Molecular Targeting of the BRAF Proto-Oncogene/Mitogen-Activated Protein Kinase (MAPK) Pathway across Cancers.

The mitogen-activated protein kinase (MAPK) pathway is essential for cellular proliferation, growth, and survival. Constitutive activation of this pathway by BRAF mutations can cause downstream activation of kinases, leading to uncontrolled cellular growth and carcinogenesis. Therefore, inhibition of BRAF and the downstream substrate MEK has been shown to be effective in controlling tumor growth and proliferation. Over the last decade, several BRAF and MEK inhibitors have been investigated, ranging from primarily melanoma to various cancer types with BRAF alterations. This subsequently led to several Food and Drug Administration (FDA) approvals for BRAF/MEK inhibitors for melanoma, non-small cell lung cancer, anaplastic thyroid cancer, colorectal cancer, histiocytosis neoplasms, and finally, tumor-agnostic indications. Here, this comprehensive review will cover the developments of BRAF and MEK inhibitors from melanomas to tumor-agnostic indications, novel drugs, challenges, future directions, and the importance of those drugs in personalized medicine.

Bruton's Tyrosine Kinase Inhibitors: Recent Updates.

Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the landscape for the treatment of hematological malignancies, solid tumors, and, recently, autoimmune disorders. The BTK receptor is expressed in several hematopoietic cells such as macrophages, neutrophils, mast cells, and osteoclasts. Similarly, the BTK receptor is involved in signaling pathways such as chemokine receptor signaling, Toll-like receptor signaling, and Fc receptor signaling. Due to their unique mechanism, these agents provide a diverse utility in a variety of disease states not limited to the field of malignant hematology and are generally well-tolerated.

Novel insights regarding the safety and efficacy of pyrethroid-coated nanoparticles against Hyalomma ticks.

Nanoparticles have been shown to inhibit major life cycle stages of ticks, indicative of the promising application of nanomaterials against hard ticks. The study thus probed into one of the alternative options to curtail Hyalomma by employing nanocomposites consisting of pyrethroids (cypermethrin and deltamethrin) coated nanoparticles of iron oxides and iron sulfides keeping alongside the evaluation of their toxicity through plant and mammalian cell lines. The nanoparticles used in this study were roughly spherical in morphology and exhibited various size dimensions upon characterization using SEM, EDX, and FTIR. The application of nanomaterials on female ovipositioning tick showed a decline up to 15% (females ovipositioned) in deltamethrin-coated FeO NPs, whereas this decline was up to 18% in Cyp-FeS NPs and up to 5% in Cyp-FeO NPs. Similarly, the larval hatching was also impacted, leading to a hatching percentage of 5% and only 1% by application of Cyp-FeS NPs and Cyp-FeO NPs, respectively. Similarly, the larval groups had LC90 of 4.1 and 4.73 mg/L for the Cyp-FeO NPs and Cyp-FeS NPs groups. The delta-FeO NPs and delta-FeS NPs demonstrated a promising effect against adult ticks, showing LC50= 3.5 mg/L, LC90= 6.7 mg/L and LC50= 3.8 mg/L, LC90= 7.9 mg/L, respectively. MTT assay revealed that the pyrethroids coupled with iron oxide nanoparticles showed the least cytotoxicity even at the highest concentration (10-1 µL) among other nanomaterials. The study thus concluded a safer spectrum of non-target effects of pyrethroids-coated nanomaterials in addition to their significant anti-tick activity.

Vaccination Ameliorates Cellular Inflammatory Responses in SARS-CoV-2 Breakthrough Infections.

BACKGROUND: Data on cellular immune responses in persons with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection following vaccination are limited. The evaluation of these patients with SARS-CoV-2 breakthrough infections may provide insight into how vaccinations limit the escalation of deleterious host inflammatory responses. METHODS: We conducted a prospective study of peripheral blood cellular immune responses to SARS-CoV-2 infection in 21 vaccinated patients, all with mild disease, and 97 unvaccinated patients stratified based on disease severity. RESULTS: We enrolled 118 persons (aged 50 years [SD 14.5 years], 52 women) with SARS-CoV-2 infection. Compared to unvaccinated patients, vaccinated patients with breakthrough infections had a higher percentage of antigen-presenting monocytes (HLA-DR+), mature monocytes (CD83+), functionally competent T cells (CD127+), and mature neutrophils (CD10+); and lower percentages of activated T cells (CD38+), activated neutrophils (CD64+), and immature B cells (CD127+CD19+). These differences widened with increased disease severity in unvaccinated patients. Longitudinal analysis showed that cellular activation decreased over time but persisted in unvaccinated patients with mild disease at 8-month follow-up. CONCLUSIONS: Patients with SARS-CoV-2 breakthrough infections exhibit cellular immune responses that limit the progression of inflammatory responses and suggest mechanisms by which vaccination limits disease severity. These data may have implications for developing more effective vaccines and therapies. Clinical Trials Registration. NCT04401449.

Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment.

BACKGROUND: Nirmatrelvir/ritonavir, the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, reduces the risk of hospitalization and death by coronavirus disease 2019 (COVID-19) but has been associated with symptomatic rebound after therapy completion. METHODS: Six individuals with relapse of COVID-19 symptoms after treatment with nirmatrelvir/ritonavir, 2 individuals with rebound symptoms without prior antiviral therapy and 7 patients with acute Omicron infection (controls) were studied. Soluble biomarkers and serum SARS-CoV-2 nucleocapsid protein were measured. Nasal swabs positive for SARS-CoV-2 underwent viral isolation and targeted viral sequencing. SARS-CoV-2 anti-spike, anti-receptor-binding domain, and anti-nucleocapsid antibodies were measured. Surrogate viral neutralization tests against wild-type and Omicron spike protein, as well as T-cell stimulation assays, were performed. RESULTS: High levels of SARS-CoV-2 anti-spike immunoglobulin G (IgG) antibodies were found in all participants. Anti-nucleocapsid IgG and Omicron-specific neutralizing antibodies increased in patients with rebound. Robust SARS-CoV-2-specific T-cell responses were observed, higher in rebound compared with early acute COVID-19 patients. Inflammatory markers mostly decreased during rebound. Two patients sampled longitudinally demonstrated an increase in activated cytokine-producing CD4+ T cells against viral proteins. No characteristic resistance mutations were identified. SARS-CoV-2 was isolated by culture from 1 of 8 rebound patients; Polybrene addition increased this to 5 of 8. CONCLUSIONS: Nirmatrelvir/ritonavir treatment does not impede adaptive immune responses to SARS-CoV-2. Clinical rebound corresponds to development of a robust antibody and T-cell immune response, arguing against a high risk of disease progression. The presence of infectious virus supports the need for isolation and assessment of longer treatment courses. CLINICAL TRIALS REGISTRATION: NCT04401436.

Protective Effect of Intestinal Blautia Against Neutropenic Fever in Allogeneic Transplant Recipients.

BACKGROUND: Neutropenic fever (NF) occurs in >70% of hematopoietic cell transplant (HCT) recipients, without a documented cause in most cases. Antibiotics used to prevent and treat NF disrupt the gut microbiota; these disruptions predict a higher posttransplantation mortality rate. We hypothesized that specific features in the gut microbial community may mediate the risk of NF. METHODS: We searched a large gut microbiota database in allogeneic HCT recipients (12 546 stool samples; 1278 patients) to find pairs with NF (cases) versus without NF (controls) on the same day relative to transplantation and with a stool sample on the previous day. A total of 179 such pairs were matched as to the underlying disease and graft source. Several other important clinical variables were similar between the groups. RESULTS: The gut microbiota of cases on the day before NF occurrence had a lower abundance of Blautia than their matched controls on the same day after transplantation, suggesting a protective role for Blautia. Microbiota network analysis did not find any differences in community structure between the groups, suggesting a single-taxon effect. To identify putative mechanisms, we searched a gut microbiome and serum metabolome database of patients with acute leukemia receiving chemotherapy and identified 139 serum samples collected within 24 hours after a stool sample from the same patient. Greater Blautia abundances predicted higher levels of next-day citrulline, a biomarker of total enterocyte mass. CONCLUSIONS: These findings support a model in which Blautia protects against NF by improving intestinal health. Therapeutic restoration of Blautia may help prevent NF, thus reducing antibiotic exposures and transplantation-related deaths.

Levaquin Gets a Pass.

Antibiotic-induced gut dysbiosis has been associated with poor outcomes after intensive therapy. We evaluated the effect of levofloxacin (LEVO), the most commonly used prophylactic antibacterial antibiotic during intensive chemotherapy and allogeneic hematopoietic cell transplantation (allo-HCT), on the gut microbiota in 2 cohorts of patients, 1 cohort comprising 20 patients with acute leukemia receiving intensive chemotherapy and the other cohort comprising 20 allo-HCT recipients. 16S rRNA gene sequencing of thrice-weekly collected stool samples permitted a comparison between intervals with no antibacterial antibiotic exposure and those with only LEVO exposure. In mixed-effects modeling, the only variables influenced by LEVO were the relative abundances of Parabacteroides (regression coefficient, -.063; 99% confidence interval [CI], -.102 to -.024) and Blautia (regression coefficient, .050; 99% CI, .004 to .095). Other taxa and microbiota diversity were unaffected. Overall, the effect of LEVO on the gut microbiota in these cohorts was mild.

Gut dysbiosis during antileukemia chemotherapy versus allogeneic hematopoietic cell transplantation.

BACKGROUND: In the field of malignant hematology, most microbiome studies have focused on recipients of allogeneic hematopoietic cell transplantation (allo-HCT). As a result, this population has remained the primary target for novel microbiota therapeutics. Because the types of insults to the microbiome are similar during hematopoietic cell transplantation and intensive antileukemia therapy, this study evaluated whether the dysbiosis states are similar in the 2 settings. METHODS: This study compared gut microbiota assemblages and community domination states in 2 cohorts of patients: patients with intensively treated acute leukemia (AL) and allo-HCT recipients. 16S ribosomal RNA gene profiling of thrice weekly stool samples was performed. Linear discriminant analysis effect size was used to determine differentially abundant taxa in groups of interest, and mixed modes were used to determine the predictors of microbiome states. RESULTS: Microbiome changes in both cohorts were characterized by a marked loss of diversity and domination of low-diversity communities by Enterococcus. In the AL cohort, the relative abundance of Lactobacillus was also inversely correlated with diversity. Communities dominated by these genera were compositionally different. CONCLUSIONS: Similarities in microbiota assemblages between the 2 cohorts support a broader scope for microbiota-directed therapeutics than previously considered, whereas specific differences suggest a personalized aspect to such therapeutics with the possibility of a differential response.

Influence of sample collection tube method, anticoagulant-containing plasma versus serum, on influenza virus hemagglutination inhibition titer and microneutralization titer serological assays.

BACKGROUND: The hemagglutination-inhibition (HAI) assay is a critical component for measurement of immunogenicity in influenza vaccine development. It is unknown if the results can be influenced by sample type and anticoagulants. The purpose of this study was to evaluate the influence of different sample collection methods, in particular different anticoagulants, and choice of plasma or serum, on influenza virus serological assays. METHODS: Blood samples from thirty donors previously immunized against influenza viruses were collected using six different types of blood collection tubes, two of which collect serum and four of which contain various anticoagulants for collecting plasma. Serum: (1) serum separator tubes (SST); and (2) Plus Plastic serum "red-top serum" tubes. Plasma: (3) spray-coated K2 ethylenediaminetetraacetic acid (EDTA) tubes: (4) Sodium Heparin tubes; (5) Citrate tubes with 3.2% sodium citrate solution; and (6) Glass Blood Collection tubes with acid citrate dextrose. Samples were tested against three different influenza viruses (A/California/07/2009 (H1N1pdm09), A/Texas/50/2012 (H3N2), and B/Massachusetts/2/2012) for hemagglutination inhibition titer and virus neutralization titer via a microneutralization (MN) assay, and data compared to that obtained for standard serum sample collected in SST. RESULTS: HAI and MN titers against type A viruses were within two dilutions compared to SST collection method over 96% of the time irrespective of sample type or anticoagulant. However, HAI titers for type B virus were more variable across different collection methods. EDTA plasma samples were greater than two dilutions higher than SST serum samples 70% (21 of 30 samples) of the time. In contrast, MN titers were within two dilutions over 96% of the time, with the highest deviation noted in acid citrate dextrose plasma samples (3 of 30 samples tested, 10%). CONCLUSIONS: These data provide useful guidelines for sample collection and serology testing when screening: (i) influenza vaccine immunogenicity antibody response; (ii) antibody responses to newly emerging viral strains; and (iii) clinical samples for anti-influenza antibody activity.

Multi-omics Analysis of a Fecal Microbiota Transplantation Trial Identifies Novel Aspects of Acute GVHD Pathogenesis.

Acute GVHD (aGVHD) is a major complication of allogeneic hematopoietic cell transplantation (alloHCT) associated with gut microbiota disruptions. However, whether therapeutic microbiota modulation prevents aGVHD is unknown. We conducted a randomized, placebo-controlled trial of third-party fecal microbiota transplantation (FMT) administered at the peak of microbiota injury in 100 patients with acute myeloid leukemia receiving induction chemotherapy and alloHCT recipients. Despite improvements in microbiome diversity, expansion of commensals, and shrinkage of potential pathogens, aGVHD occurred more frequently after FMT than placebo. Although this unexpected finding could be explained by clinical differences between the two arms, we asked whether a microbiota explanation might be also present. To this end, we performed multi-omics analysis of preintervention and postintervention gut microbiome and serum metabolome. We found that postintervention expansion of Faecalibacterium, a commensal genus with gut-protective and anti-inflammatory properties under homeostatic conditions, predicted a higher risk for aGVHD. Faecalibacterium expansion occurred predominantly after FMT and was due to engraftment of unique donor taxa, suggesting that donor Faecalibacterium-derived antigens might have stimulated allogeneic immune cells. Faecalibacterium and ursodeoxycholic acid (an anti-inflammatory secondary bile acid) were negatively correlated, offering an alternative mechanistic explanation. In conclusion, we demonstrate context dependence of microbiota effects where a normally beneficial bacteria may become detrimental in disease. While FMT is a broad, community-level intervention, it may need precision engineering in ecologically complex settings where multiple perturbations (e.g., antibiotics, intestinal damage, alloimmunity) are concurrently in effect. SIGNIFICANCE: Post-FMT expansion of Faecalibacterium, associated with donor microbiota engraftment, predicted a higher risk for aGVHD in alloHCT recipients. Although Faecalibacterium is a commensal genus with gut-protective and anti-inflammatory properties under homeostatic conditions, our findings suggest that it may become pathogenic in the setting of FMT after alloHCT. Our results support a future trial with precision engineering of the FMT product used as GVHD prophylaxis after alloHCT.

Long- and short-term effects of fecal microbiota transplantation on antibiotic resistance genes: results from a randomized placebo-controlled trial.

In small series, third-party fecal microbiota transplantation (FMT) has been successful in decolonizing the gut from clinically relevant antibiotic resistance genes (ARGs). Less is known about the short- and long-term effects of FMT on larger panels of ARGs. We analyzed 226 pre- and post-treatment stool samples from a randomized placebo-controlled trial of FMT in 100 patients undergoing allogeneic hematopoietic cell transplantation or receiving anti-leukemia induction chemotherapy for 47 ARGs. These patients have heavy antibiotic exposure and a high incidence of colonization with multidrug-resistant organisms. Samples from each patient spanned a period of up to 9 months, allowing us to describe both short- and long-term effects of FMT on ARGs, while the randomized design allowed us to distinguish between spontaneous changes vs. FMT effect. We find an overall bimodal pattern. In the first phase (days to weeks after FMT), low-level transfer of ARGs largely associated with commensal healthy donor microbiota occurs. This phase is followed by long-term resistance to new ARGs as stable communities with colonization resistance are formed after FMT. The clinical implications of these findings are likely context-dependent and require further research. In the setting of cancer and intensive therapy, long-term ARG decolonization could translate into fewer downstream infections.

PCM-based hybrid thermal management system for photovoltaic modules: A comparative analysis.

Proper temperature regulation of photovoltaic (PV) modules increases their performance. Among various cooling techniques, phase change materials (PCMs) represent an effective thermal management route, thanks to their large latent heat at constant temperatures. Radiative cooling (RC) is also recently explored as a passive option for PV temperature regulation. In this paper, a heat sink (HS), phase change materials, and radiative cooling are integrated with photovoltaic modules to achieve low and uniform temperature distribution along the PV module and improved performance. Eight different combinations are considered for the proposed system, including HS, PCM, and RC, and their various combinations. The PCM is selected according to the environmental conditions of the selected location. A comprehensive 2-D model is developed and analyzed in COMSOL-Multiphysics software by solving the governing equations using the finite element method. The performance analysis is carried out for the climatic conditions of the Atacama Desert, having high solar radiation and ambient temperature. The effects of PCM height, ambient temperature, wind velocity, and solar radiation on the performance of the proposed system are studied. The performance of eight different configurations is also compared. The maximum reductions in PV temperature, maximum PV power, and a minimum drop in PV conversion efficiency are observed to be 22 oC, 152 W, and 14% using a combined heat sink and radiative cooling systems, among all other configurations. The findings of this study can be used to select the best PV cooling method among different configurations.

Application of Cypermethrin-Coated ZnS and ZnO Nanoparticles against Rhipicephalus Ticks.

Rhipicephalus ticks are described as important ticks impacting the costs of livestock rearing and by-products sale. The prevalence and response of ticks towards cypermethrin sprays indicate the need to implement the rational use of acaricides. In our previous studies, ZnO nanoparticles were shown to inhibit the major life-cycle stages of Hyalomma ticks, indicative of promising application of nanomaterials against the hard ticks. The current study was designed to probe into one of alternative options to curtail Rhipicephalus ticks by employing cypermethrin-coated nanoparticles of ZnO (C-ZnO NPs) and ZnS (C-ZnS NPs). The nanocomposites showed a roughly spherical type of morphology and various size dimensions upon characterization using SEM and EDX. Female ovipositioning was declined up to only 48% in ZnS and up to 32% in ZnO NPs even after 28 days in vitro. Similarly, the larval hatching was also impacted, leading to a hatching percentage of 21% and 15% by application of C-ZnS NPs and C-ZnO NPs, respectively. The LC90 in female adult groups were 3.94 mg/L and 4.27 mg/L for the C-ZnO NPs and C-ZnS NPs groups, respectively. Similarly, the larval groups had LC90 of 8.63 and 8.95 mg/L for the C-ZnO NPs and C-ZnS NPs groups. The study is a proof of the concept for incorporating effective and safe nanocomposites as acaricides. The studies on the efficacy and spectrum of non-target effects of nanomaterial-based acaricides can further refine the research on finding novel alternatives for tick control.

Pancreatic adverse events in patients treated with immune checkpoint inhibitors.

Background and Aim: The inhibition of cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) has been a target for multiple drugs to enhance the T-cell antitumor activity. However, these immune checkpoint inhibitors (ICIs) come with a panel of immune-related adverse events (irAEs) that include mainly endocrine, skin, and gastrointestinal effects. We report seven cases of pancreatic irAEs in patients treated with ICIs at our institute. Methods: This is a case series; data was collected through chart review by 3 different data collectors and was analyzed separately by 2 physicians. Results: Of these seven cases, two had diabetic ketoacidosis (DKA), while five had pancreatitis diagnosed by a substantial rise in serum lipase. Pancreatitis was asymptomatic in two cases. A pancreatic biopsy in one case revealed type 2 autoimmune pancreatitis. The ICIs used included pembrolizumab, nivolumab, durvalumab, and avelumab. Treatment included steroids and holding the ICI therapy: three cases had complete resolution of pancreatitis while two cases required either a prolonged taper or a second course of prednisone for recurrence of pancreatitis. On the other hand, the DKA cases were treated with withdrawal of the ICI and starting insulin with no steroid therapy. Conclusions: Pancreatitis and DKA are rare adverse events of ICIs that can be controlled by holding the ICI with or without starting steroids. Rechallenging the patient with the same ICI is possible in selected cases.

Potential of Fecal Microbiota Transplantation to Prevent Acute GVHD: Analysis from a Phase II Trial.

PURPOSE: Intestinal microbiota disruptions early after allogeneic hematopoietic cell transplantation have been associated with increased risk for acute GVHD (aGVHD). In our recent randomized phase II trial of oral, encapsulated, third-party fecal microbiota transplantation (FMT) versus placebo, FMT at the time of neutrophil recovery was safe and ameliorated dysbiosis. Here, we evaluated in post hoc analysis whether donor microbiota engraftment after FMT may protect against aGVHD. EXPERIMENTAL DESIGN: We analyzed pre- and post-FMT stool samples and estimated donor microbiota engraftment (a preplanned secondary endpoint) by determining the fraction of post-FMT microbiota formed by unique donor taxa (donor microbiota fraction; dMf). RESULTS: dMf was higher in patients who later developed grade I or no aGVHD (median 33.9%; range, 1.6%-74.3%) than those who developed grade II-IV aGVHD (median 25.3%; range, 2.2%-34.8%; P = 0.006). The cumulative incidence of grade II-IV aGVHD by day 180 was lower in the group with greater-than-median dMf than the group with less-than-median dMf [14.3% (95% confidence interval, CI, 2.1-37.5) vs. 76.9% (95% CI, 39.7-92.8), P = 0.008]. The only determinant of dMf in cross-validated least absolute shrinkage and selection operator (LASSO)-regularized regression was the patient's pre-FMT microbiota diversity (Pearson correlation coefficient -0.82, P = 1.6 × 10-9), indicating more potent microbiota modulation by FMT in patients with more severe dysbiosis. Microbiota network analysis revealed major rewiring including changes in the most central nodes, without emergence of keystone species, as a potential mechanism of FMT effect. CONCLUSIONS: FMT may have protective effects against aGVHD, especially in patients with more severe microbiota disruptions.

Randomized Double-Blind Phase II Trial of Fecal Microbiota Transplantation Versus Placebo in Allogeneic Hematopoietic Cell Transplantation and AML.

PURPOSE: Gut microbiota injury in allogeneic hematopoietic cell transplantation (HCT) recipients and patients with AML has been associated with adverse clinical outcomes. Previous studies in these patients have shown improvements in various microbiome indices after fecal microbiota transplantation (FMT). However, whether microbiome improvements translate into improved clinical outcomes remains unclear. We examined this question in a randomized, double-blind, placebo-controlled phase II trial. METHODS: Two independent cohorts of allogeneic HCT recipients and patients with AML receiving induction chemotherapy were randomly assigned in a 2:1 ratio to receive standardized oral encapsulated FMT versus placebo upon neutrophil recovery. After each course of antibacterial antibiotics, patients received a study treatment. Up to three treatments were administered within 3 months. The primary end point was 4-month all-cause infection rate. Patients were followed for 9 months. RESULTS: In the HCT cohort (74 patients), 4-month infection density was 0.74 and 0.91 events per 100 patient-days in FMT and placebo arms, respectively (infection rate ratio, 0.83; 95% CI, 0.48 to 1.42; P = .49). In the AML cohort (26 patients), 4-month infection density was 0.93 in the FMT arm and 1.25 in the placebo arm, with an infection rate ratio of 0.74 (95% CI, 0.32 to 1.71; P = .48). Unique donor bacterial sequences comprised 25%-30% of the fecal microbiota after FMT. FMT improved postantibiotic recovery of microbiota diversity, restored several depleted obligate anaerobic commensals, and reduced the abundance of expanded genera Enterococcus, Streptococcus, Veillonella, and Dialister. CONCLUSION: In allogeneic HCT recipients and patients with AML, third-party FMT was safe and ameliorated intestinal dysbiosis, but did not decrease infections. Novel findings from this trial will inform future development of FMT trials.

Clinical evaluation of commercial SARS-CoV-2 serological assays in a malaria endemic setting.

The levels of immune response to SARS-CoV-2 infection or vaccination are poorly understood in African populations and is complicated by cross-reactivity to endemic pathogens as well as differences in host responsiveness. To begin to determine the best approach to minimize false positive antibody levels to SARS-CoV-2 in an African population, we evaluated three commercial assays, namely Bio-Rad Platelia SARS-CoV-2 Total Antibody (Platelia), Quanterix Simoa Semi-Quantitative SARS-CoV-2 IgG Antibody Test (anti-Spike), and the GenScript cPass™ SARS-CoV-2 Neutralization Antibody Detection Kit (cPass) using samples collected in Mali in West Africa prior to the emergence of SARS-CoV-2. A total of one hundred samples were assayed. The samples were categorized in two groups based on the presence or absence of clinical malaria. Overall, thirteen out of one hundred (13/100) samples were false positives with the Bio-Rad Platelia assay and one of the same one hundred (1/100) was a false positive with the anti-Spike IgG Quanterix assay. None of the samples tested with the GenScript cPass assay were positive. False positives were more common in the clinical malaria group, 10/50 (20%) vs. the non-malaria group 3/50 (6%); p = 0.0374 using the Bio-Rad Platelia assay. Association between false positive results and parasitemia by Bio-Rad remained evident, after adjusting for age and sex in multivariate analyses. In summary, the impact of clinical malaria on assay performance appears to depend on the assay and/or antigen being used. A careful evaluation of any given assay in the local context is a prerequisite for reliable serological assessment of anti-SARS-CoV-2 humoral immunity.

Acaricidal Potential and Ecotoxicity of Metallic Nano-Pesticides Used against the Major Life Stages of Hyalomma Ticks.

Ticks (Acari: Ixodidae) are blood-feeding parasites capable of transmitting diseases to animals (Piroplasmosis) and humans (Congo fever, Lyme disease). The non-judicious use of chemical acaricides has led to the development of acaricide-resistant ticks, making the control of ticks and tick-borne diseases difficult. This study reports the efficacy of magnesium oxide (MgO), iron oxide (Fe2O3), and zinc oxide (ZnO) nanoparticles (NPs) as alternatives to traditional acaricides/pesticides using in vitro tests against major representative stages of Hyalomma ticks. Nanopesticides were chemically synthesized as rods (Fe2O3), stars (ZnO), and spheres (MgO) and were characterized by XRD and SEM analysis. The in vitro bioassays included adult immersion, larval immersion, and larval packet tests. Non-target effects of the nanopesticides were evaluated using snails. The LC90 values of Fe2O3 NPs (4.21, 2.83, 0.89 mg/L) were lowest followed by MgO (4.27, 2.91, 0.93 mg/L) and ZnO (4.49, 3.05, 0.69 mg/L), for the tick adult, larval and egg stages, respectively. Fe2O3 NPs were capable of arresting oviposition and larval hatching in the study ticks in vitro. The snail toxicity experiments revealed minimum to mild off-target effects for all nanopesticides tested. This study is the first to report the comparative efficacy of magnesium, iron, and zinc nanomaterials for toxicity in egg, adult and larval stages of Hyalomma ticks. Further studies of NPs on establishing the efficacy against ticks and safety at host-human-environment interface could lead to promising nanopesticde applications.