Safety and efficacy of pyronaridine-artesunate paediatric granules in the treatment of uncomplicated malaria in children: insights from randomized clinical trials and a real-world study.

BACKGROUND: Children are particularly at risk of malaria. This analysis consolidates the clinical data for pyronaridine-artesunate (PA) paediatric granules in children from three randomized clinical trials and a real-world study (CANTAM). METHODS: An integrated safety analysis of individual patient data from three randomized clinical trials included patients with microscopically-confirmed Plasmodium falciparum, body weight ≥ 5 kg to < 20 kg, who received at least one dose of study drug (paediatric safety population). PA was administered once daily for 3 days; two trials included the comparator artemether-lumefantrine (AL). PCR-adjusted day 28 adequate clinical and parasitological response (ACPR) was evaluated. Real-world PA granules safety and effectiveness was also considered. RESULTS: In the integrated safety analysis, 63.9% (95% CI 60.2, 67.4; 426/667) of patients had adverse events following PA and 62.0% (95% CI 56.9, 66.9; 222/358) with AL. Vomiting was more common with PA (7.8% [95% CI 6.0, 10.1; 52/667]) than AL (3.4% [95% CI 1.9, 5.8; 12/358]), relative risk 2.3 (95% CI 1.3, 4.3; P = 0.004), occurring mainly following the first PA dose (6.7%, 45/667), without affecting re-dosing or adherence. Prolonged QT interval occurred less frequently with PA (3.1% [95% CI 2.1, 4.8; 21/667]) than AL (8.1% [95% CI 5.7, 11.4; 29/358]), relative risk 0.39 (95% CI 0.22, 0.67; P = 0.0007). In CANTAM, adverse events were reported for 17.7% (95% CI 16.3, 19.2; 460/2599) of patients, most commonly vomiting (5.4% [95% CI 4.6, 6.4; 141/2599]), mainly following the first dose, (4.5% [117/2599]), with all patients successfully re-dosed, and pyrexia (5.4% [95% CI 4.6, 6.3; 140/2599]). In the two comparative clinical trials, Day 28 ACPR in the per-protocol population for PA was 97.1% (95% CI 94.6, 98.6; 329/339) and 100% (95% CI 99.3, 100; 514/514) versus 98.8% (95% CI 95.7, 99.9; 165/167) and 98.4% (95% CI 95.5, 99.7; 188/191) for AL, respectively. In CANTAM, PA clinical effectiveness was 98.0% (95% CI 97.3, 98.5; 2273/2320). CONCLUSIONS: Anti-malarial treatment with PA paediatric granules administered once daily for 3 days was well tolerated in children and displayed good clinical efficacy in clinical trials, with effectiveness confirmed in a real-world study. Trial registration Clinicaltrials.gov: SP-C-003-05: identifier NCT00331136; SP-C-007-07: identifier NCT0541385; SP-C-021-15: identifier NCT03201770. Pan African Clinical Trials Registry: SP-C-013-11: identifier PACTR201105000286876.

Efficacy, Safety and Tolerability of Pyronaridine-artesunate in Asymptomatic Malaria-infected Individuals: a Randomized Controlled Trial.

BACKGROUND: Pyronaridine-artesunate (PA) is a registered artemisinin-based combination therapy, potentially useful for mass drug administration campaigns. However, further data are needed to evaluate its efficacy, safety and tolerability as full or incomplete treatment in asymptomatic Plasmodium falciparum-infected individuals. METHODS: This phase II, multi-center, open label, randomized clinical trial was conducted in The Gambia and Zambia. Participants with microscopically confirmed asymptomatic P. falciparum infection were randomly assigned (1:1:1) to receive a 3-day, 2-day, or 1-day treatment regimen of PA (180:60 mg), dosed according to bodyweight. The primary efficacy outcome was polymerase chain reaction (PCR)-adjusted adequate parasitological response (APR) at day 28 in the per-protocol population. RESULTS: A total of 303 participants were randomized. Day 28 PCR-adjusted APR was 100% for both the 3-day (98/98) and 2-day regimens (96/96), and 96.8% (89/94) for the 1-day regimen. Efficacy was maintained at 100% until day 63 for the 3-day and 2-day regimens but declined to 94.4% (84/89) with the 1-day regimen. Adverse event frequency was similar between the 3-day (51.5% [52/101]), 2-day (52.5% [52/99]), and 1-day (54.4% [56/103]) regimens; the majority of adverse events were of grade 1 or 2 severity (85% [136/160]). Asymptomatic, transient increases (>3 times the upper limit of normal) in alanine aminotransferase/aspartate aminotransferase were observed for 6/301 (2.0%) participants. CONCLUSIONS: PA had high efficacy and good tolerability in asymptomatic P. falciparum-infected individuals, with similar efficacy for the full 3-day and incomplete 2-day regimens. Although good adherence to the 3-day regimen should be encouraged, these results support the further investigation of PA for mass drug administration campaigns. CLINICAL TRIALS REGISTRATION: NCT03814616.

Ship Segmentation and Georeferencing from Static Oblique View Images.

Camera systems support the rapid assessment of ship traffic at ports, allowing for a better perspective of the maritime situation. However, optimal ship monitoring requires a level of automation that allows personnel to keep track of relevant variables in the maritime situation in an understandable and visualisable format. It therefore becomes important to have real-time recognition of ships present at the infrastructure, with their class and geographic position presented to the maritime situational awareness operator. This work presents a novel dataset, ShipSG, for the segmentation and georeferencing of ships in maritime monitoring scenes with a static oblique view. Moreover, an exploration of four instance segmentation methods, with a focus on robust (Mask-RCNN, DetectoRS) and real-time performances (YOLACT, Centermask-Lite) and their generalisation to other existing maritime datasets, is shown. Lastly, a method for georeferencing ship masks is proposed. This includes an automatic calculation of the pixel of the segmented ship to be georeferenced and the use of a homography to transform this pixel to geographic coordinates. DetectoRS provided the highest ship segmentation mAP of 0.747. The fastest segmentation method was Centermask-Lite, with 40.96 FPS. The accuracy of our georeferencing method was (22 ± 10) m for ships detected within a 400 m range, and (53 ± 24) m for ships over 400 m away from the camera.

Exploring health seeking behaviour among incidentally diagnosed HIV cases in Rawalpindi, Pakistan: A qualitative perspective.

Objective: To identify the determinants of health-seeking behaviour among incidentally diagnosed cases of HIV and to explore the patterns of care seeking behaviour among these HIV infected persons. METHODS: The qualitative study based on the grounded theory was conducted from February to September 2019 at the Armed Forces Institute of Transfusion, Rawalpindi, Pakistan, and comprised incidentally diagnosed new cases of human immunodeficiency virus. Data was collected using in-depth interviews to understand how local environments and settings impact healthcare-seeking behaviour. Data was analysed using the constant comparison method. RESULTS: Of the 12 patients, 10(83.3%) were male, 1(8.3%) female and 1(8.3%) transgender. The mean age of the sample was 31±5 years. Of the total, 10(83.3%) patients were receiving free antiretroviral treatment from government hospitals in Rawalpindi/Islamabad, while 2 (16.7%) opted for some alternative form of healthcare. Ten (80%) were married and were carrying the diagnosis for >6 months. Processing of human immunodeficiency virus status, value placed in one's own health, experiences with healthcare provider and medication-related factors were the main themes that emerged from the data. Better counselling services, free-of-cost medication, positive patient-provider relationship and social support were the key players, while non-disclosure due to fear of stigma and beliefs about the disease were the main stumbling blocks. CONCLUSIONS: Value placed in one's own healthcare and thus the need for healthcare services, regardless of social norms, cultural reservations and personal beliefs, was the most important factor affecting the healthcare-seeking behaviour of human immunodeficiency virus patients.

Pyronaridine-artesunate real-world safety, tolerability, and effectiveness in malaria patients in 5 African countries: A single-arm, open-label, cohort event monitoring study.

BACKGROUND: In Phase II/III randomized controlled clinical trials for the treatment of acute uncomplicated malaria, pyronaridine-artesunate demonstrated high efficacy and a safety profile consistent with that of comparators, except that asymptomatic, mainly mild-to-moderate transient increases in liver aminotransferases were reported for some patients. Hepatic safety, tolerability, and effectiveness have not been previously assessed under real-world conditions in Africa. METHODS AND FINDINGS: This single-arm, open-label, cohort event monitoring study was conducted at 6 health centers in Cameroon, Democratic Republic of Congo, Gabon, Ivory Coast, and Republic of Congo between June 2017 and April 2019. The trial protocol as closely as possible resembled real-world clinical practice for the treatment of malaria at the centers. Eligible patients were adults or children of either sex, weighing at least 5 kg, with acute uncomplicated malaria who did not have contraindications for pyronaridine-artesunate treatment as per the summary of product characteristics. Patients received fixed-dose pyronaridine-artesunate once daily for 3 days, dosed by body weight, without regard to food intake. A tablet formulation was used in adults and adolescents and a pediatric granule formulation in children and infants under 20 kg body weight. The primary outcome was the hepatic event incidence, defined as the appearance of the clinical signs and symptoms of hepatotoxicity confirmed by a >2× rise in alanine aminotransferase/aspartate aminotransferase (ALT/AST) versus baseline in patients with baseline ALT/AST >2× the upper limit of normal (ULN). As a secondary outcome, this was assessed in patients with ALT/AST >2× ULN prior to treatment versus a matched cohort of patients with normal baseline ALT/AST. The safety population comprised 7,154 patients, of mean age 13.9 years (standard deviation (SD) 14.6), around half of whom were male (3,569 [49.9%]). Patients experienced 8,560 malaria episodes; 158 occurred in patients with baseline ALT/AST elevations >2×ULN. No protocol-defined hepatic events occurred following pyronaridine-artesunate treatment of malaria patients with or without baseline hepatic dysfunction. Thus, no cohort comparison could be undertaken. Also, as postbaseline clinical chemistry was only performed where clinically indicated, postbaseline ALT/AST levels were not systematically assessed for all patients. Adverse events of any cause occurred in 20.8% (1,490/7,154) of patients, most frequently pyrexia (5.1% [366/7,154]) and vomiting (4.2% [303/7,154]). Adjusting for Plasmodium falciparum reinfection, clinical effectiveness at day 28 was 98.6% ([7,369/7,746] 95% confidence interval (CI) 98.3 to 98.9) in the per-protocol population. There was no indication that comorbidities or malnutrition adversely affected outcomes. The key study limitation was that postbaseline clinical biochemistry was only evaluated when clinically indicated. CONCLUSIONS: Pyronaridine-artesunate had good tolerability and effectiveness in a representative African population under conditions similar to everyday clinical practice. These findings support pyronaridine-artesunate as an operationally useful addition to the management of acute uncomplicated malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT03201770.

Brain profiling in murine colitis and human epilepsy reveals neutrophils and TNFα as mediators of neuronal hyperexcitability.

BACKGROUND: Patients with chronic inflammatory disorders such as inflammatory bowel disease frequently experience neurological complications including epilepsy, depression, attention deficit disorders, migraines, and dementia. However, the mechanistic basis for these associations is unknown. Given that many patients are unresponsive to existing medications or experience debilitating side effects, novel therapeutics that target the underlying pathophysiology of these conditions are urgently needed. METHODS: Because intestinal disorders such as inflammatory bowel disease are robustly associated with neurological symptoms, we used three different mouse models of colitis to investigate the impact of peripheral inflammatory disease on the brain. We assessed neuronal hyperexcitability, which is associated with many neurological symptoms, by measuring seizure threshold in healthy and colitic mice. We profiled the neuroinflammatory phenotype of colitic mice and used depletion and neutralization assays to identify the specific mediators responsible for colitis-induced neuronal hyperexcitability. To determine whether our findings in murine models overlapped with a human phenotype, we performed gene expression profiling, pathway analysis, and deconvolution on microarray data from hyperexcitable human brain tissue from patients with epilepsy. RESULTS: We observed that murine colitis induces neuroinflammation characterized by increased pro-inflammatory cytokine production, decreased tight junction protein expression, and infiltration of monocytes and neutrophils into the brain. We also observed sustained neuronal hyperexcitability in colitic mice. Colitis-induced neuronal hyperexcitability was ameliorated by neutrophil depletion or TNFα blockade. Gene expression profiling of hyperexcitable brain tissue resected from patients with epilepsy also revealed a remarkably similar pathology to that seen in the brains of colitic mice, including neutrophil infiltration and high TNFα expression. CONCLUSIONS: Our results reveal neutrophils and TNFα as central regulators of neuronal hyperexcitability of diverse etiology. Thus, there is a strong rationale for evaluating anti-inflammatory agents, including clinically approved TNFα inhibitors, for the treatment of neurological and psychiatric symptoms present in, and potentially independent of, a diagnosed inflammatory disorder.

Cutting Edge: Engineering Active IKKß in T Cells Drives Tumor Rejection.

Acquired dysfunction of tumor-reactive T cells is one mechanism by which tumors can evade the immune system. Identifying and correcting pathways that contribute to such dysfunction should enable novel anticancer therapy design. During cancer growth, T cells show reduced NF-κB activity, which is required for tumor rejection. Impaired T cell-intrinsic NF-κB may create a vicious cycle conducive to tumor progression and further T cell dysfunction. We hypothesized that forcing T cell-intrinsic NF-κB activation might break this cycle and induce tumor elimination. NF-κB was activated in T cells by inducing the expression of a constitutively active form of the upstream activator IκB kinase ß (IKKß). T cell-restricted constitutively active IKKß augmented the frequency of functional tumor-specific CD8(+) T cells and improved tumor control. Transfer of constitutively active IKKß-transduced T cells also boosted endogenous T cell responses that controlled pre-established tumors. Our results demonstrate that driving T cell-intrinsic NF-κB can result in tumor control, thus identifying a pathway with potential clinical applicability.

A 16.7 kb deletion in Sipa1l3 is associated with juvenile cataract in mice.

Congenital or juvenile cataract is a disease condition in which opacification of the lenses is present at birth or manifests early in life. It has been attributed to different monogenic factors with a high degree of heterogeneity and is often studied using mouse models. A spontaneous mutation was identified in a mouse line selected for heat loss that influenced lens formation and resulted in juvenile cataracts in mice homozygous for the recessive allele. Genetic dissection of this selection line by combining high-density genotypes and homozygosity mapping uncovered a 906 kb fragment on MMU7 encompassing 21 SNPs split into two groups of consecutive, homozygous segments specific to the cataract phenotype. Haplotype analysis revealed a 197.5 kb segment unique to cataract-affected mice that included a single known transcript consisting of the first 14 exons of Sipa1l3. In this region, we discovered a deletion of 1114 bp at the mRNA level, spanning four coding exons, predicted to produce a truncated Sipa1l3 protein lacking a portion of a Rap-GAP domain and two other potentially vital domains. At the genome level, the deletion consisted of 16,733 bp. Genotyping across different samples confirmed that only affected mice were homozygous for the deletion and normal mice were either heterozygous or homozygous for the wild-type allele. Further studies will be required to determine the impact of the truncated Sipa1l3 domains on eye development.

Emotion Socialization in the Context of Childhood Cancer: Perceptions of Parental Support Promotes Posttraumatic Growth.

Background: Examined youth's perceptions of parental reactions to youth's cancer and non-cancer event-related distress and the link between perceptions of parental reactions and youth posttraumatic growth (PTG). Method: Participants included 201 youth (8­21 years) with a history of cancer. Participants self-identified their most stressful life event, which were characterized as cancer or non-cancer related, and then completed measures in reference to this event assessing (1) their perceptions of parent reactions to event-related distress and (2) PTG. Results: Youth who identified a cancer-related event perceived their parents as reacting with more support and reassurance/distraction than those who identified a non-cancer event. Perceptions of parental support, reassurance/distraction, and magnification of youth distress were associated with more PTG, with event type (cancer vs. non-cancer) indirectly predicting PTG through perceptions of parental support. Conclusion: Youth perceive their parents as reacting differently to cancer versus non-cancer distress, which is in turn predictive of their perceptions of growth. Findings suggest that parental support and reassurance/distraction are possible mechanisms facilitating resilience and growth in children with cancer.

Empirical Approach for Estimating Reference Material Heterogeneity and Sample Minimum Test Portion Mass for "Nuggety" Precious Metals (Au, Pd, Ir, Pt, Ru).

Quantification of precious metal content is important for studies of ore deposits, basalt petrogenesis, and precious metal geology, mineralization, mining, and processing. However, accurate determination of metal concentrations can be compromised by microheterogeneity commonly referred to as the "nugget effect", i.e., spatially significant variations in the distribution of precious metal minerals at the scale of instrumental analytical beam footprints. There are few studies focused on the spatial distribution of such minerals and its detrimental effects on quantification of the existing suite of relevant reference materials (RM). In order to assess the nugget effect in RM, pressed powder pellets of MASS-1, MASS-3, WMS-1a, WMS-1, and KPT-1 (dominantly sulfides) as well as CHR-Pt+ and CHR-Bkg (chromite-bearing) were mapped with micro-XRF. The number of verified nuggets observed was used to recalculate an effective concentration of precious metals for the analytical aliquot, allowing for an empirical estimate of a minimum mass test portion. MASS-1, MASS-3, and WMS-1a did not contain any nuggets; therefore, a convenient small test portion could be used here (<0.1 g), while CHR-Pt+ would require 0.125 g and WMS-1 would need 23 g to be representative. For CHR-Bkg and KPT-1, the minimum test portion mass would have to be ∼80 and ∼342 g, respectively. Minimum test portions masses may have to be greater still in order to provide detectable analytical signals. Procedures for counteracting the detrimental manifestations of microheterogeneity are presented. It is imperative that both RM and pristine samples are treated in exactly the same way in the laboratory, lest powders having an unknown nugget status (in effect all field samples for analysis) can not be documented to be representing a safe minimum mass basis.

Capturing the carer's experience: a researcher's reflections.

AIM: To reflect on the methodological challenges of conducting a study exploring the effects on quality of life of being an informal carer for a person with palliative heart failure, as well as the factors that influence a carer's perception of caring. BACKGROUND: There are multi-faceted influences on the positive and negative effects of being a carer for a patient with palliative heart failure. By conducting a mixed methods study the aim was to examine and explore similarities and differences of the phenomenon of being a carer. DATA SOURCES: Quantitative data obtained from the Family Quality of Life Questionnaire (FAMQOL), and qualitative data obtained from 14 interviews with informal carers of patients living with palliative heart failure. REVIEW METHODS: The study was conducted as part of a PhD, University of Sheffield, and the supervisory team reviewed the research process throughout the study. DISCUSSION: The study had a two-phase sequential mixed methods design. A sample of carers was recruited from heart failure nurse service caseloads in a UK urban setting. Carers were invited to complete the Family Quality of Life Questionnaire, a tool developed for carers of patients with heart failure. Participants were also asked to provide contact details if they were willing to be interviewed for the second phase of the study. CONCLUSION: The study highlights important methodological considerations for recruiting carers. As the intention was to begin the analysis of the questionnaires before beginning the second phase of the study, the researcher was compelled to consider how integration was maintained and how to improve access to carers for research. IMPLICATIONS FOR PRACTICE: The complexities associated with the population in this study led the researcher to use a pragmatic design to address research questions. When reflecting on the research and the challenges associated with recruiting to the quantitative phase of the study, the researcher used an iterative approach to meet the unfolding complexities. Such an approach could prove beneficial for mixed methods studies that aim to engage with hard to reach populations.

Profiles of Connectedness: Processes of Resilience and Growth in Children With Cancer.

OBJECTIVE: Identified patterns of connectedness in youth with cancer and demographically similar healthy peers. METHOD: Participants included 153 youth with a history of cancer and 101 youth without a history of serious illness (8-19 years). Children completed measures of connectedness, posttraumatic stress symptoms (PTSS), and benefit-finding. Parents also reported on children's PTSS. RESULTS: Latent profile analysis revealed four profiles: high connectedness (45%), low connectedness (6%), connectedness primarily to parents (40%), and connectedness primarily to peers (9%). These profiles did not differ by history of cancer. However, profiles differed on PTSS and benefit-finding. Children highly connected across domains displayed the lowest PTSS and highest benefit-finding, while those with the lowest connectedness had the highest PTSS, with moderate PTSS and benefit-finding for the parent and peer profiles. CONCLUSION: Children with cancer demonstrate patterns of connectedness similar to their healthy peers. Findings support connectedness as a possible mechanism facilitating resilience and growth.

Adaptive Immunity and Antigen-Specific Activation in Obesity-Associated Insulin Resistance.

Type 2 diabetes mellitus (T2D) is a metabolic disease that is strongly tied to obesity and often preceded by insulin resistance (IR). It has been established that chronic inflammation of hypertrophic adipose tissue depots in obese individuals leads to obesity-associated IR and is mediated by cells of the innate immune system, particularly macrophages. More recently, cells of the adaptive immune system, B and T lymphocytes, have also emerged as important regulators of glucose homeostasis, raising the intriguing possibility that antigen-driven immune responses play a role in disease. In this review, we critically evaluate the roles that various B and T cell subsets play in IR, and then we examine the data suggesting that antigen-driven mechanisms, such as antigen presentation and costimulation, may drive the activity of these lymphocytes.

Pharmacokinetic interaction between pyronaridine-artesunate and metoprolol.

The objectives of this study were to characterize any drug-drug interaction between the antimalarial Pyramax (pyronaridine-artesunate [PA]) and the CYP2D6 probe substrate metoprolol and to assess the safety of 60-day or 90-day PA redosing, particularly with regard to liver biochemistry parameters. Healthy adult subjects were randomized to arm A (n = 26) or arm B (n = 30), with the arm A subjects administered 100 mg metoprolol tartrate in the first period, 100 mg metoprolol tartrate with the third of three daily doses of PA in the second period, and three daily doses of PA alone in the 90-day redosing period. The arm B subjects received the three-day PA regimen in the first period, with redosing of the regimen after 60 days in the second period. The noncompartmental pharmacokinetic parameters were computed for metoprolol, its metabolite alpha-hydroxymetoprolol, and pyronaridine. The coadministration of metoprolol and PA was associated with an average 47.93% (90% confidence interval [CI], 30.52, 67.66) increase in the maximum concentration of metoprolol and a 25.60% (90% CI, 15.78, 36.25) increase in the metoprolol area under the concentration-time curve from time zero to the last quantifiable concentration obtained (AUC0-t); these increases most likely resulted from pyronaridine-mediated CYP2D6 inhibition. No interaction effect of metoprolol with pyronaridine was apparent. Following dosing with PA, some subjects experienced rises in liver function tests above the upper limit of normal during the first few days following PA administration. All such elevations resolved typically within 10 days, and up to 30 days at most. In subjects who were redosed, the incidences of alanine aminotransferase (ALT) or aspartate transaminase (AST) level elevations were similar on the first and second administrations, with no marked difference between the 60-day and 90-day redosing.

Variation in time and magnitude of immune response and viremia in experimental challenges with Porcine circovirus 2b.

BACKGROUND: Porcine circovirus 2 is the primary agent responsible for inducing a group of associated diseases known as Porcine Circovirus Associated Diseases (PCVAD), which can have detrimental effects on production efficiency as well as causing significant mortality. The objective of this study was to evaluate variation in viral replication, immune response and growth across pigs (n = 974) from different crossbred lines. The approach used in this study was experimental infection with a PCV2b strain of pigs at an average of 43 days of age. RESULTS: The sequence of the PCV2b isolate used in the challenge was similar with a cluster of PCV2b isolates known to induce PCVAD and increased mortality rates. The swine leukocyte antigen class II (SLAII) profile of the population was diverse, with nine DQB1 haplotypes being present. Individual viremia and antibody profiles during challenge demonstrate variation in magnitude and time of viral surge and immune response. The correlations between PCV2 specific antibodies and average daily gain (ADG) were relatively low and varied between - 0.14 to 0.08 for IgM and -0.02 and 0.11 for IgG. In contrast, PCV2 viremia was an important driver of ADG decline following infection; a moderate negative correlation was observed between viral load and overall ADG (r = - 0.35, P < 0.001). The pigs with the lowest 10% level of viral load maintained a steady increase in weekly ADG (P < 0.0001) compared to the pigs that had the 10% greatest viral load (P < 0.55). In addition, the highly viremic group expressed higher IgM and IgG starting with d 14 and d 21 respectively, and higher tumor necrosis factor - alpha (TNF-α) at d 21 (P < 0.005), compared to low viremic group. CONCLUSIONS: Molecular sources of the observed differences in viremia and immune response could provide a better understanding of the host factors that influence the development of PCVAD and lead to improved knowledge of swine immunity.

Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria.

Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC(50) values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.

Patient perspectives on their outcomes from strabismus surgery undertaken for psychosocial reasons.

BACKGROUND: Strabismus surgery undertaken for psychosocial reasons aims to align the eyes in a straighter position, reduce the psychosocial symptoms experienced and improve health related quality of life (HRQoL). Greater evidence of the postoperative outcomes in adults undergoing strabismus surgery for psychosocial reasons is required to inform funding and commissioning decisions about strabismus surgery. METHODS: Semi-structured interviews were conducted with adults who had previously undergone strabismus surgery for psychosocial reasons to explore their perceptions of their postoperative outcomes. Maximum variation sampling was used to recruit males and females, younger and older participants. Interviews were transcribed and analysed using thematic analysis following the principles of grounded theory. RESULTS: Thirteen adults were recruited and interviewed, mean 12.2 months postoperatively (range 4.5-20 months). Participants reported a range of improvements in vision, task performance, physical symptoms and confidence and emotions. Some worsening of physical symptoms was reported. CONCLUSION: Despite undergoing strabismus surgery for psychosocial reasons, a range of improvements in vision, task performance and physical symptoms were reported by adult patients postoperatively, in addition to the expected improvements in confidence and emotions.

Strabismus Surgery for Psychosocial Reasons-A Literature Review.

Introduction: Strabismus surgery may be undertaken for visual benefit, to improve or eliminate diplopia symptoms, or to restore or improve binocular single vision (BSV). In patients without visual symptoms or expected visual benefit, strabismus surgery may still be undertaken if the presence of strabismus causes the patient psychosocial symptoms. To evaluate strabismus surgery undertaken for psychosocial reasons, evidence of postoperative outcomes in this specific cohort is needed. Methods: A systematic search of the literature was conducted (1946-2023) to identify evidence where postoperative outcomes were reported for adult patients (age 18 years and above) who had undergone strabismus surgery for psychosocial reasons. Results: Sixty-nine papers were included in the literature review. Most sources of evidence included patients within heterogeneous cohorts of strabismus surgery outcomes, with a range of symptoms and differing surgical aims. Discussion: In adults who underwent strabismus surgery for psychosocial reasons, improved postoperative ocular alignment and/or improved health related quality of life (HRQoL) were common. Strabismus surgery outcomes appeared to be measured satisfactorily at three months postoperatively. Additional surgical outcomes, including an expanded field of vision, unexpected BSV, improved binocular summation, improved task performance and improved eye movements have been reported, but not fully investigated. There was a lack of consensus on how postoperative success should be defined and measured. A core outcome set for strabismus has been suggested and there is potential to add to the available evidence by investigating which outcome measures are most relevant to those with strabismus and psychosocial symptoms. There is a growing need for robust evidence in this specific subgroup of patients due to a lack of evidence specifically reporting postoperative outcomes in adults with strabismus and psychosocial symptoms.

Cadherin-7 and cadherin-6B differentially regulate the growth, branching and guidance of cranial motor axons.

Cadherin-7 (Cad7) and cadherin-6B (Cad6B) are expressed in early and late phases of cranial motoneuron development, respectively. Cad7 is expressed by cranial motoneurons soon after they are generated, as well as in the environment through which their axons extend. By contrast, Cad6B is expressed by mature cranial motoneurons. We demonstrate in chick that these cadherins play distinct roles in cranial motor axon morphology, branching and projection. Using in vitro approaches, we show that Cad7 enhances motor axon outgrowth, suppresses the formation of multiple axons and restricts interstitial branching, thus promoting the development of a single unbranched axon characteristic of differentiating motoneurons. Conversely, Cad6B in vitro promotes motor axon branching, a characteristic of mature motoneurons. In vivo gain- and loss-of-function experiments for these cadherins yielded phenotypes consistent with this interpretation. In particular, a loss of cadherin-mediated interactions in vivo led to dysregulation of the cranial motoneuron normal branching programme and caused axon navigation defects. We also demonstrate that Cad6B functions via the phosphatidylinositol 3-kinase pathway. Together, these data show that Cad7 and Cad6B differentially regulate cranial motoneuron growth, branching and axon guidance.