Pharmacokinetics of Monoclonal Antibodies Throughout Pregnancy: A Systematic Literature Review.

BACKGROUND AND OBJECTIVE: Although little information is available on the pharmacokinetics (PK) of monoclonal antibodies (mAbs) during pregnancy, multiple mAbs are being used during pregnancy for various indications. The aim of this systematic literature review was to characterize the PK of mAbs throughout pregnancy. METHODS: A systematic literature search was carried out in PubMed and Embase on 21 April 2023. Articles were included when information on PK or exposure parameters of mAbs in pregnant women was available. RESULTS: A total of 42 relevant articles were included, of which eight discussed adalimumab, three certolizumab pegol, five eculizumab, one golimumab, 12 infliximab (IFX), two natalizumab, one canakinumab, one omalizumab, five tocilizumab, eight ustekinumab, and five vedolizumab. One of the 42 studies reported information on clearance (CL) and volume of distribution (VD) of IFX; all other studies only reported on serum concentrations in the pre-pregnancy state, different trimesters, and the postpartum period. For all of the assessed mAbs except IFX, serum concentrations were similar to concentrations in the pre-pregnancy state or modestly decreased. In contrast, IFX trough concentrations generally increased in the second and third trimesters in comparison to the non-pregnant state. CONCLUSION: Available information suggests that the anatomical and physiological changes throughout pregnancy may have meaningful effects on the PK of mAbs. For most mAbs (not IFX), modestly higher dosing (per mg) maybe needed during pregnancy to sustain a similar serum exposure compared to pre-pregnancy.

Dinuclear gold(I) complexes based on carbene and diphosphane ligands: bis[2-(dicyclohexylphosphano)ethyl]amine complex inhibits the proteasome activity, decreases stem cell markers and spheroid viability in lung cancer cells.

Three new dinuclear gold(I) complexes (1-3) containing a carbene (1,3-Bis(2,6-di-isopropylphenyl)imidazol-2-ylidene (IPr)) and diphosphane ligands [bis(1,2-diphenylphosphano)ethane (Dppe), bis(1,3-diphenylphosphano)propane (Dppp) and bis[2-(dicyclohexylphosphano)ethyl]amine (DCyPA)], were synthesized and characterized by elemental analysis and, ESI-MS, mid FT-IR and NMR spectroscopic methods. The structures of complexes 2 and 3 were determined by X-ray crystallography, which revealed that the complexes are dinuclear having gold(I) ions linearly coordinated. The anticancer activities of the complexes (1-3) were evaluated in lung (A549), breast (MC-F7), prostate (PC-3), osteosarcoma (MG-63) and ovarian (A2780 and A2780cis) cancer models. Growth inhibition by the new complexes was higher than cisplatin in all cell lines tested. The mechanism of action of complex 3 was investigated in A549 cells using 2-dimensional (2D) models and 3D-multicellular tumor spheroids. Treatment of A549 cells with complex 3 caused: the induction of apoptosis and the generation of reactive oxygen species; the cell cycle arrest in the G0/G1 phase; the inhibition of both the proteasome and the NF-kB activity; the down-regulation of lung cancer stem cell markers (NOTCH1, CD133, ALDH1 and CD44). Complex 3 was more active than cisplatin also in 3D models of A549 lung cancer cells.

Assessment of carbon footprint of milk production and identification of its major determinants in smallholder dairy farms in Karnataka, India.

Indian dairy enterprise is dominated by smallholder dairy farms that contribute 72% of the country's total milk production. These smallholder dairy farms are often considered to emit substantial greenhouse gases (GHG) but are poor in productive performances. Therefore, it is crucial to estimate the carbon footprint (CF) of milk production of the smallholder Indian dairy farms. The primary objectives of the study were (1) Assessing the CF of milk production of smallholder dairy farms through life cycle analysis in south-interior Karnataka, India; (2) Identifying the hotspots of GHG emissions and significant factors influencing the CF of milk production in smallholder dairy production system. The study accounted GHG emissions from different sources and considered multiple functions of the smallholder production system. Estimations were made based on primary data collected from 47 farms and associated secondary data. For estimating the CF of milk production, the emissions of carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) on a CO2-equivalent (CO2-eq) basis from feed production, enteric fermentation, manure management, transport and energy usage were allocated to fat- and protein-corrected milk (FPCM) based on mass balance, price (crop byproducts and residues) and feed digestibility. Principal component analysis and stepwise linear regression analysis were performed to identify the major factors influencing the CF. The average total GHG emissions (kg CO2-eq yr-1 farm-1) attributable to milk production based on mass, economic, and digestibility allocations were 8,936, 8,641, and 8,759, respectively. The contributions of CH4, N2O, and CO2 to the total farm GHG emission were 70.6%, 20.5%, and 7.69%, respectively. The major emission hotspots were CH4 emission from enteric fermentation (66.8%) and GHG emission from feed production (23.0%). The average CF of cradle-to-dairy cooperative milk production varied from 1.45 to 1.81 kg CO2-eq kg FPCM-1. The CF of milk production was more than 2-fold greater, when milk yield was below 3,500 kg lactating cow-1 yr-1. The FPCM yield 100 kg body weight-1, dry matter intake, and CH4 emission from manure management were the strongest determinants of the CF and explained 83.4% of the observed variation. The study emphasized the importance of considering multiple functions of a mixed crop-livestock-based dairy production system for estimating CF per unit of product. The results suggest that maintaining high-yielding dairy animals and adopting appropriate feeding strategies for better feed utilization are the possible effective interventions for reducing the CF of milk production.

Unveiling meta-Alkyloxy/-Silyloxy-Substituted N-Aryl PNP Ligands for Efficient Cr-Catalyzed Ethylene Tetramerization.

Novel N-aryl-functionalized PNP ligands (1-4) bearing m-alkyloxy/-silyloxy substituents were prepared and evaluated for chromium-catalyzed ethylene oligomerization using MMAO-3A as an activator. The selected Cr/PNP system under optimized condition exhibited high 1-octene-selective (up to 70 wt %) ethylene tetramerization at a remarkable rate (over 3000 kg gCr-1 h-1). More importantly, the undesirable polyethylene selectivity was restricted to a minimum level of ∼1-2 wt % for pre-catalysts derived with ligands 1 and 2. Employing chlorobenzene as a reaction medium yielded best productivity in conjunction to the total α-olefin (1-C6 + 1-C8) selectivity (∼88 wt %). N-aryl PNP ligands (3 and 4) incorporating m-silyloxy substituents in the phenyl ring exhibited relatively poorer tetramerization performance while yielding higher PE fraction as compared to their m-alkyloxy derivatives. A detailed molecular structure of the best-performing pre-catalyst 1-Cr was established by single-crystal X-ray diffraction analysis. The stability of 1/Cr-based catalyst system was investigated for a reaction time of up to 2 h under optimized condition.

A phase II study of metformin plus pemetrexed and carboplatin in patients with non-squamous non-small cell lung cancer (METALUNG).

Immune checkpoint inhibitors (ICIs) ± chemotherapy is the standard treatment for driver mutation-negative non-small cell lung cancer (NSCLC). However, accessibility to ICIs in LMICs is limited due to high cost, and platinum-based chemotherapy remains the mainstay of treatment. Metformin has anticancer properties, and studies suggest synergism between metformin and pemetrexed. Based on preclinical evidence, this combination may be more beneficial for STK11-mutated NSCLC, a subgroup, inherently resistant to ICIs. In this Simon two-stage, single-arm phase 2 trial, we investigated metformin with pemetrexed-carboplatin (PC) in patients with treatment-naive stage IV non-squamous NSCLC. The primary outcome was 6-month progression-free survival (PFS) rate. Secondary outcomes were safety, overall survival (OS), overall response rate (ORR), proportion of STK11 mutation, and effect of STK11 mutation on 6-month PFS rate. The study was terminated for futility after interim analysis. The median follow-up was 34.1 months. The 6-month PFS rate was 28% (95% CI 12.4-0.46). The median PFS and OS were 4.5 (95% CI 2.2-6.1) and 7.4 months (95% CI 5.3-15.3), respectively. The ORR was 72%. Gastrointestinal toxicities were the most common. No grade 4/5 toxicities were reported. Targeted sequencing was possible in nine cases. Two patients had STK11 mutation and a poor outcome (PFS < 12 weeks). We could not demonstrate the benefit of metformin with CP in terms of improvement in 6-month PFS rate; however, the combination was safe (CTRI/2019/02/017815).

Diversity of rumen microbiota using metagenome sequencing and methane yield in Indian sheep fed on straw and concentrate diet.

An in vivo study aiming to investigate the rumen methanogens community structure was conducted in Mandya sheep fed on straw and concentrate diet. The ruminal fluid samples were collected and processed for unravelling the rumen microbiota and methanogens diversity. Further, the daily enteric methane emission and methane yield was also quantified using the SF6 tracer technique. Results indicated that the Bacteroidetes (∼57%) and Firmicutes (25%) were two prominent affiliates of the bacterial community. Archaea represented about 2.5% of the ruminal microbiota. Methanobacteriales affiliated methanogens were the most prevalent in sheep rumen. The study inveterate that the ruminal archaea community in sheep is composed of 9 genera and 18 species. Methanobrevibacter represented the largest genus of the archaeome, while methylotrophs genera constituted only 13% of the community. Methanobrevibacter gottschalkii was the prominent methanogen, and Methaobrevibacter ruminantium distributed at a lower frequency (∼2.5%). Among Methanomassiliicoccales, Group 12 sp. ISO4-H5 constituted the most considerable fraction (∼11%). KEGG reference pathway for methane metabolism indicated the formation of methane through hydrogenotrophic and methylotrophic pathways, whereas the acetoclastic pathway was not functional in sheep. The enteric methane emission and methane yield was 19.7 g/d and 20.8 g/kg DMI, respectively. Various species of Methanobrevibacter were differently correlated, and the distribution of hydrogenotrophic methanogens mainly explained the variability in methane yield between the individual sheep. It can be inferred from the study that the hydrogenotrophic methanogens dominate the rumen archaeal community in sheep and methylotrophic/aceticlastic methanogens represent a minor fraction of the community. Further studies are warranted for establishing the metabolic association between the prevalent hydrogenotrophs and methylotrophs to identify the key reaction for reducing methane emission.

Highly Efficient Ethylene Tetramerization Using Cr Catalysts Constructed with Trifluoromethyl-Substituted N-Aryl PNP Ligands.

Tetramerization of ethylene by chromium catalysts stabilized with functionalized N-aryl phosphineamine ligands C6H4(m-CF3)N(PPh2)2 (1), C6H4(p-CF3)N(PPh2)2 (2), C6H4(o-CF3)N=PPh2-PPh2 (3), and C6H3(3,5-bis(CF3))N(PPh2)2 (4) was evaluated. The parameter optimization includes temperature, co-catalyst, and solvent. Upon activation with MMAO-3A, the new catalyst system especially with m-functional PNP ligand (1) exhibited high 1-octene selectivity and productivity while giving minimum undesirable polyethylene and C10 + olefin by-products. Using PhCl as a solvent at 75 °C led to a remarkable α-olefin (1-C6 + 1-C8) selectivity (>90 wt %) at a reaction rate of 2000 kg·gCr -1·h-1. Under identical conditions, analogous PNP ligands bearing -CH3, -Et, and -Cl functional moieties at the meta position of the N-phenyl ring displayed significantly lower reactivity. The catalyst with p-functional ligand (2) exhibited lower activity and comparable selectivities, while the Cr/PPN (with ligand 3) system gave no noticeable reactivity. The molecular structure of the precatalyst (1-Cr), exhibiting a monomeric structural feature, was elucidated with the aid of single-crystal X-ray diffraction study.

Physical Constraint in Pediatric Dentistry: The Lived Experience of Parents.

BACKGROUND: The use of physical constraint in pediatric dentistry is highly controversial. Papoose boards in particular, which envelop and immobilize children during treatment procedures, have been described as barbaric devices even though their goal is to protect the patient. In this debate, the voice of parents is important but still missing in the scientific literature. AIM: To understand how parents or caregivers experienced physical constraint and the use of the papoose board on their children during regular dental treatment. DESIGN: We conducted qualitative research rooted in interpretive phenomenology. Accordingly, we performed in-depth individual interviews with a purposive sample of 7 parents or caregivers. The interviews took place in Montréal, Canada, after the children had been treated with a papoose board for nonemergency dental treatments. The discussions were audio recorded, transcribed, and thematically analyzed. RESULTS: Two perspectives emerged among participants. Some explained that the papoose board calmed their children, helped the dentist to complete the procedures, and made their experience less stressful. For others, the papoose board was a horrible and traumatizing experience, leading to feelings of guilt toward their children. They expressed anger toward the dentists for not allowing them enough time to decide and for imposing use of the device. CONCLUSION: Our study raises serious ethical concerns about this practice. We believe that using a papoose board should remain an extraordinary measure and, more generally, that dental professionals should reflect on the place of children and their families in clinical encounters. KNOWLEDGE TRANSFER STATEMENT: The findings of this study should encourage policy makers, dental professionals and ethicists to consider the following points: 1) the traumatizing experiences described by parents raise serious ethical concerns about the use of papoose boards; 2) the dental profession should reflect on the place of children and their families in the clinical encounter and grapple with the importance of consent and how to ensure consent in encounters involving children and their parents.

Effect of silkworm (Bombyx mori) pupae oil supplementation on enteric methane emission and methanogens diversity in sheep.

In vitro and in vivo studies were conducted to examine the effect of silkworm pupae oil on methane (CH4) emission and methanogens diversity. Five graded levels (2, 4, 6, 8 and 10%) of silkworm pupae oil were tested in vitro. Eighteen Mandya adult sheep were divided into three groups. All the animals were fed on similar basal diet except the oil supplementation in test groups. Oil level for supplementation was decided on the basis of in vitro study. In vitro study indicated a reduction of 22% in CH4 production with 2% oil supplementation. Animals in test groups were supplemented with oil (2%) either daily (CON) or intermittently (INT) on every alternate week for all the seven days. A significant reduction of 17-20% in enteric CH4 emission (g/d) was achieved due to oil supplementation in sheep. However, No variation was established between test groups CON and INT. In present study, Methanobrevibacter was major genus contributed ∼90% of the total rumen methanogens; whilst Methanobrevibacter gottschalkii was the most abundant methanogens species. Abundance of Methanobrevibacter ruminantium was affected with the oil supplementation. It can be concluded that the silkworm pupae oil at 2% can decrease CH4 emission by 15-20%.

MRI Patterns in Pediatric CNS Hemophagocytic Lymphohistiocytosis.

BACKGROUND AND PURPOSE: Neuroimaging has an important role in detecting CNS involvement in children with systemic or CNS isolated hemophagocytic lymphohistiocytosis. We characterized a cohort of pediatric patients with CNS hemophagocytic lymphohistiocytosis focusing on neuroradiologic features and assessed whether distinct MR imaging patterns and genotype correlations can be recognized. MATERIALS AND METHODS: We retrospectively enrolled consecutive pediatric patients diagnosed with hemophagocytic lymphohistiocytosis with CNS involvement treated at 2 pediatric neurology centers between 2010 and 2018. Clinical and MR imaging data were analyzed. RESULTS: Fifty-seven children (40 primary, 70%) with a median age of 36 months (interquartile range, 5.5-80.8 months) were included. One hundred twenty-three MR imaging studies were assessed, and 2 broad imaging patterns were identified. Pattern 1 (significant parenchymal disease, 32/57, 56%) was seen in older children (P = .004) with worse clinical profiles. It had 3 onset subpatterns: multifocal white matter lesions (21/32, 66%), brainstem predominant disease (5, 15%), and cerebellitis (6, 19%). All patients with the brainstem pattern failed to meet the radiologic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. An attenuated imaging phenotype (pattern 2) was seen in 25 patients (44%, 30 studies) and was associated with younger age. CONCLUSIONS: Distinct MR imaging patterns correlating with clinical phenotypes and possible genetic underpinnings were recognized in this cohort of pediatric CNS hemophagocytic lymphohistiocytosis. Disruptive mutations and missense mutations with absent protein expression correlate with a younger onset age. Children with brainstem and cerebellitis patterns and a negative etiologic work-up require directed assessment for CNS hemophagocytic lymphohistiocytosis.

Gastrointestinal nematode and Eimeria spp. infections in dairy cattle along a rural-urban gradient.

Endoparasite infections can lead to considerable economic losses in dairy cattle due to decreases in milk yield and quality. Environmental and host-related factors contribute to endoparasite infection intensity and probability. Moreover, advancing urbanization influences parasite infection dynamics in livestock due to close human-animal cohabitation and changes in animal housing conditions. The aim of the present study was to investigate social-ecological effects on gastrointestinal nematode (GIN) and Eimeria spp. infections in dairy cattle along a rural-urban gradient in the emerging Indian megacity Bangalore. In this regard, 726 faecal samples from 441 dairy cattle of different ages and physiological stages were collected from 101 farms and examined at three visits between June 2017 and April 2018. Based on a survey stratification index (SSI) comprising built-up density and distance to the city center, we assigned the farms to urban, mixed and rural areas. GIN eggs were identified in the faeces of 243 cattle (33.5%; 95% confidence interval [CI]: 30.1-36.9%), and Eimeria spp. oocysts in the faeces of 151 cattle (20.8%; 95% CI: 17.9-23.7%). Co-infection rates of GIN and Eimeria spp. were 8.5 to 12.2% higher in rural compared to urban and mixed areas. The SSI effect significantly influenced Eimeria spp. infection probability and oocyst per gram of faeces (OpG; P < 0.001) with an infection probability and OpG higher than 26% and 40% for cattle kept in rural areas compared to cattle from urban areas. However, the SSI effect was not significant for the infection probability of GIN and for GIN eggs per gram of faeces (EpG). Infection probabilities and EpG/OpG were significantly higher in calves and heifers compared to lactating and dry cows. Moreover, we estimated significantly lower OpG values in summer compared to the other seasons. No differences were estimated for GIN and Eimeria spp. infection probabilities and EpG/OpG with regard to pasture access and breed. The variations in endoparasite infection intensity and probability observed along the rural-urban gradient of Bangalore reflect the variability in dairy husbandry systems governed by the social-ecological context.

Dose-dense Paclitaxel and Carboplatin as Neoadjuvant Chemotherapy for Stage IIB/IIIA Non-small Cell Lung Cancer - A Phase II trial.

AIMS: The approach to potentially resectable non-small cell lung cancer (NSCLC) remains controversial. There is a benefit of neoadjuvant chemotherapy (NACT), but the ideal regimen is unknown. We evaluated the efficacy and safety of dose-dense NACT in potentially resectable NSCLC in this phase II trial. MATERIALS AND METHODS: Paclitaxel at 80 mg/m2 on days 1, 8 and 15 with AUC-6 carboplatin on day 1, 3 weekly for four cycles was evaluated as NACT. Patients with Eastern Cooperative Oncology Group performance status 0-2, stage IIB and IIIA (with only non-bulky N2 nodes) were included. The primary end point was the objective response rate. Secondary end points included toxicity, progression-free survival, recurrence-free survival, complete resection rate and overall survival. The relative dose intensity (RDI) was calculated to define tolerability (CTRI/2016/05/006916). RESULTS: In total, 37 patients were enrolled (median age 55 years). Most (78.8%) were smokers. Most patients had adenocarcinoma (57.6%) and stage IIIA disease (81.0%) according to the seventh American Joint Committee on Cancer staging system. Seventy-eight per cent of patients completed four cycles. The objective response rate was 75.6% with a complete response in 10.8%. The mean RDI of paclitaxel was 88.61%, with 68.0% of patients able to maintain an RDI ≥85.0%. In total, 187 toxicity events were recorded (120 grade 1, 64 grade 2 and three grade 3 events). Common toxicities were peripheral neuropathy (20.3%), myalgia (19.8%), nausea (15.7%) and neutropenia (10.2%). There were no treatment-related deaths. Seventeen patients underwent surgery (lobectomy 82.4%). After a median follow-up of 47 months (95% confidence interval 27-50.7 months), the median progression-free survival was 9.6 months (7.4-17.4) and overall survival was 29.2 months (16.0-37.2). CONCLUSION: Dose-dense paclitaxel-carboplatin is feasible, safe and efficacious and should be evaluated further in potentially resectable NSCLC.

Comparison of enteric methane yield and diversity of ruminal methanogens in cattle and buffaloes fed on the same diet.

An in vivo study was conducted to compare the enteric methane emissions and diversity of ruminal methanogens in cattle and buffaloes kept in the same environment and fed on the same diet. Six cattle and six buffaloes were fed on a similar diet comprising Napier (Pennisetum purpureum) green grass and concentrate in 70:30. After 90 days of feeding, the daily enteric methane emissions were quantified by using the SF6 technique and ruminal fluid samples from animals were collected for the diversity analysis. The daily enteric methane emissions were significantly greater in cattle as compared to buffaloes; however, methane yields were not different between the two species. Methanogens were ranked at different taxonomic levels against the Rumen and Intestinal Methanogen-Database. The archaeal communities in both host species were dominated by the phylum Euryarchaeota; however, Crenarchaeota represented <1% of the total archaea. Methanogens affiliated with Methanobacteriales were most prominent and their proportion did not differ between the two hosts. Methanomicrobiales and Methanomassillicoccales constituted the second largest group of methanogens in cattle and buffaloes, respectively. Methanocellales (Methanocella arvoryza) were exclusively detected in the buffaloes. At the species level, Methanobrevibacter gottschalkii had the highest abundance (55-57%) in both the host species. The relative abundance of Methanobrevibacter wolinii between the two hosts differed significantly. Methanosarcinales, the acetoclastic methanogens were significantly greater in cattle than the buffaloes. It is concluded that the ruminal methane yield in cattle and buffaloes fed on the same diet did not differ. With the diet used in this study, there was a limited influence (<3.5%) of the host on the structure of the ruminal archaea community at the species level. Therefore, the methane mitigation strategies developed in either of the hosts should be effective in the other. Further studies are warranted to reveal the conjunctive effect of diet and geographical locations with the host on ruminal archaea community composition.

Barriers to inclusion: Service dog handlers in science laboratories.

Despite institutional claims of the importance of diversity, equity, and inclusion in STEM, people with disabilities remain under-represented. Current policies neglect to explicitly address inclusion of the growing population of students with disabilities who rely on service dogs, specifically in accessing teaching and research laboratories. With the increase in students registering for post-secondary disability services, the science community has outgrown general policies that primarily outline steps for exclusion of student service dog handlers. Here we discuss barriers and areas in need of improvement and then outline explicit guidelines for inclusion that are currently absent from existing policies. Particular concerns arise in teaching and research laboratories where live animals are present, and we recommend further research is needed to make informed decisions. In order to realize our vision of a diverse STEM workforce, academic institutions and professionals need to recognize barriers to inclusion and consider their role in making science accessible.

Mixed-Metal Cu-BTC Metal-Organic Frameworks as a Strong Adsorbent for Molecular Hydrogen at Low Temperatures.

The advancement of hydrogen and fuel cell technologies hinges on the development of hydrogen storage methods. Metal-organic frameworks (MOFs) are one of the most favorable materials for hydrogen storage. In this study, we synthesized a series of isostructural mixed-metal metal-organic frameworks (MM-MOFs) of 1,3,5-benzenetricarboxylate (BTC), M-Cu-BTC, where M = Zn2+, Ni2+, Co2+, and Fe2+ using the post-synthetic exchange (PSE) method with metal ions. The powder X-ray diffraction patterns of MM-MOFs were similar with those of single-metal Cu-BTC. Scanning electron microscopy indicates the absence of amorphous phases. Inductively coupled plasma mass spectroscopy of the MM-MOFs shows successful metal exchanges using the PSE method. The N2 adsorption measurements confirmed the successful synthesis of porous MM-MOFs. The metal exchanged materials Ni-Cu-BTC, Zn-Cu-BTC, Fe-Cu-BTC, and Co-Cu-BTC were studied for hydrogen storage and showed a gravimetric uptake of 1.6, 1.63, 1.63, and 1.12 wt %; respectively. The increase in hydrogen adsorption capacity for the three metal exchanged materials is about 60% relative to that of the parent MOF (Cu-BTC). The improvement of gravimetric uptake in M-Cu-BTC (where M = Ni2+, Zn2+, and Fe2+) is probably due to the increase in binding enthalpy of H2 with the unsaturated metal sites after the partial exchange from Cu2+ to other metal ions. The higher charge density of metal ions strongly polarizes hydrogen and provides the primary binding sites inside the pores of Cu-BTC and subsequently enhances the gravimetric uptake of hydrogen.

Country-wide distribution of bluetongue virus with expanding host spectrum and evidence of vector competence in Hungary.

Following the introduction of bluetongue virus type 4 (BTV-4) in 2014, country-wide monitoring of bluetongue (BT) disease was performed to see whether the virus has become enzootic in Hungary. To analyse the epizootiology of BT, over 110,000 samples collected from domestic and wild ruminants were screened for the presence of BTV RNA and virus-specific antibodies using real-time RT-PCR assay and commercial ELISA kit, respectively. During laboratory analysis, specimens collected from 333 (0.8%) cattle, 79 (2.2%) sheep, 4 (0.9%) goats, and 1 (2.3%) mouflon were found to be positive by viral RNA-detection assay. In addition, antibody to BTV was detected in 5.5% (3158/57,250) of cattle, 10.1% (517/5120) of sheep, 40% (116/290) of goat, and 5.6% (16/284) of buffalo origin samples. The majority of positive samples originated from south-western counties; however, 18 out of 19 counties reported cases or antibody prevalence in the examined animals. Genome sequencing of a representative BTV-4 strain from 2015 was also performed. When comparing this strain with the isolate BTV4-HUN2014 detected only a year earlier in Hungary, mutations at 14 sites were identified within the amplified and sequenced genome. Our findings reinforce the need for continued surveillance of BT disease in Hungary. Keywords: reoviridae; orbivirus; cattle; sheep; goat; biting midge.

Effect of dietary supplementation with phytogenic blend on growth performance, apparent ileal digestibility of nutrients, intestinal morphology, and cecal microflora of broiler chickens.

The effects of dietary supplementation with phytogenic blend (PB) of Aerva lanata, Piper betle, Cynodon dactylon, and Piper nigrum on growth performance, ileal nutrient digestibility, intestinal morphology, and cecal microflora were determined in a 42-day broiler feeding trial. A total of 192 broilers were assigned to 4 dietary treatments (6 replicates and 8 birds/replicate): basal diet, basal diet supplemented with antibiotic (chlortetracycline), 1% and 2% PB, respectively. The body weight gain (BWG) of starter chicks increased linearly (P = 0.023) as dietary supplementation levels of PB increased. At grower phase, broilers fed diet supplemented with 1% PB had similar BWG with the antibiotic group, but other treatments had reduced (P = 0.0001) BWG. Dietary supplementation with 1% PB resulted in the highest (P < 0.0001) BWG during the study. Feed intake was not affected by the treatments during the starter, finisher, and overall rearing periods. Broilers fed diet supplemented with 1% PB had the best (P < 0.0001) feed conversion ratio during the study. Overall, broilers fed only basal diet had the highest (P = 0.0450) mortality. Ileal organic matter (OM) digestibility increased linearly (P = 0.044) with broilers fed diet supplemented with PB, but reduced with antibiotic group. Dietary supplementation with 1% PB had the highest (P = 0.0402) ileal digestibility of tryptophan. In the duodenum, broilers fed diet supplemented with PB had longer (P = 0.0006) villi heights than the birds fed only basal diet, but similar with antibiotic group. Broilers fed diet supplemented with PB had longer (P = 0.0064) villi height in the jejunum than the antibiotic group. Bifidobacterium concentration of the cecum content showed a slight increase (P = 0.053) with increasing supplementation levels of PB. In conclusion, the current study shows that dietary supplementation with PB improves growth performance, intestinal morphology, and apparent ileal digestibility of OM and tryptophan in a dose-dependent manner with the best response at 1% inclusion level.

Toxicology study for magnetic injection of prednisolone into the rat cochlea.

This paper investigates the safety of a novel 'magnetic injection' method of delivering therapy to the cochlea, in a rodent model. In this method of administration, a magnetic field is employed to actively transport drug-eluting superparamagnetic iron-oxide core nanoparticles into the cochlea, where they then release their drug payload (we delivered the steroid prednisolone). Our study design and selection of control groups was based on published regulatory guidance for safety studies that involve local drug delivery. We tested for both single and multiple delivery doses to the cochlea, and found that magnetic delivery did not harm hearing. There was no statistical difference in hearing between magnetically treated ears versus ears that received intra-tympanic steroid (a mimic of a standard-of-care for sudden sensorineural hearing loss), both 2 and 30 days after treatment. Since our treatment is local to the ear, the levels of steroid and iron circulating systemically after our treatment were low, below mass-spectrometry detection limits for the steroid and no different from normal for iron. No adverse findings were observed in ear tissue histopathology or in animal gross behavior. At 2 and 30 days after treatment, inflammatory changes examined in the ear were limited to the middle ear, were very mild in severity, and by day 90 there was ongoing and almost complete reversibility of these changes. There were no ear tissue scarring or hemorrhage trends associated with magnetic delivery. In summary, after conducting a pre-clinical safety study, no adverse safety issues were observed.

Studying the result of underlay myringoplasty using platelet-rich plasma.

OBJECTIVE: Perforations of the tympanic membrane are treated with various surgical techniques and materials. This study aimed to determine the efficacy of platelet-rich plasma during underlay myringoplasty. METHODS: The study included 40 patients. Autologous platelet-rich plasma was applied in-between temporalis fascia graft and tympanic membrane remnant during underlay myringoplasty in group 1 (n = 20). The outcome was evaluated after three months and compared with group 2 (n = 20), a control group that underwent routine underlay tympanoplasty. RESULTS: After three months' follow up, graft uptake was 95 per cent in group 1 and 85 per cent in group 2 (p < 0.03). Mean hearing threshold gain was 18.62 dB in group 1 and 13.15 dB in group 2. This difference was statistically significant (p < 0.01). CONCLUSION: Platelet-rich plasma, with its ease of preparation technique, availability, low cost, autologous nature and good graft uptake rate, justifies its use in tympanoplasty type I procedures.

Association between the intima-media thickness of the extracranial carotid arteries and metabolic syndrome in ethnic Kyrgyzs.

BACKGROUND: It is known that atherosclerosis is the leading cause of cardiovascular disease. We aimed to study the correlation between components of metabolic syndrome (MS) and subclinical carotid atherosclerosis in a group of ethnic Kyrgyzs. METHODS: In а descriptive study we assessed 144 ethnic Kyrgyzs (69 males, 75 females) aged 36-73 years (average age 51.03 ± 8.2). All participants underwent a clinical investigation and an anthropometric evaluation (weight, height, waist circumference (WC)). Abdominal obesity (АО) was confirmed at WC ≥ 94 cm in males and ≥ 88 cm in females. Fasting plasma glucose and lipid spectrum tests were performed. An ultrasound assessment of carotid intima-media thickness (IMT) was performed using a 7.5 MHz transducer (Phillips-SD 800). RESULTS: MS was revealed in 61 (42.4%; 47.8% in men and 37.3% in women) of the investigated patients. IMT was significantly increased with the presence of MS components in males (no components vs 2 components of MS: 0.67 ± 0.007 and 0.81 ± 0.009 respectively; р < 0.05) and females (no components vs 3 components of MS: 0.63 ± 0.007 and 0.76 ± 0.01 respectively; р < 0.01). IMT trended towards an increase in the presence of a greater number of MS components in patients with and without AO (р < 0.01). In order to identify independent factors affecting IMT we carried out a multifactorial logistic regression analysis. Arterial hypertension was found to have the greatest influence on the development of MS (OR = 3.81, p < 0.0001). CONCLUSION: In the group of ethnic Kyrgyzs, a greater number of MS components, with AO or without AO, is associated with higher carotid IMT.