Training South African clinician-scientists: Lessons from the University of Cape Town’s intercalated programme

In 2011, the Faculty of Health Sciences at the University of Cape Town, South Africa (SA), established the Clinician-Scientist Training Programme (UCTCSTP), consisting of intercalated BMedSci Hons/MB ChB and integrated MB ChB/MSc/PhD tracks. We report and reflect on the programme’s performance and challenges. The UCTCSTP has so far enrolled 71 students: 51 have received BMedSci Hons degrees and 4 have received Master’s degrees, while there are 14 BMedSci Hons, 4 MSc and 4 PhD candidates. Graduates have produced significant research outputs, and many remain actively engaged in research. The UCTCSTP has been successful in encouraging a cohort of future clinician-scientists, but should aim to broaden and improve its appeal to address the need to transform and grow the SA clinical academic workforce. As graduates progress with their postgraduate clinical training, they require institutional support and guidance, which may necessitate policy reform

Altered adrenergic response in myocytes bordering a chronic myocardial infarction underlies <i>in vivo</i> triggered activity and repolarization instability

Ventricular arrhythmias are a major complication early after myocardial infarction (MI). The heterogeneous peri‐infarct zone forms a substrate for re‐entry while arrhythmia initiation is often associated with sympathetic activation. We studied the mechanisms triggering these post‐MI arrhythmias in vivo and their relation to regional myocyte remodelling. In pigs with chronic MI (6 weeks), in vivo monophasic action potentials were simultaneously recorded in the peri‐infarct and remote regions during adrenergic stimulation with isoproterenol (ISO). Sham animals served as controls. During infusion of ISO in vivo, the incidence of delayed afterdepolarizations (DADs) and beat‐to‐beat variability of repolarization (BVR) was higher in the peri‐infarct than in the remote region. Myocytes isolated from the peri‐infarct region, in comparison to myocytes from the remote region, had more DADs, associated with spontaneous Ca2+ release, and a higher incidence of spontaneous action potentials when exposed to ISO (9.99 ± 4.2 vs. 0.16 ± 0.05 APs/min, p = 0.004); these were suppressed by CaMKII inhibition. Peri‐infarct myocytes also had reduced repolarization reserve and increased BVR (26 ± 10 ms vs. 9 ± 7 ms, p 2+ handling at baseline and myocyte hypertrophy were present throughout the LV. Expression of some of the related genes was however different between the regions. In conclusion, altered myocyte adrenergic responses in the peri‐infarct, but not in the remote region, provide a source of triggered activity in vivo and of repolarization instability amplifying the substrate for re‐entry. These findings stimulate further exploration of region‐specific therapies targeting myocytes and autonomic modulation

Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability

Cx43, a major cardiac connexin, forms precursor hemichannels that accrue at the intercalated disc to assemble as gap junctions. While gap junctions are crucial for electrical conduction in the heart, little is known about the potential roles of hemichannels. Recent evidence suggests that inhibiting Cx43 hemichannel opening with Gap19 has antiarrhythmic effects. Here, we used multiple electrophysiology, imaging, and super-resolution techniques to understand and define the conditions underlying Cx43 hemichannel activation in ventricular cardiomyocytes, their contribution to diastolic Ca2+ release from the sarcoplasmic reticulum, and their impact on electrical stability. We showed that Cx43 hemichannels were activated during diastolic Ca2+ release in single ventricular cardiomyocytes and cardiomyocyte cell pairs from mice and pigs. This activation involved Cx43 hemichannel Ca2+ entry and coupling to Ca2+ release microdomains at the intercalated disc, resulting in enhanced Ca2+ dynamics. Hemichannel opening furthermore contributed to delayed afterdepolarizations and triggered action potentials. In single cardiomyocytes, cardiomyocyte cell pairs, and arterially perfused tissue wedges from failing human hearts, increased hemichannel activity contributed to electrical instability compared with nonfailing rejected donor hearts. We conclude that microdomain coupling between Cx43 hemichannels and Ca2+ release is a potentially novel, targetable mechanism of cardiac arrhythmogenesis in heart failure. Copyright: © 2021, American Society for Clinical Investigation.We sincerely thank Ellen Cocquyt, Diego De Baere, Vicky Pauwelyn, Annemie Biesemans, Roxane Menten, and Mingliang Zhang for superb technical support. We would also like to thank the heart failure unit, the transplant surgical team, and the transplant coordinating team of UZ Leuven for help in providing the human explant hearts. This work was supported by the Fund for Scientific Research Flanders (project grants to LL, KRS, and GB; a postdoctoral fellowship to ED; and PhD fellowships to MDS and MA); Ghent University (a postdoctoral fellowship to KW and PhD fellowships to AL and TN); the Interuniversity Attraction Poles P7/10 to KRS and LL; NIH (project grants to ER and MD); the Fondation Leducq (transatlantic network award to MD); and a grant from the Ministry of Science and Higher Education of the Russian Federation, agreement 075-15-2020-800, to AVP

Sedation and Analgesia for Reduction of Pediatric Ileocolic Intussusception

IMPORTANCE: Ileocolic intussusception is an important cause of intestinal obstruction in children. Reduction of ileocolic intussusception using air or fluid enema is the standard of care. This likely distressing procedure is usually performed without sedation or analgesia, but practice variation exists. OBJECTIVE: To characterize the prevalence of opioid analgesia and sedation and assess their association with intestinal perforation and failed reduction. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study reviewed medical records of children aged 4 to 48 months with attempted reduction of ileocolic intussusception at 86 pediatric tertiary care institutions in 14 countries from January 2017 to December 2019. Of 3555 eligible medical records, 352 were excluded, and 3203 medical records were eligible. Data were analyzed in August 2022. EXPOSURES: Reduction of ileocolic intussusception. MAIN OUTCOMES AND MEASURES: The primary outcomes were opioid analgesia within 120 minutes of reduction based on the therapeutic window of IV morphine and sedation immediately before reduction of intussusception. RESULTS: We included 3203 patients (median [IQR] age, 17 [9-27] months; 2054 of 3203 [64.1%] males). Opioid use was documented in 395 of 3134 patients (12.6%), sedation 334 of 3161 patients (10.6%), and opioids plus sedation in 178 of 3134 patients (5.7%). Perforation was uncommon and occurred in 13 of 3203 patients (0.4%). In the unadjusted analysis, opioids plus sedation (odds ratio [OR], 5.92; 95% CI, 1.28-27.42; P = .02) and a greater number of reduction attempts (OR, 1.48; 95% CI, 1.03-2.11; P = .03) were significantly associated with perforation. In the adjusted analysis, neither of these covariates remained significant. Reductions were successful in 2700 of 3184 attempts (84.8%). In the unadjusted analysis, younger age, no pain assessment at triage, opioids, longer duration of symptoms, hydrostatic enema, and gastrointestinal anomaly were significantly associated with failed reduction. In the adjusted analysis, only younger age (OR, 1.05 per month; 95% CI, 1.03-1.06 per month; P \u3c .001), shorter duration of symptoms (OR, 0.96 per hour; 95% CI, 0.94-0.99 per hour; P = .002), and gastrointestinal anomaly (OR, 6.50; 95% CI, 2.04-20.64; P = .002) remained significant. CONCLUSIONS AND RELEVANCE: This cross-sectional study of pediatric ileocolic intussusception found that more than two-thirds of patients received neither analgesia nor sedation. Neither was associated with intestinal perforation or failed reduction, challenging the widespread practice of withholding analgesia and sedation for reduction of ileocolic intussusception in children

Myocardial stiffness assessed by shear wave elastography relates to pressure-volume loop derived measurements of chamber stiffness

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Foundations Flanders Background Increased myocardial stiffness is an important cause of diastolic dysfunction. Currently, invasive pressure-volume loop analysis is the gold standard method for the assessment of the left ventricular (LV) chamber stiffness. Its non-invasive assessment in the clinic is cumbersome, requires the combination of several parameters and has limited reliability. Shear wave elastography (SWE) is a novel method that evaluates the propagation of shear waves travelling along the myocardium using high frame rate echocardiography. The propagation speed is directly related to myocardial stiffness. Shear waves can be induced naturally by mitral valve closure (MVC). So far, the in vivo validation of SWE against an invasive gold standard reference method is still lacking. Purpose To compare myocardial stiffness assessed by shear wave propagation speed after MVC to invasive pressure-volume loop derived measurements of chamber stiffness. Methods Fifteen pigs (31.2 ± 4.1 kg) were included in the study. The instantaneous stiffness of the myocardium was altered by performing the following interventions: 1) preload reduction, 2) afterload increase, 3) preload increase and 4) induction of ischemia/reperfusion (I/R) injury by balloon occlusion of the proximal LAD for 90 min. with subsequent reperfusion of 40 min. To obtain the end-diastolic pressure-volume loop relation (EDPVR), a set of pressure-volume loops was acquired under preload reduction. From the EDPVR, the chamber stiffness constant β and operating chamber stiffness dP/dV were derived. SWE datasets in a parasternal long-axis view were acquired with an experimental ultrasound scanner at an average frame rate of 1304 ± 115 Hz. Shear waves after MVC were visualized on tissue acceleration maps by drawing an M-mode line along the interventricular septum (Figure 1A). The propagation speed was calculated by semi-automatically measuring the spatiotemporal slope. Results The chamber stiffness constant β significantly increased after the induction of the I/R injury (0.05 ± 0.01 1/ml vs. 0.09 ± 0.03 1/ml; p < 0.001). The operating chamber stiffness dP/dV decreased by reducing preload and increased by increasing afterload, increasing preload or by inducing an I/R injury (0.50 ± 0.18 mmHg/ml vs. 0.09 ± 0.05 mmHg/ml, 0.67 ± 0.19 mmHg/ml, 0.78 ± 0.35 mmHg/ml and 1.09 ± 0.38 mmHg/ml, respectively; p < 0.01). Likewise, shear wave propagation speed after MVC increased by increasing pre- and afterload (p = 0.001) and by inducing I/R injury (p < 0.001) (Figure 1B). Preload reduction had no significant influence (p = 0.118). Shear wave speed had a strong positive correlation with β (r = 0.63; p < 0.001) (Figure 1C) and dP/dV (r = 0.81; p < 0.001) (Figure 1D). Conclusions Shear wave speed after MVC is strongly related to invasive pressure-volume loop derived measures of chamber stiffness. The results of this study indicate the potential of SWE as a novel non-invasive method for the assessment of the instantaneous stiffness of the myocardium

Myocardial stiffness assessed by natural shear wave elastography is related to pressure-volume loop derived parameters

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On the development of spatial/temporal solar radiation maps: a Minas Gerais (Brazilian) case study.

Appropriate information on solar resources is very important for a variety of technological areas, such as agriculture, meteorology, forestry engineering, and water resources, particularly for an innovative technology such as solar energy. In the market entry process of an innovative technol-ogy such as solar energy, the increased and sustained deployment of this energy technology strongly depends on the economy and reliability of the solar systems installed. The economy and reliability of a system are the consequences of a well-prepared project, resulting from an accurate knowledge of the solar resource available. Therefore, knowing the potential of the solar resource accurately is not only a need but also an imperative for the larger diffusion and use of the solar energy. The existing sources of the information on radiation in MG are quite varied, both at the in-stitutional level and in different types of publications. The publications containing this informa-tion are project reports, internal reports of institutions, and several magazines. Thus, the quality of the data varies considerably, the information presents spatial and temporal discontinuity

Natural shear wave propagation speed is influenced by both changes in myocardial structural properties as well as loading conditions

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Foundation - Flanders (FWO) Background Shear wave elastography (SWE) is a promising tool for the non-invasive assessment of myocardial stiffness. It is based on the evaluation of the propagation speed of shear waves by high frame rate echocardiography. These waves can be induced by for instance mitral valve closure (MVC) and the speed at which they travel is related to the instantaneous stiffness of the myocardium. Myocardial stiffness is defined by the local slope of the stress-strain relation and can therefore be altered by both changes in structural properties of the myocardium as well as loading conditions. Purpose The aim of this study was to investigate how changes in myocardial structural properties as well as loading conditions affect shear wave speed after MVC. Methods Until now, 8 pigs (weight: 33.6 ± 5.4 kg) were included. The following interventions were performed: 1) preload was reduced by balloon occlusion of the vena cava inferior, 2) afterload was increased by balloon occlusion of descending aorta, 3) preload was increased by intravenous administration of 500 ml of saline and 4) ischemia/reperfusion injury (I/R injury) was induced in the septal wall by balloon occlusion of the LAD for 90 min. with subsequent reperfusion for 40 min. Echocardiographic and left ventricular pressure recordings were simultaneously obtained during each intervention. Left ventricular parasternal long-axis views were acquired with an experimental high frame rate ultrasound scanner (average frame rate: 1279 ± 148 Hz). Shear waves were visualized on tissue acceleration maps by drawing an M-mode line along the interventricular septum. Shear wave propagation speed after MVC was calculated by assessing the slope of the wave pattern on the tissue acceleration map (Figure A). Results The change in left ventricular end-diastolic pressure (LVEDP) and shear wave speed after MVC between baseline and each intervention are shown in Figure B and C, respectively. Preload reduction resulted in significant lower LVEDP compared to baseline (p < 0.01), while the other loading changes did not have a significant effect. Shear wave speed after MVC significantly increased by afterload and preload increase (p < 0.01). I/R injury resulted in increased shear wave speed (p < 0.01) without significantly altering LVEDP. There was a good positive correlation between the change in LVEDP and the change in shear wave speed induced by loading changes (r = 0.76; p < 0.001) (Figure D). However, the correlation became less strong if data of I/R injury was taken into account as well (r = 0.63; p < 0.001). Conclusion Our results suggest that SWE is capable to characterize myocardial tissue properties and besides has the potential as a novel method for the estimation of left ventricular filling pressures. However, in the presence of structural changes of the myocardium, care should be taken when estimating filling pressures based on shear wave propagation speed