Evidence that conflict regarding size of haemodynamic response to interventricular delay optimization of cardiac resynchronization therapy may arise from differences in how atrioventricular delay is kept constant.

Aims: Whether adjusting interventricular (VV) delay changes haemodynamic efficacy of cardiac resynchronization therapy (CRT) is controversial, with conflicting results. This study addresses whether the convention for keeping atrioventricular (AV) delay constant during VV optimization might explain these conflicts. / Method and results: Twenty-two patients in sinus rhythm with existing CRT underwent VV optimization using non-invasive systolic blood pressure. Interventricular optimization was performed with four methods for keeping the AV delay constant: (i) atrium and left ventricle delay kept constant, (ii) atrium and right ventricle delay kept constant, (iii) time to the first-activated ventricle kept constant, and (iv) time to the second-activated ventricle kept constant. In 11 patients this was performed with AV delay of 120 ms, and in 11 at AV optimum. At AV 120 ms, time to the first ventricular lead (left or right) was the overwhelming determinant of haemodynamics (13.75 mmHg at ±80 ms, P < 0.001) with no significant effect of time to second lead (0.47 mmHg, P = 0.50), P < 0.001 for difference. At AV optimum, time to first ventricular lead again had a larger effect (5.03 mmHg, P < 0.001) than time to second (2.92 mmHg, P = 0.001), P = 0.02 for difference. / Conclusion: Time to first ventricular activation is the overwhelming determinant of circulatory function, regardless of whether this is the left or right ventricular lead. If this is kept constant, the effect of changing time to the second ventricle is small or nil, and is not beneficial. In practice, it may be advisable to leave VV delay at zero. Specifying how AV delay is kept fixed might make future VV delay research more enlightening

The fractal heart — embracing mathematics in the cardiology clinic

For clinicians grappling with quantifying the complex spatial and temporal patterns of cardiac structure and function (such as myocardial trabeculae, coronary microvascular anatomy, tissue perfusion, myocyte histology, electrical conduction, heart rate, and blood-pressure variability), fractal analysis is a powerful, but still underused, mathematical tool. In this Perspectives article, we explain some fundamental principles of fractal geometry and place it in a familiar medical setting. We summarize studies in the cardiovascular sciences in which fractal methods have successfully been used to investigate disease mechanisms, and suggest potential future clinical roles in cardiac imaging and time series measurements. We believe that clinical researchers can deploy innovative fractal solutions to common cardiac problems that might ultimately translate into advancements for patient care

The global-scale impacts of climate change on water resources and flooding under new climate and socio-economic scenarios

This paper presents a preliminary assessment of the relative effects of rate of climate change (four Representative Concentration Pathways - RCPs), assumed future population (five Shared Socio-economic Pathways - SSPs), and pattern of climate change (19 CMIP5 climate models) on regional and global exposure to water resources stress and river flooding. Uncertainty in projected future impacts of climate change on exposure to water stress and river flooding is dominated by uncertainty in the projected spatial and seasonal pattern of change in climate. There is little clear difference in impact between RCP2.6, RCP4.5 and RCP6.0 in 2050, and between RCP4.5 and RCP6.0 in 2080. Impacts under RCP8.5 are greater than under the other RCPs in 2050 and 2080. For a given RCP, there is a difference in the absolute numbers of people exposed to increased water resources stress or increased river flood frequency between the five SSPs. With the ‘middle-of-the-road’ SSP2, climate change by 2050 would increase exposure to water resources stress for between approximately 920 and 3400 million people under the highest RCP, and increase exposure to river flood risk for between 100 and 580 million people. Under RCP2.6, exposure to increased water scarcity would be reduced in 2050 by 22-24%, compared to impacts under the RCP8.5, and exposure to increased flood frequency would be reduced by around 16%. The implications of climate change for actual future losses and adaptation depend not only on the numbers of people exposed to changes in risk, but also on the qualitative characteristics of future worlds as described in the different SSPs. The difference in ‘actual’ impact between SSPs will therefore be greater than the differences in numbers of people exposed to impact

Novel cardiac pacemaker-based human model of periodic breathing to develop real-time, pre-emptive technology for carbon dioxide stabilisation

Background: Constant flow and concentration CO2 has previously been efficacious in attenuating ventilatory oscillations in periodic breathing (PB) where oscillations in CO2 drive ventilatory oscillations. However, it has the undesirable effect of increasing end-tidal CO2, and ventilation. We tested, in a model of PB, a dynamic CO2 therapy that aims to attenuate pacemaker-induced ventilatory oscillations while minimising CO2 dose. / Methods: First, pacemakers were manipulated in 12 pacemaker recipients, 6 with heart failure (ejection fraction (EF)=23.7±7.3%) and 6 without heart failure, to experimentally induce PB. Second, we applied a real-time algorithm of pre-emptive dynamic exogenous CO2 administration, and tested different timings. / Results: We found that cardiac output alternation using pacemakers successfully induced PB. Dynamic CO2 therapy, when delivered coincident with hyperventilation, attenuated 57% of the experimentally induced oscillations in end-tidal CO2: SD/mean 0.06±0.01 untreated versus 0.04±0.01 with treatment (p<0.0001) and 0.02±0.01 in baseline non-modified breathing. This translated to a 56% reduction in induced ventilatory oscillations: SD/mean 0.19±0.09 untreated versus 0.14±0.06 with treatment (p=0.001) and 0.10±0.03 at baseline. Of note, end-tidal CO2 did not significantly rise when dynamic CO2 was applied to the model (4.84±0.47 vs 4.91± 0.45 kPa, p=0.08). Furthermore, mean ventilation was also not significantly increased by dynamic CO2 compared with untreated (7.8±1.2 vs 8.4±1.2 L/min, p=0.17). / Conclusions: Cardiac pacemaker manipulation can be used to induce PB experimentally. In this induced PB, delivering CO2 coincident with hyperventilation, ventilatory oscillations can be substantially attenuated without a significant increase in end-tidal CO2 or ventilation. Dynamic CO2 administration might be developed into a clinical treatment for PB. / Trial Registration number: ISRCTN29344450

Spatially Resolved Magnetic Field Structure in the Disk of a T Tauri Star

Magnetic fields in accretion disks play a dominant role during the star formation process but have hitherto been observationally poorly constrained. Field strengths have been inferred on T Tauri stars themselves and possibly in the innermost part of the accretion disk, but the strength and morphology of the field in the bulk of the disk have not been observed. Unresolved measurements of polarized emission (arising from elongated dust grains aligned perpendicular to the field) imply average fields aligned with the disks. Theoretically, the fields are expected to be largely toroidal, poloidal, or a mixture of the two, which imply different mechanisms for transporting angular momentum in the disks of actively accreting young stars such as HL Tau. Here we report resolved measurements of the polarized 1.25 mm continuum emission from HL Tau's disk. The magnetic field on a scale of 80 AU is coincident with the major axis (~210 AU diameter) of the disk. From this we conclude that the magnetic field inside the disk at this scale cannot be dominated by a vertical component, though a purely toroidal field does not fit the data well either. The unexpected morphology suggests that the magnetic field's role for the accretion of a T Tauri star is more complex than the current theoretical understanding.Comment: Accepted for publication in Natur

Point-of-care screening for a current Hepatitis C virus infection: influence on uptake of a concomitant offer of HIV screening

Eliminating hepatitis C as a public health threat requires an improved understanding of how to increase testing uptake. We piloted point-of-care testing (POCT) for a current HCV infection in an inner-city Emergency Department (ED) and assessed the influence on uptake of offering concomitant screening for HIV. Over four months, all adults attending ED with minor injuries were first invited to complete an anonymous questionnaire then invited to test in alternating cycles offering HCV POCT or HCV+HIV POCT. Viral RNA was detected in finger-prick blood by GeneXpert. 814/859 (94.8%) questionnaires were returned and 324/814 (39.8%) tests were accepted, comprising 211 HCV tests and 113 HCV+HIV tests. Offering concomitant HIV screening reduced uptake after adjusting for age and previous HCV testing (odds ratio 0.51; 95% confidence interval [CI] 0.38–0.68; p < 0.001). HCV prevalence was 1/324 (0.31%; 95% CI 0.05–1.73); no participant tested positive for HIV. 167/297 (56.2%) POCT participants lived in the most deprived neighbourhoods in England. HCV RNA testing using finger-prick blood was technically feasible. Uptake was moderate and the offer of concomitant HIV screening showed a detrimental impact on acceptability in this low prevalence population. The findings should be confirmed in a variety of other community settings

Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts

Mycobacterium ulcerans disease: experience with primary oral medical therapy in an Australian cohort

Mycobacterium ulcerans (MU) is responsible for disfiguring skin infections which are challenging to treat. The recommended treatment for MU has continued to evolve from surgery to remove all involved tissue, to the use of effective combination oral antibiotics with surgery as required. Our study describes the oral medical treatment utilised for consecutive cases of MU infection over a 15 month period at our institution, in Victoria, Australia. Managing patients primarily with oral antibiotics results in high cure rates and excellent cosmetic outcomes. The success with medical treatment reported in this study will aid those treating cases of MU infection, and will add to the growing body of knowledge about the relative roles of antibiotics and surgery for treating this infection

RepSeq-A database of amino acid repeats present in lower eukaryotic pathogens

BACKGROUND Amino acid repeat-containing proteins have a broad range of functions and their identification is of relevance to many experimental biologists. In human-infective protozoan parasites (such as the Kinetoplastid and Plasmodium species), they are implicated in immune evasion and have been shown to influence virulence and pathogenicity. RepSeq http://repseq.gugbe.com is a new database of amino acid repeat-containing proteins found in lower eukaryotic pathogens. The RepSeq database is accessed via a web-based application which also provides links to related online tools and databases for further analyses. RESULTS The RepSeq algorithm typically identifies more than 98% of repeat-containing proteins and is capable of identifying both perfect and mismatch repeats. The proportion of proteins that contain repeat elements varies greatly between different families and even species (3 - 35% of the total protein content). The most common motif type is the Sequence Repeat Region (SRR) - a repeated motif containing multiple different amino acid types. Proteins containing Single Amino Acid Repeats (SAARs) and Di-Peptide Repeats (DPRs) typically account for 0.5 - 1.0% of the total protein number. Notable exceptions are P. falciparum and D. discoideum, in which 33.67% and 34.28% respectively of the predicted proteomes consist of repeat-containing proteins. These numbers are due to large insertions of low complexity single and multi-codon repeat regions. CONCLUSION The RepSeq database provides a repository for repeat-containing proteins found in parasitic protozoa. The database allows for both individual and cross-species proteome analyses and also allows users to upload sequences of interest for analysis by the RepSeq algorithm. Identification of repeat-containing proteins provides researchers with a defined subset of proteins which can be analysed by expression profiling and functional characterisation, thereby facilitating study of pathogenicity and virulence factors in the parasitic protozoa. While primarily designed for kinetoplastid work, the RepSeq algorithm and database retain full functionality when used to analyse other species