Why has positive inotropy failed in chronic heart failure? Lessons from prior inotrope trials.

Current pharmacological therapies for heart failure with reduced ejection fraction are largely either repurposed anti-hypertensives that blunt overactivation of the neurohormonal system or diuretics that decrease congestion. However, they do not address the symptoms of heart failure that result from reductions in cardiac output and reserve. Over the last few decades, numerous attempts have been made to develop and test positive cardiac inotropes that improve cardiac haemodynamics. However, definitive clinical trials have failed to show a survival benefit. As a result, no positive inotrope is currently approved for long-term use in heart failure. The focus of this state-of-the-art review is to revisit prior clinical trials and to understand the causes for their findings. Using the learnings from those experiences, we propose a framework for future trials of such agents that maximizes their potential for success. This includes enriching the trials with patients who are most likely to derive benefit, using biomarkers and imaging in trial design and execution, evaluating efficacy based on a wider range of intermediate phenotypes, and collecting detailed data on functional status and quality of life. With a rapidly growing population of patients with advanced heart failure, the epidemiologic insignificance of heart transplantation as a therapeutic intervention, and both the cost and morbidity associated with ventricular assist devices, there is an enormous potential for positive inotropic therapies to impact the outcomes that matter most to patients

Taxation and Democratization

Anecdotal evidence from pre-modern Europe and North America suggests that rulers are forced to become more democratic once they impose a significant fiscal burden on their citizens. One difficulty in testing this taxation causes democratization hypothesis empirically is the endogeneity of public revenues. I use introductions of value added taxes and autonomous revenue authorities as sources of quasi-exogenous variation to identify the causal effect of the fiscal burden borne by citizens on democracy. The instrumental variables regressions with a panel of 122 countries over the period 1981-2008 suggest that revenues had on average a mild positive effect on democracy

Socio-Economic Burden of Myocardial Infarction Among Cancer Patients

Cancer patients face a higher risk of future myocardial infarction (MI), even after completion of anticancer therapies. MI is a critical source of physical and financial stress in non-cancer patients, but its impacts associated with cancer patients also saddled with the worry (stress) of potential reoccurrence is unknown. Therefore, we aimed to quantify MI's stress and financial burden after surviving cancer and compare to those never diagnosed with cancer. Utilizing cross-sectional national survey data from 2013-2018 derived from publicly available U.S. datasets, the National Health Interview Survey (NHIS), and economic data from the National Inpatient Sample (NIS), we compared the socio-economic outcomes among those with MI by cancer-status. We adjusted for social, demographic, and clinical factors. Overall, 19,504 (10.2%) of the 189,836 NHIS survey responders reported having cancer for more than 1 year. There was an increased prevalence of MI among cancer survivors compared to non-cancer patients (8.8% vs. 3.2%, P0.05). There was no difference in annual residual family income by cancer status; however, 3 lowest deciles of residual income representing 21.1% cancer-survivor with MI had a residual income of <$9,000. Myocardial infarction continues to represent an immense source of financial and perceived stress. In conclusion, although cancer patients face a higher risk of subsequent MI, this does not appear to advance their reported stress significantly

Cataract surgery by appointment – a pilot study

BACKGROUND: "Cataract Surgery by Appointment" is a new method of delivery of cataract surgery that reduces the time a patient spends in hospital by their direct arrival at the operating theatre, having self-prepared for surgery, thus avoiding admission to the ward or time spent in the Day Case Unit. The patient can stay as little as 20 minutes from their arrival to going home. We describe the process in detail, and seek to evaluate the visual outcome, safety and patient satisfaction of same. METHODS: Visual outcome and safety data were obtained from patients' medical records, prospectively. Patients were also surveyed by a questionnaire to determine their satisfaction with the service and viability as a prospect for providing a more efficient cataract surgery service. RESULTS: In 2002, fifty-one eyes of 39 consecutive patients underwent "Cataract Surgery by Appointment". There were 16 male and 23 female. The pre-operative best-corrected visual acuity was 6/9 or better in 17 (33%) eyes. The post-operative best-corrected visual acuity was 6/9 or better in 44 (86%) eyes. There were no per-operative complications. Post-operative complications occurred in 3 (6%) eyes. The average number of days from surgery to final discharge was 14.5 days. Twenty-eight (72%) completed questionnaires were returned. The results show that the majority of patients were satisfied with their overall experience of this mode of delivery for cataract surgery. CONCLUSION: "Cataract Surgery by Appointment" performed under local anaesthesia by a skilled ophthalmic surgeon appears to be safe and effective for highly selected cases. This method of delivery gave a high level of patient satisfaction, and is the ultimate form of day case cataract surgery. The method may gain widespread use should per-operative intracameral pupil dilatation prove to be effective and acceptable. Attention should be paid to risk-stratification, so complex cases are allocated more time on the operating list

Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresposiveness by inhibiting UPR transducers

© 2019 American Society for Clinical Investigation. Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma. Whether CBAs exert their beneficial effects on allergic airway responses via 1 arm or several arms of the UPR, or alternatively through the signaling pathways for conserved bile acid receptor, remains largely unknown. We used a house dust mite-induced (HDM-induced) murine model of asthma to evaluate and compare the effects of 5 CBAs and 1 unconjugated bile acid in attenuating allergen-induced UPR and airway responses. Expression of UPRassociated transcripts was assessed in airway brushings from human patients with asthma and healthy subjects. Here we show that CBAs, such as alanyl β-muricholic acid (AβM) and TUDCA, significantly decreased inflammatory, immune, and cytokine responses; mucus metaplasia; and airway hyperresponsiveness, as compared with other CBAs in a model of allergic airway disease. CBAs predominantly bind to activating transcription factor 6α (ATF6α) compared with the other canonical transducers of the UPR, subsequently decreasing allergen-induced UPR activation and resolving allergic airway disease, without significant activation of the bile acid receptors. TUDCA and AβM also attenuated other HDM-induced ER stress markers in the lungs of allergic mice. Quantitative mRNA analysis of airway epithelial brushings from human subjects demonstrated that several ATF6α-related transcripts were significantly upregulated in patients with asthma compared with healthy subjects. Collectively, these results demonstrate that CBA-based therapy potently inhibits the allergen-induced UPR and allergic airway disease in mice via preferential binding of the canonical transducer of the UPR, ATF6α. These results potentially suggest a novel avenue to treat allergic asthma using select CBAs

Antibodies That Induce Phagocytosis of Malaria Infected Erythrocytes: Effect of HIV Infection and Correlation with Clinical Outcomes

HIV infection increases the burden of disease of malaria in pregnancy, in part by impairing the development of immunity. We measured total IgG and phagocytic antibodies against variant surface antigens of placental-type CS2 parasites in 187 secundigravidae (65% HIV infected). In women with placental malaria infection, phagocytic antibodies to CS2VSA were decreased in the presence of HIV (p = 0.011) and correlated positively with infant birth weight (coef = 3.57, p = 0.025), whereas total IgG to CS2VSA did not. Phagocytic antibodies to CS2VSA are valuable tools to study acquired immunity to malaria in the context of HIV co-infection. Secundigravidae may be an informative group for identification of correlates of immunity

RNAi Screening in Drosophila Cells Identifies New Modifiers of Mutant Huntingtin Aggregation

The fruitfly Drosophila melanogaster is well established as a model system in the study of human neurodegenerative diseases. Utilizing RNAi, we have carried out a high-throughput screen for modifiers of aggregate formation in Drosophila larval CNS-derived cells expressing mutant human Huntingtin exon 1 fused to EGFP with an expanded polyglutamine repeat (62Q). 7200 genes, encompassing around 50% of the Drosophila genome, were screened, resulting in the identification of 404 candidates that either suppress or enhance aggregation. These candidates were subjected to secondary screening in normal length (18Q)-expressing cells and pruned to remove dsRNAs with greater than 10 off-target effects (OTEs). De novo RNAi probes were designed and synthesized for the remaining 68 candidates. Following a tertiary round of screening, 21 high confidence candidates were analyzed in vivo for their ability to modify mutant Huntingtin-induced eye degeneration and brain aggregation. We have established useful models for the study of human HD using the fly, and through our RNAi screen, we have identified new modifiers of mutant human Huntingtin aggregation and aggregate formation in the brain. Newly identified modifiers including genes related to nuclear transport, nucleotide processes, and signaling, may be involved in polyglutamine aggregate formation and Huntington disease cascades

Effects of Short-Term Continuous Montmorency Tart Cherry Juice Supplementation in Participants with Metabolic Syndrome

© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s00394-020-02355-5Purpose: Metabolic Syndrome (MetS) augments the incidence of cardiovascular disease by two-fold and type II diabetes mellitus by five-fold. Montmorency tart cherries are rich in phytochemicals shown to improve biomarkers related to cardio-metabolic health in humans. This study aimed to examine cardio-metabolic responses after 7-days Montmorency tart cherry juice (MTCJ) supplementation and also acute on short-term supplementation responses to a single bolus, in humans with MetS. Methods: In a randomised, single-blind, placebo-controlled, crossover trial, 12 participants with MetS (50 ± 10 years; 6M/6F), consumed MTCJ or placebo (PLA) for 7 days. Blood-based and functional cardio-metabolic biomarkers were measured pre- and post-supplementation, and acute responses measured pre-bolus and up to 5 h post-bolus on the 7th day. Results: 24-h ambulatory systolic (P = 0.016), diastolic (P = 0.009) blood pressure and mean arterial pressure (P = 0.041) were significantly lower after 7-days MTCJ supplementation compared to PLA. Glucose (P = 0.038), total cholesterol (P = 0.036), LDL (P = 0.023) concentrations, total cholesterol:HDL ratio (P = 0.004) and respiratory exchange ratio values (P = 0.009) were significantly lower after 6-days MTCJ consumption compared to PLA. Conclusions: This study revealed for the first time in humans that MTCJ significantly improved 24-h BP, fasting glucose, total cholesterol and total cholesterol:HDL ratio, and also lowered resting respiratory exchange ratio compared to a control group. Responses demonstrated clinically relevant improvements on aspects of cardio-metabolic function, emphasising the potential efficacy of MTCJ in preventing further cardio-metabolic dysregulation in participants with MetS. Registered at clinicaltrials.gov (NCT03619941).Peer reviewedFinal Accepted Versio

Ratio of the Isolated Photon Cross Sections at \sqrt{s} = 630 and 1800 GeV

The inclusive cross section for production of isolated photons has been measured in \pbarp collisions at $\sqrt{s} = 630$ GeV with the \D0 detector at the Fermilab Tevatron Collider. The photons span a transverse energy ($E_T$) range from 7-49 GeV and have pseudorapidity $|\eta| < 2.5$. This measurement is combined with to previous \D0 result at $\sqrt{s} = 1800$ GeV to form a ratio of the cross sections. Comparison of next-to-leading order QCD with the measured cross section at 630 GeV and ratio of cross sections show satisfactory agreement in most of the $E_T$ range.Comment: 7 pages. Published in Phys. Rev. Lett. 87, 251805, (2001

The "smoker's paradox" in patients with acute coronary syndrome: a systematic review

<p>Abstract</p> <p>Background</p> <p>Smokers have been shown to have lower mortality after acute coronary syndrome than non-smokers. This has been attributed to the younger age, lower co-morbidity, more aggressive treatment and lower risk profile of the smoker. Some studies, however, have used multivariate analyses to show a residual survival benefit for smokers; that is, the "smoker's paradox". The aim of this study was, therefore, to perform a systematic review of the literature and evidence surrounding the existence of the "smoker's paradox".</p> <p>Methods</p> <p>Relevant studies published by September 2010 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1963) and the Cochrane Central Register of Controlled Trials, with a combination of text words and subject headings used. English-language original articles were included if they presented data on hospitalised patients with defined acute coronary syndrome, reported at least in-hospital mortality, had a clear definition of smoking status (including ex-smokers), presented crude and adjusted mortality data with effect estimates, and had a study sample of > 100 smokers and > 100 non-smokers. Two investigators independently reviewed all titles and abstracts in order to identify potentially relevant articles, with any discrepancies resolved by repeated review and discussion.</p> <p>Results</p> <p>A total of 978 citations were identified, with 18 citations from 17 studies included thereafter. Six studies (one observational study, three registries and two randomised controlled trials on thrombolytic treatment) observed a "smoker's paradox". Between the 1980s and 1990s these studies enrolled patients with acute myocardial infarction (AMI) according to criteria similar to the World Health Organisation criteria from 1979. Among the remaining 11 studies not supporting the existence of the paradox, five studies represented patients undergoing contemporary management.</p> <p>Conclusion</p> <p>The "smoker's paradox" was observed in some studies of AMI patients in the pre-thrombolytic and thrombolytic era, whereas no studies of a contemporary population with acute coronary syndrome have found evidence for such a paradox.</p