Ecological roles and importance of sharks in the Anthropocene Ocean.

In ecosystems, sharks can be predators, competitors, facilitators, nutrient transporters, and food. However, overfishing and other threats have greatly reduced shark populations, altering their roles and effects on ecosystems. We review these changes and implications for ecosystem function and management. Macropredatory sharks are often disproportionately affected by humans but can influence prey and coastal ecosystems, including facilitating carbon sequestration. Like terrestrial predators, sharks may be crucial to ecosystem functioning under climate change. However, large ecosystem effects of sharks are not ubiquitous. Increasing human uses of oceans are changing shark roles, necessitating management consideration. Rebuilding key populations and incorporating shark ecological roles, including less obvious ones, into management efforts are critical for retaining sharks' functional value. Coupled social-ecological frameworks can facilitate these efforts.

Laue-DIALS: open-source software for polychromatic X-ray diffraction data.

Most X-ray sources are inherently polychromatic. Polychromatic ("pink") X-rays provide an efficient way to conduct diffraction experiments as many more photons can be used and large regions of reciprocal space can be probed without sample rotation during exposure-ideal conditions for time-resolved applications. Analysis of such data is complicated, however, causing most X-ray facilities to discard >99% of X-ray photons to obtain monochromatic data. Key challenges in analyzing polychromatic diffraction data include lattice searching, indexing and wavelength assignment, correction of measured intensities for wavelength-dependent effects, and deconvolution of harmonics. We recently described an algorithm, Careless, that can perform harmonic deconvolution and correct measured intensities for variation in wavelength when presented with integrated diffraction intensities and assigned wavelengths. Here, we present Laue-DIALS, an open-source software pipeline that indexes and integrates polychromatic diffraction data. Laue-DIALS is based on the dxtbx toolbox, which supports the DIALS software commonly used to process monochromatic data. As such, Laue-DIALS provides many of the same advantages: an open-source, modular, and extensible architecture, providing a robust basis for future development. We present benchmark results showing that Laue-DIALS, together with Careless, provides a suitable approach to the analysis of polychromatic diffraction data, including for time-resolved applications.

Ecological lifestyle and gill slit height across sharks.

Metabolic morphology-the morphological features related to metabolic rate-offers broad comparative insights into the physiological performance and ecological function of species. However, some metabolic morphological traits, such as gill surface area, require costly and lethal sampling. Measurements of gill slit height from anatomically accurate drawings, such as those in field guides, offer the opportunity to understand physiological and ecological function without the need for lethal sampling. Here, we examine the relationship between gill slit height and each of the three traits that comprise ecological lifestyle: activity, maximum body size, and depth across nearly all sharks (n = 455). We find that gill slit heights are positively related to activity (measured by the aspect ratio of the caudal fin) and maximum size but negatively related to depth. Overall, gill slit height is best explained by the suite of ecological lifestyle traits rather than any single trait. These results suggest that more active, larger and shallower species (and endothermic species) have higher metabolic throughput as indexed by gill slit height (oxygen uptake) and ecological lifestyle (oxygen expenditure). We show that meaningful ecophysiological relationships can be revealed through measurable metabolic morphological traits from anatomically accurate drawings, which offers the opportunity to estimate class-wide traits for analyses of life history theory and the relationship between biodiversity and ecological function.

A chimeric vaccine derived from Australian genotype IV Japanese encephalitis virus protects mice from lethal challenge.

In 2022, a genotype IV (GIV) strain of Japanese encephalitis virus (JEV) caused an unprecedented and widespread outbreak of disease in pigs and humans in Australia. As no veterinary vaccines against JEV are approved in Australia and all current approved human and veterinary vaccines are derived from genotype (G) III JEV strains, we used the recently described insect-specific Binjari virus (BinJV) chimeric flavivirus vaccine technology to produce a JEV GIV vaccine candidate. Herein we describe the production of a chimeric virus displaying the structural prM and E proteins of a JEV GIV isolate obtained from a stillborn piglet (JEVNSW/22) in the genomic backbone of BinJV (BinJ/JEVNSW/22-prME). BinJ/JEVNSW/22-prME was shown to be antigenically indistinguishable from the JEVNSW/22 parental virus by KD analysis and a panel of JEV-reactive monoclonal antibodies in ELISA. BinJ/JEVNSW/22-prME replicated efficiently in C6/36 cells, reaching titres of >107 infectious units/mL - an important attribute for vaccine manufacture. As expected, BinJ/JEVNSW/22-prME failed to replicate in a variety of vertebrate cells lines. When used to immunise mice, the vaccine induced a potent virus neutralising response against JEVNSW/22 and to GII and GIII JEV strains. The BinJ/JEVNSW/22-prME vaccine provided complete protection against lethal challenge with JEVNSW/22, whilst also providing partial protection against viraemia and disease for the related Murray Valley encephalitis virus. Our results demonstrate that BinJ/JEVNSW/22-prME is a promising vaccine candidate against JEV.

Iris melanoma in an Australian cohort.

BACKGROUND: To report the clinicopathological features and epidemiology of iris melanoma in Queensland, Australia. METHODS: This was a retrospective study of 86 patients with iris melanoma treated between 2001 and 2022 at the Queensland Ocular Oncology Service, Brisbane, Australia. Main outcome measures included demographics, clinical and phenotypic features, age-adjusted incidence and relative survival. RESULTS: Eighty-six patients (63% female) were included. Mean age was 54 years (range 17-82 years). The majority of patients (97%) were Caucasian, with blue eyes, fair skin and Fitzpatrick Skin Type I or II. Demographic features and clinical history showed a tendency for high ultraviolet radiation (UVR) exposure in the cohort. Histopathology was available in 69 cases (82%), and of these, 77% tumours were of spindle cell origin, with low-risk genetic profiles. Patients were followed for a mean of 8 years (median 7, range 1-21 years) after diagnosis, and only one case of metastasis was documented. CONCLUSIONS: The association of iris freckles, history of UVR exposure and dermatologic findings supports the role of UVR in iris melanoma. Occupation and avocation history, as well as evaluation of iris freckles may offer an easily accessible way of stratifying the risk of an individual for development of UVR-related uveal melanoma.

Maintaining Survival While Improving Quality of Life: An Advanced Practitioner-Led Pilot Feasibility Study to Reduce Radiation Dose in Children With Brain Tumors.

Purpose: Oncology advanced practitioners (APs) are on the front line in treating adverse effects. Among children with brain tumors, treatments such as craniospinal irradiation (CSI) cause neurocognitive injury, endocrinopathies, and ototoxicity. High-dose CSI with concurrent chemotherapy allows high-risk embryonal tumors (non-anaplastic) good survival (70%), but significant distressing effects are commonly treated by APs in multidisciplinary long-term follow-up. The aim of this study was to test feasibility of reducing radiation dose with an AP-led protocol. Methods: An interdisciplinary team developed this pilot study with the primary outcome of fewer than two deaths in 10 patients (80% survival). Secondary outcomes were feasibility of an AP-led treatment protocol and acute/late effects of treatment. The AP held a pioneering role as principal investigator of a tumor treatment study. Exclusion criteria included age less than 3 years and anaplasia. The CSI was reduced from 36 to 24 Gy. All other treatment was standard. Results: Survival rate exceeded the primary outcome threshold (88%); the accrual rate (80%) and follow-up neurocognitive testing rate (75%) were acceptable. Eight children ages 3 to 19 years (M = 8) with tumors of varied molecular subtyping were enrolled. The single death occurred 2.5 years from diagnosis of multiorgan failure (without evidence of tumor). The mean survival is 11 years, with two college and one graduate degrees. Acute and late effects were decreased compared with the higher-dose CSI. Conclusion: APs who treat cancer adverse effects can also conduct clinical prospective studies to maintain survival rates and improve quality-of life-outcomes.

Evaluation of education initiatives to increase delivery of age-friendly care in retail clinics.

BACKGROUND: The Age-Friendly Health Systems model, encompassing four key elements (4Ms)-What Matters, Medication, Mentation, Mobility-is integral to delivering high-quality care to older adult patients. In May 2020, the MinuteClinic at CVS implemented the 4Ms model in all 1100+ store locations nationwide. To prepare healthcare providers to deliver 4Ms care, educational modules were developed to provide an understanding of the gerontology principles that support the 4Ms model of care. Our goal was to evaluate the effectiveness of these education modules on improving reliable 4Ms delivery during retail clinic visits. METHODS: Educational modules were provided to nurse practitioners and physician associates to complete in a self-directed manner. These included an orientation module with scenarios comparing usual care and 4Ms care, 12 monthly grand rounds focusing on 4Ms case studies, and 10 video vignettes on 4Ms integration. We examined the association between number of education modules completed with the average number of Ms delivered per visit (M-Score) using descriptive statistics and a generalized linear mixed-effects model. RESULTS: Over 70% of 2783 providers completed at least one education module. Rates of 4Ms care delivery were 1.37 (1.36-1.39, p < 0.001) times higher among those that completed an orientation course compared to those that did not. Higher uptake of education exhibited a dose-response relationship with rate ratios between 1.77 (1.74-1.80, p < 0.001) for 1-2 modules beyond orientation, up to 2.94 (2.90-2.99, p < 0.001) for eight or more modules. CONCLUSIONS: The self-directed learning environment (e.g., providers self-select the number and type of courses) reflects real-world variation in engagement. Despite this variation, significant improvements in 4Ms delivery were observed at any level of educational exposure, underscoring the value of prioritizing education time with quality improvement initiatives.

BRCA Status Dictates Wnt Responsiveness in Epithelial Ovarian Cancer.

The association of BRCA1 and BRCA2 mutations with increased risk for developing epithelial ovarian cancer is well established. However, the observed clinical differences, particularly the improved therapy response and patient survival in BRCA2-mutant patients, are unexplained. Our objective is to identify molecular pathways that are differentially regulated upon the loss of BRCA1 and BRCA2 functions in ovarian cancer. Transcriptomic and pathway analyses comparing BRCA1-mutant, BRCA2-mutant, and homologous recombination wild-type ovarian tumors showed differential regulation of the Wnt/ß-catenin pathway. Using Wnt3A-treated BRCA1/2 wild-type, BRCA1-null, and BRCA2-null mouse ovarian cancer cells, we observed preferential activation of canonical Wnt/ß-catenin signaling in BRCA1/2 wild-type ovarian cancer cells, whereas noncanonical Wnt/ß-catenin signaling was preferentially activated in the BRCA1-null ovarian cancer cells. Interestingly, BRCA2-null mouse ovarian cancer cells demonstrated a unique response to Wnt3A with the preferential upregulation of the Wnt signaling inhibitor Axin2. In addition, decreased phosphorylation and enhanced stability of ß-catenin were observed in BRCA2-null mouse ovarian cancer cells, which correlated with increased inhibitory phosphorylation on GSK3ß. These findings open venues for the translation of these molecular observations into modalities that can impact patient survival. SIGNIFICANCE: We show that BRCA1 and BRCA2 mutation statuses differentially impact the regulation of the Wnt/ß-catenin signaling pathway, a major effector of cancer initiation and progression. Our findings provide a better understanding of molecular mechanisms that promote the known differential clinical profile in these patient populations.

Examining Heart Failure Outcomes Amid Housing Insecurity.

BACKGROUND: How housing insecurity might affect patients with heart failure (HF) is not well characterized. Housing insecurity increases risks related to both communicable and noncommunicable diseases. For patients with HF, housing insecurity is likely to increase the risk for worse outcomes and rehospitalizations. METHODS AND RESULTS: We analyzed hospitalizations due to HF in the United States by using the 2020 National Inpatient Sample and Nationwide Readmissions Database to evaluate the impacts of housing insecurity on HF outcomes and hospital use. Individuals were identified as having housing insecurity by using diagnostic International Classification of Disease (ICD)-10 codes. Demographics and comorbidities were compared between patients with HF with and without housing insecurity. An adjusted logistic regression was performed to evaluate the relationships between housing insecurity and socioeconomic status on in-hospital mortality. Using a Cox proportional hazards model, patients with HF and without housing insecurity were evaluated for the risk of all-cause and HF-specific readmissions over time. Of the 1,003,270 hospitalizations for HF in the U.S. in 2020, 16,150 were identified as having housing insecurity (1.6%), and 987,120 were identified as having no housing insecurity (98.4%). The median age of patients with housing insecurity who were hospitalized for HF was 57, as compared to 73 in the population with no housing insecurity. A higher proportion of patients in the housing-insecurity group were Black (35% vs 20.1%) or Hispanic (11.1% vs 7.3%). Patients with housing insecurity were more likely to carry a diagnosis of alcohol-use disorder (15.2% vs 3.3%) or substance-use disorder (70.2% vs 17.8%) but were less likely to use tobacco (18.3% vs 28.7%). Patients with housing insecurity were over 4.5 times more likely to have Medicaid (52.4% vs 11.3%). Median length of stay did not differ between patients with housing insecurity vs those without it. Patients with housing insecurity were more likely to discharge against medical advice (11.4% vs 2.03%). After adjusting for patients' characteristics, housing insecurity was associated with lower in-hospital mortality rates (OR 0.60, 95% CI 0.39-0.92). Housing insecurity was associated with a higher risk of all-cause readmissions at 180 days (HR 1.13, 95% CI 1.12-1.14). However, there was no significant difference in the risk of HF-specific readmissions at 180 days (HR 1.07, 95% CI 0.998-1.14) CONCLUSIONS: Patients with HF and housing insecurity have distinct demographic characteristics. They are also more likely to be readmitted after their initial hospitalization when compared to those without housing insecurity. Identifying and addressing specific comorbid conditions for patients with housing insecurity who are hospitalized for HF may allow clinicians to provide more focused care, with the goal of preventing morbidity, mortality and unnecessary readmissions.

Contextual coherence increases perceived numerosity independent of semantic content.

Number perception emerges from multiple stages of visual processing. Understanding how systematic biases in number perception occur within a hierarchy of increasingly complex feature representations helps uncover the multistage processing underlying our visual number sense. Recent work demonstrated that reducing coherence of low-level visual attributes, such as color and orientation, systematically reduces perceived number. Here, we ask when in the visual processing hierarchy coherence affects numerosity perception and specifically whether the coherence effect is exclusive to low-level visual features or instead whether it can be driven by contextual or semantic relationships. We tested adults in an ordinal numerical comparison task with contextual coherence mathematically manipulated using a statistical model of visual object co-occurrence. Across several experiments, we found that arrays with high contextual coherence were perceived as numerically larger than arrays with low contextual coherence. This contextual coherence effect was not attenuated even when we reduced objects to texforms (unrecognizable images that preserve midlevel visual features) or removed semantic content from the images through box scrambling and diffeomorphic warping. Together, these results suggest that visual coherence derived from natural statistics of object co-occurrence systematically alters perceived numerosity at low-level visual processing, even before later stages at which items can be explicitly categorized and identified. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Dupilumab improves pruritus and skin lesions in patients with prurigo nodularis: Pooled results from 2 phase 3 trials (LIBERTY-PN PRIME and PRIME2).

Background: Phase 3 PRIME/PRIME2 trials independently demonstrated efficacy and an acceptable safety profile of dupilumab adults with moderate-to-severe prurigo nodularis. Objective: To obtain a more precise estimate of onset and magnitude of treatment effect using PRIME/PRIME2 pooled data. Methods: In PRIME/PRIME2, patients were randomized to dupilumab or placebo for 24 weeks. Pooled analysis assessed proportion of patients achieving clinically meaningful improvement in itch, clear/almost-clear skin, or both; at weeks 12 and 24; overall and by demographic subgroups and changes from baseline to week 24 in symptoms, signs, and quality of life. Results: Patients receiving dupilumab (n = 153) vs placebo (n = 158) experienced significant improvements in all tested endpoints. At week 24, 90 (58.8%) dupilumab-treated vs 30 (19.0%) placebo-treated patients achieved clinically meaningful improvement in itch, 71 (46.4%) vs 27 (17.1%) clear/almost clear skin, and 54 (35.3%) vs 14 (8.9%) achieved both (P < .0001 for all). Treatment benefits were independent of baseline demographics. Safety to week 36 was generally consistent with the known dupilumab safety profile. Limitations: On-treatment data limited to 24 weeks. Conclusions: Pooled analysis confirmed improvements reported in individual trials and revealed earlier effect onset in itch and skin pain. Dupilumab treatment showed benefits across demographics.

Pathological and clinical outcomes following neoadjuvant dual HER2 therapy for early-stage breast cancer: An Australian institutional real-world experience.

AIM: There has been significant progress made in developing novel targeted therapies in the neoadjuvant setting for non-metastatic HER2-positive breast cancer, which may be used in combination with conventional chemotherapy to optimise pathological responses at surgery. However, these therapies, particularly the chemotherapeutic components, may portend significant and long-lasting toxicity. Hence, de-escalation of treatment intensity has been an area of interest and was evaluated in the phase II NeoSphere study. Herein, we report the real-world pathological and survival outcomes from neoadjuvant taxane and dual HER2 blockade recorded at our centre. METHODS: This was a retrospective cohort study of patients receiving neoadjuvant pertuzumab, trastuzumab and taxane chemotherapy for non-metastatic HER2-positive breast cancer at a single centre in Sydney, Australia. We collected data pertaining to baseline demographic characteristics, pathological response rates, post-surgical prescribing patterns and also undertook survival analyses for invasive disease-free survival (iDFS) as well as exploratory analyses for correlations between pre-specified clinicopathologic factors and pathological response at surgery. RESULTS: Our population was largely similar at baseline to the NeoSphere study. 71 patients were included in the final analysis. 61% achieved a pathological complete response (pCR). Three patients received conventional chemotherapy in the adjuvant setting. 92% of included patients were alive and disease-free at 3 years of follow-up. Only 3 events of recurrence or death were recorded at a median follow-up of 32 months. No significant difference in iDFS was noted between patients achieving pCR and those with residual disease at surgery. CONCLUSION: This study demonstrates that de-escalated adjuvant treatment for HER2-positive early breast cancer achieved favourable pathological and long-term outcomes comparable to large trials, some utilising more intensive chemotherapeutic components.

Excess prevalence of preexisting chronic conditions in older adults with incident epilepsy.

OBJECTIVE: Prior studies have examined chronic conditions in older adults with prevalent epilepsy, but rarely among those with incident epilepsy. Identifying the chronic conditions with which older adults present at epilepsy incidence assists with the evaluation of disease burden in this patient population and informs coordinated care development. The aim of this study was to identify preexisting chronic conditions with excess prevalence in older adults with incident epilepsy compared to those without. METHODS: Using a random sample of 4 999 999 fee-for-service Medicare beneficiaries aged >65 years, we conducted a retrospective cohort study of epilepsy incidence in 2019. Non-Hispanic Black and Hispanic beneficiaries were oversampled. We identified preexisting chronic conditions from the 2016-2018 Medicare Beneficiary Summary Files and compared chronic condition prevalence between Medicare beneficiaries with and without incident epilepsy in 2019. We characterized variations in preexisting excess chronic condition prevalence by age, sex, and race/ethnicity, adjusting for the racial/ethnic oversampling. RESULTS: We observed excess prevalence of most preexisting chronic conditions in beneficiaries with incident epilepsy (n = 20 545, weighted n = 19 631). For stroke, for example, the adjusted prevalence rate ratio (APRR) was 4.82 (99% CI:4.60, 5.04), meaning that, compared to those without epilepsy, beneficiaries with incident epilepsy in 2019 had 4.82 times the stroke prevalence. Similarly, beneficiaries with incident epilepsy had a higher prevalence rate for preexisting neurological conditions (APRR = 3.17, 99% CI = 3.08-3.27), substance use disorders (APRR = 3.00, 99% CI = 2.81-3.19), and psychiatric disorders (APRR = 1.98, 99% CI = 1.94-2.01). For most documented chronic conditions, excess prevalence among beneficiaries with incident epilepsy in 2019 was larger for younger age groups compared to older age groups, and for Hispanic beneficiaries compared to both non-Hispanic White and non-Hispanic Black beneficiaries. SIGNIFICANCE: Compared to epilepsy-free Medicare beneficiaries, those with incident epilepsy in 2019 had a higher prevalence of most preexisting chronic conditions. Our findings highlight the importance of health promotion and prevention, multidisciplinary care, and elucidating shared pathophysiology to identify opportunities for prevention.

An Analysis of the Association of Arrival Hemoglobin With Overtransfusion at 24 Hours in a Trauma Population.

BACKGROUND: Hemorrhage control and resuscitative concepts have evolved in recent years, leading to aggressive use of blood products in trauma patients. There is subsequently a potential risk for overtransfusion, adverse effects, and waste associated with unnecessary transfusion. Methods for conserving blood products are of particular importance in future large-scale combat operations where supply chains are likely to be strained. This study examined the association of emergency department (ED) arrival hemoglobin (HGB) with overtransfusion among survivors at 24 hours after major trauma at a military trauma center. MATERIALS AND METHODS: We performed a retrospective cohort study of patients who had a "major trauma" activation and received any red blood cells. Overtransfusion was defined as a HGB level ≥11.0 g/dL at 24 hours (outcome variable). Multivariable logistic regression statistics were used to compare groups and adjust for confounders (injury severity score, arrival modified shock index, injury type, age, and gender). A receiver operating characteristic was constructed with overtransfusion at 24 hours as the outcome (binary) and arrival HGB (continuous) as the independent variable. RESULTS: A total of 382 patients met inclusion criteria. Overtransfusion occurred in 30.4% (n = 116) of patients, with mean ED HGB levels of 13.2 g/dL (12.9 to 13.6) versus 11.6 g/dL (11.3 to 11.8, P < .001). Receiver operating characteristic analysis showed that ED HGB was highly sensitive (0.931) for predicting 24-hour overtransfusion. In our multivariable logistic regression analysis, when adjusting for injury severity score, arrival modified shock index, injury type, age, and gender, we found that the ED HGB value had a per-unit odds ratio of 1.60 (95% CI, 1.38 to 1.86) for 24-hour overtransfusion. Hospital and intensive care unit length of stay, mechanical ventilator days, and mortality did not increase. CONCLUSION: We found that the arrival HGB value was associated with overtransfusion among 24-hour survivors in a civilian trauma setting. Our findings will inform future prospective studies that investigate blood sparing clinical practice guidelines.

3D Nanocrystallography and the Imperfect Molecular Lattice.

Crystallographic analysis relies on the scattering of quanta from arrays of atoms that populate a repeating lattice. While large crystals built of lattices that appear ideal are sought after by crystallographers, imperfections are the norm for molecular crystals. Additionally, advanced X-ray and electron diffraction techniques, used for crystallography, have opened the possibility of interrogating micro- and nanoscale crystals, with edges only millions or even thousands of molecules long. These crystals exist in a size regime that approximates the lower bounds for traditional models of crystal nonuniformity and imperfection. Accordingly, data generated by diffraction from both X-rays and electrons show increased complexity and are more challenging to conventionally model. New approaches in serial crystallography and spatially resolved electron diffraction mapping are changing this paradigm by better accounting for variability within and between crystals. The intersection of these methods presents an opportunity for a more comprehensive understanding of the structure and properties of nanocrystalline materials.

Maternal investment evolves with larger body size and higher diversification rate in sharks and rays.

Across vertebrates, live bearing evolved at least 150 times from ancestral egg laying into diverse forms and degrees of prepartum maternal investment.1,2 A key question is how reproductive diversity arose and whether reproductive diversification underlies species diversification.3,4,5,6,7,8,9,10,11 To test this, we evaluate the most basal jawed vertebrates: the sharks, rays, and chimaeras, which have one of the greatest ranges of reproductive and ecological diversity among vertebrates.2,12 We reconstruct the sequence of reproductive mode evolution across a phylogeny of 610 chondrichthyans.13 We reveal egg laying as ancestral, with live bearing evolving at least seven times. Matrotrophy evolved at least 15 times, with evidence of one reversal. In sharks, transitions to live bearing and matrotrophy are more prevalent in larger-bodied tropical species. Further, the evolution of live bearing is associated with a near doubling of the diversification rate, but there is only a small increase associated with the appearance of matrotrophy. Although pre-copulatory sexual selection is associated with increased rates of speciation in teleosts,3 sexual size dimorphism in chondrichthyans does not appear to be related to sexual selection,14,15 and instead we find increased rates of speciation associated with the colonization of novel habitats. This highlights a potential key difference between chondrichthyans and other fishes, specifically a slower rate of evolution of reproductive isolation following speciation, suggesting different rate-limiting mechanisms for diversification between these clades.16 The chondrichthyan diversification and radiation, particularly throughout shallow tropical shelf seas and oceanic pelagic habitats, appear to be associated with the evolution of live bearing and proliferation of a wide range of maternal investment in developing offspring.

Efficacy and safety of single-dose artesunate plus sulfalene/pyrimethamine combined with praziquantel for the treatment of children with Schistosoma mansoni or Schistosoma haematobium in western Kenya: a randomised, open-label controlled trial.

BACKGROUND: Reliance on praziquantel for the treatment and control of schistosomiasis is likely to facilitate the emergence of drug resistance. Combination therapy targeting adult and juvenile schistosome worms is urgently needed to improve praziquantel efficacy and delay the potential development of drug resistance. We assessed the efficacy and safety of single-dose praziquantel combined with single-dose artesunate plus sulfalene-pyrimethamine in the treatment of Kenyan children with schistosomiasis. METHODS: This was an open-label, randomised clinical trial involving 426 school-aged children (7-15 years old) diagnosed with Schistosoma mansoni (by Kato-Katz) or S. haematobium (by urine filtration). They were randomly assigned (1:1:1) to receive a single dose of praziquantel (40 mg/kg), a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate) or combination therapy using a single dose of praziquantel (40 mg/kg) combined with a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate). The primary outcome was cure and egg reduction rates at 6 weeks post-treatment in the available case population. Adverse events were assessed within 3 h after treatment. RESULTS: Of the 426 children enrolled, 135 received praziquantel, 150 received artesunate plus sulfalene-pyrimethamine, and 141 received combination therapy. Outcome data were available for 348 (81.7%) children. For S. mansoni-infected children (n = 335), the cure rates were 75.6%, 60.7%, and 77.8%, and the egg reduction rates were 80.1%, 85.0%, and 88.4% for praziquantel, artesunate plus sulfalene-pyrimethamine, and combination therapy, respectively. For S. haematobium-infected children (n = 145), the corresponding cure rates were 81.4%, 71.1%, and 82.2%, and the egg reduction rates were 95.6%, 97.1%, and 97.7%, respectively. Seventy-one (16.7%) children reported mild-intensity adverse events. The drugs were well tolerated and no serious adverse events were reported. CONCLUSIONS: A single oral dose of praziquantel combined with artesunate plus sulfalene-pyrimethamine cured a high proportion of children with S. haematobium but did not significantly improve the treatment efficacy for either urinary or intestinal schistosomiasis. Sequential administration of praziquantel and artesunate plus sulfalene-pyrimethamine may enhance the efficacy and safety outcomes.