in two Omenn patients and also examined the gene expression profile associated with good clinical response to such therapy. T cell receptor diversity was studied in cells obtained from OS patients during CsA therapy. Characterization of gene expression in these cells was carried out by using the TaqMan low-density array. One patient showed complete resolution of his symptoms after CsA therapy. The other patient showed selective response of his oligoclonal T cell population and combination therapy was required to control his symptoms. Transcriptional profile associated with good clinical response to CsA therapy revealed significant changes in 26·6% of the tested genes when compared with the transcriptional profile of the cells before treatment. Different clinical response to CsA in two OS patients is correlated with their immunological response. Varying clonal expansions in OS patients can cause autoimmune features and can respond differently to immunosuppressive therapy; therefore, additional treatment is sometimes indicated. CsA for OS patients causes regulation of genes that are involved closely with self-tolerance and autoimmunity.

The p38 mitogen-activated protein kinase (p38MAPK) signal transduction pathway is an important regulator of cell processes, whose deregulation leads to the development and progression of cancer. Defining the role of each p38MAPK family member in these processes has been difficult. To date, most studies of the p38MAPK pathways focused on function of the p38α isoform, which is widely considered to negatively regulate malignant transformation ; nonetheless, few reports address the p38γ and p388 isoforms. Here, we used embryonic fibroblasts derived from mice lacking p38γ or p38δ and show evidence that these isoforms participate in several processes involved in malignant transformation. We observed that lack of either p38γ or p388 increased cell migration and metalloproteinase-2 secretion, whereas only p388 deficiency impaired cell contact inhibition. In addition, lack of p38γ in K-Ras-transformed fibroblasts led to increased cell proliferation as well as tumorigenesis both in vitro and in vivo. Our results indicate that p38γ and p388 have a role in the suppression of tumor development.

We have identified a highly transformable strain of Actinobacillus pleuropneumoniae whose competence is regulated by the competence-activator Sxy as in other Pasteurellaceae. Other strains were poorly transformable or nontransformable. The genomes of two poorly transformable strains contain intact sets of competence genes. Moreover, we show that the low competence of one of these strains is not due to an inability to induce sxy expression or to a defect in Sxy function, suggesting that some other component of the competence system is defective. Although the A. pleuropneumoniae sxy gene has only 24% identity to its Haemophilus influenzae homologue, both genes fully complemented an H. influenzae sxy knockout, demonstrating that Sxy function is conserved throughout the Pasteurellaceae.

The 22q11.2 deletion syndrome (velocardiofacial/DiGeorge syndrome) is a neurogenetic condition associated with visuospatial deficits, as well as elevated rates of attentional disturbance, mood disorder, and psychosis. Previously, we detected pronounced cortical thinning in superior parietal and right parieto-occipital cortices in patients with this syndrome, regions critical for visuospatial processing. Here we applied cortical pattern-matching algorithms to structural magnetic resonance images obtained from 21 children with confirmed 22q11.2 deletions (ages 8–17) and 13 demographically matched comparison subjects, in order to map cortical thickness across the medial hemispheric surfaces. In addition, cortical models were remeshed in frequency space to compute their surface complexity. Cortical maps revealed a pattern of localized thinning in the ventromedial occipital–temporal cortex, critical for visuospatial representation, and the anterior cingulate, a key area for attentional control. However, children with 22q11.2DS showed significantly increased gyral complexity bilaterally in occipital cortex. Regional gray matter volumes, particularly in medial frontal cortex, were strongly correlated with both verbal and nonverbal cognitive functions. These findings suggest that aberrant parieto-occipital brain development, as evidenced by both increased complexity and cortical thinning in these regions, may be a neural substrate for the deficits in visuospatial and numerical understanding characteristic of this syndrome.

The 22q11.2 deletion syndrome (velocardiofacial/DiGeorge syndrome, 22q11.2DS) involves cardiac and craniofacial anomalies, marked deficits in visuospatial cognition, and elevated rates of psychosis. Although the mechanism is unknown, characteristic brain alterations may predispose to development of psychosis and cognitive deficits in 22q11DS. We applied cortical pattern matching and new methods for measuring cortical thickness in millimeters to structural magnetic resonance images of 21 children with confirmed 22q11.2 deletions and 13 demographically matched healthy comparison subjects. Thickness was mapped at 65 536 homologous points, based on 3-dimensional distance from the cortical gray-white matter interface to the external gray-cerebrospinal fluid boundary. A pattern of regionally specific cortical thinning was observed in superior parietal cortices and right parietooccipital cortex, regions critical for visuospatial processing, and bilaterally in the most inferior portion of the inferior frontal gyrus (pars orbitalis), a key area for language development. Several of the 30 genes encoded in the deleted segment are highly expressed in the developing brain and known to affect early neuronal migration. These brain maps reveal how haploinsufficiency for such genes can affect cortical development and suggest a possible underlying pathophysiology of the neurobehavioral phenotype.