bluuebunny/crossref_metadata_2025 huggingface dataset:
Replicates Number for Drug Stability Testing during Bioanalytical Method Validation—An Experimental and Retrospective Approach
Authors: Gniazdowska Elżbieta , Goch Wojciech , Giebułtowicz Joanna , Rudzki Piotr J.
Published: January 2022

Background: The stability of a drug or metabolites in biological matrices is an essential part of bioanalytical method validation, but the justification of its sample size (replicates number) is insufficient. The international guidelines differ in recommended sample size to study stability from no recommendation to at least three quality control samples. Testing of three samples may lead to results biased by a single outlier. We aimed to evaluate the optimal sample size for stability testing based on 90% confidence intervals. Methods: We conducted the experimental, retrospective (264 confidence intervals for the stability of nine drugs during regulatory bioanalytical method validation), and theoretical (mathematical) studies. We generated experimental stability data (40 confidence intervals) for two analytes—tramadol and its major metabolite (O-desmethyl-tramadol)—in two concentrations, two storage conditions, and in five sample sizes (n = 3, 4, 5, 6, or 8). Results: The 90% confidence intervals were wider for low than for high concentrations in 18 out of 20 cases. For n = 5 each stability test passed, and the width of the confidence intervals was below 20%. The results of the retrospective study and the theoretical analysis supported the experimental observations that five or six repetitions ensure that confidence intervals fall within 85–115% acceptance criteria. Conclusions: Five repetitions are optimal for the assessment of analyte stability. We hope to initiate discussion and stimulate further research on the sample size for stability testing.
Insulin Complexation with Cyclodextrins—A Molecular Modeling Approach
Authors: Bucur Pálma , Fülöp Ibolya , Sipos Emese
Published: January 2022

Around 5% of the population of the world is affected with the disease called diabetes mellitus. The main medication of the diabetes is the insulin; the active form is the insulin monomer, which is an instable molecule, because the long storage time, or the high temperature, can cause the monomer insulin to adapt an alternative fold, rich in β-sheets, which is pharmaceutically inactive. The aim of this study is to form different insulin complexes with all the cyclodextrin used for pharmaceutical excipients (native cyclodextrin, methyl, hydroxyethyl, hydroxypropyl and sulfobutylether substituted β-cyclodextrin), in silico condition, with the AutoDock molecular modeling program, to determine the best type of cyclodextrin or cyclodextrin derivate to form a complex with an insulin monomer, to predict the molar ratio, the conformation of the complex, and the intermolecular hydrogen bonds formed between the cyclodextrin and the insulin. From the results calculated by the AutoDock program it can be predicted that insulin can make a stable complex with 5–7 molecules of hydroxypropyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin, and by forming a complex potentially can prevent or delay the amyloid fibrillation of the insulin and increase the stability of the molecule.
Synthesis and Biological Investigation of Bile Acid-Paclitaxel Hybrids
Authors: Melloni Elisabetta , Marchesi Elena , Preti Lorenzo , Casciano Fabio , Rimondi Erika , Romani Arianna , Secchiero Paola , Navacchia Maria Luisa , Perrone Daniela
Published: January 2022

Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line.
Photoinitiated Multicomponent Anti-Markovnikov Alkoxylation over Graphene Oxide
Authors: Nie Liang , Peng Xiangjun , He Haiping , Hu Jian , Yao Zhiyang , Zhou Linyi , Yang Ming , Li Fan , Huang Qing , Liu Liangxian
Published: January 2022

The development of graphene oxide–based heterogeneous materials with an economical and environmentally–friendly manner has the potential to facilitate many important organic transformations but proves to have few relevant reported reactions. Herein, we explore the synergistic role of catalytic systems driven by graphene oxide and visible light that form nucleophilic alkoxyl radical intermediates, which enable an anti-Markovnikov addition exclusively to the terminal alkenes, and then the produced benzyl radicals are subsequently added with N–methylquinoxalones. This photoinduced cascade radical difunctionalization of olefins offers a concise and applicable protocol for constructing alkoxyl–substituted N–methylquinoxalones.
Defect-Induced π-Magnetism into Non-Benzenoid Nanographenes
Authors: Biswas Kalyan , Yang Lin , Ma Ji , Sánchez-Grande Ana , Chen Qifan , Lauwaet Koen , Gallego José M. , Miranda Rodolfo , Écija David , Jelínek Pavel , Feng Xinliang , Urgel José I.
Published: January 2022

The synthesis of nanographenes (NGs) with open-shell ground states have recently attained increasing attention in view of their interesting physicochemical properties and great prospects in manifold applications as suitable materials within the rising field of carbon-based magnetism. A potential route to induce magnetism in NGs is the introduction of structural defects, for instance non-benzenoid rings, in their honeycomb lattice. Here, we report the on-surface synthesis of three open-shell non-benzenoid NGs (A1, A2 and A3) on the Au(111) surface. A1 and A2 contain two five- and one seven-membered rings within their benzenoid backbone, while A3 incorporates one five-membered ring. Their structures and electronic properties have been investigated by means of scanning tunneling microscopy, noncontact atomic force microscopy and scanning tunneling spectroscopy complemented with theoretical calculations. Our results provide access to open-shell NGs with a combination of non-benzenoid topologies previously precluded by conventional synthetic procedures.
Advances in Laser Drilling of Structural Ceramics
Authors: Jia Xianshi , Chen Yongqian , Liu Lei , Wang Cong , Duan Ji’an
Published: January 2022

The high-quality, high-efficiency micro-hole drilling of structural ceramics to improve the thermal conductivity of hot-end parts or achieve high-density electronic packaging is still a technical challenge for conventional processing techniques. Recently, the laser drilling method (LDM) has become the preferred processing tool for structural ceramics, and it plays an irreplaceable role in the industrialized processing of group holes on structural ceramic surfaces. A variety of LDMs such as long pulsed laser drilling, short pulsed laser drilling, ultrafast pulsed laser drilling, liquid-assisted laser drilling, combined pulse laser drilling have been developed to achieved high-quality and high-efficiency micro-hole drilling through controlling the laser–matter interaction. This article reviews the characteristics of different LDMs and systematically compares the morphology, diameter, circularity, taper angle, cross-section, heat affect zone, recast layer, cracks, roughness, micro–nano structure, photothermal effect and photochemical reaction of the drilling. Additionally, exactly what processing parameters and ambient environments are optimal for precise and efficient laser drilling and their recent advancements were analyzed. Finally, a summary and outlook of the LDM technology are also highlighted.
Stability and Free Radical Production for CO2 and H2 in Air Nanobubbles in Ethanol Aqueous Solution
Authors: Han Zhenyao , Kurokawa Hiromi , Matsui Hirofumi , He Chunlin , Wang Kaituo , Wei Yuezou , Dodbiba Gjergj , Otsuki Akira , Fujita Toyohisa
Published: January 2022

In this study, 8% hydrogen (H2) in argon (Ar) and carbon dioxide (CO2) gas nanobubbles was produced at 10, 30, and 50 vol.% of ethanol aqueous solution by the high-speed agitation method with gas. They became stable for a long period (for instance, 20 days), having a high negative zeta potential (−40 to −50 mV) at alkaline near pH 9, especially for 10 vol.% of ethanol aqueous solution. The extended Derjaguin, Landau, Verwey, and Overbeek (DLVO) theory was used to evaluate the nanobubble stability. When the nanobubble in ethanol alkaline aqueous solution changed to an acidic pH of around 5, the zeta potential of nanobubbles was almost zero and the decrease in the number of nanobubbles was identified by the particle trajectory method (Nano site). The collapsed nanobubbles at zero charge were detected thanks to the presence of few free radicals using G-CYPMPO spin trap reagent in electron spin resonance (ESR) spectroscopy. The free radicals produced were superoxide anions at collapsed 8%H2 in Ar nanobubbles and hydroxyl radicals at collapsed CO2 nanobubbles. On the other hand, the collapse of mixed CO2 and H2 in Ar nanobubble showed no free radicals. The possible presence of long-term stable nanobubbles and the absence of free radicals for mixed H2 and CO2 nanobubble would be useful to understand the beverage quality.
Long Non-Coding RNAs as Emerging Regulators of Pathogen Response in Plants
Authors: Sharma Yashraaj , Sharma Alok , Madhu  , Shumayla  , Singh Kashmir , Upadhyay Santosh Kumar
Published: January 2022

Long non-coding RNAs (lncRNAs) are transcripts without protein-coding potential that contain more than 200 nucleotides that play important roles in plant survival in response to different stresses. They interact with molecules such as DNA, RNA, and protein, and play roles in the regulation of chromatin remodeling, RNA metabolism, and protein modification activities. These lncRNAs regulate the expression of their downstream targets through epigenetic changes, at the level of transcription and post-transcription. Emerging information from computational biology and functional characterization of some of them has revealed their diverse mechanisms of action and possible roles in biological processes such as flowering time, reproductive organ development, as well as biotic and abiotic stress responses. In this review, we have mainly focused on the role of lncRNAs in biotic stress response due to the limited availability of knowledge in this domain. We have discussed the available molecular mechanisms of certain known lncRNAs against specific pathogens. Further, considering that fungal, viral, and bacterial diseases are major factors in the global food crisis, we have highlighted the importance of lncRNAs against pathogen responses and the progress in plant research to develop a better understanding of their functions and molecular mechanisms.
Secreted Non-Coding RNAs: Functional Impact on the Tumor Microenvironment and Clinical Relevance in Triple-Negative Breast Cancer
Authors: Di Agostino Silvia , Vahabi Mahrou , Turco Chiara , Fontemaggi Giulia
Published: January 2022

Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma characterized by poor prognosis and high rate of metastasis. Current treatment is based on chemo- and/or radiotherapy and surgery. TNBC is devoid of estrogen, progesterone and HER2 receptors. Although precision medicine has come a long way to ameliorate breast cancer disease management, targeted therapies for the treatment of TNBC patients are still limited. Mounting evidence has shown that non-coding RNAs (ncRNAs) drive many oncogenic processes at the basis of increased proliferation, invasion and angiogenesis in TNBC, strongly contributing to tumor progression and resistance to treatments. Many of these ncRNAs are secreted in the tumor microenvironment (TME) and impinge on the activity of the diverse immune and stromal cell types infiltrating the TME. Importantly, secreted ncRNAs may be detected as circulating molecules in serum/plasma from cancer patients and are emerging a promising diagnostic/therapeutic tools in TNBC. This review aims to discuss novel insights about the role of secreted circulating ncRNAs in the intercellular communication in the tumor microenvironment and their potential clinical use as diagnostic and prognostic non-invasive biomarkers in TNBC.
Ibrutinib in Refractory or Relapsing Primary Central Nervous System Lymphoma: A Systematic Review
Authors: Nepal Gaurav , Khurana Mahika , Bucheli Domenica Herrera , Bhandari Siddhartha , Joshi Utsav , Bhagat Riwaj , Rehrig Jessica Holly , Pudasainee Prasun , Shing Yow Ka , Ortiz Juan Fernando , Ojha Rajeev , Gajurel Bikram Prasad , Quinonez Jonathan , Ruxmohan Samir , Albert Trevine , Licata Steven , Stien Joel
Published: January 2022

Primary Central Nervous System Lymphoma (PCNSL) is a rare variant of Non-Hodgkin Lymphoma (NHL) representing 1–2% of all NHL cases. PCNSL is defined as a lymphoma that occurs in the brain, spinal cord, leptomeninges, or eyes. Efforts to treat PCNSL by traditional chemotherapy and radiotherapy have generally been unsuccessful as a significant proportion of patients have frequent relapses or are refractory to treatment. The prognosis of patients with Refractory or Relapsed (R/R) PCNSL is abysmal. The optimal treatment for R/R PCNSL is poorly defined as there are only a limited number of studies in this setting. Several studies have recently shown that ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, has promising results in the treatment of R/R PCNSL. However, these are preliminary studies with a limited sample size. In this systematic review, we explored and critically appraised the evidence about the efficacy of the novel agent ibrutinib in treating R/R PCNSL.
Illustration of the Importance of Adjustment for within- and between-Person Variability in Dietary Intake Surveys for Assessment of Population Risk of Micronutrient Deficiency/Excess Using an Example Data Set
Authors: Nel Johanna H. , Steyn Nelia P. , Senekal Marjanne
Published: January 2022

Nutrition intervention decisions should be evidence based. Single 24-h recalls are often used for measuring dietary intake in large dietary studies. However, this method does not consider the day-to-day variation in populations’ diets. We illustrate the importance of adjustment of single 24-h recall data to remove within-person variation using the National Cancer Institute method to calculate usual intake when estimating risk of deficiency/excess. We used an example data set comprising a single 24-h recall in a total sample of 1326 1–<10-year-old children, and two additional recalls in a sub-sample of 11%, for these purposes. Results show that risk of deficiency was materially overestimated by the single unadjusted 24-h recall for vitamins B12, A, D, C and E, while risk of excess was overestimated for vitamin A and zinc, when compared to risks derived from usual intake. Food sources rich in particular micronutrients seemed to result in overestimation of deficiency risk when intra-individual variance is not removed. Our example illustrates that the application of the NCI method in dietary surveys would contribute to the formulation of more appropriate conclusions on risk of deficiency/excess in populations to advise public health nutrition initiatives when compared to those derived from a single unadjusted 24-h recall.
Tryptophan Metabolism Is Associated with BMI and Adipose Tissue Mass and Linked to Metabolic Disease in Pediatric Obesity
Authors: Lischka Julia , Schanzer Andrea , Baumgartner Margot , de Gier Charlotte , Greber-Platzer Susanne , Zeyda Maximilian
Published: January 2022

The obesity epidemic has contributed to an escalating prevalence of metabolic diseases in children. Overnutrition leads to increased tryptophan uptake and availability. An association between the induction of the tryptophan catabolic pathway via indoleamine 2,3-dioxygenase (IDO) activity and obesity-related inflammation has been observed. This study aimed to investigate the impact of pediatric obesity on tryptophan metabolism and the potential relationship with metabolic disease. In this prospective cohort study, plasma kynurenine, tryptophan, and serotonin levels were measured by ELISA, and IDO activity was estimated by calculating the kynurenine/tryptophan ratio in a clinically characterized population with severe obesity (BMI ≥ 97th percentile) aged 9 to 19 (n = 125). IDO activity and its product kynurenine correlated with BMI z-score and body fat mass, whereas concentrations of serotonin, the alternative tryptophan metabolite, negatively correlated with these measures of adiposity. Kynurenine and tryptophan, but not serotonin levels, were associated with disturbed glucose metabolism. Tryptophan concentrations negatively correlated with adiponectin and were significantly higher in prediabetes and metabolically unhealthy obesity. In conclusion, BMI and body fat mass were associated with increased tryptophan catabolism via the kynurenine pathway and decreased serotonin production in children and adolescents with severe obesity. The resulting elevated kynurenine levels may contribute to metabolic disease in obesity.
Dietary Quality of Women of Reproductive Age in Low-Income Settings: A Cross-Sectional Study in Kyrgyzstan
Authors: Otunchieva Aiperi , Smanalieva Jamila , Ploeger Angelika
Published: January 2022

Dietary diversity and adequate nutrient intake are essential for conducting a healthy life. However, women in low-income settings often face difficulties in ensuring dietary quality. This research assessed relationships between the dietary diversity, nutrient adequacy, and socio-economic factors among women of reproductive age (WRA) in Kyrgyzstan. A cross-sectional study was undertaken in four locations, including two rural and two urban areas in the north and south of Kyrgyzstan. A survey with pre-coded and open-ended questions was employed during the interviews of 423 WRAs aged 18–49. Data collection was conducted in March–May 2021. The average value body mass index (BMI) of WRA was 24.2 ± 4.6 kg/m2. The dietary diversity score (DDS) was higher among rural women (common language effect size) cles = 0.67, adjusted p < 0.001) in the northern region (cles = 0.61, p < 0.05) who have cropland (cles = 0.60, p < 0.001) and a farm animal (cles = 0.60, p < 0.05). Mean nutrient adequacy ratio (NAR) was below 1 in most micronutrients, whereas thiamine, riboflavin, vitamins B6 and C, folic acid, calcium, and magnesium were even lower than 0.5. Women with a kitchen garden or a cropland had better NAR energy (cles = 0.57), NAR carbohydrate (cles = 0.60), NAR fiber (cles = 0.60), NAR vitamin B1 (cles = 0.53), and NAR folic acid (cles = 0.54). Respondents who receive remittances and a farm animal have better NARs for energy, carbohydrates, fiber, vitamin B1, folic acid, iron, zinc, and mean adequacy ratio for 16 nutrients (MAR 16) than those who do not. Education and income have a negative correlation with dietary quality. This study contributes to the limited literature on the quality of diets in Kyrgyzstan. Hidden hunger and undernutrition are a severe problem among WRA in low-income settings. Recommendations are including study programs in nutrition, teaching households farming practices, and raising awareness on adequate nutrition.
The Role of Bovine and Non-Bovine Milk in Cardiometabolic Health: Should We Raise the “Baa”?
Authors: Penhaligan Jack , Poppitt Sally D. , Miles-Chan Jennifer L.
Published: January 2022

Although causality is yet to be confirmed, a considerable volume of research has explored the relationships between cow milk consumption, type II diabetes, and cardiovascular disease. Contrastingly, it has not been comprehensively examined whether milk of non-bovine origin can provide cardiometabolic protection. This narrative review outlines the marked differences in macronutrient composition, particularly protein and lipid content, and discusses how whole milk product (and individual milk ingredients) from different species could impact cardiometabolic health. There is some data, although primarily from compositional analyses, animal studies, and acute clinical trials, that non-bovine milk (notably sheep and goat milk) could be a viable substitute to cow milk for the maintenance, or enhancement, of cardiometabolic health. With a high content of medium-chain triglycerides, conjugated linoleic acid, leucine, and essential minerals, sheep milk could assist in the prevention of metabolic-related disorders. Similarly, albeit with a lower content of such functional compounds relative to sheep milk, goat and buffalo milk could be plausible counterparts to cow milk. However, the evidence required to generate nutritional recommendations for ‘non-bovine milk’ is currently lacking. Longer-term randomised controlled trials must assess how the bioactive ingredients of different species’ milks collectively influence biomarkers of, and subsequently incidence of, cardiometabolic health.
Interactive Effects of Maternal Vitamin D Status and Socio-Economic Status on the Risk of Spontaneous Abortion: Evidence from Henan Province, China
Authors: Lin Shiqi , Zhang Yuan , Jiang Lifang , Li Jiajia , Chai Jian , Pei Lijun , Shang Xuejun
Published: January 2022

Background: Maternal vitamin D deficiency might generate adverse reproductive outcomes, and socio-economic inequalities in micronutrient-related diseases have often been found. This study aimed to explore the interactive effects of maternal vitamin D status and socio-economic status (SES) on risk of spontaneous abortion. Methods: A population-based case–control study was conducted including 293 women with spontaneous abortion and 498 control women in December 2009 and January, 2010 in Henan Province, China. Information on pregnancy outcomes, maternal demographic, lifestyle and exposure factors and blood samples were collected at the same time. Vitamin D deficiency was defined as 25(OH)D < 20 ng/mL. SES index was constructed with principal component analysis by aggregating women’s and their husbands’ education level and occupation, and household income and expenditure. Interactive effects were assessed on a multiplicative scale with ratio of the odds ratio (ROR). Results: Compared to those with high SES and vitamin D sufficiency, women with vitamin D deficiency and low SES index had an increased risk of spontaneous abortion (aOR: 1.99; 95% CI: 1.23–3.23). The ROR was 2.06 (95% CI: 1.04–4.10), indicating a significant positive multiplicative interaction. Conclusions: Maternal low SES may strengthen the effect of vitamin D deficiency exposure on spontaneous abortion risk in this Chinese population.
Protein Intake among Community-Dwelling Older Adults: The Influence of (Pre-) Motivational Determinants
Authors: Verwijs Marije H. , Haveman-Nies Annemien , Borkent Jos W. , Linschooten Joost O. , Roodenburg Annet J. C. , de Groot Lisette C. P. G. M. , de van der Schueren Marian A. E.
Published: January 2022

An adequate protein intake is important for healthy ageing, yet nearly 50% of Dutch community-dwelling older adults do not meet protein recommendations. This study explores protein intake in relation to eight behavioral determinants (I-Change model) among Dutch community-dwelling older adults. Data were collected through an online questionnaire from October 2019–October 2020. Protein intake was assessed by the Protein Screener 55+, indicating a high/low chance of a low protein intake (<1.0 g/kg body weight/day). The behavioral determinants of cognizance, knowledge, risk perception, perceived cues, attitude, social support, self-efficacy and intention were assessed by evaluating statements on a 7-point Likert scale. A total of 824 Dutch community-dwelling older adults were included, recruited via online newsletters, newspapers and by personal approach. Poisson regression was performed to calculate quartile-based prevalence ratios (PRs). Almost 40% of 824 respondents had a high chance of a low protein intake. Univariate analyses indicated that lower scores for all different behavioral determinants were associated with a higher chance of a low protein intake. Independent associations were observed for knowledge (Q4 OR = 0.71) and social support (Q4 OR = 0.71). Results of this study can be used in future interventions aiming to increase protein intake in which focus should lie on increasing knowledge and social support.
Factors Influencing Implementation, Sustainability and Scalability of Healthy Food Retail Interventions: A Systematic Review of Reviews
Authors: Gupta Adyya , Alston Laura , Needham Cindy , Robinson Ella , Marshall Josephine , Boelsen-Robinson Tara , Blake Miranda R. , Huggins Catherine E. , Peeters Anna
Published: January 2022

The aim of this systematic review of reviews was to synthesise the evidence on factors influencing the implementation, sustainability and scalability of food retail interventions to improve the healthiness of food purchased by consumers. A search strategy to identify reviews published up until June 2020 was applied to four databases. The Risk of Bias in Systematic Review tool was used. Review findings were synthesised narratively using the socio-ecological model. A total of 25 reviews met the inclusion criteria. A number of factors influenced implementation; these included retailers’ and consumers’ knowledge and preferences regarding healthy food; establishing trust and relationships; perceived consumer demand for healthy food; profitability; store infrastructure; organizational support, including resources; and enabling policies that promote health. Few reviews reported on factors influencing sustainability or scalability of the interventions. While there is a large and rapidly growing body of evidence on factors influencing implementation of interventions, more work is needed to identify factors associated with their sustainability and scalability. These findings can be used to develop implementation strategies that consider the multiple levels of influence (individual, intrapersonal and environmental) to better support implementation of healthy food retail interventions.
Beneficial Impact of Pork Dry-Cured Ham Consumption on Blood Pressure and Cardiometabolic Markers in Individuals with Cardiovascular Risk
Authors: Montoro-García Silvia , Velasco-Soria Ángeles , Mora Leticia , Carazo-Díaz Carmen , Prieto-Merino David , Avellaneda Antonio , Miranzo Domingo , Casas-Pina Teresa , Toldrá Fidel , Abellán-Alemán José
Published: January 2022

Background: Evidence suggests that bioactive peptides reduce hypertension and affect certain metabolic pathways. Methods: Fifty-four volunteers with stage 1 prehypertension and/or hypercholesterolemia and/or basal glucose >100 mg/dL were recruited and randomized to pork dry-cured ham (n = 35) or cooked ham (placebo group; n = 19) for 28 days. After a wash-out period, meat products were changed for 28 additional days. Bioactive peptides composition and enzyme inhibitory activities of both products were characterized. Treatment comparisons for the main effects were made using a two (treatment) × two (times) repeated measures minus the effect of cooked ham (placebo). Results: 24 h mean systolic and diastolic pressures decreased up to 2.4 mmHg in the dry-cured ham period (treatment effect, p = 0.0382 y p = 0.0233, respectively) as well as the number of systolic pressure measures > 135 mmHg (treatment effect, p = 0.0070). Total cholesterol levels also decreased significantly after dry-cured ham intake (p = 0.049). No significant differences were observed between the two treatments for basal glucose, HOMA-IR index and insulin levels (p > 0.05). However, a significant rise of ghrelin levels was observed (treatment effect, p = 0.0350), while leptin plasma values slightly decreased (treatment effect, p = 0.0628). Conclusions: This study suggested the beneficial effects of regular dry-cured ham consumption on the improvement of systolic/diastolic blood pressures and facilitated the maintenance of metabolic pathways, which may be beneficial in the primary prevention of cardiovascular disease.
Adherence to the Mediterranean Diet among Children and Youth in the Mediterranean Region in Croatia: A Comparative Study
Authors: Matana Antonela , Franić Ivana , Radić Hozo Endica , Burger Ante , Boljat Petra
Published: January 2022

The Mediterranean diet (MD) is considered one of the healthiest dietary patterns. The aim of this study was to assess MD adherence in children and youth living in the Mediterranean region in Croatia and evaluate the differences in adherence to the MD among different educational stages. In total, 2722 individuals aged 2 to 24 years were enrolled in this study. Subjects were divided into different groups according to the Croatian educational system. Mediterranean Diet Quality Index (KIDMED) was used to assess adherence to the MD. In the total sample, the adherence to the MD was poor in 19.2%, average in 60.8%, and good in 20.1% of the study participants. The prevalence rate of poor adherence to the MD increased with higher educational stage, i.e., the highest prevalence rate of poor MD adherence was observed for college students (39.3%). Children having a higher number of snacks on days-off, those with lower physical activity, and not having breakfast together with a family are more likely to have poor MD adherence, while children having a higher number of snacks on working days are less likely to have a poor MD. The results of this study showed low adherence to the principles of the MD, confirming the need for improvement of adherence to the MD pattern in the studied population.
Critical Appraisal of Large Vitamin D Randomized Controlled Trials
Authors: Pilz Stefan , Trummer Christian , Theiler-Schwetz Verena , Grübler Martin R. , Verheyen Nicolas D. , Odler Balazs , Karras Spyridon N. , Zittermann Armin , März Winfried
Published: January 2022

As a consequence of epidemiological studies showing significant associations of vitamin D deficiency with a variety of adverse extra-skeletal clinical outcomes including cardiovascular diseases, cancer, and mortality, large vitamin D randomized controlled trials (RCTs) have been designed and conducted over the last few years. The vast majority of these trials did not restrict their study populations to individuals with vitamin D deficiency, and some even allowed moderate vitamin D supplementation in the placebo groups. In these RCTs, there were no significant effects on the primary outcomes, including cancer, cardiovascular events, and mortality, but explorative outcome analyses and meta-analyses revealed indications for potential benefits such as reductions in cancer mortality or acute respiratory infections. Importantly, data from RCTs with relatively high doses of vitamin D supplementation did, by the vast majority, not show significant safety issues, except for trials in critically or severely ill patients or in those using very high intermittent vitamin D doses. The recent large vitamin D RCTs did not challenge the beneficial effects of vitamin D regarding rickets and osteomalacia, that therefore continue to provide the scientific basis for nutritional vitamin D guidelines and recommendations. There remains a great need to evaluate the effects of vitamin D treatment in populations with vitamin D deficiency or certain characteristics suggesting a high sensitivity to treatment. Outcomes and limitations of recently published large vitamin D RCTs must inform the design of future vitamin D or nutrition trials that should use more personalized approaches.
Low-Glycemic Index Diets as an Intervention in Metabolic Diseases: A Systematic Review and Meta-Analysis
Authors: Ni Chunxiao , Jia Qingqing , Ding Gangqiang , Wu Xifeng , Yang Min
Published: January 2022

We aimed to investigate the effects of a low-glycemic index (GI) diet on the body mass and blood glucose of patients with four common metabolic diseases by conducting a systematic review and meta-analysis of studies comparing a low-GI diet (LGID) and other types of diet. Search terms relating to population, intervention, comparator, outcomes, and study design were used to search three databases: PubMed, Embase, and the Cochrane Library. We identified 24 studies involving 2002 participants. Random-effects models were used for 16 studies in the meta-analysis and stratified analyses were performed according to the duration of the intervention. The systematic review showed that LGIDs slightly reduced body mass and body mass index (BMI) (p < 0.05). BMI improved more substantially after interventions of >24 weeks and there was no inter-study heterogeneity (I2 = 0%, p = 0.48; mean difference (MD) = −2.02, 95% confidence interval (CI): −3.05, −0.98). Overall, an LGID had superior effects to a control diet on fasting blood glucose (FBG) and glycosylated hemoglobin. When the intervention exceeded 30 days, an LGID reduced FBG more substantially (MD = −0.34, 95% CI: −0.55, −0.12). Thus, for patients with metabolic diseases, an LGID is more effective at controlling body mass and blood glucose than a high-GI or other diet.
Prescription, Compliance, and Burden Associated with Salt-Restricted Diets in Heart Failure Patients: Results from the French National OFICSel Observatory
Authors: Damy Thibaud , Benedyga Véronique , Pezel Théo , Berthelot Emmanuelle , Gauthier Jacques , Habib Gilbert , Iliou Marie-Christine , Aupetit Jean-François , Baudry Guillaume , De Groote Pascal , Logeart Damien , Chaufourier Laure , Ciobotaru Vlad , Pousset Françoise , Beauvais Florence , Bauer Fabrice , Zores Florian , Lairez Olivier , Richard Kevin , Hittinger Luc , Teiger Emmanuel , Taieb Charles , Audureau Etienne
Published: January 2022

(1) Background: There is much debate about the use of salt-restricted diet for managing heart failure (HF). Dietary guidelines are inconsistent and lack evidence. (2) Method: The OFICSel observatory collected data about adults hospitalised for HF. The data, collected using study-specific surveys, were used to describe HF management, including diets, from the cardiologists’ and patients’ perspectives. Cardiologists provided the patients’ clinical, biological, echocardiography, and treatment data, while the patients provided dietary, medical history, sociodemographic, morphometric, quality of life, and burden data (burden scale in restricted diets (BIRD) questionnaire). The differences between the diet recommended by the cardiologist, understood by the patient, and the estimated salt intake (by the patient) and diet burden were assessed. (3) Results: Between March and June 2017, 300 cardiologists enrolled 2822 patients. Most patients (90%) were recommended diets with <6 g of salt/day. Mean daily salt consumption was 4.7 g (standard deviation (SD): 2.4). Only 33% of patients complied with their recommended diet, 34% over-complied, and 19% under-complied (14% unknown). Dietary restrictions in HF patients were associated with increased burden (mean BIRD score of 8.1/48 [SD: 8.8]). (4) Conclusion: Healthcare professionals do not always follow dietary recommendations, and their patients do not always understand and comply with diets recommended. Restrictive diets in HF patients are associated with increased burden. An evidence-based approach to developing and recommending HF-specific diets is required.
Prebiotic Galacto-Oligosaccharides Impact Stool Frequency and Fecal Microbiota in Self-Reported Constipated Adults: A Randomized Clinical Trial
Authors: Schoemaker Marieke H. , Hageman Jeske H. J. , ten Haaf Dominique , Hartog Anita , Scholtens Petra A. M. J. , Boekhorst Jos , Nauta Arjen , Bos Rolf
Published: January 2022

Constipation is a major issue for 10–20% of the global population. In a double-blind randomized placebo-controlled clinical trial, we aimed to determine a dose-response effect of galacto-oligosaccharides (GOS) on stool characteristics and fecal microbiota in 132 adults with self-reported constipation according to Rome IV criteria (including less than three bowel movements per week). Subjects (94% females, aged: 18–59 years) received either 11 g or 5.5 g of BiotisTM GOS, or a control product, once daily for three weeks. Validated questionnaires were conducted weekly to study primarily stool frequency and secondary stool consistency. At base- and endline, stool samples were taken to study fecal microbiota. A trend towards an increased stool frequency was observed after the intervention with 11 g of GOS compared to control. While during screening everybody was considered constipated, not all subjects (n = 78) had less than three bowel movements per week at baseline. In total, 11 g of GOS increased stool frequency compared to control in subjects with a low stool frequency at baseline (≤3 bowel movements per week) and in self-reported constipated adults 35 years of age or older. A clear dose-response of GOS was seen on fecal Bifidobacterium, and 11 g of GOS significantly increased Anaerostipes hadrus. In conclusion, GOS seems to be a solution to benefit adults with a low stool frequency and middle-aged adults with self-reported constipation.
The Periodontopathic Pathogen, Porphyromonas gingivalis, Involves a Gut Inflammatory Response and Exacerbates Inflammatory Bowel Disease
Authors: Lee Yu-Chen , Liu Chih-Yi , Lee Chia-Long , Zhang Ruo-Han , Huang Chi-Jung , Yen Ting-Lin
Published: January 2022

Periodontal disease (PD) is one of the most prevalent disorders globally and is strongly associated with many other diseases. Inflammatory bowel disease (IBD), an inflammatory condition of the colon and the small intestine, is reported to be associated with PD through undetermined mechanisms. We analyzed taxonomic assignment files from the Crohn’s Disease Viral and Microbial Metagenome Project (PRJEB3206). The abundance of Porphyromonadaceae in fecal samples was significantly different between patients with Crohn’s disease and control volunteers. Dextran sulfate sodium was used to induce colitis in mice to reveal the effect of this periodontopathic pathogen in vivo. After intrarectal implantation of Porphyromonas gingivalis (Pg)—the primary pathogen causing PD—the disease activity index score, colonic epithelial loss, and inflammatory cell infiltration were intensified. In addition, tumor necrosis factor-α and interleukin-6 showed the highest levels in Pg-infected colons. This revealed the importance of Pg in the exacerbation of IBD. Thus, simultaneous treatment of PD should be considered for people with IBD. Moreover, implantation of Pg in the rectum worsened the clinical symptoms of colitis in mice. Because Pg participates in the pathogenesis of IBD, reducing the chances of it entering the intestine might prevent the worsening of this disorder.
Utility of Three-Dimensional Printing for Preoperative Assessment of Children with Extra-Cranial Solid Tumors: A Systematic Review
Authors: Anand Sachit , Krishnan Nellai , Goel Prabudh , Dhua Anjan Kumar , Jain Vishesh , Yadav Devendra Kumar , Bajpai Minu
Published: January 2022

Background: In cases with solid tumors, preoperative radiological investigations provide valuable information on the anatomy of the tumor and the adjoining structures, thus helping in operative planning. However, due to a two-dimensional view in these investigations, a detailed spatial relationship is difficult to decipher. In contrast, three-dimensional (3D) printing technology provides a precise topographic view to perform safe surgical resections of these tumors. This systematic review aimed to summarize and analyze current evidence on the utility of 3D printing in pediatric extra-cranial solid tumors. Methods: The present study was registered on PROSPERO—international prospective register of systematic reviews (registration number: CRD42020206022). PubMed, Embase, SCOPUS, and Google Scholar databases were explored with appropriate search criteria to select the relevant studies. Data were extracted to study the bibliographic information of each article, the number of patients in each study, age of the patient(s), type of tumor, organ of involvement, application of 3D printing (surgical planning, training, and/or parental education). The details of 3D printing, such as type of imaging used, software details, printing technique, printing material, and cost were also synthesized. Results: Eight studies were finally included in the systematic review. Three-dimensional printing technology was used in thirty children with Wilms tumor (n = 13), neuroblastoma (n = 7), hepatic tumors (n = 8), retroperitoneal tumor (n = 1), and synovial sarcoma (n = 1). Among the included studies, the technology was utilized for preoperative surgical planning (five studies), improved understanding of the surgical anatomy of solid organs (two studies), and improving the parental understanding of the tumor and its management (one study). Computed tomography and magnetic resonance imaging were either performed alone or in combination for radiological evaluation in these children. Different types of printers and printing materials were used in the included studies. The cost of the 3D printed models and time involved (range 10 h to 4–5 days) were reported by two studies each. Conclusions: 3D printed models can be of great assistance to pediatric surgeons in understanding the spatial relationships of tumors with the adjacent anatomic structures. They also facilitate the understanding of families, improving doctor–patient communication.
Ten Years of Experience Support Pharmacogenetic Testing to Guide Individualized Drug Therapy
Authors: Peña-Martín María Celsa , García-Berrocal Belén , Sánchez-Martín Almudena , Marcos-Vadillo Elena , García-Salgado María Jesús , Sánchez Santiago , Lorenzo Carolina , González-Parra David , Sans Francisco , Franco Manuel , Gaedigk Andrea , Mateos-Sexmero María José , Sanz Catalina , Isidoro-García María
Published: January 2022

Precision medicine utilizing the genetic information of genes involved in the metabolism and disposition of drugs can not only improve drug efficacy but also prevent or minimize adverse events. Polypharmacy is common among multimorbid patients and is associated with increased adverse events. One of the main objectives in health care is safe and efficacious drug therapy, which is directly correlated to the individual response to treatment. Precision medicine can increase drug safety in many scenarios, including polypharmacy. In this report, we share our experience utilizing precision medicine over the past ten years. Based on our experience using pharmacogenetic (PGx)-informed prescribing, we implemented a five-step precision medicine protocol (5SPM) that includes the assessment of the biological–clinical characteristics of the patient, current and past prescription history, and the patient’s PGx test results. To illustrate our approach, we present cases highlighting the clinical relevance of precision medicine with a focus on patients with a complex history and polypharmacy.
Efficient Treatment of Rheumatoid Arthritis by Degradable LPCE Nano-Conjugate-Delivered p65 siRNA
Authors: Chen Xiaohua , Zhou Bailing , Gao Yan , Wang Kaiyu , Wu Jieping , Shuai Ming , Men Ke , Duan Xingmei
Published: January 2022

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases worldwide, causing severe cartilage damage and disability. Despite the recent progress made in RA treatment, limitations remain in achieving early and efficient therapeutic intervention. Advanced therapeutic strategies are in high demand, and siRNA-based therapeutic technology with a gene-silencing ability represents a new approach for RA treatment. In this study, we created a cationic delivery micelle consisting of low-molecular-weight (LMW) polyethylenimine (PEI)–cholesterol–polyethylene glycol (PEG) (LPCE) for small interfering RNA (siRNA)-based RA gene therapy. The carrier is based on LMW PEI and modified with cholesterol and PEG. With these two modifications, the LPCE micelle becomes multifunctional, and it efficiently delivered siRNA to macrophages with a high efficiency greater than 70%. The synthesized LPCE exhibits strong siRNA protection ability and high safety. By delivering nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 siRNA, the p65 siRNA/LPCE complex efficiently inhibited macrophage-based cytokine release in vitro. Local administration of the p65 siRNA/LPCE complex exhibited a fast and potent anti-inflammatory effect against RA in a mouse model. According to the results of this study, the functionalized LPCE micelle that we prepared has potential gene therapeutic implications for RA.
Superparamagnetic Iron Oxide Nanoparticles Decorated Mesoporous Silica Nanosystem for Combined Antibiofilm Therapy
Authors: Álvarez Elena , Estévez Manuel , Gallo-Cordova Alvaro , González Blanca , Castillo Rafael R. , Morales María del Puerto , Colilla Montserrat , Izquierdo-Barba Isabel , Vallet-Regí María
Published: January 2022

A crucial challenge to face in the treatment of biofilm-associated infection is the ability of bacteria to develop resistance to traditional antimicrobial therapies based on the administration of antibiotics alone. This study aims to apply magnetic hyperthermia together with controlled antibiotic delivery from a unique magnetic-responsive nanocarrier for a combination therapy against biofilm. The design of the nanosystem is based on antibiotic-loaded mesoporous silica nanoparticles (MSNs) externally functionalized with a thermo-responsive polymer capping layer, and decorated in the outermost surface with superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs are able to generate heat upon application of an alternating magnetic field (AMF), reaching the temperature needed to induce a change in the polymer conformation from linear to globular, therefore triggering pore uncapping and the antibiotic cargo release. The microbiological assays indicated that exposure of E. coli biofilms to 200 µg/mL of the nanosystem and the application of an AMF (202 kHz, 30 mT) decreased the number of viable bacteria by 4 log10 units compared with the control. The results of the present study show that combined hyperthermia and antibiotic treatment is a promising approach for the effective management of biofilm-associated infections.