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The tolerability of oral iron supplementation for the treatment of iron deficiency anemia is disputed. Our aim was to quantify the odds of GI side-effects in adults related to current gold standard oral iron therapy, namely ferrous sulfate. Systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating GI side-effects that included ferrous sulfate and a comparator that was either placebo or intravenous (i.v.) iron. Random effects meta-analysis modelling was undertaken and study heterogeneity was summarised using I2 statistics. Forty three trials comprising 6831 adult participants were included. Twenty trials (n = 3168) had a placebo arm and twenty three trials (n = 3663) had an active comparator arm of i.v. iron. Ferrous sulfate supplementation significantly increased risk of GI side-effects versus placebo with an odds ratio (OR) of 2.32 [95% CI 1.74-3.08, p<0.0001, I2 = 53.6%] and versus i.v. iron with an OR of 3.05 [95% CI 2.07-4.48, p<0.0001, I2 = 41.6%]. Subgroup analysis in IBD patients showed a similar effect versus i.v. iron (OR = 3.14, 95% CI 1.34-7.36, p = 0.008, I2 = 0%). Likewise, subgroup analysis of pooled data from 7 RCTs in pregnant women (n = 1028) showed a statistically significant increased risk of GI side-effects for ferrous sulfate although there was marked heterogeneity in the data (OR = 3.33, 95% CI 1.19-9.28, p = 0.02, I2 = 66.1%). Meta-regression did not provide significant evidence of an association between the study OR and the iron dose. Our meta-analysis confirms that ferrous sulfate is associated with a significant increase in gastrointestinal-specific side-effects but does not find a relationship with dose.

Notably, real problems are increasingly complex and require sophisticated models and algorithms capable of quickly dealing with large data sets and finding optimal solutions. However, there is no perfect method or algorithm; all of them have some limitations that can be mitigated or eliminated by combining the skills of different methodologies. In this way, it is expected to develop hybrid algorithms that can take advantage of the potential and particularities of each method (optimization and machine learning) to integrate methodologies and make them more efficient. This paper presents an extensive systematic and bibliometric literature review on hybrid methods involving optimization and machine learning techniques for clustering and classification. It aims to identify the potential of methods and algorithms to overcome the difficulties of one or both methodologies when combined. After the description of optimization and machine learning methods, a numerical overview of the works published since 1970 is presented. Moreover, an in-depth state-of-art review over the last three years is presented. Furthermore, a SWOT analysis of the ten most cited algorithms of the collected database is performed, investigating the strengths and weaknesses of the pure algorithms and detaching the opportunities and threats that have been explored with hybrid methods. Thus, with this investigation, it was possible to highlight the most notable works and discoveries involving hybrid methods in terms of clustering and classification and also point out the difficulties of the pure methods and algorithms that can be strengthened through the inspirations of other methodologies; they are hybrid methods.

In this open-label, randomized trial in patients newly receiving mechanical ventilatory support for Covid-19–associated ARDS, those who received convalescent plasma had lower 28-day mortality than those who received standard care.

Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8 + T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing. Senescent cells increase with ageing and may cause inflammatory conditions, but how this accumulation is mediated is still unclear. Here the authors show that senescent cells express HLA-E to suppress NKG2A-mediated natural killer and CD8 T cell activation to avoid targeted elimination, while blocking NKG2A helps promote immunity against senescent cells.

This retrospective, comparative, multicenter study aimed to evaluate the real-world outcomes and predictors of failure of Gonioscopy-assisted transluminal trabeculotomy (GATT) at 12 months in glaucoma patients. Predictors of failure of absolute success in bilateral cases (422 eyes of 308 patients) included pre-operative intraocular pressure (IOP; IRR = 1.02; p  = 0.01), and pre-operative mean deviation (IRR = 0.98; p  = 0.007). The significant predictors of failure of relative success included binocularity (IRR = 4.05; p  = 0.001) and pre-operative IOP (IRR = 1.04; p  = 0.022). Only one eye per patient (308 eyes) was included in the second analysis. IOP reduced from 21.84 ± 7.96 mmHg to 11.97 ± 2.89 mmHg at 12 months; the number of hypotensive eye drop medications decreased from 3.07 ± 1.04 to 1.06 ± 1.08 ( p  < 0.001 for both). The pre-operative IOP was a predictive factor for failure of absolute (IRR = 1.02; p  = 0.026) and relative successes (IRR = 1.05; p  = 0.014). The preoperative number of hypotensive medications only affected absolute success (IRR = 1.25; p  = 0.004). The Kaplan–Meier graph revealed relative and absolute success in 88.9% and 43.9% of cases, respectively. In conclusion, GATT is a safe and effective treatment option for diverse forms of open-angle glaucoma with varying severity. Pre-operative number of medications and IOP, race, and the outcomes of the contralateral eye (if applicable) were identified as predictors of failure of the procedure.

Mixotrophic cultivation of microalgae provides a very promising alternative for producing carbohydrate-rich biomass to convert into bioethanol and value-added biocompounds, such as vitamins, pigments, proteins, lipids and antioxidant compounds. Spirulina platensis may present high yields of biomass and carbohydrates when it is grown under mixotrophic conditions using cheese whey. However, there are no previous studies evaluating the influence of this culture system on the profile of fatty acids or antioxidant compounds of this species, which are extremely important for food and pharmaceutical applications and would add value to the cultivation process. S. platensis presented higher specific growth rates, biomass productivity and carbohydrate content under mixotrophic conditions; however, the antioxidant capacity and the protein and lipid content were lower than that of the autotrophic culture. The maximum biomass yield was 2.98 ±0.07 g/L in growth medium with 5.0% whey. The phenolic compound concentration was the same for the biomass obtained under autotrophic and mixotrophic conditions with 2.5% and 5.0% whey. The phenolic compound concentrations showed no significant differences except for that in the growth medium with 10.0% whey, which presented an average value of 22.37±0.14 mg gallic acid/g. Mixotrophic cultivation of S. platensis using whey can be considered a viable alternative to reduce the costs of producing S. platensis biomass and carbohydrates, shorten cultivation time and produce carbohydrates, as it does not require adding expensive chemical nutrients to the growth medium and also takes advantage of cheese whey, an adverse dairy industry byproduct.

Understanding how the gut microbiome confers immune protection in early life remains a fundamental challenge, particularly in high-infection-burden, underrepresented populations. Here, we analyse longitudinal stool microbiome and illness data from 633 Gambian children aged 7–37 months enroled in a randomised, double-blind iron supplementation trial (NCT02941081). The primary endpoint was correction of iron deficiency anaemia, and the secondary endpoint was diarrhoea incidence and other adverse events; IHAT was non-inferior to ferrous sulphate for iron correction and showed fewer moderate-to-severe diarrhoea episodes. Using 16S rRNA sequencing at three timepoints (Days 1, 15, and 85), we find that children who remained infection-free harboured a consistently higher relative abundance of Prevotella stercorea , a keystone taxon of non-industrialised gut ecologies. In contrast, Escherichia coli and other opportunistic pathogens were enriched in children who developed infections. These taxonomic signatures were temporally stable and embedded within distinct, co-occurring microbial networks. Strikingly, higher P. stercorea abundance was inversely associated with both infection frequency and duration, with the greatest differences observed in children aged 1–2 years, potentially explaining their increased infectious risk. Our findings reveal a Prevotella -dominated enterotype associated with reduced infection risk, with implications for vaccine responsiveness, child survival, and microbiota-targeted interventions in global child health. Here, the authors analyze longitudinal stool microbiome and illness data from Gambian children enroled in a randomised, double-blind iron supplementation trial, showing that those who remained infection-free exhibit higher abundance of Prevotella stercorea , while Escherichia coli and other opportunistic pathogens are enriched in those who developed infection.

Iron plays a key role in human immune responses; however, the influence of iron deficiency on the coronavirus disease 2019 (COVID-19) vaccine effectiveness is unclear. To assess the effectiveness of the BNT162b2 messenger RNA COVID-19 vaccine in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19-related hospitalization and death in individuals with or without iron deficiency. This large retrospective, longitudinal cohort study analyzed real-world data from the Maccabi Healthcare Services database (covering 25% of Israeli residents). Eligible adults (aged ≥16 years) received a first BNT162b2 vaccine dose between December 19, 2020, and February 28, 2021, followed by a second dose as per approved vaccine label. Individuals were excluded if they had SARS-CoV-2 infection before vaccination, had hemoglobinopathy, received a cancer diagnosis since January 2020, had been treated with immunosuppressants, or were pregnant at the time of vaccination. Vaccine effectiveness was assessed in terms of incidence rates of SARS-CoV-2 infection confirmed by real-time polymerase chain reaction assay, relative risks of COVID-19-related hospitalization, and mortality in individuals with iron deficiency (ferritin <30 ng/mL or transferrin saturation <20%). The two-dose protection period was Days 7 to 28 after the second vaccination. Data from 184,171 individuals with (mean [standard deviation; SD] age 46.2 [19.6] years; 81.2% female) versus 1,072,019 without (mean [SD] age 46.9 [18.0] years; 46.2% female) known iron deficiency were analyzed. Vaccine effectiveness in the two-dose protection period was 91.9% (95% confidence interval [CI] 83.7-96.0%) and 92.1% (95% CI 84.2-96.1%) for those with versus without iron deficiency (P = 0.96). Of patients with versus without iron deficiency, hospitalizations occurred in 28 and 19 per 100,000 during the reference period (Days 1-7 after the first dose), and in 19 and 7 per 100,000 during the two-dose protection period, respectively. Mortality rates were comparable between study groups: 2.2 per 100,000 (4/181,012) in the population with iron deficiency and 1.8 per 100,000 (19/1,055,298) in those without known iron deficiency. Results suggest that the BNT162b2 COVID-19 vaccine is >90% effective in preventing SARS-CoV-2 infection in the 3 weeks after the second vaccination, irrespective of iron-deficiency status. These findings support the use of the vaccine in populations with iron deficiency.

Aging is associated with profound changes in the human immune system, a phenomenon referred to as immunosenescence. This complex immune remodeling affects the adaptive immune system and the CD8 T cell compartment in particular, leading to the accumulation of terminally differentiated T cells, which can rapidly exert their effector functions at the expenses of a limited proliferative potential. In this review, we will discuss evidence suggesting that senescent αβCD8 T cells acquire the hallmarks of innate-like T cells and use recently acquired NK cell receptors as an alternative mechanism to mediate rapid effector functions. These cells concomitantly lose expression of co-stimulatory receptors and exhibit decreased T cell receptor signaling, suggesting a functional shift away from antigen-specific activation. The convergence of innate and adaptive features in senescent T cells challenges the classic division between innate and adaptive immune systems. Innate-like T cells are particularly important for stress and tumor surveillance, and we propose a new role for these cells in aging, where the acquisition of innate-like functions may represent a beneficial adaptation to an increased burden of malignancy with age, although it may also pose a higher risk of autoimmune disorders.

Sleep is controlled by a cocktail of neurotransmitters, but it is difficult to measure these in the brain. A new study by Tamaki et al. reveals how the balance between excitation and inhibition oscillates as the brain moves through sleep stages and how this impacts upon memory consolidation and stabilization.