Genetic background influences tumour development in heterozygous Men1 knockout mice

Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder caused by MEN1 germline mutations, is characterised by parathyroid, pancreatic and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP), a milder condition causing hyperparathyroidism only. Identical mutations can cause either MEN1 or FIHP in different families, thereby implicating a role for genetic modifiers in altering phenotypic expression of tumours. We therefore investigated the effects of genetic background and potential for genetic modifiers on tumour development in adult Men1+/- mice, which develop tumours of the parathyroids, pancreatic islets, anterior pituitary, adrenal cortex and gonads, that had been backcrossed to generate C57BL/6 and 129S6/SvEv congenic strains. A total of 275 Men1+/- mice, aged 5–26 months were macroscopically studied, and this revealed that genetic background significantly influenced the development of pituitary, adrenal and ovarian tumours, which occurred in mice over 12 months of age and more frequently in C57BL/6 females, 129S6/SvEv males and 129S6/SvEv females, respectively. Moreover, pituitary and adrenal tumours developed earlier, in C57BL/6 males and 129S6/SvEv females, respectively, and pancreatic and testicular tumours developed earlier in 129S6/SvEv males. Furthermore, glucagon-positive staining pancreatic tumours occurred more frequently in 129S6/SvEv Men1+/- mice. Whole genome sequence analysis of 129S6/SvEv and C57BL/6 Men1+/- mice revealed >54,000 different variants in >300 genes. These included, Coq7, Dmpk, Ccne2, Kras, Wnt2b, Il3ra and Tnfrsf10a, and qRT-PCR analysis revealed that Kras was significantly higher in pituitaries of male 129S6/SvEv mice. Thus, our results demonstrate that Kras and other genes could represent possible genetic modifiers of Men1

A Comparative Evaluation of the Clinical Course, Laboratory Data and Chest CT scan Findings in Pediatric Patients with Covid-19 and Their Prognostic Value in Disease Outcome Estimation

Background: Most research on children and adolescents with COVID-19, had limited sample sizes and little clinical, laboratory, and radiological findings. The purpose of this research was to examine the features of children and adolescents with COVID-19 infection.Methods: This analytical retrospective study was conducted on children (1 to 12 years old) and adolescents (13 to 19 years old) with COVID-19 in Shahid Beheshti Hospital, Kashan, Iran. The data were then collected, entered into SPSS and analyzed.Results: In the adolescent group, the frequency of dyspnea (47.1 % vs. 11.9%), cough (67.1 % vs. 39.2%), lethargy (42.9 % vs. 25.9%), headache (35.7 % vs. 10.5%), myalgia (38.6 % vs. 14%), and chest pain (12.9 % vs. 0.7%) were significantly higher than those in children (p<0.05). Furthermore, in terms of laboratory findings, the normal range of neutrophils (13.8% vs. 1.4%), Cr (95% vs. 75.7%), and CRP (77.9% vs. 58%) were higher in children. Moreover, we found that the CT severity score among adolescent patients was significantly higher than that in children (4.84 ± 5.21 vs. 1.76 ± 3.25, p=0.006). Also, the frequency of consolidation (61.3 % vs. 19%), and ground-glass opacity (58.1 % vs. 28.6%) among adolescents were significantly higher compared to child cases (p<0.05) while only the frequency of mosaic pattern of pulmonary parenchymal attenuation was significantly higher among children (p=0.035).Conclusion: This research found milder clinical, biochemical, and radiological symptoms in children with COVID-19 than adolescents. However, radiological examinations showed greater rates of pulmonary parenchymal mosaic attenuation, which might help early diagnosis of COVID-19

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Gene modifiers and novel therapies for multiple endocrine neoplasia type 1

Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of pituitary, pancreatic islet and parathyroid tumours. MEN1-associated tumours show loss of heterozygosity and the MEN1 gene encodes a putative tumour-suppressor, menin, whose over-expression in vitro inhibits cell proliferation. MEN1-associated tumours present earlier, are more aggressive and more difficult to treat than sporadic endocrine tumours. Strategies for earlier identification of index cases and novel therapies may contribute towards reduced morbidity and mortality from the condition.In this study, I first investigated the safety and efficacy of MEN1 gene replacement therapy using a modified adenoviral vector in pituitary tumours of heterozygous Men1 knockout mice. This revealed that MEN1 gene replacement was safe, effective and induced reduction of tumour cell proliferation. I also performed an in vivo phage-displayed peptide library screening study in heterozygous Men1 knockout mice to identify novel peptides that specifically bind pancreatic islet tumours. This identified one peptide sequence that likely targets pancreatic islet tumours. To further elucidate the role of menin I carried out phenotypic characterization of the mouse model for MEN1 in two mouse strains to investigate the effect of different genetic backgrounds and the potential for genetic modifiers on tumour phenotype. The frequency of pituitary and adrenal tumours was significantly influenced by the mouse strain, demonstrating the importance of genetic background on MEN1 tumour occurrence, implicating the role of genetic modifiers. Finally, I investigated the prevalence of MEN1 mutations in a cohort of patients presenting with primary hyperparathyroidism under 40 years of age. This revealed that 6% of under 40 year-olds with apparently sporadic parathyroid tumours have MEN1 mutations, and are likely to present with multiple parathyroid tumours. Pre-operative genetic screening of under 40 year-old patients with multiglandular parathyroid disease may reduce post-operative recurrence of hyperparathyroidism in those patients with MEN1 mutations.This thesis is not currently available via ORA

Investigating the effect of graphene oxide nanosheets on the barrier properties of high density polyethylene coated by layer-by-layer assembly method

Hypothesis: A nanocomposite layer including graphene nanosheets could be used to enhance the barrier properties of high density polyethylene through a layer-by-layer assembly method. Planar graphene nanoparticles help to decrease the gas permeability of polyethylene substrates by making a tortuous pathway for gas molecules transmittance.Methods: Two different methods were used to increase the barrier properties of high density polyethylene and the results were compared with each other. In the first method, a thin film of polymer nanocomposite including graphene oxide nanoparticles and polyvinyl alcohol was coated on the surface of high density polyethylene film using a film applicator. The effective variables in this method were the weight fraction of graphene oxide particles in polyvinyl alcohol and thickness of the nanocomposite layer. In the second method, a layer-by-layer assembly was used. Chitosan solution acted as a positive charge and graphene oxide suspension in water was utilized as a negative charge.Findings: In high density polyethylene samples coated by polyvinyl alcohol nanocomposite (10 micrometers), the oxygen transmittance rate decreased drastically to 3 cm3m2 bar. This decrease was expected due to the structure of polyvinyl alcohol and its inherent barrier properties. By adding graphene oxide into polyvinyl alcohol, the permeability values showed a slight decrease and reached 0.8 cm3 m2 bar.Statistical analysis based on the surface response method for the layer-by-layer method showed that permeability depends on pH, number of bilayers and graphene concentration. At high pH, the graphene oxide sheets take on a smoother and more stretched shape and are more likely to aggregate, which increases permeability

Diagnostic accuracy and prognostic value of lung ultrasound in coronavirus disease (COVID-19)

Purpose: This study aimed to assess the correlation between lung ultrasound (LUS) and computed tomography (CT) findings and the predictability of LUS scores to anticipate disease characteristics, lab data, clinical severity, and mortality in patients with COVID-19. Material and methods: Fifty consecutive hospitalized PCR-confirmed COVID-19 patients who underwent chest CT scan and LUS on the first day of admission were enrolled. The LUS score was calculated based on the presence, severity, and distribution of parenchymal abnormalities in 14 regions. Results: The participants’ mean age was 54.60 ± 19.93 years, and 26 (52%) were female. All patients had CT and LUS findings typical of COVID-19. The mean value of CT and LUS severity scores were 11.80 ± 3.89 (ranging from 2 to 20) and 13.74 ± 6.43 (ranging from 1 to 29), respectively. The LUS score was significantly higher in females (p = 0.016), and patients with dyspnoea (p = 0.048), HTN (p = 0.034), immunodeficiency (p = 0.034), room air SpO2 ≤ 93 (p = 0.02), and pleural effusion (p = 0.036). LUS findings were strongly correlated with CT scan results regarding lesion type, distribution, and severity in a region-by-region fashion (92-100% agreement). An LUS score of 14 or higher was predictive of room air SpO2 ≤ 93 and ICU admission, while an LUS score ≥ 12 was predictive of death (p = 0.011, 0.023, and 0.003, respectively). Conclusions: Our results suggested that LUS can be used as a valuable tool for detecting COVID-19 pneumonia and determining high-risk hospitalized patients, helping to triage and stratify high-risk patients, which waives the need to undertake irradiating chest CT and reduces the burden of overworked CT department staff

Vancomycin Capped with Silver Nanoparticles as an Antibacterial Agent against Multi-Drug Resistance Bacteria

Purpose: Many antimicrobial medications are available to combat infections. However, the indiscriminate use of antibiotics has produced antibiotic resistance in the case of many bacterial pathogens. This study focuses on the development of nanoparticles (NPs) that enhance the in vitro antibiotic activity of vancomycin against multi-drug resistant (MDR) organisms. Methods: Spherical shaped thioglycolic acid-stabilized silver nanoparticles (TGA-AgNPs) were prepared by using a simple chemical reduction method. Then, vancomycin was conjugated to the terminal carboxyl of TGA in the presence of N-Hydroxysuccinimide (NHS) and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC). Afterwards, the antibacterial activity of these nanoconjugates was examined by using the minimum inhibitory concentration (MIC) assay against MDR bacteria. Results: The rate of vancomycin bound to the AgNPs was 19.6%. The MIC values of vancomycin (Van)-capped AgNPs against tested pathogens were in the range of (3.2, 1.6, 0.8, 0.4, 0.2, 0.1, 0.05, and 0.025 µl/ml). The MIC was 0.1 µg/ml for VRE, MIC≤0.02 µg/ml for MRSE, and 0.05 µg/ml for S. aureus. The MIC corresponded to the MBC for all bacterial species. Conclusion: This study indicated that some antimicrobial agents like vancomycin can be conjugated with AgNPs. This can lead to increased antimicrobial activity against MDR microorganisms

The effect of endometrial scratching on reproductive outcomes in infertile women undergoing IVF treatment cycles

This study was a Randomised Controlled Trial aiming to evaluate the effect of Endometrial Scratching (ES) on fertility rate. Participants were primary infertile women undergoing IVF treatment. ES for the intervention group was done using endometrial aspiration in the luteal phase of the cycle before embryo transfer. In both groups, 2–3 8-celled embryos were transferred after endometrial preparation by Oestrogen and Progesterone. There were no significant differences between the two groups in terms of age, BMI and endometrial thickness (ET). No significant differences were found between intervention and control groups in chemical pregnancy rate (p = 0.410), clinical pregnancy (p = 0.822), the number of abortions (p = 0.282) and the implantation rate (p = 0.777). Local ES had no significant effects in improving the IVF success rate and reducing the embryo abortion rate.Impact statement What is already known on this subject? Endometrial scratching (ES) is a local injury to the endometrium that was assumed to affect implantation in IVF and IUI cycles positively. However, various studies have shown conflicting results on this matter. What do the results of this study add? Local ES had no significant effects on improving the IVF success rate and reducing the embryo abortion rate in patients with the first IVF cycle. What are the implications of these findings for clinical practice and/or further research? Larger clinical trials can measure the usefulness of ES with higher powers. However, this study, along with other clinical trials, can help evaluate the ES effect in future meta-analyses