Electrocardiographic safety evaluation of extended artemether-lumefantrine treatment in patients with uncomplicated Plasmodium falciparum malaria in Bagamoyo District, Tanzania.

BACKGROUND: Extended artemisinin-based combination therapy (ACT) for treatment of uncomplicated Plasmodium falciparum malaria with already existing drug regimens, such as artemether-lumefantrine, might be effective in tackling the emerging ACT resistance. However, given the history of cardiotoxicity among anti-malarial drugs structurally similar to lumefantrine, the potential effect of extended artemether-lumefantrine treatment on the electrocardiographic (ECG) QTc interval is of high concern. METHODS: Male and non-pregnant females aged 1-65 years, diagnosed with uncomplicated P. falciparum malaria in Bagamoyo district, Tanzania, were randomized into two arms. The intervention arm received an extended, i.e. 6-day, course of artemether-lumefantrine and an additional single low-dose primaquine (0.25 mg/kg) administered together with the last artemether-lumefantrine dose. The control arm received the standard weight-based 3-day course. ECGs were performed at day 0 and 4-5 h after the last dose at day 5. QT intervals were read manually using the tangent method and automatically. Bazett's (QTcB) and Fridericia's (QTcF) formulae were used for correction for heart rate. Descriptive statistics were used to calculate baseline characteristics and the number of supra-thresholds QTc intervals (QTc prolongation > 500, change in QTc interval (ΔQTc) > 60 ms). The mean change in QTc interval in and between the two arms was compared using the paired t-test and independent samples t-test, respectively. RESULTS: A total of 195 patients were enrolled, 103 and 92 in the intervention and control arm, respectively. No patient experienced QTc intervals > 500 ms on day 5 by both formulae. Patients with ΔQTc > 60 ms, for QTcF were 6/103 (5.8%) vs 2/92 (2.2%) and for QTcB 2/103 (1.9%) vs 1/92 (1.1%) in the intervention and control arms, respectively. The mean difference in ΔQTc interval was statistically significant between the two arms with both correction formulae, 11.4 ms (95% CI 2.7-20.0, p = 0.010) and 13.4 ms (95% CI 5.3-21.5, p = 0.001), for QTcB and QTcF, respectively. CONCLUSION: The extended 6-day course of artemether-lumefantrine did not reveal clinically relevant QTc prolonging effects. However, significant QTcF prolongation and presence of patients with supra-threshold QTc values observed in the intervention arm underscore the importance of further monitoring of QTc parameters in extended artemether-lumefantrine treatment. Trial registration ClinicalTrials.gov, NCT03241901. Registered July 27, 2017. https://clinicaltrials.gov/show/NCT03241901.

Tissue expansion 1984-1999: a 15-year review.

We assessed all patients who underwent tissue expansion, excluding breast reconstructions, between 1984 and 1999. A total of 237 patients had 257 expansions, normally for distorted scars, 202 of 257 cases (79%). Their mean age was 27 (range 7-67) years, most being women, 149 of 237 (63%). The mean duration of expansion was 16 weeks (range 0.4-118). The most common site was the skull (61/257). Prophylactic antibiotics were used in 224 of 257 (86%) at the time of expander insertion and 147 of 257 (56%) at the removal of the expander. Sixty-two patients (24%) had minor complications and 34 (13%) had major complications. Tissue expansion can be used with a currently acceptable failure rate though we continue to strive to lower this further.

Patients' satisfaction after ear reconstruction with autologous rib cartilage.

Patients' satisfaction is an important outcome measure in reconstructive surgery and quality assurance is today central in the clinical practice. The aim of this study was to evaluate the patients' satisfaction with the process and final result after reconstruction for congenital microtia. A questionnaire was designed and sent to 78 patients who had undergone unilateral ear reconstruction with autologous rib cartilage during the period 2000-2010. For a multidimensional view the patients answered 42 questions about aesthetic, functional, psychosocial, and clinic-related outcomes. The response rate was 76% (59/78 patients). The patients were generally satisfied with the aesthetic result of the ear and had function gain in being able to wear glasses; however, some patients did report new different functional problems after the operation. Still, almost all patients felt that the ear was a part of them and would have chosen the same operative procedure if they could do it again. The patients were overall highly satisfied with the care process. This surgery-specific questionnaire is an important tool for quality assurance in this clinical practice. These findings can help to improve the preoperative information to meet the patients' notions, expectations, and fears.

Blood flow dynamics in reconstructed auricles.

Ear reconstruction with autologous rib cartilage is performed in stages. Restitution of blood flow between the separate stages is crucial to obtain a good result. Laser Doppler perfusion imaging (LDPI) and local temperature were measured in reconstructed and normal ears in response to indirect heating. Ten persons who had had a unilateral ear reconstruction were included in the study. At a minimum, 157 days had passed since the last operation. LDPI showed no difference in blood flow between the reconstructed ear and the normal ear, neither before nor after indirect heating. The upper part of the normal ear was slightly cooler than the corresponding part in the reconstructed ear. Indirect heating caused an increase of LDPI-values and temperatures in the upper, middle, and lower part of the ear both in the reconstructed ear and the normal one. Skin blood flow recovers after 3-stage ear reconstruction and shows normal dynamic response upon indirect heating.

A comparison of digital morphometry and clinical measurements of ears.

Clinical measurements are necessary in many routine follow-ups and scientific evaluations, but the accuracy of these measurements is seldom challenged. The size of the reconstructed ear is one important parameter in the follow-up regarding patients operated on due to microtia. With the introduction of digital morphometry one was obliged to evaluate its accuracy in comparison to its analogue equivalents. In a first series of measurements the ears of 30 persons were assessed using digital morphometry, compass and ruler, and calliper to test the accuracy of these methods. In a second series of measurements, 10 patients with reconstructed unilateral microtia were assessed with digital morphometry to test the inter-individual variation of this method. The accuracy of digital morphometry was of the same magnitude as the manual methods. When the inter-individual variation of accuracy was assessed in digital morphometry it was found that random error differed from person to person. In scientific settings, for instance when evaluating possible growth of the cartilage framework, the specific individual accuracy must therefore be taken into account in order to draw safe conclusions.

Threshold of tactile perception in a reconstructed auricle.

There are more important outcome variables than the aesthetic when it comes to a successful result in reconstruction of the ear for microtia. The protective sensitivity, for example, is important to avoid damage to the skin covering the cartilaginous framework. We studied 39 patients with unilateral microtia and recorded their skin sensitivity more than six months after the last operation. The Semmes-Weinstein Monofilament Test (SWMT) was used to assess the threshold of protective sensitivity in three particular areas: the helix, the anthelix, and the lobule. The opposite ear served as control. A monofilament of 4.31 or less was regarded as acceptable protective sensitivity. Thirty-two patients had acceptable sensitivity in the whole ear, but the helix gave a poor result in seven patients and in one of them so did the anthelix.