Current Status of Malaria Control and Elimination in Africa: Epidemiology, Diagnosis, Treatment, Progress and Challenges.

The African continent carries the greatest malaria burden in the world. Falciparum malaria especially has long been the leading cause of death in Africa. Climate, economic factors, geographical location, human intervention and unstable security are factors influencing malaria transmission. Due to repeated infections and early interventions, the proportion of clinically atypical malaria or asymptomatic plasmodium carriers has increased significantly, which easily lead to misdiagnosis and missed diagnosis. African countries have made certain progress in malaria control and elimination, including rapid diagnosis of malaria, promotion of mosquito nets and insecticides, intermittent prophylactic treatment in high-risk groups, artemisinin based combination therapies, and the development of vaccines. Between 2000 and 2022, there has been a 40% decrease in malaria incidence and a 60% reduction in mortality rate in the WHO African Region. However, many challenges are emerging in the fight against malaria in Africa, such as climate change, poverty, substandard health services and coverage, increased outdoor transmission and the emergence of new vectors, and the growing threat of resistance to antimalarial drugs and insecticides. Joint prevention and treatment, identifying molecular determinants of resistance, new drug development, expanding seasonal malaria chemo-prevention intervention population, and promoting the vaccination of RTS, S/AS01 and R21/Matrix-M may help to solve the dilemma. China's experience in eliminating malaria is conducive to Africa's malaria prevention and control, and China-Africa cooperation needs to be constantly deepened and advanced. Our review aims to help the global public develop a comprehensive understanding of malaria in Africa, thereby contributing to malaria control and elimination.

State of the art: The Unilateral Cleft lip and Nose Deformity and Anatomic Subunit Approximation.

The anatomic subunit approximation approach to unilateral cleft lip repair was developed over 20 years ago. While the underlying principles of the repair are unchanged, its description has been simplified, additional landmarks and creases have been added, and objective analysis of perioperative changes have provided better clarity regarding goals and desired alterations. We review recent insights regarding the deformity; describe the repair in a simplified manner; and link a stepwise approach to foundation-based primary rhinoplasty as a part of the avenue to creating nasolabial balance and harmony.

L'approximation de la sous-unité anatomique pour réparer la fissure palatine unilatérale a été mise au point il y a plus de 20 ans. Les principes fondamentaux de la réparation n'ont pas changé, mais la description est simplifiée et des repères et des plis ont été ajoutés, sans compter qu'une analyse objective de la malformation et des changements chirurgicaux ont permis de mieux comprendre les objectifs ainsi que les modifications souhaitées. Les auteurs analysent la malformation dans le contexte de récentes études objectives, décrivent la réparation selon des concepts contemporains et relient une approche graduelle à la rhinoplastie primaire fondamentale dans le cadre de la trajectoire visant à créer une harmonie et un équilibre nasolabiaux.

Are Higher Body Mass Index and Worse Metabolic Parameters Associated with More Aggressive Differentiated Thyroid Cancer? A Retrospective Cohort Study.

Obesity is a risk factor for differentiated thyroid cancer (DTC), but the association with DTC aggressiveness is controversial. To evaluate the association between preoperative body mass index (BMI)/other metabolic parameters and DTC aggressiveness in our surgical cohort, we retrospectively evaluated patients following thyroid surgery who were diagnosed with DTC between December 2013 and January 2021. Baseline characteristics, histopathological features, treatment modalities, and follow-up data were studied. We conducted logistic regression to analyze the association between BMI/other metabolic parameters and adverse DTC features. The final study cohort included 211 patients (79.6% women; mean age± standard deviation 48.7 ± 15.9 years): 66 (31.3%) with normal weight, 81 (38.4%) with overweight, and 64 (30.3%) with obesity. The median follow-up was 51 months (range 7-93). Complete versus partial thyroidectomy was more common among patients living with overweight or obesity than in normal weight patients (79.7% versus 61.7%, p = 0.017, respectively). Logistic regression demonstrated that higher BMI was associated with mildly increased risk for lymph nodes metastases (odds ratio [OR] 1.077, 95% CI: 1.013-1.145), and higher triglycerides/high-density lipoprotein-cholesterol (TG/HDL-C) ratio was associated with aggressive histological variants of DTC (OR 1.269, 95% CI 1.001-1.61). To conclude, specific adverse clinical and histopathological DTC features were indeed associated with higher BMI and higher TG/HDL-C ratio.

Indirect genetic effects should make group size more evolvable than expected.

Group size is an important trait for many ecological and evolutionary processes. However, it is not a trait possessed by individuals but by social groups, and as many genomes contribute to group size understanding its genetic underpinnings and so predicting its evolution is a conceptual challenge. Here I suggest how group size can be modelled as a joint phenotype of multiple individuals, and so how models for evolution accounting for indirect genetic effects are essential for understanding the genetic variance of group size. This approach makes it clear that (a) group size should have a larger genetic variance than initially expected as indirect genetic effects always contribute exactly as much as direct genetic effects and (b) the response to selection of group size should be faster than expected based on direct genetic variance alone as the correlation between direct and indirect effects is always at the maximum positive limit of 1. Group size should therefore show relatively rapid evolved increases and decreases, the consequences of which and evidence for I discuss.

Examining online international health professions education: a mixed methods review of barriers, facilitators, and early outcomes☠.

BACKGROUND: Access to quality healthcare education across the world is disproportionate. This study explores the potential for Cardiovascular Perfusion education to be delivered online to reach international students. METHODS: Exploratory mixed methods were used to identify the barriers, facilitators, and early outcomes of online international health professions education. RESULTS: Qualitative analysis yielded four primary and nine subthemes. Multiple interventions were implemented in the planning of a novel online international Extracorporeal Science (ECS) program based on these themes. Quantitative data from the first semester of the new ECS program was collected along with data from the traditional entry-level program and historic data from previous entry-level cohorts. No significant correlations or differences were found between students. Student satisfaction surveys were determined to be equivalent for each group. Mixed data analysis revealed exceptional student satisfaction in areas where qualitative feedback was incorporated into the program design. CONCLUSIONS: Online international education may be a viable option in the health professions. Barriers and facilitators to this mode of education were identified and utilized in designing one such program. Early outcomes from the novel ECS program reveal that student performance and satisfaction are equivalent to those of a traditional in-person training program.

Bilateral Cleft lip Simulation.

OBJECTIVE: To evaluate the features, anatomic accuracy, and educational value of a high-fidelity bilateral cleft lip simulator. DESIGN: Evaluation of the simulator by expert cleft surgeons after performing a simulated bilateral cleft lip repair. SETTING: The simulator was evaluated by the surgeons during the Latin American Craniofacial Association meeting. PARTICIPANTS: Eleven experienced cleft surgeons evaluated the simulator. The cleft surgeons were selected based on their availability during the meeting. INTERVENTIONS: The participants performed a simulated bilateral cleft lip repair. They were each provided with a questionnaire assessing the simulator's features, realism and value as a training tool. MAIN OUTCOME MEASURE (S): The main outcome measure are the scores obtained from a Likert-type questionnaire assessing the simulators features, realism and value. RESULTS: Overall, the surgeons agreed with the simulator's realism and anatomic accuracy (average score of 3.7 out of 5). Overall, the surgeons strongly agreed with the value of the simulator as a training tool (average score of 4.6 out of 5). CONCLUSIONS: A high-fidelity bilateral cleft lip simulator was developed that is realistic and valuable as a training tool. The simulator provides a comprehensive training platform to gain hands-on experience in bilateral cleft lip repair before operating on real patients.

The History of Controlling and Treating Infectious Diseases in Ancient China.

Infectious diseases are the common enemies of mankind. In the course of historical development, they persistently threaten human health and safety. Even today, despite the developments in medical science, we cannot escape the fear and suffering caused by infectious diseases. Whether in ancient or modern times, the source of infection, route of transmission, and a susceptible population are the three key conditions for the prevalence and spread of infectious diseases. All factors closely related to these three conditions can affect the prevalence of infectious diseases. China is one of the cradles of world civilization. The ancient people accumulated a great deal of experience and lessons in the long struggle against infectious diseases. In the face of the current threat posed by widespread infectious disease, it is imperative to review and summarize ancient Chinese ideas and health policies on epidemic prevention and control to inspire contemporary efforts in the prevention and control of infectious disease. The combination of prevention-oriented epidemic prevention ideology and traditional medicine provides valuable insights, especially for impoverished and medically underserved regions.

Using reflective practice to support PhD students in the biosciences.

Postgraduate study can be mentally, physically and emotionally challenging. The levels of anxiety and depression in postgraduate students are much higher than those in the general population, and isolation can also be a problem, especially for students who are marginalised due to gender, race, sexuality, disability or being a first-generation and/or international student. These challenges are not new, but awareness of them has increased over the past decade, as have efforts by institutions to make students feel supported. Under the umbrella of a Doctoral Training Partnership, we developed a programme in which reflective practice is employed to help postgraduate students navigate work environments, deal with difficult supervisory or professional relationships, and improve their work-life balance. Additionally, this reflective practice is allowing the training partnership to tailor support to its students, enabling them to effectively nurture our next generation of bioscientists.

Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL.

ABSTRACT: We previously reported high rates of undetectable minimal residual disease <10-4 (uMRD4) with ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) followed by 2-year ibrutinib maintenance (I-M) in treatment-naïve chronic lymphocytic leukemia (CLL). Here, we report updated data from this phase 2 study with a median follow-up of 63 months. Of 85 patients enrolled, including 5 (6%) with deletion 17p or TP53 mutation, 91% completed iFCR and 2-year I-M. Five-year progression-free survival (PFS) and overall survival were 94% (95% confidence interval [CI], 89%-100%) and 99% (95% CI, 96%-100%), respectively. No additional deaths have occurred with this extended follow-up. No difference in PFS was observed by immunoglobulin heavy-chain variable region gene status or duration of I-M. High rates of peripheral blood (PB) uMRD4 were maintained (72% at the end of iFCR, 66% at the end of 2-year I-M, and 44% at 4.5 years from treatment initiation). Thirteen patients developed MRD conversion without clinical progression, mostly (77%) after stopping ibrutinib. None had Bruton tyrosine kinase (BTK) mutations. One patient had PLCG2 mutation. Six of these patients underwent ibrutinib retreatment per protocol. Median time on ibrutinib retreatment was 34 months. The cumulative incidence of atrial fibrillation was 8%. Second malignancy or nonmalignant hematologic disease occurred in 13%, mostly nonmelanoma skin cancer. Overall, iFCR with 2-year I-M achieved durably deep responses in patients with diverse CLL genetic markers. Re-emergent clones lacked BTK mutation and retained sensitivity to ibrutinib upon retreatment. This trial is registered at www.clinicaltrials.gov as #NCT02251548.

Development and Evaluation of a High-Fidelity Rhinoplasty Simulator.

SUMMARY: Rhinoplasty is a challenging procedure with a steep learning curve. Surgical simulators provide a safe platform to gain hands-on experience without compromising patient outcomes. Therefore, rhinoplasty is an ideal procedure to benefit from an effective surgical simulator. A high-fidelity rhinoplasty simulator was developed using three-dimensional computer modeling, three-dimensional printing, and polymer techniques. The simulator was tested by six surgeons with experience in rhinoplasty to assess realism, anatomic accuracy, and value as a training tool. The surgeons performed common rhinoplasty techniques and were provided a Likert-type questionnaire assessing the anatomic features of the simulator. A variety of surgical techniques were performed successfully using the simulator, including open and closed approaches. Bony techniques performed included endonasal osteotomies and rasping. Submucous resection with harvest of septal cartilage, cephalic trim, and tip suturing, as well as grafting techniques including alar rim, columellar strut, spreader, and shield grafts, were performed successfully. Overall, there was agreement on the simulator's anatomic accuracy of bony and soft-tissue features. There was strong agreement on the simulator's overall realism and value as a training tool. The simulator provides a high-fidelity, comprehensive training platform to learn rhinoplasty techniques to augment real operating experience without compromising patient outcomes.

A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma.

Antibodies targeting PD-1 or 4-1BB achieve objective responses in follicular lymphoma (FL), but only in a minority of patients. We hypothesized that targeting multiple immune receptors could overcome immune resistance and increase response rates in patients with relapsed/refractory FL. We therefore conducted a phase 1b trial testing time-limited therapy with different immunotherapy doublets targeting 4-1BB (utomilumab), OX-40 (ivuxolimab), and PD-L1 (avelumab) in combination with rituximab among patients with relapsed/refractory grade 1-3A FL. Patients were enrolled onto 2 of 3 planned cohorts (cohort 1 - rituximab/utomilumab/avelumab; cohort 2 - rituximab/ivuxolimab/utomilumab). 3+3 dose escalation was followed by dose expansion at the recommended phase 2 dose (RP2D). Twenty-four patients were enrolled (16 in cohort 1 and 9 in cohort 2, with one treated in both cohorts). No patients discontinued treatment due to adverse events and the RP2D was the highest dose level tested in both cohorts. In cohort 1, the objective and complete response rates were 44% and 19%, respectively (50% and 30%, respectively, at RP2D). In cohort 2, no responses were observed. The median progression-free survivals in cohorts 1 and 2 were 6.9 and 3.2 months, respectively. In cohort 1, higher density of PD-1+ tumor-infiltrating T-cells on baseline biopsies and lower density of 4-1BB+ and TIGIT+ T-cells in on-treatment biopsies were associated with response. Abundance of Akkermansia in stool samples was also associated with response. Our results support a possible role for 4-1BB agonist therapy in FL and suggest that features of the tumor microenvironment and stool microbiome may be associated with clinical outcomes (NCT03636503).

Use of multiple covariates in assessing treatment-effect modifiers: A methodological review of individual participant data meta-analyses.

Individual participant data (IPD) meta-analyses of randomised trials are considered a reliable way to assess participant-level treatment effect modifiers but may not make the best use of the available data. Traditionally, effect modifiers are explored one covariate at a time, which gives rise to the possibility that evidence of treatment-covariate interaction may be due to confounding from a different, related covariate. We aimed to evaluate current practice when estimating treatment-covariate interactions in IPD meta-analysis, specifically focusing on involvement of additional covariates in the models. We reviewed 100 IPD meta-analyses of randomised trials, published between 2015 and 2020, that assessed at least one treatment-covariate interaction. We identified four approaches to handling additional covariates: (1) Single interaction model (unadjusted): No additional covariates included (57/100 IPD meta-analyses); (2) Single interaction model (adjusted): Adjustment for the main effect of at least one additional covariate (35/100); (3) Multiple interactions model: Adjustment for at least one two-way interaction between treatment and an additional covariate (3/100); and (4) Three-way interaction model: Three-way interaction formed between treatment, the additional covariate and the potential effect modifier (5/100). IPD is not being utilised to its fullest extent. In an exemplar dataset, we demonstrate how these approaches lead to different conclusions. Researchers should adjust for additional covariates when estimating interactions in IPD meta-analysis providing they adjust their main effects, which is already widely recommended. Further, they should consider whether more complex approaches could provide better information on who might benefit most from treatments, improving patient choice and treatment policy and practice.

Root development differences between cleft-adjacent teeth on the cleft side in comparison to their analogs on the noncleft side in patients with nonsyndromic cleft lip and palate who received secondary alveolar bone grafting.

OBJECTIVE: To assess differences in root development between the cleft side (CS) and noncleft side (NCS) for permanent maxillary central incisor and canine longitudinally in patients with nonsyndromic complete unilateral cleft lip and palate (cUCLP) who received secondary alveolar bone grafting (SABG) and to evaluate the effects of SABG on the acceleration of root development of these teeth. MATERIALS AND METHODS: Permanent maxillary central incisors and canines of 44 subjects with nonsyndromic cUCLP who had all their cleft-related surgeries performed by the same surgeon were analyzed retrospectively from chart notes and radiographs. Panoramic and periapical radiographs at time point 1 (T1) (age, 7.55 years), at SABG (time point 2 [T2], 10.13 years), and a minimum of 2 years after SABG were studied. Root development rating scores on the NCS and CS were compared using paired t-tests and analyses of proportions. RESULTS: Mean root development score differences (NCS - CS) for canines and central incisors were greatest at T2 but diminished at time point 3 (T3). A larger proportion of teeth on the CS trailed the teeth on the NCS by at least 1 point at T2 than at T1 or T3, with the smallest proportion being observed at T3. The change in root development scores from T1 to T2 and from T2 to T3 showed relative CS acceleration from T2 to T3, indicating a catch-up of root development of cleft-adjacent teeth after SABG. CONCLUSIONS: Root development of cleft-adjacent central incisors and canines is slow in comparison with their noncleft analogs. Root development of these teeth accelerates following SABG.

Efficacy and moderators of efficacy of cognitive behavioural therapies with a trauma focus in children and adolescents: an individual participant data meta-analysis of randomised trials.

BACKGROUND: Existing clinical trials of cognitive behavioural therapies with a trauma focus (CBTs-TF) are underpowered to examine key variables that might moderate treatment effects. We aimed to determine the efficacy of CBTs-TF for young people, relative to passive and active control conditions, and elucidate putative individual-level and treatment-level moderators. METHODS: This was an individual participant data meta-analysis of published and unpublished randomised studies in young people aged 6-18 years exposed to trauma. We included studies identified by the latest UK National Institute of Health and Care Excellence guidelines (completed on Jan 29, 2018) and updated their search. The search strategy included database searches restricted to publications between Jan 1, 2018, and Nov 12, 2019; grey literature search of trial registries ClinicalTrials.gov and ISRCTN; preprint archives PsyArXiv and bioRxiv; and use of social media and emails to key authors to identify any unpublished datasets. The primary outcome was post-traumatic stress symptoms after treatment (<1 month after the final session). Predominantly, one-stage random-effects models were fitted. This study is registered with PROSPERO, CRD42019151954. FINDINGS: We identified 38 studies; 25 studies provided individual participant data, comprising 1686 young people (mean age 13·65 years [SD 3·01]), with 802 receiving CBTs-TF and 884 a control condition. The risk-of-bias assessment indicated five studies as low risk and 20 studies with some concerns. Participants who received CBTs-TF had lower mean post-traumatic stress symptoms after treatment than those who received the control conditions, after adjusting for post-traumatic stress symptoms before treatment (b=-13·17, 95% CI -17·84 to -8·50, p<0·001, τ2=103·72). Moderation analysis indicated that this effect of CBTs-TF on post-traumatic stress symptoms post-treatment increased by 0·15 units (b=-0·15, 95% CI -0·29 to -0·01, p=0·041, τ2=0·03) for each unit increase in pre-treatment post-traumatic stress symptoms. INTERPRETATION: This is the first individual participant data meta-analysis of young people exposed to trauma. Our findings support CBTs-TF as the first-line treatment, irrespective of age, gender, trauma characteristics, or carer involvement in treatment, with particular benefits for those with higher initial distress. FUNDING: Swiss National Science Foundation.

The First Alveolar Bone Graft Simulator.

Alveolar bone graft (ABG) surgery in cleft patients is technically challenging. The procedure requires design, dissection and release of soft tissue flaps to create a seal around the bone graft. In addition, visualization during the procedure is challenging within the confines of the cleft. These features make ABG surgery difficult to learn and teach, and it is, therefore, a suitable procedure for the use of a simulator. A high-fidelity cleft ABG simulator was developed using three-dimensional printing, polymer, and adhesive techniques. Simulated ABG surgery was performed by two expert cleft surgeons for a total of five simulation sessions to test the simulator's features and the ability to perform the critical steps of an ABG. ABG surgery was successfully performed on the simulator. The simulations involved interacting with realistic dissection planes as well as multi-layered synthetic soft (periosteum, mucosa, gingiva, adipose tissue) and hard (teeth, bone) tissue. The simulator allowed performance of cleft marginal incisions, dissection, and elevation of a muco-gingival-periosteal flap, creation of nasal upturned and palatal downturned flaps, nasal and palatal side closure, insertion of simulated bone graft material, and advancement of the muco-gingival-periosteal flap for closure of the anterior wall of the cleft. The ABG simulator allowed performance of the critical steps of ABG surgery. This is the first ABG simulator developed, which incorporates the features necessary to practice the procedure from start to finish.

MITF regulates IDH1 and NNT and drives a transcriptional program protecting cutaneous melanoma from reactive oxygen species.

Microphthalmia-associated transcription factor (MITF) plays pivotal roles in melanocyte development, function, and melanoma pathogenesis. MITF amplification occurs in melanoma and has been associated with resistance to targeted therapies. Here, we show that MITF regulates a global antioxidant program that increases survival of melanoma cell lines by protecting the cells from reactive oxygen species (ROS)-induced damage. In addition, this redox program is correlated with MITF expression in human melanoma cell lines and patient-derived melanoma samples. Using a zebrafish melanoma model, we show that MITF decreases ROS-mediated DNA damage in vivo . Some of the MITF target genes involved, such as IDH1 and NNT , are regulated through direct MITF binding to canonical enhancer box (E-BOX) sequences proximal to their promoters. Utilizing functional experiments, we demonstrate the role of MITF and its target genes in reducing cytosolic and mitochondrial ROS. Collectively, our data identify MITF as a significant driver of the cellular antioxidant state. One Sentence Summary: MITF promote melanoma survival via increasing ROS tolerance.

Dolphin social phenotypes vary in response to food availability but not the North Atlantic Oscillation index.

Social behaviours can allow individuals to flexibly respond to environmental change, potentially buffering adverse effects. However, individuals may respond differently to the same environmental stimulus, complicating predictions for population-level response to environmental change. Here, we show that bottlenose dolphins (Tursiops truncatus) alter their social behaviour at yearly and monthly scales in response to a proxy for food availability (salmon abundance) but do not respond to variation in a proxy for climate (the North Atlantic Oscillation index). There was also individual variation in plasticity for gregariousness and connectedness to distant parts of the social network, although these traits showed limited repeatability. By contrast, individuals showed consistent differences in clustering with their immediate social environment at the yearly scale but no individual variation in plasticity for this trait at either timescale. These results indicate that social behaviour in free-ranging cetaceans can be highly resource dependent with individuals increasing their connectedness over short timescales but possibly reducing their wider range of connection at longer timescales. Some social traits showed more individual variation in plasticity or mean behaviour than others, highlighting how predictions for the responses of populations to environmental variation must consider the type of individual variation present in the population.

Measuring the Unilateral Cleft Lip Nasal Deformity: Lateral Deviation of Subnasale Is a Clinical and Morphologic Index of Unrepaired Severity.

OBJECTIVE: Objective measurement of pre-operative severity is important to optimize evidence-based practices given that the wide spectrum of presentation likely influences outcomes. The purpose of this study was to determine the correlation of objective measures of form with a subjective standard of cleft severity. DESIGN: 3D images were ranked according to severity of nasal deformity by 7 cleft surgeons so that the mean rank could be used as the severity standard. PATIENTS: 45 patients with unilateral cleft lip and 5 normal control subjects. INTERVENTIONS: Each image was assessed using traditional anthropometric analysis, 3D landmark displacements, and shape-based analysis to produce 81 indices for each subject. MAIN OUTCOME: The correlation of objective measurements with the clinical severity standard. RESULTS: Lateral deviation of subnasale from midline was the best predictor of severity (0.86). Other strongly-correlated anthropometric measurements included columellar angle, nostril width ratio, and lateral lip height ratio (0.72, 0.80, 0.79). Almost all shape-based measurements had tight correlation with the severity standard, however, dorsum deviation and point difference nasolabial symmetry were the most predictive (0.84, 0.82). CONCLUSIONS: Quantitative measures of severity transcend cleft type and can be used to grade clinical severity. Lateral deviation of subnasale was the best measure of severity and may be used as a surrogate of uncoupled premaxillary growth; it should be recorded as an index of pre-operative severity with every cleft lip repair. The correlation of other measures evaluated clarify treatment priorities and could potentially be used to grade outcomes.