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The Effect of the Zonular Fiber Angle of Insertion on Accommodation
No full textPurpose: With age, there is an anterior shift of the ciliary body in the eye, which alters the angle of zonular insertion in older eyes compared with younger eyes. This study aims to simulate lens accommodation with different zonular angles to consider the influence of zonular position on lens accommodative capacity. Methods: Models were constructed based on lenses aged 11, 29, and 45 years using a 2D axisymmetric structure that included a capsule, cortex, nucleus, and zonular fibers. The different zonular fibers were simulated by changing the position of the point where the zonular fibers connect to the ciliary body. The effect of the different zonular fiber insertion angles on the model shape and optical power was analyzed. Results: The models show that smaller angles made by zonular fibers to the surface of the lens lead to larger optical power changes with simulated stretching. When the models were stretched, and when varying the zonule angles, the optical power of the 11-, 29-, and 45-year-old models changed up to 0.17 D, 0.24 D, and 0.30 D, respectively. The effect of zonular angles on the anterior radius of curvature of the anterior surface varied by 0.29 mm, 0.23 mm, and 0.25 mm for the 11-, 29-, and 45-year-old models, respectively. Conclusions: Larger zonular fiber insertion angles cause smaller deformation and less accommodative change, while parallel zonules induce the largest change in lens shape.</p
Exploring Disulfiram’s Anticancer Potential: PLGA Nano-Carriers for Prolonged Drug Delivery and Potential Improved Therapeutic Efficacy
No full textDisulfiram (DS) has been shown to have potent anti-cancer activity; however, it is also characterised by its low water solubility and rapid metabolism in vivo. Biodegradable polylactic-co-glycolic acid (PLGA) polymers have been frequently employed in the manufacturing of PLGA nano-carrier drug delivery systems. Thus, to develop DS-loaded PLGA nanoparticles (NPs) capable of overcoming DS’s limitations, two methodologies were used to formulate the NPs: direct nanoprecipitation (DNP) and single emulsion/solvent evaporation (SE), followed by particle size reduction. The DNP method was demonstrated to produce NPs of superior characteristics in terms of size (151.3 nm), PDI (0.083), charge (−37.9 mV), and loading efficiency (65.3%). Consequently, NPs consisting of PLGA and encapsulated DS coated with mPEG2k-PLGA at adjustable ratios were prepared using the DNP method. Formulations were then characterised, and their stability in horse serum was assessed. Results revealed the PEGylated DS-loaded PLGA nano-carriers to be more efficient; hence, in-vitro studies testing these formulations were subsequently performed using two distinct breast cancer cell lines, showing great potential to significantly enhance cancer therapy.</p
Resveratrol and female fertility: a systematic review
No full textResveratrol is a natural polyphenolic compound that may have multiple influences on human health, including antiaging, anti-inflammatory, anti-neoplastic, antioxidant, insulin-sensitizing, cardioprotective and vasodilating activities. Growing evidence also suggests a potential positive effect of resveratrol on female fertility. The aim of the present study was to collate and appraise the scientific literature on the relationship between resveratrol and female fertility. We systematically searched Medline, PubMed, Web of Science and Embase from the databases’ inception (1951, 1951, 1947 and 1900, respectively) until 9th May 2024. All in vivo or in vitro retrospective or prospective studies reporting the effects of resveratrol interventions on women’s fertility were included. We ultimately incorporated twenty-four studies into a systematic review with a narrative summary of the results; of those studies, nine were performed on women seeking natural or assisted fertility, and fifteen were in vitro studies performed on human cells and tissues in different stages of the reproductive cascade. The current literature, though limited, suggests that resveratrol may play a role in female infertility. Specifically, it may significantly and positively impact reproductive outcomes, owing to its potential therapeutic effects improving ovarian function. Further studies are now needed to better understand resveratrol’s effects and define the optimal dosage and periods of intake to maximize beneficial effects, as well as to prevent adverse outcomes on implantation, subsequent pregnancy and the fetus.</p
Membrane structures and functional correlates in the bi-segmented eye lens of the cephalopod
No full textThe cephalopod eye lens is unique because it has evolved as a compound structure with two physiologically distinct segments. However, the detailed ultrastructure of this lens and precise optical role of each segment are far from clear. To help elucidate structure–function relationships in the cephalopod lens, we conducted multiple structural investigations on squid. Synchrotron x-ray scattering and transmission electron microscopy disclose that an extensive network of structural features that resemble cell membrane complexes form a substantial component of both anterior and posterior lens segments. Optically, the segments are distinct, however, and Talbot interferometry indicates that the posterior segment possesses a noticeably higher refractive index gradient. We propose that the hitherto unrecognised network of membrane structures in the cephalopod lens has evolved to act as an essential conduit for the internal passage of ions and other metabolic agents through what is otherwise a highly dense structure owing to a very high protein concentration.</p
Temporal changes in smoking prevalence among adolescents across 23 countries
No full textAim: This study aimed to investigate temporal changes in smoking prevalence among adolescents aged 13–15 across 23 countries and to assess individual and country-level factors influencing smoking behaviour.Methods: This study used data from 168 286 young adolescents aged 13–15 years obtained from the Global School-based Student Health, 2003–2021. Linear regression models and meta-analyses were conducted to analyse the changes in current smoking prevalence among young adolescents.Results: Among the 23 countries, smoking prevalence decreased in six countries, including Argentina, Fiji, Jamaica, Samoa, Tonga and Uruguay, while it increased in four countries, namely Guyana, Morocco, Thailand and Vanuatu. The prevalence of smoking was higher among male adolescents at 15.5% (95% CI 13.8%–17.2%) compared to females at 8.0% (95% CI 6.7%–9.3%). Adolescents exposed to secondhand smoke had a prevalence of 16.3% (95% CI 14.5%–18.2%), significantly higher than 4.2% (95% CI 3.7–4.6) in those not exposed. Smoking prevalence was 16.5% (95% CI 14.8%–18.2%) among those with smoking parents or guardians, compared to 8.1% (95% CI 7.1%–9.1%) among those without.Conclusion: The findings highlight the need for tailored tobacco control measures to reduce adolescent smoking globally. Strengthening policy enforcement and addressing social determinants of smoking are critical to achieving further reductions.</p
From data to hope: deep neural network-based prediction of poisoning (DNNPPS) suicide cases
No full textBackground: Suicide is a pressing issue in modern society, causing significant societal and economic consequences. To address and minimize the negative impacts, it is crucial to implement effective prevention strategies. With the rising popularity of deep neural network (DNN) algorithms, they have been utilized in various health sectors. In our research, we examined the effectiveness of DNNs in predicting suicide cases.Methods: In our study, we conducted a descriptive-analytical, cross-sectional investigation using a DNN algorithm with a sequential model consisting of four dense layers to analyze suicide data (DNNPPS). In this study, we utilized a suicide dataset comprising 1,500 data points, which were provided by a health research center.Results: Factors such as history of psychiatric hospitals, days of the week, and job were identified as the most important risk factors for predicting suicide attempts. We obtained promising results by applying the DNNPPS algorithm to a dataset of 1453 individuals with a history of suicide. We approached the problem as a binary classification task, with suicide history as the target variable. We performed preprocessing techniques, including class balancing, and constructed a DNN model using a sequential architecture with four dense layers. Conclusion: It is important to note that the success of the DNN algorithm relies on the quality and quantity of the available data, as well as the model’s architecture. For example, high-quality data should be accurate, representative, and relevant to the problem. In terms of quantity large dataset allows the DNN to learn more features. Nonetheless, in our study, the overall performance of the DNNPPS algorithm was satisfactory. For example, the f1-score value reached 91%, which indicates that the model has a high level of accuracy in predicting the positive class (in this case, suicide cases) and maintains a good balance between precision and recall.</p
Botensilimab, an Fc-Enhanced Anti–CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy
No full textAbstract
Conventional immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) elicit durable survival but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti–CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA coengagement seems critical for activity, potentially explaining the modest clinical benefits of approved anti–CTLA-4 antibodies. We demonstrate that anti–CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T-cell responsiveness, reduce intratumoral regulatory T cells, and enhance antigen-presenting cell activation. Fc-enhanced anti–CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti–CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti–CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment–refractory cancers. Efficacy was independent of tumor neoantigen burden or FCGR3A genotype. However, FCGR2A and FCGR3A expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti–CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy.
Significance:
This study reveals that Fc-enhanced anti–CTLA-4 harnesses novel mechanisms to overcome the limitations of conventional anti–CTLA-4, effectively treating poorly immunogenic and treatment-refractory cancers. Our findings support the development of a new class of immuno-oncology agents, capable of extending clinical benefit to patients with cancers resistant to current immunotherapies
The effectiveness of prolonged downregulation with gonadotrophin-releasing hormone analogue (GnRHa) treatment in women with adenomyosis undergoing IVF/ICSI: A systematic review and meta-analysis
No full textImportance: Adenomyosis can reduce the chance of clinical pregnancy in women undergoing assisted conception. Treatment with prolonged gonadotrophin-releasing hormone analogue (GnRHa) downregulation prior to IVF/ICSI has been postulated to improve pregnancy outcomes. Objective: We aimed to evaluate the effectiveness and safety of prolonged GnRHa treatment (minimum one month) versus no pre-treatment in women with adenomyosis undergoing IVF/ICSI using a systematic review and meta-analysis. Data sources: We searched electronic databases: Embase (OVID), MEDLINE® (OVID), APA PsycInfo (OVID), Maternity & Infant Care Database (MIDIRS (OVID), HMIC Health Management Information Consortium (OVID) and ClinicalTrials.gov from inception until 27th of March 2023. Study selection and synthesis: We included studies that reported on women with adenomyosis receiving GnRHa to down-regulate the hypothalamic-pituitary-ovarian axis for one to six months before IVF/ICSI. We pooled data using the Haensel-Mantel method and reported using Odds Ratio (OR) with 95 % confidence intervals (CI). We assessed the quality of included studies using the Newcastle-Ottowa Scale and confidence in evidence using the GRADE criteria. Bias analysis was conducted via the Cochrane recommended tool (RevMan Web, Academic License). Main outcomes and results: We screened 365 citations and eight retrospective studies were included in the meta-analysis (n = 2422 women). The median age was 34 years [IQR 31.95–35.05], median BMI 21.30 kg/m2 [IQR 21.05–23.55] and median duration of GnRHa downregulation was 2.5 months [Range 1–4; IQR 1.37–3]. Women with adenomyosis receiving prolonged GnRHa treatment had a higher implantation rate 1/OR 1.69 [95 % CI 1.09, 2.56], I2 = 81 %, (P = 0.02) and clinical pregnancy rate 1/OR 1.42 [95 % CI 1.03, 2.0], I2 70 %, P = 0.03. There was no overall difference in live birth rate 1/OR 1.12 [95 % CI 0.70, 1.79], I2 = 78 %, p = 0.63), miscarriage rate 1/OR 0.92 [95 % CI 0.63, 1.28, P = 0.61, I2 0 % or mean number of oocytes retrieved (10 oocytes [IQR 8.95; 11.15] vs. 9.28 [IQR 8; 10.20], p = 0.22) between groups. Conclusions and relevance: The benefit of prolonged GnRHa treatment in women with adenomyosis undergoing assisted conception treatment is uncertain based on existing retrospective studies. Implantation and clinical pregnancy rates were higher following prolonged downregulation in this population, though there was no statistically significant difference in live birth and miscarriage rates. Given the limited, low-quality existing data, there is a need for a well-designed, prospective randomised controlled trial to precisely evaluate the effectiveness of prolonged GnRHa treatment in this population.</p
Demographic characteristics, gambling engagement, mental health, and associations with harmful gambling risk among UK Armed Forces serving personnel
No full textIntroductionHarmful gambling negatively impacts individuals, families and communities. Growing international evidence indicates that the Armed Forces (AF) community may be at a comparatively higher risk of experiencing harm from gambling than the general population. The current study sought to identify general predictors of harmful gambling and gambling engagement among UK AF serving personnel (AFSP).MethodsWe conducted a cross-sectional, exploratory survey to identify associations between demographic factors, mental health, gambling engagement and gambling type in a sample (N=608) of AFSP.ResultsMost of the sample reported past-year gambling, with 23% having experienced harm. Male gender, younger age and lower educational attainment all predicted harmful gambling, as did mental health variables of prior generalised anxiety and post-traumatic stress symptomatology. Strategy-based gambling and online sports betting were also predictive of experiencing harm from gambling.ConclusionsThe risk of harm from gambling is associated with demographic, mental health and gambling engagement variables among AFSP. Better understanding of these predictors is important for the development of individualised treatment approaches for harmful gambling.</p
Mechano-thermochemical preparation of nanostructured 1 (FeCoNiCr/Mn)3O4 high and medium entropy oxides: structural, microstructural, magnetic and Li-ion storage characterization
No full textMechano-thermochemical synthesis of (FeCoNiCrMn)3O4 high-entropy oxide (HEO) and (FeCoNiCr)3O4 medium-entropy oxide (MEO), and their structural, microstructural, magnetic, surface and electrochemical characteristics are investigated. Ball milling substantially reduces crystalline sizes of oxide precursors, causing their partial solid-state dissolution, driving the rapid formation of HEO and MEO during the subsequent thermal treatment. Nanostructured HEO prepared at 900 °C (HEO-900) comprises single-phase octahedral crystals mostly within the range 60–80 nm, while MEO-900 crystals (80–120 nm) exhibit a greater degree of agglomeration. The contribution of oxygen vacancies to total surface oxygen in MEO-900 (20.6 %) is lower than that of HEO-900 (27.6 %). HEO-900 exhibits a superior reversible Li-ion storage capacity of 1050.6 mAh/g after 300 cycles at 100 mA/g, outperforming MEO-900. However, at the higher current density of 500 mA/g, MEO-900 shows superior performance, with a reversible capacity of 432.2 mAh/g (70.3 % retention) after 750 cycles. The charge transfer resistance of fresh HEO-900 (359.0 Ω) is greater than that of MEO-900 (241.4 Ω), and the average Li-ion diffusion coefficient in HEO-900 (10-13.3 cm2 s−1) is lower than that on MEO-900 at (10-13.1 cm2 s−1) due to the greater structural complexity of the former. Full cells incorporating HEO-900 and MEO-900 anodes with LiFePO4 cathode demonstrate an energy density of 296.4 and 274.6 Wh kg−1, respectively. The saturation magnetization of HEO-900 and MEO-900 is significantly high at 33.98 and 33.80 emu/g, respectively, enabling the easy magnetic recovery of electrodes made from these compounds in spent LIBs. </p
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