Effects of a neuromuscular joint-protective exercise therapy program for treatment of wrist osteoarthritis: a randomized controlled trial.

BACKGROUND: Individuals with wrist osteoarthritis (OA) can suffer from pain, muscular weakness, and impaired motion of the wrist, which can reduce the quality of life. While there is strong evidence that all patients with OA should receive first-line treatment with education and exercises, this approach has not yet been proposed for individuals with wrist OA. Therefore, this trial aimed to evaluate the effectiveness of a first line neuromuscular joint-protective exercise therapy program compared to a training program with range of motion (ROM) exercises in patients with wrist OA. METHODS: In this randomized controlled trial (RCT), 48 patients with symptomatic and radiographically confirmed wrist OA were randomly allocated to a 12-week self-management program with either a neuromuscular joint-protective exercise therapy program (intervention group) or a training program with ROM exercises only (control group). Our primary outcome measure was the Patient-Rated Wrist Evaluation (PRWE) with secondary outcome measures of grip strength, range of wrist motion, the Numerical Pain Rating, Scale (NPRS), the Disabilities of the Arm, Shoulder, and Hand (DASH) and the Generalized Self-Efficacy Scale (GSES). The outcome measures were evaluated by a blinded assessor at baseline and 12 weeks. Between-groups differences were analyzed using the Mann-Whitney U test and within-group differences were analyzed with the Wilcoxon signed-rank test. RESULTS: A total of 41 participants were analyzed at 12 weeks. There were no significant differences in PRWE between the groups at 12 weeks (p = 0.27). However, DASH improved significantly in the intervention group compared to the control group (p = 0.02) and NPRS on load within the intervention group (p = 0.006). The difference in DASH should be interpreted with caution since it could be due to a non-significant increase (worsening) from baseline in the control group in combination with a non-significant decrease (improvement) in the intervention group. CONCLUSIONS: This RCT showed that the novel neuromuscular joint-protective exercise therapy program was not superior in reducing pain and improving function compared to a training program with ROM exercises at 12 weeks. Future research is warranted to evaluate the effectiveness of forthcoming exercise therapy treatment programs for patients with wrist OA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05367817. Retrospectively registered on 10/05/2022. https://clinicaltrials.gov .

Efficacy of Single-Dose Primaquine With Artemisinin Combination Therapy on Plasmodium falciparum Gametocytes and Transmission: An Individual Patient Meta-Analysis.

BACKGROUND: Since the World Health Organization recommended single low-dose (0.25 mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant Plasmodium falciparum, several single-site studies have been conducted to assess efficacy. METHODS: An individual patient meta-analysis to assess gametocytocidal and transmission-blocking efficacy of PQ in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (1) gametocyte carriage in the first 2 weeks post treatment; and (2) the probability of infecting at least 1 mosquito or of a mosquito becoming infected. RESULTS: In 2574 participants from 14 studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytemia on day 0 (odds ratio [OR], 0.22; 95% confidence interval [CI], .17-.28 and OR, 0.12; 95% CI, .08-.16, respectively). Rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (P = .010 for day 7). Addition of 0.25 mg/kg PQ was associated with near complete prevention of transmission to mosquitoes. CONCLUSIONS: Transmission blocking is achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.

Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide: a systematic review and meta-analysis of individual patient data.

BACKGROUND: In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns. METHODS: A systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models. RESULTS: Data comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17-0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19-0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb < 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms. CONCLUSIONS: Our results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient individuals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient individuals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients. TRIAL REGISTRATION: PROSPERO, CRD42019128185.

Visualization of wrist anatomy-a comparison between 7T and 3T MRI.

OBJECTIVE: Injuries to the wrist are, due to its small size and complex anatomical structures, difficult to assess by MR, and surgical interventions such as diagnostic arthroscopy are often necessary. Therefore, improved visualization using non-invasive methods could be of clinical value. As a first step of improvement, the purpose of this study was to evaluate visualization of anatomical structures at 7T compared with 3T MR. METHODS: Eighteen healthy volunteers (three males and three females from each age decade between 20 and 49 years) were examined with 7T and 3T MR. Four musculoskeletal radiologists graded 2D and 3D images on a five-level grading scale for visibility of ligaments, cartilage, nerves, trabecular bone, and tendons, as well as overall image quality (i.e., edge sharpness, perceived tissue contrast, and presence of artefacts). Statistical analysis was done using a visual grading characteristics (VGC) analysis. RESULTS: Visibility of cartilage, trabecular bone, tendons, nerves, and ligaments was graded significantly higher at 7T with an area under the curve (AUCVGC) of 0.62-0.88 (95% confidence interval [CI] 0.50-0.97, p = < 0.0001-0.03) using either 2D or 3D imaging. Imaging with 3T was not graded as superior to 7T for any structure. Image quality was also significantly superior at 7T, except for artefacts, where no significant differences were found. CONCLUSIONS: Tendons, trabecular bone, nerves, and ligaments were all significantly better visualized at 7T compared to 3T. KEY POINTS: • MRI of the wrist at 7T with a commercially available wrist coil is feasible at similar acquisition times as for 3T MRI. • The current study showed 7T to be superior to 3T in the visualization of anatomical structures of the wrist, including ligaments, tendons, nerves, and trabecular bone. • Image quality was significantly superior at 7T, except for artefacts, where no significant differences were found.

Pneumococcal concentration and serotype distribution in preschool children with radiologically confirmed pneumonia compared to healthy controls prior to introduction of pneumococcal vaccination in Zanzibar: an observational study.

BACKGROUND: The World Health Organization recommends pneumococcal vaccination (PCV) in the first year of life. We investigated pneumococcal serotypes in children with clinical or radiologically confirmed pneumonia and healthy controls prior to PCV13 vaccine introduction in Zanzibar. METHODS: Children (n = 677) with non-severe acute febrile illness aged 2-59 months presenting to a health centre in Zanzibar, Tanzania April-July 2011 were included. Nasopharyngeal swabs collected at enrolment were analysed by real-time PCR to detect and quantify pneumococcal serotypes in patients (n = 648) and in healthy asymptomatic community controls (n = 161). Children with clinical signs of pneumonia according to the Integrated Management of Childhood illness guidelines ("IMCI pneumonia") were subjected to a chest-X-ray. Consolidation on chest X-ray was considered "radiological pneumonia". RESULTS: Pneumococcal DNA was detected in the nasopharynx of 562/809 (69%) children (70% in patients and 64% in healthy controls), with no significant difference in proportions between patients with or without presence of fever, malnutrition, IMCI pneumonia or radiological pneumonia. The mean pneumococcal concentration was similar in children with and without radiological pneumonia (Ct value 26.3 versus 27.0, respectively, p = 0.3115). At least one serotype could be determined in 423 (75%) participants positive for pneumococci of which 33% had multiple serotypes detected. A total of 23 different serotypes were identified. One serotype (19F) was more common in children with fever (86/648, 13%) than in healthy controls (12/161, 7%), (p = 0.043). Logistic regression adjusting for age and gender showed that serotype 9A/V [aOR = 10.9 (CI 2.0-60.0, p = 0.006)] and 14 [aOR = 3.9 (CI 1.4-11.0, p = 0.012)] were associated with radiological pneumonia. The serotypes included in the PCV13 vaccine were found in 376 (89%) of the 423 serotype positive participants. CONCLUSION: The PCV13 vaccine introduced in 2012 targets a great majority of the identified serotypes. Infections with multiple serotypes are common. PCR-determined concentrations of pneumococci in nasopharynx were not associated with radiologically confirmed pneumonia. Trial registration Clinicaltrials.gov (NCT01094431).

Visualization of wrist ligaments with 3D and 2D magnetic resonance imaging at 3 Tesla.

BACKGROUND: Wrist ligaments are challenging to visualize using magnetic resonance imaging (MRI). Injuries involving the scapholunate ligament (SLL), the lunotriquetral ligament (LTL), and the triangular fibrocartilage complex (TFCC) are common and difficult to diagnose, often requiring diagnostic arthroscopy. PURPOSE: To compare the visualization of wrist ligaments on a three-dimensional (3D) sequence with two-dimensional (2D) sequences on 3-T MRI. MATERIAL AND METHODS: Eighteen healthy volunteers were examined with a 3D SPACE (sampling perfection with application optimized contrasts using different flip angle evolution) sequence and 2D coronal, axial, and sagittal proton density-weighted (PD) sequences. Four musculoskeletal radiologists graded the anatomical visibility of the SLL, LTL, TFCC, and the image quality, using five grades in a visual grading characteristics (VGC) evaluation. After Bonferroni correction, a P value ≤0.005 was considered statistically significant. RESULTS: The 3D images were graded significantly better than the 2D images in the visualization of the dorsal and palmar parts of the SLL and the LTL. Regarding the TFCC, the 3D images were graded significantly better for visualization of the foveal attachment. 2D imaging was not found significantly superior to 3D imaging in any aspect. CONCLUSION: The 3D SPACE sequence was scored as superior to the 2D sequences at 3 T in the assessment of the SLL, the LTL, and the foveal attachment of the TFCC. Thus, 3D SPACE can replace 2D PD sequences when these ligaments need to be assessed.

Psychometric properties of patient-reported outcome measures (PROMs) in wrist osteoarthritis: test-retest reliability and construct validity.

BACKGROUND: Patient-reported outcome measures (PROMs) are frequently used to assess the effects of treatments in patients with wrist osteoarthritis (OA), but their psychometric properties have not been evaluated in this group of patients. Our aim was to evaluate the psychometric properties of the Numeric Rating Scale (NRS pain at rest, pain on motion without load, and pain on load), the Disabilities of the Arm, Shoulder and Hand (DASH) and the Patient Rated Wrist Evaluation (PRWE) questionnaires in patients with wrist OA regarding test-retest reliability and construct validity. METHODS: The NRS, DASH and PRWE were self-administered by 50 patients (40 men and 10 women, mean age 66 years) in a postal survey on two occasions, two weeks apart. Test-retest reliability was evaluated by Kappa statistics and the Spearman rank correlation coefficients (rho) were calculated to evaluate construct validity. RESULTS: The Kappa coefficients for DASH, PRWE and NRS pain on motion without load and NRS pain on load were > 0.90, 95% CI ranging from 0.84 to 0.98, while NRS pain at rest was 0.83, 95% CI 0.73-0.92. The construct validity of the PROMs was confirmed by three formulated hypotheses: a higher correlation between PRWE and NRS (rho 0.80-0.91, p < 0.001) was found, compared to DASH and NRS (rho 0.68-0.80, p < 0.001); the NRS pain on motion without load and NRS pain on load correlated more strongly to PRWE and DASH (rho 0.71-0.91, p < 0.001) compared to NRS pain at rest (rho 0.68-0.80) and a high correlation between PRWE and DASH was found (rho 0.86, p < 0.001). CONCLUSIONS: The NRS, DASH and PRWE demonstrate excellent test-retest reliability and moderate to high construct validity in patients with wrist OA. These PROMs are highly related, but they also differ. Therefore, they complement each other in ensuring a comprehensive evaluation of perceived disability in wrist OA. As PRWE showed the highest test-retest reliability and the highest relation to the other PROMs, the sole use of the PRWE can be recommended in clinical practice.

Evaluation of Simple Algorithms for Proportional Control of Prosthetic Hands Using Intramuscular Electromyography.

Although seemingly effortless, the control of the human hand is backed by an elaborate neuro-muscular mechanism. The end result is typically a smooth action with the precise positioning of the joints of the hand and an exerted force that can be modulated to enable precise interaction with the surroundings. Unfortunately, even the most sophisticated technology cannot replace such a comprehensive role but can offer only basic hand functionalities. This issue arises from the drawbacks of the prosthetic hand control strategies that commonly rely on surface EMG signals that contain a high level of noise, thus limiting accurate and robust multi-joint movement estimation. The use of intramuscular EMG results in higher quality signals which, in turn, lead to an improvement in prosthetic control performance. Here, we present the evaluation of fourteen common/well-known algorithms (mean absolute value, variance, slope sign change, zero crossing, Willison amplitude, waveform length, signal envelope, total signal energy, Teager energy in the time domain, Teager energy in the frequency domain, modified Teager energy, mean of signal frequencies, median of signal frequencies, and firing rate) for the direct and proportional control of a prosthetic hand. The method involves the estimation of the forces generated in the hand by using different algorithms applied to iEMG signals from our recently published database, and comparing them to the measured forces (ground truth). The results presented in this paper are intended to be used as a baseline performance metric for more advanced algorithms that will be made and tested using the same database.

Patients' experiences before and after total wrist fusion or total wrist arthroplasty: A qualitative study of patients with wrist osteoarthritis.

INTRODUCTION: For patients with advanced wrist osteoarthritis (OA), total wrist fusion (TWF) is the standard surgical treatment, although total wrist arthroplasty (TWA) has become a plausible motion-preserving alternative. PURPOSE: To explore patients' experiences of living with advanced wrist OA before and after surgery with either a TWF or a TWA. Furthermore, we wanted to explore the expectations of surgery, appraisal of results, and the adaptation strategies used to overcome challenges in everyday life. STUDY DESIGN: Qualitative descriptive. METHODS: A purposive sample of 13 patients with advanced wrist OA surgically treated with TWF (n = 7) or TWA (n = 6) was recruited. Semistructured interviews were conducted and analyzed using qualitative content analysis. RESULTS: Four categories are described: the problematic wrist, the breakpoint, appraisal of the results, and adaptation to challenges in everyday life. Pain relief was the primary expectation of surgery, and involvement in the discussion regarding different surgical options had a positive effect on the appraisal of results. The participants' ability to perform tasks in everyday life appeared to be more related to their level of pain than the range of wrist motion. Successful coping strategies were developed, enabling the participants to become more independent and adapt to challenges in daily life. CONCLUSIONS: Previous surgical experiences, occupation, and amount of wrist motion influenced the participants' expectations, surgical choice with either a TWF or a TWA, and the appraisal of results. The findings contribute valuable insights to both surgeons and hand therapists about the importance of having the patient's individual expectations and needs in focus.

Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate-amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar.

BACKGROUND: The anti-malarial drug, amodiaquine, a commonly used, long-acting partner drug in artemisinin-based combination therapy, is metabolized to active desethyl-amodiaquine (DEAQ) by cytochrome P450 2C8 (CYP2C8). The CYP2C8 gene carries several polymorphisms including the more frequent minor alleles, CYP2C8*2 and CYP2C8*3. These minor alleles have been associated with decreased enzymatic activity, slowing the amodiaquine biotransformation towards DEAQ. This study aimed to assess the influence of these CYP2C8 polymorphisms on the efficacy and tolerability of artesunate-amodiaquine (AS-AQ) treatment for uncomplicated Plasmodium falciparum malaria in Zanzibar. METHODS: Dried blood spots on filter paper were collected from 618 children enrolled in two randomized clinical trials comparing AS-AQ and artemether-lumefantrine in 2002-2005 in Zanzibar. Study participant were under five years of age with uncomplicated falciparum malaria. Human CYP2C8*2 and CYP2C8*3 genotype frequencies were determined by PCR-restriction fragment length polymorphism. Statistical associations between CYP2C8*2 and/or CYP2C8*3 allele carriers and treatment outcome or occurrence of adverse events were assessed by Fisher's exact test. RESULTS: The allele frequencies of CYP2C8*2 and CYP2C8*3 were 17.5 % (95 % CI 15.4-19.7) and 2.7 % (95 % CI 1.8-3.7), respectively. There was no significant difference in the proportion of subjects carrying either CYP2C8*2 or CYP2C8*3 alleles amongst those with re-infections (44.1 %; 95 % CI 33.8-54.8) or those with recrudescent infections (48.3 %; 95 % CI 29.4-67.5), compared to those with an adequate clinical and parasitological response (36.7 %; 95 % CI 30.0-43.9) (P = 0.25 and P = 0.31, respectively). However, patients carrying either CYP2C8*2 or CYP2C8*3 alleles were significantly associated with an increased occurrence of non-serious adverse events, when compared with CYP2C8 *1/*1 wild type homozygotes (44.9 %; 95 % CI 36.1-54.0 vs. 28.1 %; 95 % CI 21.9-35.0, respectively; P = 0.003). CONCLUSIONS: CYP2C8 genotypes did not influence treatment efficacy directly, but the tolerability to AS-AQ may be reduced in subjects carrying the CYP2C8*2 and CYP2C8*3 alleles. The importance of this non-negligible association with regard to amodiaquine-based malaria chemotherapy warrants further investigation.

Learning regularized representations of categorically labelled surface EMG enables simultaneous and proportional myoelectric control.

BACKGROUND: Processing the surface electromyogram (sEMG) to decode movement intent is a promising approach for natural control of upper extremity prostheses. To this end, this paper introduces and evaluates a new framework which allows for simultaneous and proportional myoelectric control over multiple degrees of freedom (DoFs) in real-time. The framework uses multitask neural networks and domain-informed regularization in order to automatically find nonlinear mappings from the forearm sEMG envelope to multivariate and continuous encodings of concurrent hand- and wrist kinematics, despite only requiring categorical movement instruction stimuli signals for calibration. METHODS: Forearm sEMG with 8 channels was collected from healthy human subjects (N = 20) and used to calibrate two myoelectric control interfaces, each with two output DoFs. The interfaces were built from (I) the proposed framework, termed Myoelectric Representation Learning (MRL), and, to allow for comparisons, from (II) a standard pattern recognition framework based on Linear Discriminant Analysis (LDA). The online performances of both interfaces were assessed with a Fitts's law type test generating 5 quantitative performance metrics. The temporal stabilities of the interfaces were evaluated by conducting identical tests without recalibration 7 days after the initial experiment session. RESULTS: Metric-wise two-way repeated measures ANOVA with factors method (MRL vs LDA) and session (day 1 vs day 7) revealed a significant ([Formula: see text]) advantage for MRL over LDA in 5 out of 5 performance metrics, with metric-wise effect sizes (Cohen's [Formula: see text]) separating MRL from LDA ranging from [Formula: see text] to [Formula: see text]. No significant effect on any metric was detected for neither session nor interaction between method and session, indicating that none of the methods deteriorated significantly in control efficacy during one week of intermission. CONCLUSIONS: The results suggest that MRL is able to successfully generate stable mappings from EMG to kinematics, thereby enabling myoelectric control with real-time performance superior to that of the current commercial standard for pattern recognition (as represented by LDA). It is thus postulated that the presented MRL approach can be of practical utility for muscle-computer interfaces.

Electrotactile Feedback for the Discrimination of Different Surface Textures Using a Microphone.

Most commercial prosthetic hands lack closed-loop feedback, thus, a lot of research has been focusing on implementing sensory feedback systems to provide the user with sensory information during activities of daily living. This study evaluates the possibilities of using a microphone and electrotactile feedback to identify different textures. A condenser microphone was used as a sensor to detect the friction sound generated from the contact between different textures and the microphone. The generated signal was processed to provide a characteristic electrical stimulation presented to the participants. The main goal of the processing was to derive a continuous and intuitive transfer function between the microphone signal and stimulation frequency. Twelve able-bodied volunteers participated in the study, in which they were asked to identify the stroked texture (among four used in this study: Felt, sponge, silicone rubber, and string mesh) using only electrotactile feedback. The experiments were done in three phases: (1) Training, (2) with-feedback, (3) without-feedback. Each texture was stroked 20 times each during all three phases. The results show that the participants were able to differentiate between different textures, with a median accuracy of 85%, by using only electrotactile feedback with the stimulation frequency being the only variable parameter.

Outcome of carpal tunnel release in patients with normal nerve conduction studies.

BACKGROUND: We evaluated outcome after carpal tunnel release (CTR) in patients with clinically diagnosed carpal tunnel syndrome (CTS) but normal results in nerve conduction studies (NCS), and compared these results with those from a prospective group of patients with NCS-verified CTS. METHODS: Over a 5-year period, we prospectively included 103 patients with clinical CTS. NCS were done at inclusion, with surgeon and patient being kept blind regarding the result. The patients underwent endoscopic CTR. QuickDASH and satisfaction score were recorded preoperatively and 4 months after surgery. 94 patients, 47 of whom had NCS-verified CTS, completed the study. RESULTS: A significant improvement in QuickDASH score (18 and 20 points respectively, p < 0.01) was found for both groups. Satisfaction score was significantly higher in the group with NCS-verified CTS. However, the overall satisfaction rates were 87% in the normal NCS group and 95% in the group with abnormal NCS. CONCLUSIONS: Clinical outcome after CTR in patients with normal NCS was favourable and similar to that obtained in patients with NCS-verified CTS. Nonetheless, patients with normal result in NCS gave a lower satisfaction score.

Increased Sensitivity of Plasmodium falciparum to Artesunate/Amodiaquine Despite 14 Years as First-Line Malaria Treatment, Zanzibar.

Artemisinin-based combination therapies (ACTs) are first-line treatments for uncomplicated Plasmodium falciparum malaria. ACT resistance is spreading in Asia but not yet in Africa. Reduced effects of ACT partner drugs have been reported but with little information regarding widely used artesunate/amodiaquine (ASAQ). We studied its efficacy in Zanzibar after 14 years as first-line treatment directly by an in vivo, single-armed trial and indirectly by prevalences of different genotypes in the P. falciparum chloroquine-resistance transporter, multidrug-resistance 1, and Kelch 13 propeller domain genes. In vivo efficacy was higher during 2017 (100%; 95% CI 97.4%-100%) than during 2002-2005 (94.7%; 95% CI 91.9%-96.7%) (p = 0.003). Molecular findings showed no artemisinin resistance-associated genotypes and major increases in genotypes associated with high sensitivity/efficacy for amodiaquine than before ASAQ was introduced. Thus, the efficacy of ASAQ is maintained and appears to be increased after long-term use in contrast to what is observed for other ACTs used in Africa.

Parasite clearance, cure rate, post-treatment prophylaxis and safety of standard 3-day versus an extended 6-day treatment of artemether-lumefantrine and a single low-dose primaquine for uncomplicated Plasmodium falciparum malaria in Bagamoyo district, Tanzania: a randomized controlled trial.

BACKGROUND: Artemisinin-based combination therapy (ACT) resistant Plasmodium falciparum represents an increasing threat to Africa. Extended ACT regimens from standard 3 to 6 days may represent a means to prevent its development and potential spread in Africa. METHODS: Standard 3-day treatment with artemether-lumefantrine (control) was compared to extended 6-day treatment and single low-dose primaquine (intervention); in a randomized controlled, parallel group, superiority clinical trial of patients aged 1-65 years with microscopy confirmed uncomplicated P. falciparum malaria, enrolled in Bagamoyo district, Tanzania. The study evaluated parasite clearance, including proportion of PCR detectable P. falciparum on days 5 and 7 (primary endpoint), cure rate, post-treatment prophylaxis, safety and tolerability. Clinical, and laboratory assessments, including ECG were conducted during 42 days of follow-up. Blood samples were collected for parasite detection (by microscopy and PCR), molecular genotyping and pharmacokinetic analyses. Kaplan-Meier survival analyses were done for both parasite clearance and recurrence. RESULTS: A total of 280 patients were enrolled, 141 and 139 in the control and intervention arm, respectively, of whom 121 completed 42 days follow-up in each arm. There was no difference in proportion of PCR positivity across the arms at day 5 (80/130 (61.5%) vs 89/134 (66.4%), p = 0.44), or day 7 (71/129 (55.0%) vs 70/134 (52.2%), p = 0.71). Day 42 microscopy determined cure rates (PCR adjusted) were 97.4% (100/103) and 98.3% (110/112), p = 0.65, in the control and intervention arm, respectively. Microscopy determined crude recurrent parasitaemia during follow-up was 21/121 (17.4%) in the control and 14/121 (11.6%) in the intervention arm, p = 0.20, and it took 34 days and 42 days in the respective arms for 90% of the patients to remain without recurrent parasitaemia. Lumefantrine exposure was significantly higher in intervention arm from D3 to D42, but cardiac, biochemical and haematological safety was high and similar in both arms. CONCLUSION: Extended 6-day artemether-lumefantrine treatment and a single low-dose of primaquine was not superior to standard 3-day treatment for ACT sensitive P. falciparum infections but, importantly, equally efficacious and safe. Thus, extended artemether-lumefantrine treatment may be considered as a future treatment regimen for ACT resistant P. falciparum, to prolong the therapeutic lifespan of ACT in Africa. Trial registration ClinicalTrials.gov, NCT03241901. Registered July 27, 2017 https://clinicaltrials.gov/show/NCT03241901.

Falciparum malaria from coastal Tanzania and Zanzibar remains highly connected despite effective control efforts on the archipelago.

BACKGROUND: Tanzania's Zanzibar archipelago has made significant gains in malaria control over the last decade and is a target for malaria elimination. Despite consistent implementation of effective tools since 2002, elimination has not been achieved. Importation of parasites from outside of the archipelago is thought to be an important cause of malaria's persistence, but this paradigm has not been studied using modern genetic tools. METHODS: Whole-genome sequencing (WGS) was used to investigate the impact of importation, employing population genetic analyses of Plasmodium falciparum isolates from both the archipelago and mainland Tanzania. Ancestry, levels of genetic diversity and differentiation, patterns of relatedness, and patterns of selection between these two populations were assessed by leveraging recent advances in deconvolution of genomes from polyclonal malaria infections. RESULTS: Significant decreases in the effective population sizes were inferred in both populations that coincide with a period of decreasing malaria transmission in Tanzania. Identity by descent analysis showed that parasites in the two populations shared long segments of their genomes, on the order of 5 cM, suggesting shared ancestry within the last 10 generations. Even with limited sampling, two of isolates between the mainland and Zanzibar were identified that are related at the expected level of half-siblings, consistent with recent importation. CONCLUSIONS: These findings suggest that importation plays an important role for malaria incidence on Zanzibar and demonstrate the value of genomic approaches for identifying corridors of parasite movement to the island.

Increased perfusion in dynamic gadolinium-enhanced MRI correlates with areas of bone repair and of bone necrosis in patients with Kienböck's disease.

BACKGROUND: Osteonecrosis of the lunate, Kienböck's disease, can lead to fragmentation of the lunate, carpal collapse, and severe osteoarthritis. Since the etiology of Kienböck's disease is impaired circulation, a diagnostic method capable of assessing perfusion would be valuable. Recent studies have suggested that dynamic contrast-enhanced (DCE) MR examinations at 3 T can assess perfusion in healthy carpal bones. PURPOSE: To evaluate the use of DCE-MR for assessing perfusion in the lunate bone in patients with Kienböck's disease. Furthermore, to compare perfusion with histopathology with a focus on bone viability. STUDY TYPE: Prospective case-control study. POPULATION: Fourteen patients with Kienböck's disease and a control group of 19 healthy subjects. Field Strength: 3 T with T1 -weighted fat-saturated contrast-enhanced gradient echo series. ASSESSMENT: Features of the enhancement curves from the DCE-MR examinations, time to peak (TTP), maximum slope (MS), and maximum enhancement (ME) assessed by a radiologist. Six of 14 patients were surgerized with lunate excision, allowing comparison between features of the enhancement curves and histopathology. STATISTICAL TESTS: Mann-Whitney U-test. P < 0.05 was considered a statistically significant difference. RESULTS: Patients with Kienböck's disease showed significantly higher and faster perfusion parameters compared with the control group, the mean value of the TTP in patients was 126.73 sec, in controls 189.79 sec (P = 0.024), ME in patients 173.55 AU, in controls 28.46 AU (P < 0.001), and MS in patients 5.04 AU, in controls 1.06 AU (P < 0.001). When compared with histopathology, increased perfusion was seen in areas of bone formation but also in necrosis. Areas of normal bone showed low perfusion. DATA CONCLUSION: DCE-MRI at 3 T can diagnose altered perfusion in patients with Kienböck's disease. Increased perfusion cannot definitely be used as a marker of bone viability. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:481-489.

An online mapping database of molecular markers of drug resistance in Plasmodium falciparum: the ACT Partner Drug Molecular Surveyor.

BACKGROUND: Prior to this project, only a handful of online visualizations existed for exploring the published literature on molecular markers of antimalarial drug resistance, and none specifically for the markers associated with Plasmodium falciparum resistance to the partner drugs in artemisinin-based combination therapy (ACT). Molecular information is collected in studies with different designs, using a variety of molecular methodologies and data analysis strategies, making it difficult to compare across studies. The purpose of this project was to develop a free online tool, which visualizes the widely published data on molecular markers of antimalarial drug resistance, starting with the two genes pfcrt and pfmdr-1, associated with resistance to the three most common partner drugs; amodiaquine, lumefantrine and mefloquine. METHODS: A literature review was conducted, and a standardized method was used to extract data from publications, and critical decisions on visualization were made. A global geospatial database was developed of specific pfmdr1 and pfcrt single nucleotide polymorphisms and pfmdr1 copy number variation. An informatics framework was developed that allowed flexibility in development of the tool over time and efficient adaptation to different source data. RESULTS: The database discussed in this paper has pfmdr1 and pfcrt marker prevalence information, from 579 geographic sites in 76 different countries, including results from over 86,000 samples from 456 articles published January 2001-May 2017. The ACT Partner Drugs Molecular Surveyor was launched by the WorldWide Antimalarial Resistance Network (WWARN) in March 2015 and it has attracted over 3000 unique visitors since then. Presented here is a demonstration of how the Surveyor database can be explored to monitor local, temporal changes in the prevalence of molecular markers. Here publications up to May 2017 were included, however the online ACT partner drug Molecular Surveyor is continuously updated with new data and relevant markers. CONCLUSIONS: The WWARN ACT Partner Drugs Molecular Surveyor summarizes data on resistance markers in the pfmdr1 and pfcrt genes. The database is fully accessible, providing users with a rich resource to explore and analyze, and thus utilize a centralized, standardized database for different purposes. This open-source software framework can be adapted to other data, as demonstrated by the subsequent launch of the Artemisinin Molecular Surveyor and the Vivax Surveyor.

Plasmodium falciparum Plasmepsin 2 Duplications, West Africa.

Dihydroartemisinin/piperaquine (DHA/PPQ) is increasingly deployed as antimalaria drug in Africa. We report the detection in Mali of Plasmodium falciparum infections carrying plasmepsin 2 duplications (associated with piperaquine resistance) in 7/65 recurrent infections within 2 months after DHA/PPQ treatment. These findings raise concerns about the long-term efficacy of DHA/PPQ treatment in Africa.

Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis.

BACKGROUND: The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. METHODS AND FINDINGS: A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. CONCLUSIONS: Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.