Efficacy of a spatial repellent for control of Aedes-borne virus transmission: A cluster-randomized trial in Iquitos,Peru

Over half the world’s population is at risk for viruses transmitted by Aedes mosquitoes, such as dengue and Zika. The primary vector, Aedes aegypti, thrives in urban environments. Despite decades of effort, cases and geographic range of Aedes-borne viruses (ABVs) continue to expand. Rigorously proven vector control interventions that measure protective efficacy against ABV diseases are limited to Wolbachia in a single trial in Indonesia and do not include any chemical intervention. Spatial repellents, a new option for efficient deployment, are designed to decrease human exposure to ABVs by releasing active ingredients into the air that disrupt mosquito–human contact. A parallel, cluster-randomized controlled trial was conducted in Iquitos, Peru, to quantify the impact of a transfluthrin-based spatial repellent on human ABV infection. From 2,907 households across 26 clusters (13 per arm), 1,578 participants were assessed for seroconversion (primary endpoint) by survival analysis. Incidence of acute disease was calculated among 16,683 participants (secondary endpoint). Adult mosquito collections were conducted to compare Ae. aegypti abundance, blood-fed rate, and parity status through mixed-effect difference-in-difference analyses. The spatial repellent significantly reduced ABV infection by 34.1% (one-sided 95% CI lower limit, 6.9%; one-sided P value = 0.0236, z = 1.98). Aedes aegypti abundance and blood-fed rates were significantly reduced by 28.6 (95% CI 24.1%, ∞); z = −9.11) and 12.4% (95% CI 4.2%, ∞); z = −2.43), respectively. Our trial provides conclusive statistical evidence from an appropriately powered, preplanned cluster-randomized controlled clinical trial of the impact of a chemical intervention, in this case a spatial repellent, to reduce the risk of ABV transmission compared to a placebo.

Aedes-borne viral diseases (ABVDs) [e.g., dengue (DENV), chikungunya, Zika (ZIKV), and yellow fever] are devastating, expanding global public health threats that disproportionally affect low- and middle-income countries. DENV, one of the most rapidly increasing vector-borne infectious diseases, results in ∼400 million infections each year (1, 2), with 4 billion people at risk for infection annually (3). Currently, the primary means for ABVD prevention is controlling the primary mosquito vector, Aedes aegypti. Existing vector control interventions, however, have failed to prevent ABV transmission and epidemics (4–6).There is an urgent need to develop evidence-based guidance for the use of new and existing ABV vector control tools. The evidence base for vector control against ABVs is weak, despite considerable government investments in World Health Organization (WHO)-recommended control of larval habitats (larviciding, container removal) and ultra-low-volume insecticide spraying (4, 5, 7–9). These strategies continue to be implemented despite the lack of rigorously generated data from controlled clinical trials demonstrating they reduce ABV infection or disease (6). The only ABV intervention with a proven epidemiological impact in a cluster-randomized control trial (cRCT) assessed community mobilization to reduce mosquito larval habitats (10). A recent test-negative trial with Wolbachia-infected mosquitoes reported a significant reduction of DENV illness in Indonesia (11).Spatial repellents (SRs) are devices that contain volatile active ingredients that disperse in air. The active ingredients can repel mosquitoes from entering a treated space, inhibit attraction to human host cues, or disrupt mosquito biting and blood-feeding behavior and, thus, interfere with mosquito–human contact (12–14). Any of these outcomes reduce the probability of pathogen transmission. Pyrethroid-based SRs have shown efficacy in reducing malaria infections in China (15) and Indonesia (16). There have, however, been no clinical trials evaluating the protective efficacy (PE) of SRs against ABV infection or disease.To generate evidence for public health consideration, we conducted a double-blinded, parallel cRCT to demonstrate and quantify the PE of a transfluthrin-based SR to reduce ABV infection incidence over 2 y in a human cohort in Iquitos, Peru.     

Investigating the Human Host—ssRNA Virus Interaction Landscape Using the SMEAGOL Toolbox

Viruses have evolved numerous mechanisms to exploit the molecular machinery of their host cells, including the broad spectrum of host RNA-binding proteins (RBPs). However, the RBP interactomes of most viruses are largely unknown. To shed light on the interaction landscape of RNA viruses with human host cell RBPs, we have analysed 197 single-stranded RNA (ssRNA) viral genome sequences and found that the majority of ssRNA virus genomes are significantly enriched or depleted in motifs for specific human RBPs, suggesting selection pressure on these interactions. To facilitate tailored investigations and the analysis of genomes sequenced in future, we have released our methodology as a fast and user-friendly computational toolbox named SMEAGOL. Our resources will contribute to future studies of specific ssRNA virus—host cell interactions and support the identification of antiviral drug targets.     

Amphiphilic Antimony(V) Complexes for Oral Treatment of Visceral Leishmaniasis

The need for daily parenteral administration is an important limitation in the clinical use of pentavalent antimonial drugs against leishmaniasis. In this study, amphiphilic antimony(V) complexes were prepared from alkylmethylglucamides (L8 and L10, with carbon chain lengths of 8 and 10, respectively), and their potential for the oral treatment of visceral leishmaniasis (VL) was evaluated. Complexes of Sb and ligand at 1:3 (SbL8 and SbL10) were obtained from the reaction of antimony(V) with L8 and L10, as evidenced by elemental and electrospray ionization-tandem mass spectrometry (ESI-MS) analyses. Fluorescence probing of hydrophobic environment and negative-staining transmission electron microscopy showed that SbL8 forms kinetically stabilized nanoassemblies in water. Pharmacokinetic studies with mice in which the compound was administered by the oral route at 200 mg of Sb/kg of body weight indicated that the SbL8 complex promoted greater and more sustained Sb levels in serum and liver than the levels obtained for the conventional antimonial drug meglumine antimoniate (Glucantime [Glu]). The efficacy of SbL8 and SbL10 administered by the oral route was evaluated in BALB/c mice infected with Leishmania infantum after a daily dose of 200 mg of Sb/kg for 20 days. Both complexes promoted significant reduction in the liver and spleen parasite burdens in relation to those in the saline-treated control group. The extent of parasite suppression (>99.96%) was similar to that achieved after Glu given intraperitoneally at 80 mg of Sb/kg/day. As expected, there was no significant reduction in the parasitic load in the group treated orally with Glu at 200 mg of Sb/(kg day). In conclusion, amphiphilic antimony(V) complexes emerge as an innovative and promising strategy for the oral treatment of VL.     

Continuous and intermittent running to exhaustion at maximal lactate steady state: Neuromuscular,biochemical and endocrinal responses

ObjectiveThe aim of the present study was to characterize the neuromuscular, biochemical, and endocrinal responses from a running to exhaustion mode at the maximal lactate steady state intensity during continuous and intermittent protocols.DesignPre-post test measures.MethodsTwelve athletes performed an incremental treadmill test, several constant speed tests to determine the maximal lactate steady state at continuous and intermittent (5:1 ratio) models and two randomized tests until exhaustion at such intensities. Knee extension torque and blood sampling were collected before and immediately after the time to exhaustion tests.ResultsThe results showed a significant decrement (～15%) in torque production after time to exhaustion tests for both exercise models. In addition to neuromuscular impairment, an acute increase of 65% and 38% was observed creatine kinase, during continuous and intermittent running, respectively. Regarding hormonal responses when compared to baseline measurements, cortisol increased by 132% and 121% in the continuous and intermittent protocols, respectively. No correlation was found between biochemical, endocrinal and the neuromuscular variables.ConclusionsThe present findings showed that running until exhaustion performed at maximal lactate steady state, significantly impaired muscle strength and increased hormonal and muscle damage markers in two different protocols (i.e. continuous and intermittent) amongst trained runners.     

Teriparatide Followed by Denosumab in Premenopausal Idiopathic Osteoporosis: Bone Microstructure and Strength by HR-pQCT

Premenopausal women with idiopathic osteoporosis (PreMenIOP) have marked deficits in skeletal microstructure. We have reported that sequential treatment with teriparatide and denosumab improves central skeletal bone mineral density (BMD) by dual-energy X-ray absorptiometry and central QCT in PreMenIOP. We conducted preplanned analyses of high-resolution peripheral quantitative computed tomography (HR-pQCT) scans from teriparatide and denosumab extension studies to measure effects on volumetric BMD (vBMD), microarchitecture, and estimated strength at the distal radius and tibia. Of 41 women enrolled in the parent teriparatide study (20 mcg daily), 34 enrolled in the HR-pQCT study. HR-pQCT participants initially received teriparatide (N = 24) or placebo (N = 10) for 6 months; all then received teriparatide for 24 months. After teriparatide, 26 enrolled in the phase 2B denosumab extension (60 mg q6M) for 24 months. Primary outcomes were percentage change in vBMD, microstructure, and stiffness after teriparatide and after denosumab. Changes after sequential teriparatide and denosumab were secondary outcomes. After teriparatide, significant improvements were seen in tibial trabecular number (3.3%, p = 0.01), cortical area and thickness (both 2.7%, p < 0.001), and radial trabecular microarchitecture (number: 6.8%, thickness: 2.2%, separation: −5.1%, all p < 0.02). Despite increases in cortical porosity and decreases in cortical density, whole-bone stiffness and failure load increased at both sites. After denosumab, increases in total (3.5%, p < 0.001 and 3.3%, p = 0.02) and cortical vBMD (1.7% and 3.2%; both p < 0.01), and failure load (1.1% and 3.6%; both p < 0.05) were seen at tibia and radius, respectively. Trabecular density (3.5%, p < 0.001) and number (2.4%, p = 0.03) increased at the tibia, while thickness (3.0%, p = 0.02) increased at the radius. After 48 months of sequential treatment, significant increases in total vBMD (tibia: p < 0.001; radius: p = 0.01), trabecular microstructure (p < 0.05), cortical thickness (tibia: p < 0.001; radius: p = 0.02), and whole bone strength (p < 0.02) were seen at both sites. Significant increases in total vBMD and bone strength parameters after sequential treatment with teriparatide followed by denosumab support the use of this regimen in PreMenIOP. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Alport syndrome associated with diffuse leiomyomatosis: COL4A5-COL4A6 deletion associated with a mild form of Alport nephropathy.

BACKGROUND: The X-linked Alport syndrome (AS) is an inherited nephropathy due to mutations in the COL4A5 gene, encoding the alpha5 chain of type IV collagen, a major component of the glomerular basement membrane (GBM). Here, we report a new kindred with the rare association of X-linked AS and diffuse leiomyomatosis (DL), which is a tumourous process involving smooth muscle cells of the oesophagus, the tracheobronchial tree and, in females, the genital tract. For this syndrome, an almost constant association of large COL4A5 rearrangements with a severe juvenile form of nephropathy has been described for male patients. METHODS: DNA rearrangement at the COL4A5-COL4A6 locus was studied in several members of this family using polymerase chain reaction and pulsed field gel electrophoresis. Furthermore, immunohistochemical staining of tumour and skin samples was performed. RESULTS: The affected patients in this family carry a 120 kb deletion by which the COL4A5 exon 1 and COL4A6 exons 1, 1', and 2 are removed. Immunohistochemical investigation of a skin biopsy of an affected male patient confirmed the absence of both the alpha5 and the alpha6 chains of type IV collagen in the basement membrane of the skin. Surprisingly, both affected male patients had a rather mild renal phenotype. CONCLUSIONS: This report shows that, contrary to what has been reported to date, patients suffering from AS associated with DL can be associated with a late onset renal failure (adult) form of nephropathy.     

Liver preservation with HTK: salutary effect of hypothermic aerobiosis by either gaseous oxygen or machine perfusion

The aim of the present study was to improve the viability of marginal livers from non-heart beating donors upon cold preservation using two different techniques for the provision of tissue aerobiosis. Livers from male Wistar rats (250-300 g bw) were harvested after 60 min of cardiac arrest, flushed via the portal vein with 20 mL of heparinized Ringer's solution and 60 mL of histidine-tryptophan-ketoglutarate (HTK) preservation solution. Control livers were then stored submerged in HTK for 24 h at 4 degrees C while other organs were subjected to aerobic conditions by either insufflation of gaseous oxygen via the venous vascular system of the cold stored organ (VSOP) or pulsatile machine perfusion (MP) with oxygenated HTK at 5 mL/min at 4 degrees C. Superoxide dismutase (SOD) (7500 IU) was added to the last 10 mL of HTK in order to prevent adverse effects of high oxygen tensions at hypothermia. Viability of the livers was assessed upon isolated perfusion in vitro with oxygenated Krebs-Henseleit buffer at constant flow. VSOP or MP, both significantly improved vascular conductivity upon reperfusion as evaluated by portal venous pressure, reduced hepatic enzyme release and led to a rise in hepatic bile production upon reperfusion. Induction of apoptosis was also looked for in tissue homogenates by Western analysis for cleavage of poly(ADP-ribose)polymerase (PARP). Expression of cleaved PARP fragment could be found in reperfused control livers but also, though to a lesser extend, after VSOP or MP. In conclusion, provision of oxygen during cold preservation significantly contributes to improve organ viability upon reperfusion and must be regarded as a useful adjunct for marginal or pre-damaged livers. HTK has been shown for the first time to be also suitable for long-term MP preservation of the liver, but, as inferred from these data, simple insufflation of gaseous O2 may be considered a feasible alternative.     

Gastric Emptying of Solids and Semi-solids in Morbidly Obese and Non-obese Subjects: An Assessment Using the <Superscript>13</Superscript>C-Octanoic Acid and <Superscript>13</Superscript>C-Acetic Acid Breath Tests

Background It has been suggested that obesity is associated with an altered rate of gastric emptying. The objective of the present study was to determine whether the rates of solid and semi-solid gastric emptying differ between morbidly obese patients and lean subjects. Methods The Gastric-emptying time (GET) of solid and semi-solid meals were compared between lean healthy subjects and morbidly obese patients enrolled in two previously published studies. GET of solid and semi-solid meals was measured using the ¹³C-octanoic acid breath test and ¹³C-acetic acid breath test, respectively, in 24 lean and 14 morbidly obese individuals of both sexes. Student t-test was used to compare the mean data between the lean and morbidly obese groups. The influence of sex, gender, BMI and morbid obesity on the GET of solid meals was verified by linear regression analysis. Results Mean t(1/2) values of solid GET (± standard deviation) were 203.6 ±  76.0 min and 143.5 ± 19.1 min for lean and obese subjects, respectively (P = 0.0010). Mean t(lag) values of solid GET were 127.3 ± 42.7 min and 98.4 ± 13.0 min for lean and obese subjects, respectively (P = 0.0044). No significant difference in semi-solid GET was observed between the lean and morbidly obese groups. Conclusion The present study demonstrated a significantly enhanced gastric emptying of the solid meal test in morbidly obese patients when compared to lean subjects. This finding is compatible with the hypothesis that rapid gastric emptying in morbidly obese subjects increases caloric intake due to a more rapid loss of satiety.     

Injectable semi rigid penile prosthesis: study in rabbits and future perspectives

BackgroundPenile prostheses are the third option in the treatment of erectile dysfunction, however, despite their proven effectiveness, the occurrence of infections, advanced age of patients and comorbidities are the main limiting factors for this treatment modality. In the continuous search for biointegrated, clinically durable and minimally invasive treatment options, a possible model of penile prosthesis was sought through the use of intracavernous bacterial cellulose (BC) gel, in an experimental model of orchiectomized rabbits.MethodsThirty adult New Zealand rabbits were equally distributed into three groups: BC; vehicle and control. Each group was then subdivided according to the follow-up time of 3 and 6 months. Bilateral orchiectomy was performed 3 weeks before injection in the BC and vehicle groups. Pachymetry measurements of the penile axis, diameter and length were performed in situ. Histomorphometry analyzes of the corpora cavernosa (CC), thickness of the tunica albuginea, cell density, collagen and elastic fibers post-injection were also performed, in addition to immunohistochemistry for newly formed vessels.ResultsThe implant of BC increased both the length and thickness of the penis three and six months after the last injection, with a consequent increase in the diameter of the CC. On the other hand, the filling effect was not observed in the control and vehicle groups, confirming the degradation of this tissue after orchiectomy and the effectiveness of BC as a filling agent. Histomorphometry analyzes corroborate the mass effect of BC integrated into the tissue, permeated by predominantly lymphomononuclear inflammatory infiltrate, multinucleated giant foreign body cells, fibroblasts, elastic fibers and newly formed vessels, without degradation or loss of volume, even after six months of implantation.ConclusionsBiocompatibility and biointegration to the host tissue make BC a prosperous penile filling material, with local application and minimally invasive.