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INTRODUCTION: Leptospirosis and dengue are two significant public health concerns in tropical and subtropical regions, often resulting in severe forms of disease and fatality. This study addresses the pressing public health issues of leptospirosis and dengue in the Dakshina Kannada district of Karnataka, India. Both diseases pose significant health risks and are relatively understudied in this region, making it essential to investigate their prevalence and clinical presentations for targeted healthcare planning. AIM: The primary aim is to determine the frequency of leptospirosis and dengue among febrile illness cases to understand the epidemiological patterns and assess co-infection rates in Dakshina Kannada. METHOD: Between 2020 and 2021, serum samples suspected of leptospirosis were tested using IgM ELISA (n = 1629) and the Microscopic Agglutination Test (MAT) (n = 92) for leptospirosis, while dengue was tested using NS1Ag and IgM antibodies ELISA (n = 1415). Data were collected through medical records and patient interviews. Seasonal trends, gender, and age distributions were analyzed. RESULT: The study found a significant prevalence of leptospirosis (21 %) and dengue (10 %) among febrile illness cases in the study area, with a 1.3 % co-infection rate. Clinically, fever was common to both diseases, but leptospirosis also frequently exhibited symptoms such as abdominal pain, myalgia, and jaundice. MAT screening revealed a predominance of anti-leptospiral antibodies against the Djasiman, Pyrogenes, Hurstbridge, Hebdomadis, and Grippotyphosa serogroups in Dakshina Kannada. CONCLUSION: The study highlights the urgent need for focused public health interventions, improved diagnostic tools, and targeted epidemiological studies to manage these diseases. The findings underscore the necessity of enhancing diagnostic capabilities and public health awareness, particularly considering the significant health risks posed by leptospirosis and dengue in the region.
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Zingiber zerumbet Sm. (Family: Zingiberaceae) is an important perennial medicinal oil-bearing herb that is native to the Southeast Asia. This study examines the impact of different durations of post-harvest shade drying (ranging from 1 to 12 months) on essential oil yield and chemical composition of Z. zerumbet, in comparison to the freshly collected oil sample. This study explores how post-harvest shade drying impact the composition and longevity of Z. zerumbet rhizomes as well as its antimicrobial, antibiofilm activity. The oils were analyzed for their chemical composition analysis using a gas chromatography-flame ionization detector (GC-FID) and gas chromatography-mass spectrometry (GC-MS). The post-harvest periods of drying (1-12 months) were discovered to enhance the concentration of marker constituents in the oil. The primary constituent, Zerumbone, was detected in concentrations ranging from 69.38 ± 5.63% to a maximum of 80.19 ± 1.53% as the drying duration of the rhizome was extended. The output of the essential oil was not significantly affected by drying times; however, it did have a noticeable impact on the proportions of monoterpenes. Both disc diffusion and broth microdilution assay were used in freshly collected Z. zerumbet oil for its antimicrobial potential against S. aureus, L. monocytogens, S. hominis, Salmonella enterica serovar Typhimurium, P. aeruginosa, S. intermedius, E. coli, and C. albicans. For the first time, the oil reported to exhibit antibiofilm activity against S. aureus which was validated using fluorescence microscopy, and effectively disrupts the biofilm by 47.38% revealing that essential oil was able to disintegrate the clusters of the pathogen. Z. zerumbet rhizome oil is effective to reduce food-borne microorganisms. Therefore, its essential oil, a natural source of bioactive zerumbone, may improve flavor, aroma, and preservation.
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Introduction: Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder that typically presents with painless, central visual loss, hyperaemia of the optic nerve head, and peripapillary telangiectasias. Most LHON cases are due to one of three variants, but several less common variants also exist. We describe a clinical case of LHON associated with the variant m.3866T>C, which is possibly linked to LHON. Case Presentation: A 59-year-old Caucasian woman experienced acute, bilateral, and painless visual loss. She reported cigarette smoking, and elevated phosphatidylethanol suggested harmful alcohol consumption. Her best-corrected visual acuity (BCVA) was 20/100 for the right eye and 20/50 for the left eye. She could only read the Ishihara demonstration plate, and threshold perimetry demonstrated reduced central sensitivity bilaterally. Her optic nerve heads were hyperaemic, with peripapillary telangiectasias. The visual symptoms and clinical findings suggested LHON. Magnetic resonance imaging demonstrated a tuberculum sella meningioma and two cerebral aneurysms, which we regarded as incidental findings. Genetic testing did not identify common LHON variants but a rare homoplasmic variant, m.3866T>C, which studies suggest might cause LHON or act in synergy with other variants to increase the disease penetrance. After initiating test-of-treatment with idebenone 900 mg per day, the patient's BCVA improved to 20/32 for both eyes and then stabilized. Conclusion: This case strengthens the evidence for m.3866T>C as a causative LHON variant. The case also raises the question as to whether this particular variant can respond favourably to treatment with idebenone.
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This study employs plasma-liquid interaction technique to synthesize different phases of molybdenum oxide using air and argon as plasma-forming gases. In situ plasma-generated nitrogen species primarily NO3-/NO2- and hydrogen species (H+) facilitate the reduction of the molybdenum precursor anion (Mo7O24-). The reduced Mo species subsequently reacts with reactive oxygen species, forming MoO6 octahedra, which is the building block of a molybdenum oxide crystal. Varied concentrations of NO3-/NO2- and H+ species in air and argon plasma treatment significantly influence the growth process. Air plasma synthesis yields hexagonal molybdenum oxide microrods, which upon calcination changes its phase to orthorhombic 2D layered structure. Moreover, the argon plasma synthesized sample exhibits a mixed phase of hexagonal and orthorhombic molybdenum oxide due to the heavy argon ion bombardment, inducing material porosity and surface oxygen vacancies. The mixed-phase material exhibits superior adsorption and photo-degradation towards cationic dye compared to the other two phases. The higher photocatalytic performance may be responsible for the extended lifetime of the photo-generated charge carriers possessed by the mixed-phase material. Radical scavenging tests have identified holes and hydroxyl radicals as the key reactive species that take part in the photo-degradation process.
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BACKGROUND: Typhoid fever is a common cause of febrile illness in low- and middle-income countries. While multidrug-resistant (MDR) Salmonella Typhi (S. Typhi) has spread globally, fluoroquinolone resistance has mainly affected Asia. METHODS: Consecutively, 1038 blood cultures were obtained from patients of all age groups with fever and/or suspicion of serious systemic infection admitted at Mnazi Mmoja Hospital, Zanzibar in 2015-2016. S. Typhi were analyzed with antimicrobial susceptibility testing and with short read (61 strains) and long read (9 strains) whole genome sequencing, including three S. Typhi strains isolated in a pilot study 2012-2013. RESULTS: Sixty-three S. Typhi isolates (98%) were MDR carrying blaTEM-1B, sul1 and sul2, dfrA7 and catA1 genes. Low-level ciprofloxacin resistance was detected in 69% (43/62), with a single gyrase mutation gyrA-D87G in 41 strains, and a single gyrA-S83F mutation in the non-MDR strain. All isolates were susceptible to ceftriaxone and azithromycin. All MDR isolates belonged to genotype 4.3.1 lineage I (4.3.1.1), with the antimicrobial resistance determinants located on a composite transposon integrated into the chromosome. Phylogenetically, the MDR subgroup with ciprofloxacin resistance clusters together with two external isolates. CONCLUSIONS: We report a high rate of MDR and low-level ciprofloxacin resistant S. Typhi circulating in Zanzibar, belonging to genotype 4.3.1.1, which is widespread in Southeast Asia and African countries and associated with low-level ciprofloxacin resistance. Few therapeutic options are available for treatment of typhoid fever in the study setting. Surveillance of the prevalence, spread and antimicrobial susceptibility of S. Typhi can guide treatment and control efforts.
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Antibacterianos , Ciprofloxacina , Farmacorresistencia Bacteriana Múltiple , Genotipo , Pruebas de Sensibilidad Microbiana , Salmonella typhi , Fiebre Tifoidea , Humanos , Salmonella typhi/genética , Salmonella typhi/efectos de los fármacos , Salmonella typhi/aislamiento & purificación , Salmonella typhi/clasificación , Ciprofloxacina/farmacología , Farmacorresistencia Bacteriana Múltiple/genética , Antibacterianos/farmacología , Fiebre Tifoidea/microbiología , Fiebre Tifoidea/epidemiología , Tanzanía/epidemiología , Adolescente , Masculino , Niño , Adulto , Adulto Joven , Femenino , Preescolar , Secuenciación Completa del Genoma , Persona de Mediana Edad , Lactante , AncianoRESUMEN
Plastic pollution, including micro- and nanoplastics, is a growing concern. Tyre-wear particles (TWPs) are the second largest source of microplastics in the ocean following abrasion of synthetic fibres. In addition to the particles themselves, TWPs contain many harmful chemicals, including 6PPD. This chemical reacts with atmospheric ozone and forms the toxic compound 6PPD-quinone (6PPDq), which poses a danger to aquatic life. There is a knowledge gap in understanding risks associated with the combined toxicity of nanoplastics (NPs) and 6PPDq. The present study aimed to investigate the toxicity of NPs and 6PPDq on adult zebrafish using phenotypic (behaviour, histology) and transcriptomic endpoints. Zebrafish were exposed to four treatments: control (contaminant-free), 50 µg/L 6PPDq, 3 mg/L polystyrene (PS)-NPs, and a combination of 50 µg/L 6PPDq and 3 mg/L PS-NPs. We did not observe locomotory dysregulation in zebrafish exposed to NPs. However, we found significant hyperlocomotion in zebrafish exposed to 6PPDq and this effect was even more substantial after co-exposure with PS-NPs. This study explores the molecular mechanisms behind these effects, identifying genes associated with neurotransmitters and fatty acid metabolism that were dysregulated by the co-exposure. Transcriptomic analysis further showed that both 6PPDq and PS-NPs impacted cellular processes associated with sterol biosynthesis, cholesterol metabolism, and muscle tissue development. The effects on these mechanisms were stronger in co-exposed zebrafish, indicating a heightened risk to cellular integrity and mitochondrial dysfunction. These results highlight the significance of mixture toxicity when studying the effects of NPs and associated chemicals like 6PPDq.
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Benzoquinonas , Nanopartículas , Contaminantes Químicos del Agua , Animales , Pez Cebra , Microplásticos/toxicidad , Poliestirenos/toxicidad , Plásticos/toxicidad , Quinonas , Contaminantes Químicos del Agua/toxicidadRESUMEN
PURPOSE: No consensus exists as the gold standard for Cushing's Syndrome (CS) screening. This study aimed to evaluate the diagnostic accuracy and utility of late-night salivary cortisol (LNSC) and cortisone (LNSE), overnight dexamethasone suppression test (ODST), and urinary free cortisol (UFC) in developing a screening algorithm for CS. METHODS: A retrospective, single-centre analysis on 93 adult patients referred to the Oxford Centre for Diabetes, Endocrinology, and Metabolism for CS evaluation (2017-2022). Data were analysed using binomial logistic regression and area under the receiver-operating curve (AUROC). RESULTS: Fifty-three patients were diagnosed with CS. LNSC (sensitivity 87.5%, specificity 64.9%, AUC 0.76), LNSE (sensitivity 72.4%, specificity 85.7%, AUC 0.79), and ODST (sensitivity 94.7%, specificity 52.1%; AUC 0.74) demonstrated comparable effectiveness for CS diagnosis. Their combined application increased diagnostic accuracy (AUC 0.91). UFC was not statistically significant. Pre-test clinical symptom inclusion improved screening test performance (AUC LNSC: 0.83; LNSE: 0.84; ODST: 0.82). For CD diagnosis, LNSE + LNSC (AUC 0.95) outperformed ODST. Combining these with ACTH levels < 12.6 pmol/L perfectly distinguished MACS (AUC 1.00). ODST (AUC 0.76) exhibited superior performance (sensitivity 100.0%, specificity 52.2%) in MACS detection. CONCLUSIONS: LNSC, LNSE, and ODST are robust tools for CS screening, with their combined use offering the highest diagnostic precision. LNSE, especially when used with LNSC, is highly effective for CD diagnosis, exceeding ODST accuracy. ODST is preferable for MACS identification. Integrating ACTH levels markedly improves differentiation between CD and MACS. Conversely, UFC shows limited diagnostic utility.
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Nanoplastics (NPs) and persistent organic pollutants such as polychlorinated biphenyls (PCBs) are ubiquitous aquatic pollutants. The coexistence of these pollutants in the environment emphasises the need to study their combined toxicity. NPs can cross biological membranes and act as vectors for other pollutants, whereas PCBs are known for their ability to bioaccumulate and biomagnify. The present work aimed to study the combined toxicity of polystyrene NPs and PCB-153 using physiological (development, heart rate, respiration), behavioural (swimming behaviour) and molecular (transcriptome) endpoints in zebrafish larvae. The results show that exposure to NPs, PCB and their mixture significantly affected the development and respiration in zebrafish larvae. Larvae co-exposed to NPs and PCB exhibited significant hyperlocomotion, whereas no such effect was observed after exposure to NPs or PCB alone. The transcriptomic results revealed that NPs exposure significantly affected several pathways associated with DNA compaction and nucleosome assembly, whereas PCB exposure significantly affected critical neurogenic pathways. In contrast, co-exposure to NPs and PCB generated multi-faceted toxicity and suppressed neurobehavioural, immune-related and detoxification pathways. The study highlights the complex interplay between NPs and PCBs, and documents how the two toxicants in combination give a stronger effect than the single toxicants alone. Understanding the mixture toxicity of these two pollutants is important to assess the environmental risks and developing effective management strategies, ultimately safeguarding ecosystems and human health.
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Contaminantes Ambientales , Bifenilos Policlorados , Contaminantes Químicos del Agua , Humanos , Animales , Bifenilos Policlorados/toxicidad , Pez Cebra/metabolismo , Poliestirenos/toxicidad , Poliestirenos/metabolismo , Microplásticos/toxicidad , Larva/metabolismo , Ecosistema , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/metabolismoRESUMEN
Here we evaluated the gill epithelial cell line ASG-10 from Atlantic salmon, as an in vitro model for research on known water quality challenges in aquaculture. Ammonia/ammonium (NH3/NH4+), a recognized challenge in water-intensive recirculating aquaculture systems (RAS), induced lysosomal vacuolization, reduced protein degradation and cell migration of the ASG-10 cells. Aluminium (Aln+), another challenge in freshwater aquaculture facilities had only minor effects. Next, we investigated the tolerance for direct water exposure of ASG-10. The cells tolerated water with osmolarity between 169 and 419 mOsmol/kg for 24 h. However, cells exposed for 3 h to water at 863 mOsmol/kg changed cellular morphology and induced gene expression related to stress (gpx1, casp3, hsp70), and after 24 h exposure cellular viability was severely reduced. Nevertheless, when the cells were grown in transwell inserts, they tolerated 863 mOsmol/kg for 3 h and induction of stress response associated genes was considerably reduced. Lastly, the ASG-10 cells were exposed to water samples, with no known quality issues, from different aquaculture facilities. The cells showed no differences in viability or morphology compared to their representative control. In conclusion, the ASG-10 cell line is a promising in vitro model to study water quality challenges and whole water samples.
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Salmo salar , Animales , Branquias , Calidad del Agua , Células Epiteliales , AcuiculturaRESUMEN
Till the day the rectal cancer deaths in the world is in eighth position. For rectal cancer surgery, short-term benefits are expected to be similar for laparoscopic resection of rectum (LRR) and open resection of rectum (ORR). In Bangladesh though the rectal cancer is the sixteenth most common cause of cancer deaths, there is lack of data regarding outcomes of laparoscopic and open surgical approaches for carcinoma rectum. Purpose of study was to compare oncopathological outcomes by quality of surgical resection between LRR and ORR groups. The quasi experimental study was conducted among 46 subjects who attended in the Department of Colorectal Surgery, Bangabandhu Sheikh Mujib Medical University, Bangladesh from July 2020 to June 2021 with rectal adenocarcinoma within 15cm from the anal verge. Equal number of subjects were allocated for LRR and ORR group. Oncopathological end points such as circumferential resection margin (CRM), distal resection margin (DRM), lymph nodes and quality of mesorectal excision were assessed and compared. Here every patients have given their written consent for this study. Mean age of the subjects for LRR and ORR were 45.47±12.66 and 44.47±12.48 years respectively. Majority of the subjects were in age above 40 years (67.0%). The proportion of male (56.5%) were higher than those of female (43.5%). The complete resection was better in LRR (91.3%) than ORR (87.0%) group though statistically not significant. CRM was lower in LRR (0.0%) than ORR (13.0%) group in respect of frequency distribution. DRM was negative for both LRR and ORR group (95.7% each) and it was not statistically significant. ORR met the National Comprehensive Cancer Network (NCCN) criteria of harvesting 12 lymph nodes were as in LRR group 10 lymph nodes were harvested. The mean harvested lymph nodes were 12.2±5.55 and 10.1±5.55 in LRR and ORR group respectively. The study demonstrated that LRR is better (though statistically not significant) in respect of complete resection and CRM while in harvesting lymph nodes, ORR met the NCCN criteria but LRR does not. There is no difference observed regarding DRM in both groups. On oncopathological point of view both the group showed almost equally effective results. Laparoscopic surgery can be opted as the standard operative technique for surgical management of rectal cancer.
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Carcinoma , Laparoscopía , Neoplasias del Recto , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Recto/cirugía , Márgenes de Escisión , Resultado del Tratamiento , Laparoscopía/métodos , Neoplasias del Recto/cirugía , Neoplasias del Recto/patología , Carcinoma/patologíaRESUMEN
The interaction between two edge dislocations in a sheared lyotropic lamellar liquid-crystalline medium is examined. The model is a mesoscale hydrodynamic model based on a free-energy functional that is minimised for a sinusoidal concentration modulation coupled with concentration and momentum equations. The defect dynamics are analysed as a function of the system size and the Ericksen number, the ratio of the shear stress and the characteristic free-energy density for deformation. Three different regimes are observed as the Ericksen number is increased when the edge dislocations are sheared towards each other, such that there is compression of layers between the defects: (a) defect motion that reduces the cross-stream separation till there is a steady spacing with plug flow between the defects, (b) defect attraction and cancellation resulting in a well-aligned state, and (c) defect creation due to a compressional instability between the defects resulting in an increase in the disorder. When the edge dislocations are sheared away from each other, such that there is extension of the layers between the defects, two distinct regimes are observed as the Ericksen number is increased: (a) bending of layers and a plug flow between the defects at their initial separation, and (b) buckling of the layers leading to creation of more defects and a dynamical steady state between defect creation and cancellation. These regimes are found to be robust for different values of the system size, from 32 to 128 layers, and for different values of the dimensionless groups that characterise the ratio of mass/momentum convection and diffusion.
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Lufenuron is a benzoylurea insecticide currently in use to combat sea lice infestation in salmon aquaculture in Chile. With pending approval in Norway, the aim of this work was to study the uptake and toxicity of lufenuron in liver tissue of Atlantic salmon. Juvenile salmon weighing 40 g were given a standard 7-day oral dose, and bioaccumulation and transcriptional responses in the liver were examined 1 day after the end-of-treatment (day 8) and after 1 week of elimination (day 14). Bioaccumulation levels of lufenuron were 29 ± 3 mg/kg at day 8 and 14 ± 1 mg/kg at day 14, indicating relatively rapid clearance. However, residues of lufenuron were still present in the liver after 513 days of depuration. The exposure gave a transient inhibition of transcription in the liver at day 8 (2437 significant DEGs, p-adj < .05), followed by a weaker compensatory response at day 14 (169 significant DEGs). Pathways associated with RNA metabolism such as the sumoylation pathway were most strongly affected at day 8, while the apelin pathway was most profoundly affected at day 14. In conclusion, this study shows that lufenuron easily bioaccumulates and that a standard 7-day oral dose induces a transient inhibition of transcription in liver of salmon.
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Copépodos , Enfermedades de los Peces , Salmo salar , Animales , Salmo salar/genética , Enfermedades de los Peces/genética , Hígado/metabolismo , Expresión Génica , Copépodos/fisiologíaRESUMEN
Acid mine drainage (AMD) is widely acknowledged as a substantial threat to the biodiversity of aquatic ecosystems. The present study aimed to study the toxicological effects of Cu-rich AMD from the Sulitjelma mine in zebrafish larvae. The AMD from this mine was found to contain elevated levels of dissolved metals including Mg (46.7 mg/L), Al (20.2 mg/L), Cu (18.3 mg/L), Fe (19.8 mg/L) and Zn (10.6 mg/L). To investigate the toxicological effects, the study commenced by exposing zebrafish embryos to various concentrations of AMD (ranging from 0.75% to 9%) to determine the median lethal concentration (LC50). Results showed that 96 h LC50 for zebrafish larvae following AMD exposure was 2.86% (95% CI: 2.32-3.52%). Based on acute toxicity results, zebrafish embryos (<2 hpf) were exposed to 0.1% AMD (Cu: 21.7 µg/L) and 0.45% AMD (Cu: 85.7 µg/L) for 96 h to assess development, swimming behaviour, heart rate, respiration and transcriptional responses at 116 hpf. Light microscopy results showed that both 0.1% and 0.45% AMD reduced the body length, eye size and swim bladder area of zebrafish larvae and caused phenotypic abnormalities. Swimming behaviour results showed that 0.45% AMD significantly decreased the locomotion of zebrafish larvae. Heart rate was not affected by AMD exposure. Furthermore, exposure caused a significant increase in oxygen consumption indicating vascular stress in developing larvae. Taken altogether, the study shows that even heavily diluted AMD with environmentally relevant levels of Cu caused toxicity in zebrafish larvae.
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Contaminantes Químicos del Agua , Pez Cebra , Animales , Pez Cebra/fisiología , Larva , Ecosistema , Metales/farmacología , Modelos Animales , Contaminantes Químicos del Agua/análisis , Embrión no MamíferoRESUMEN
INTRODUCTION: The impact of moderate haemophilia on health-related quality of life (HRQoL) and physical activity (PA) is not well known. In previous studies, persons with factor VIII/factor IX activity (FVIII/FIX:C) below 3 IU/dL were associated with a more severe bleeding phenotype than predicted. AIM: To explore HRQoL and PA in patients with moderate haemophilia A (MHA) and B (MHB). METHODS: A cross-sectional, multicentre study covering patients with MHA and MHB in Sweden, Finland, and Norway. HRQoL was assessed with the EuroQoL 5-Dimensions (EQ-5D) form and PA with the International Physical Activity Questionnaire among participants aged ≥15 years. RESULTS: We report on 104 patients aged 15-84 years from the MoHem study. Overall, EQ-5D utility was .85 (median) (Q1-Q3 0.73-1.0) with corresponding visual analogue scale (VAS) 80 (70-90), which were similar regardless of treatment modality, FVIII/FIX:C, and MHA or MHB. Pain and mobility were most frequently affected dimensions. Utility (r = -.54), VAS (r = -.42), and PA (r = -.32) correlated negatively with arthropathy (HJHS). Only patients aged 41-50 years displayed lower utility (p = .02) and VAS (p < .01) than the Norwegian population norm. Patients on prophylaxis aged 35-54 years reported higher PA than those treated on-demand (p = .01). CONCLUSION: Haemophilic arthropathy had negative impact on HRQoL and PA in Nordic patients with moderate haemophilia. Middle-aged patients captured lower utility and VAS than observed in the general population. Tailored prophylaxis and improved joint health may influence positively on HRQoL and PA also in moderate haemophilia.
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Hemofilia A , Artropatías , Persona de Mediana Edad , Humanos , Hemofilia A/tratamiento farmacológico , Calidad de Vida , Estudios Transversales , Artropatías/complicaciones , Factor IX/uso terapéutico , Ejercicio FísicoRESUMEN
AIM: The aim of this study was to investigate the role of human factors in pelvic exenteration and how team performance is optimized in the preoperative, intraoperative and postoperative phases. METHOD: Qualitative analysis of focus groups was used to capture authentic human interactions that reflect real-world multiprofessional performance. Theatre teams were treated as clusters, with a particular focus group containing participants who worked together regularly. RESULTS: Three focus groups were conducted. Four themes emerged - driving force, technical skills, nontechnical skills and operational aspects - with a total of 16 subthemes. Saturation was reached by group 2, with no new subthemes emerging after this. There was some interaction between the themes and the subthemes. Broadly speaking, driving force led to the development of specialised technical skills and nontechnical skills, which were operationalized into successful service through operational aspects. CONCLUSION: This study of teams performing pelvic exenteration is the first in the field using this methodology. It has generated rich qualitative data with authentic insights into the pragmatic aspects of developing and delivering a service. In addition, it shows how the themes are connected or 'coupled' in a network, for example technical and non-technical skills. In a complex system, 'tight coupling' leads to both high performance and adverse events. In this paper, we report the qualitative aspects of high performance by pelvic exenteration teams in a complex sociotechnical system, which depends on tight coupling of several themes.
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Exenteración Pélvica , Humanos , Grupos FocalesRESUMEN
Gadolinium (Gd) is one of the rare earth elements (REY) and is widely used in magnetic resonance imaging (MRI) contrast agents. Anthropogenic Gd enrichment has frequently been found in wastewater treatment plant effluents in industrialised countries, rising concerns regarding effects on aquatic biota. This study investigates the acute toxicity and sublethal effects of Gd in two forms, as inorganic salt (GdCl3) and as Gd-based contrast agent (GBCA), on early life stages of zebrafish (Danio rerio). Nominal exposure concentrations ranged from 3 to 3000 µg L-1, with an exposure duration of 96 h. None of the two tested compounds were acutely toxic to embryos and larvae. Similarly, we did not observe any effects on larval development and locomotive behaviour. However, we found significant changes in the brain activity of larvae exposed to the highest concentrations of GdCl3 and the GBCA. Our findings show that Gd can have sublethal effects on developing fish at lower concentrations than reported previously, highlighting the necessity of investigating the long-term fate and effects of GBCAs released into the aquatic environment.
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Metales de Tierras Raras , Perciformes , Contaminantes Químicos del Agua , Animales , Medios de Contraste/toxicidad , Gadolinio/toxicidad , Pez Cebra , Gadolinio DTPA , Imagen por Resonancia Magnética , Larva , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/análisisRESUMEN
Here we report the discovery of MED6-189, a new analogue of the kalihinol family of isocyanoterpene (ICT) natural products. MED6-189 is effective against drug-sensitive and -resistant P. falciparum strains blocking both intraerythrocytic asexual replication and sexual differentiation. This compound was also effective against P. knowlesi and P. cynomolgi. In vivo efficacy studies using a humanized mouse model of malaria confirms strong efficacy of the compound in animals with no apparent hemolytic activity or apparent toxicity. Complementary chemical biology, molecular biology, genomics and cell biological analyses revealed that MED6-189 primarily targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses in P. falciparum revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. The high potency of MED6-189 in vitro and in vivo, its broad range of efficacy, excellent therapeutic profile, and unique mode of action make it an excellent addition to the antimalarial drug pipeline.
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BACKGROUND: Early phase cancer clinical trials (EPCTs) involve experimental drugs being used for the first time in humans. These studies are designed for dose determination and safety, and represent the most time intensive of all clinical trials for both clinicians and patients. We sought to quantify the amount of patient time consumed through EPCT participation. PATIENTS AND METHODS: A retrospective audit of patients treated in the EPCT unit at Liverpool Hospital, Sydney was carried out from 2013 to 2023. We defined 'time toxicity' (TT) as a composite measure where time-toxic days were considered days with any health care system contact, including clinic visits, infusions, procedures or blood work. RESULTS: A total of 219 patients across 36 EPCTs were included. The median age was 65 years (range 31-81 years). Patients spent a median of 29% (range 4%-100%) of their days in direct contact with the health care system during their study. Protocol-specified visits accounted for the greatest contribution to total TT in 101 (46%) patients. In 7% (n = 16) of patients, unscheduled visits due to either adverse events or cancer-related symptoms accounted for the greatest TT. TT reduced as patients completed additional cycles of treatment. Patients who completed >10 cycles spent 14% of their days interacting with health care systems compared with 35% for those who completed ≤2 cycles. No statistically significant difference in TT was noted between dose-expansion and dose-escalation studies or trials focusing on immune-oncology versus targeted therapy. CONCLUSIONS: Our study is the first to report TT in EPCTs with an extended follow-up. Clinicians should be aware of TT when discussing risks and benefits. TT also may not be the appropriate term when describing the time patients invest during EPCTs. Toxicity implies a negative impact, but for many patients, trial participation would be seen as positive. There should be efforts to streamline health care visits to limit TT in EPCTs.
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Neoplasias , Humanos , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estudios Retrospectivos , Neoplasias/tratamiento farmacológicoRESUMEN
Background: New treatment modalities have not been widely adopted for patients with glioblastoma (GBM) after the addition of temozolomide to radiotherapy. We hypothesize that increased extent of resection (EOR) has resulted in improved survival for surgically treated patients with glioblastoma at the population level. Methods: Retrospective analysis of adult patients operated for glioblastoma in the population of South-Eastern Norway. Patients were stratified into Pre-temozolomide- (2003-2005), temozolomide- (2006-2012), and resection-focused period (2013-2019) and evaluated according to age and EOR. Results: The study included 1657 adult patients operated on for supratentorial glioblastoma. The incidence of histologically confirmed glioblastoma increased from 3.7 in 2003 to 5.3 per 100 000 in 2019. The median survival was 11.4 months. Complete resection of contrast-enhancing tumor (CRCET) was achieved in 386 patients, and this fraction increased from 13% to 32% across the periods. Significant improvement in median survival was found between the first 2 periods and the last (10.5 and 10.6 vs. 12.3 months; Pâ <â .01), with a significant increase in 3- and 5-year survival probability to 12% and 6% (Pâ <â .01). Patients with CRCET survived longer than patients with non-CRCET (16.1 vs. 10.8 months; Pâ <â .001). The median survival doubled in patientsâ ≥70 years and (12.1 months). Survival was similar between the time periods in patients where CRCET was achieved. Conclusions: We demonstrate an improved survival of GBM patients at the population level associated with an increased fraction of patients with CRCET. The data support the importance of CRCET to improve glioblastoma patient outcomes.