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Purpose: To provide a detailed description of the recommended surgical technique for gas injection during Descemet's Membrane Endothelial Keratoplasty (DMEK) surgery and highlight intraoperative sign that emerged in case of fluid retention in the interface., Methods: Gas injection recommended surgical technique is 2 steps procedure using a 1 ml syringe: the first step consists in injecting centrally to the graft and very slowly a bubble of gas smaller than the DMEK graft size, the second step, after checking the absence of fluid interface (no bagel sign), consists in enlarging the gas bubble to the desired filling., Results: Bagel sign allows surgeons to look for interface fluid and correct for potential issues leading to graft detachment. The recommended surgical technique for gas injection also may help to prevent fluid retention in the interface and reduce the risk of graft detachment., Conclusion: Detecting a fluid interface retention at the end of DMEK surgery through iOCT or simply looking for the bagel sign may help to prevent post-operative complications., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The study investigates the impact of the d-lactic acid units content on the crystallinity and crystal structure of commercial poly(lactic acid) (PLA) grades, which are copolymers of poly(l-lactic acid) (PLLA) containing a minor amount of d-units. As the d-units content increases, a detectable decrease in crystallinity was observed along with a simultaneous rise in mobile amorphous fraction (MAF) and a reduction in rigid amorphous fraction (RAF). The percentage of d-units was found not to significantly affect RAF thickness, suggesting that the d-units are not completely excluded from the crystals. The inclusion of d-units as defects in the PLA crystal lattice was confirmed by XRD analysis, which disclosed that the crystal phase gets gradually richer of d-units as the crystallization time evolves. FT-IR analysis proved that the incorporation of d-units in the crystal phase is promoted by the formation of local CH 3 ···O=C interactions, similar to those massively active between PLLA and poly(d-lactic acid) (PDLA) in the stereocomplex. The establishment of these interactions leads to a contraction of the interplanar distances and a decrease in the crystal cell volume with increasing the crystallization time and the d-units percentage. In summary, the study proves that for PLA copolymers containing a d-units percentage at least up to about 8 %, d-units are included in the crystal lattice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The flavonoid chrysin is an effective vascular Ca V 1.2 channel blocker. The aim of this study was to explore the chemical space around chrysin to identify the structural features that can be modified to develop novel and more effective blockers. Four derivatives (Chrysin 1-4) were synthesised and a functional, electrophysiology and molecular docking approach was pursued to assess their binding mode to Ca V 1.2 channels and their activity in vascular preparations. Methylation of the 5- and 7-OH of the chrysin backbone caused a marked reduction of the Ca 2+ antagonistic potency and efficacy. However, C-8 derivatives showed biophysical features similar to those of the parent compound and, like nicardipine, bound with high affinity to and stabilised the Ca V 1.2 channel in its inactivated state. The vasorelaxant effects of the four derivatives appeared vessel-specific, addressing the molecules' derivatization towards different targets. In conclusion, the scaffold of chrysin may be considered a valuable starting point for the development of innovative vascular Ca V 1.2 channel blockers., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Free fatty acid receptor 1 (FFAR1) has emerged as the most targeted isoform of the free fatty acid receptors because of its involvement in the modulation of energy balance and its potential role in the control of inflammatory and pain conditions. Quercetin-3-oleate (AV2), recognized as a new FFAR1 partial agonist, was investigated for its ability to modulate inflammation and nociception. Human immortal neuroblastoma SH and the murine macrophagic RAW 264.7 cells were used to evaluate cell viability, the potential cytoprotective activity, and the anti-inflammatory properties of AV2 in vitro. Paw edema, caused by zymosan-A, and the formalin test were used to assess the in vivo anti-inflammatory and antinociceptive effects in CD-1 mice. In vitro, AV2 was devoid of cytotoxicity, significantly reduced ROS in both cell types, and protected RAW 264.7 cells from lipopolysaccharide damage by reducing tumor necrosis factor-α production. Interestingly, AV2 induced a transient elevation of intracellular calcium that was reduced in cells, pre-incubated with the FFAR1 antagonist DC260126. In vivo, AV2 reduced formalin-induced nociception and zymosan A-induced paw edema, and both effects were reversed by the FFAR1 antagonist GW1100. In conclusion, these data strongly support the AV2-mediated antioxidant, anti-inflammatory, and antinociceptive activity. AV2 represents a promising molecule for the clinical management of inflammatory-related pain conditions.

Mastering of analytical methods for accurate quantitative determinations of enantiomeric excess is a crucial aspect in asymmetric catalysis, chiral synthesis, and pharmaceutical applications. In this context, the phenomenon of Self-Induced Diastereomeric Anisochronism (SIDA) can be exploited in NMR spectroscopy for accurate determinations of enantiomeric composition, without using a chiral auxiliary that could interfere with the spectroscopic investigation. This phenomenon can be particularly useful for improving the quantitative analysis of mixtures with low enantiomeric excesses, where direct integration of signals can be tricky. Here, we describe a novel analysis protocol to correctly determine the enantiomeric composition of scalemic mixtures and investigate the thermodynamic and stereochemical features at the basis of SIDA. Dipeptide derivatives were chosen as substrates for this study, given their central role in drug design. By integrating the experiments with a conformational stochastic search that includes entropic contributions, we provide valuable information on the dimerization thermodynamics, the nature of non-covalent interactions leading to self-association, and the differences in the chemical environment responsible for the anisochronism, highlighting the importance of different stereochemical arrangement and tight association for the distinction between homochiral and heterochiral adducts. An important role played by the counterion was pointed out by computational studies., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

Purpose: To compare the postoperative complications and clinical outcomes of Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping automated endothelial keratoplasty (DSAEK) in eyes with previous glaucoma filtering surgery. Methods: In this retrospective comparative case series, we analysed postoperative visual acuity and intraocular pressure, graft survival, rate of graft detachment and/or dislocation, number of rebubbling and/or graft repositioning procedures, and graft rejection or failure (primary and secondary). Results: Sixteen eyes with DMEK and 80 eyes with DSAEK with previous glaucoma surgery were studied. The results were recorded at 3 and 12 months postoperatively. No statistically significant differences in postoperative visual acuity were found between the two groups at any stage of the follow-up. Intraocular pressure was lower in the DMEK group at the follow-up stage of 3 ( p = 0.0022) and 12 months ( p = 0.0480). Visually significant graft detachment was recorded in 31.3% and 22.5% of DMEK and DSAEK cases, respectively ( p = 0.4541). All DMEK detachments (n = 5) were managed with slit-lamp rebubbling. Out of 18 graft detachments in the DSAEK group, 2 grafts were observed due to small graft detachment, 6 large graft detachments underwent rebubbling performed in the operating theatre, and 10 eyes needed primary graft repositioning for graft dislocation. Conclusions: DMEK is a feasible option to treat endothelial failure in complex eyes with previous glaucoma surgery. In the DMEK group, visual acuity outcomes and possibly postoperative intraocular pressure control were better compared with the DSAEK group.

This exploratory video analysis study aimed to review characteristics of potential head injury situations during a men's professional international football tournament. For 64 matches of the FIFA World Cup Qatar 2022™ FIFA analysts used match footage to record all potential head injury situations. A potential head injury situation was defined as a player staying down for more than 5 s and/or requesting medical attention, and where the body impact location included the player's head. Characteristics were further recorded for match, player (i.e. player action including aerial duels), medical assessment, and outcome (e.g. substitution). Descriptive statistics are reported as well as Pearson's Chi-squared test (or Fisher's exact test) to explore potential head injury situations more likely to result in medical attention. In total, 149 potential head injury situations occurred in 56 matches (mean 2.33/match, range 0-6) involving 117 players. Eight matches resulted in no incidents. Aerial duels were the most frequent match characteristic leading to a potential head injury situation. Injury stoppage with on-pitch medical assessment occurred in 35 of the 149 potential head injury situations (23%), with pitch-side assessment also occurring in 15 situations (10%), resulting in four concussion substitutions. Players were more likely to require medical attention for potential head injuries sustained when the ball was loose (χ 2  = 6.88; p  = 0.038) when the injured player was jumping (FET p  = 0.044) and for head-to-head contact (FET p = <0.001). Further exploration of aerial duels during match play which do and do not lead to potential and actual head injuries is recommended.

The rising demand for healthier alternatives to traditional sugary products has driven the exploration of natural substitutes for sucrose. This study aimed to investigate carob pulp flour (CPF) as a viable alternative to sucrose in the production of high-value jellies with enhanced health benefits. Carob pulp flour was spectroscopically characterized, revealing the presence of bioactive molecules, such as natural antidiabetic polyols and polyphenols. Colorimetric tests demonstrated a significant concentration of polyphenolic molecules in CPF, with a remarkable scavenging activity against radical species in both organic and aqueous environments. Jellies based on CPF (CGC) were successfully prepared and exhibited strong antioxidant activity against ABTS (IC 50 0.158 mg mL -1 ) and DPPH (IC 50 0.175 mg mL -1 ) radicals, maintaining their properties over 15 days, unlike the sucrose-based control, which showed no antioxidant activity. The CPF-enhanced jellies consistently demonstrated higher G' values (in the range 20-35 °C) than the sucrose-based jellies, indicating improved consistency, elasticity, and strong gel properties, even at higher temperatures. Sensory analysis revealed significant differences, with CPF-based jellies displaying enhanced chocolate (2.3 ± 1.0), ripe fruit (2.3 ± 1.8), and caramel odors (2.0 ± 0.9), as well as increased bitterness and astringency, reduced sweetness, and improved texture. Additionally, CPF-based jellies exhibited significant hypoglycemic properties, with dose-dependent inhibitory effects on α-amylase (57.7 %) and α-glucosidase (50.3 %), and a moderate lipase inhibitory effect (48.6 %) at the maximum concentrations tested. The findings of this study highlight the potential of CPF as a functional ingredient in the food industry, offering a healthier alternative to sucrose in jelly production. The inclusion of CPF not only enhances the antioxidant and sensory properties of jellies but also contributes to significant hypoglycemic effects, making it a promising candidate for the development of functional foods with added health benefits., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Donatella Restuccia reports a relationship with Cell Press that includes: board membership. Associate Editor-Food Nutrition Section (Heliyon) If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Carob pulp flour has antidiabetic and antioxidant activities, is naturally sweet, and is rich in fibers. It is obtained from carob pod pulp from the evergreen tree Ceratonia siliqua L., which is grown in Mediterranean areas and is known for locust bean gum production. Despite its valuable effects on health, such as the modulation of the glycemic index, this ingredient has a tremendous impact on technological and hedonic features, mainly on color, flavor, and texture. In this paper, the qualitative features and consumers' acceptance of a carob-based gluten-free bakery product where rice flour was substituted at 40% with carob pulp flour were studied. A panel group of experts described the bread as dark, quite dense, sweet, aromatic, and with a limited bubble dispersion. On the other hand, the sensory assessment and the willingness to pay of consumers were assessed in two groups (a fully informed one about heathy attributes of the food and a blind one). The results indicated a moderate appreciation of the overall quality of the product (average score between 4 and 5 points on a 9-point Likert scale). The information about the food's healthy properties and the ability to maintain a low glycemic index did not enhance the consumers' perception of the product, while previous knowledge and involvement in the product consumption were perceived to have primary importance regarding the final consumers' choice. Finally, an accelerated shelf-life test was run on the packaged snack to evaluate the general quality and stability. The protective packaging helped in limiting bread decay and maintaining the textural characteristics.

Background : The aim of this study was to evaluate the intraoperative complications and visual outcomes of manual deep anterior lamellar keratoplasty (mDALK) in patients who underwent previous radial keratotomy (RK) for myopia. Methods : The notes of patients who underwent mDALK after RK at three different hospitals-San Giovanni Addolorata Hospital (Rome, Italy), Mount Saint Joseph Hospital (Vancouver, Canada), and Tor Vergata University Hospital (Rome, Italy)-were retrospectively reviewed. We analyzed the manual dissection success rate and conversion to penetrating keratoplasty (PK), the residual recipient stromal thickness, the postoperative corrected distance visual acuity (CDVA), postoperative refraction, and topographic astigmatism. Results : Thirteen eyes of eleven patients were included in the analysis (male 7/11, 63.6%). Preoperatively, mean topographic astigmatism was 5.4 ± 3.5 D (range 1.6-14.8 D), and mean CDVA was 0.47 ± 0.2 logMAR (range 0.3-1.0 logMAR) [Snellen equivalent 20/50]. Manual dissection was performed in all cases. None of the examined eyes were converted to PK. An improvement in both topographic astigmatism (2.8 ± 0.9 D, p = 0.0135) and CDVA (0.23 ± 0.2 LogMAR, p = 0.0122) was recorded at 12-month follow-up. Conclusions : mDALK is a safe and effective surgical technique when applied to eyes previously treated with RK, with an observed improvement in CDVA and topographic astigmatism.

Background: Transcranial magnetic stimulation-electroencephalography (TMS-EEG) has demonstrated decreased excitability in the primary motor cortex (M1) and increased excitability in the pre-supplementary motor area (pre-SMA) in moderate-advanced Parkinson's disease (PD)., Objectives: The aim was to investigate whether these abnormalities are evident from the early stages of the disease, their behavioral correlates, and relationship to cortico-subcortical connections., Methods: Twenty-eight early, drug-naive (de novo) PD patients and 28 healthy controls (HCs) underwent TMS-EEG to record TMS-evoked potentials (TEPs) from the primary motor cortex (M1) and the pre-SMA, kinematic recording of finger-tapping movements, and a 3T-MRI (magnetic resonance imaging) scan to obtain diffusion tensor imaging (DTI) reconstruction of white matter (WM) tracts connecting M1 to the ventral lateral anterior thalamic nucleus and pre-SMA to the anterior putamen., Results: We found reduced M1 TEP P30 amplitude in de novo PD patients compared to HCs and similar pre-SMA TEP N40 amplitude between groups. PD patients exhibited smaller amplitude and slower velocity in finger-tapping movements and altered structural integrity in WM tracts of interest, although these changes did not correlate with TEPs., Conclusions: M1 hypoexcitability is a characteristic of PD from early phases and may be a marker of the parkinsonian state. Pre-SMA hyperexcitability is not evident in early PD and possibly emerges at later stages of the disease. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Topic: To provide an overview on the incidence of Acanthamoeba keratitis (AK)., Clinical Relevance: Although being a sight-threatening cause of infectious keratitis, a comprehensive assessment of the incidence of AK is lacking., Methods: Incidence of AK was computed as the number of eyes with AK per health care center, per year (annualized center incidence [ACI]). Two meta-analytical ratios also were calculated: (1) the ratio of eyes with AK to the count of eyes with nonviral microbial keratitis (MK) and (2) the ratio of eyes with AK to the overall population (i.e., the total number of people in a nation or region, as indicated by the authors in each study). Center was defined as the health care facility where the study took place. Actual and projected estimates of the number of eyes with AK in years were calculated multiplying the ratio of eyes with AK to the total population and the corresponding population estimates, sourced from the United Nations Population Prospects., Results: Overall, 105 articles were included, published between 1987 and 2022. The total number of eyes identified was 91 951, with 5660 eyes affected by AK and 86 291 eyes affected by nonviral MK. The median ACI was 1.9 eyes with AK per health care center per year (95% confidence interval [CI], 1.5-2.6 eyes), with no statistically significant differences among continents. The ratio of eyes with AK to the total number of eyes with MK was 1.52% (95% CI, 1.03%-2.22%), whereas the ratio of eyes with AK in relationship to the entire population was estimated at 2.34 eyes per 1 000 000 people (95% CI, 0.98-5.55 per 1 000 000 people). The projected increase in the numbers of eyes with AK indicated an increase of 18.5% (n = 15 355 eyes with AK) in 2053 and 25.5% (n = 16 253 eyes with AK) in 2073, compared with the baseline of 2023 (n = 12 953 eyes with AK)., Discussion: Acanthamoeba keratitis emerged as a relatively low-incident disorder, and no significant differences in terms of its incidence were found among different continents., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Research on the energy metabolism of cancer cells is becoming a central element in oncology, and in recent decades, it has allowed us to better understand the mechanisms underlying the onset and chemoresistance of oncological pathologies. Mitochondrial bioenergetic processes, in particular, have proven to be fundamental for the survival of tumor stem cells (CSC), a subpopulation of tumor cells responsible for tumor recurrence, the onset of metastasis, and the failure of conventional anticancer therapies. Over the years, numerous natural products, in particular flavonoids, widely distributed in the plant kingdom, have been shown to interfere with tumor bioenergetics, demonstrating promising antitumor effects. Herein, the anticancer potential of Licoflavanone, a flavanone isolated from the leaves of G. glabra , was explored for the first time in breast cancer cells. The results obtained highlighted a marked antitumor activity that proved to be greater than that mediated by Glabranin or Pinocembrin, flavanones isolated from the same plant matrix. Furthermore, the investigation of Licoflavanone's effects on breast cancer energy metabolism highlighted the inhibitory activity of this natural product on tumor bioenergetics, a mechanism that could underlie its ability to reduce tumor proliferation, invasiveness, and stemness.

Purpose: This case report delineates the intricacies and challenges encountered in cataract surgery in Ehlers-Danlos syndrome type VI presenting with advanced Keratoglobus (KG), severe cataract and brittle cornea., Observations: Despite meticulous planning and intraoperative precautions, including phacoemulsification with reduced intraocular pressure (low bottle height), the patient experienced corneal ruptures necessitating a shift to Extra Capsular Cataract Extraction (ECCE). Postoperative management involved corneal suturing and vigilant follow-up., Conclusions and Importance: Cataract surgery in patients with brittle cornea poses significant challenges due to extreme corneal fragility. Exhaustive pre-operative assessment, careful intraoperative techniques, and vigilant postoperative care are paramount for successful outcomes in these complex cases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)

Purpose: To describe a new proxy of the Eye Bank (EB) activity named "Eye Bank Efficiency Index" (EBEI), calculated as the ratio between the number of corneal tissues distributed by an EB within a certain time period, and the difference between the number of procured and discarded tissues., Methods: To demonstrate the effectiveness of the new metric as compared to traditional statistics, an analysis was conducted using data from the largest Italian Eye Bank (Fondazione Banca degli Occhi del Veneto Venice, Italy). Collected data included: the number of corneas retrieved, the number of discarded grafts, and the number of distributed tissues. The analysis focused on three defined timeframes: January to December, March to May (the "Italian Lockdown period"), and June to December (the "Italian post-lockdown period")., Results: In 2020, the annual variation of the EBEI showed a significant increase of up to 3.4% compared to the previous year (0.986 in 2019; 1.020 in 2020), but then gradually decreased to 0.993 in 2022. However, during the months of lockdown in 2020, there was a significant decline of -13.8% in the EBEI compared to the same period in the previous year. The variation in the EBEI during the post-lockdown months was minimal in 2020 and 2021, with the lowest EBEI value of 0.976 being reached in 2022 (-7.8% compared to 2019)., Conclusion: The EBEI is a simple and reliable new measure of the EB activity. Its widespread adoption could ensure a more accurate and reliable analysis of EB data for academic, political, and economic purposes., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This study aims to examine and describe the characteristics of potential injury situations during a men's professional international tournament quantified using the FIFA Football Language Medical Coding. A prospective study was conducted during the 64 matches of the FIFA World Cup Qatar 2022™, during which five analysts recorded potential injury situations from video analysis. "Potential injuries" were recorded when players stayed down > 5 s and/or requested medical attention. Characteristics were further recorded for variables such as opponent's action and body location. In total, 720 potential injury situations were recorded of which 139 required medical assessment. The actions which resulted in most potential injuries were running while receiving a pass (74; 10%), while passing the ball (59; 8%), and while progressing with the ball (48; 7%). Duels and ball progression led to a potential injury in 3.0% and 2.1% of all similar actions in total. Both aerial duels and ball progression led to an potential injury that required medical assessment on 0.4% of occasions. Most potential injuries involved the head (149; 21%), foot (120; 17%), or lower leg (110; 15%) with most medical assessments of the head (35; 25%), lower leg (17; 12%), and knee (15; 11%) with a median duration of 47 seconds (IQR 28-61). This study provides a detailed overview of match circumstances that may have a higher injury risk. Although some variables within the coding system need improvement to increase reliability, its use will allow a more detailed comparison of differences between high-risk player actions leading to injury and those that do not, which can improve future prevention strategies.

Background: Genetic and environmental factors are implicated in many developmental processes. Recent evidence, however, has suggested that epigenetic changes may also influence the onset of puberty or the susceptibility to a wide range of diseases later in life. The present study aims to investigate changes in genomic DNA methylation profiles associated with pubertal onset analyzing human peripheral blood leukocytes from three different groups of subjects: 19 girls with central precocious puberty (CPP), 14 healthy prepubertal girls matched by age and 13 healthy pubertal girls matched by pubertal stage. For this purpose, the comparisons were performed between pre- and pubertal controls to identify changes in normal pubertal transition and CPP versus pre- and pubertal controls., Results: Analysis of methylation changes associated with normal pubertal transition identified 1006 differentially methylated CpG sites, 86% of them were found to be hypermethylated in prepubertal controls. Some of these CpG sites reside in genes associated with the age of menarche or transcription factors involved in the process of pubertal development. Analysis of methylome profiles in CPP patients showed 65% and 55% hypomethylated CpG sites compared with prepubertal and pubertal controls, respectively. In addition, interestingly, our results revealed the presence of 43 differentially methylated genes coding for zinc finger (ZNF) proteins. Gene ontology and IPA analysis performed in the three groups studied revealed significant enrichment of them in some pathways related to neuronal communication (semaphorin and gustation pathways), estrogens action, some cancers (particularly breast and ovarian) or metabolism (particularly sirtuin)., Conclusions: The different methylation profiles of girls with normal and precocious puberty indicate that regulation of the pubertal process in humans is associated with specific epigenetic changes. Differentially methylated genes include ZNF genes that may play a role in developmental control. In addition, our data highlight changes in the methylation status of genes involved in signaling pathways that determine the migration and function of GnRH neurons and the onset of metabolic and neoplastic diseases that may be associated with CPP in later life., (© 2024. The Author(s).)

Purpose: MKNR3 is a paternally expressed gene whose mutations are the main cause of central precocious puberty (CPP). Protein circulating levels can be easily measured, as demonstrated in idiopathic CPP and healthy controls. No data are available for patients harboring an MKRN3 mutation. Our aim was to perform MKRN3 mutation screening and to investigate if circulating protein levels could be a screening tool to identify MKRN3 mutation in CPP patients., Methods: We enrolled 140 CPP girls and performed MKRN3 mutation analysis. Patients were stratified into two groups: idiopathic CPP (iCPP) and MKRN3 mutation-related CPP (MKRN3-CPP). Clinical characteristics were collected. Serum MKRN3 values were measured by a commercially available ELISA assay kit in MKRN3-CPP and a subgroup of 15 iCPP patients., Results: We identified 5 patients with MKRN3 mutations: one was a novel mutation (p.Gln352Arg) while the others were previously reported (p.Arg328Cys, p.Arg345Cys, p.Pro160Cysfs*14, p.Cys410Ter). There was a significant difference in circulating MKRN3 values in MKRN3-CPP compared to iCPP (p < 0.001). In MKRN3-CPP, the subject harboring Pro160Cysfs*14 presented undetectable levels. Subjects carrying the missense mutations p.Arg328Cys and p.Gln352Arg showed divergent circulating protein levels, respectively 40.56 pg/mL and undetectable. The patient with the non-sense mutation reported low but measurable MKRN3 levels (12.72 pg/mL)., Conclusions: MKRN3 defect in patients with CPP cannot be predicted by MKRN3 circulating levels, although those patients presented lower protein levels than iCPP. Due to the great inter-individual variability of the assay and the lack of reference values, no precise cut-off can be identified to suspect MKRN3 defect., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

The population of adults with congenital heart disease (ACHD) is constantly growing. There seems to be a consensus that these patients are difficult to manage especially if compared to patients with acquired heart disease. The aim of this study is to compare outcomes and results of cardiac surgery in ACHD patients with a reference population of adults with acquired cardiac disease. Retrospective study of 5053 consecutive patients older than 18 years hospitalized for cardiac surgery during a 5-years period in our Institution. Two groups of patients were identified. Group I: 419 patients operated for congenital heart disease; Group II: 4634 patients operated for acquired heart disease. In each Group were identified low, medium, and high-risk patients, according to validated scores. Right ventricular outflow tract surgery was the most frequent procedure in Group I, while coronary artery by-pass grafting was the most common in Group II. Patients with ACHD were younger (37.8 vs. 67.7 years), with higher number of previous operations (32.1% vs. 6.9%), had longer post-ICU hospital stay (11 vs. 8 days) but had lower ICU stay (1 vs. 2 days), shorter assisted mechanical ventilation (12 vs. 14 h) and lower surgical mortality (1 vs. 3.7%) (all p < 0.001). No differences were found in term of post-operative complications (12.4 vs. 15%). The surgical treatment of ACHD patients can be done with excellent results and if compared with acquired cardiac disease patients they have better results with shorter ICU stay and lower mortality., (© 2024. The Author(s).)

A squaramide-based organocatalyst for asymmetric Michael reactions has been tested as a chiral solvating agent (CSA) for 26 carboxylic acids and camphorsulfonic acid, encompassing amino acid derivatives, mandelic acid, as well as some of its analogs, propionic acids like profens (ketoprofen and ibuprofen), butanoic acids and others. In many cases remarkably high enantiodifferentiations at 1 H, 13 C and 19 F nuclei were observed. The interaction likely involves a proton transfer from the acidic substrates to the tertiary amine sites of the organocatalyst, thus allowing for pre-solubilization of the organocatalyst (when a chloroform solution of the substrate is employed) or the simultaneous solubilization of both the catalyst and the substrate. DOSY experiments were employed to evaluate whether the catalyst-substrate ionic adduct was a tight one or not. ROESY experiments were employed to investigate the role of the squaramide unit in the adduct formation. A mechanism of interaction was proposed in accordance with the literature data.

Purpose: To investigate the incidence of nephrolithiasis in a cohort of children with congenital adrenal hyperplasia (CAH), and to study if there is an association with the metabolic control of the disease., Methods: This study was designed as a multicenter 1 year-prospective study involving 52 subjects (35 males) with confirmed molecular diagnosis of CAH due to 21-hydroxylase deficiency (21-OHD). Each patient was evaluated at three different time-points: T0, T1 (+6 months of follow-up), T2 (+12 months of follow up). At each follow up visit, auxological data were collected, and adrenocorticotrophic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), Δ4-androstenedione, dehydroepiandrosterone sulfate (DHEAS) serum levels, and urinary excretion of creatinine, calcium, oxalate and citrate were assayed. Moreover, a renal ultrasound was performed., Results: The incidence of nephrolithiasis, assessed by ultrasound was 17.3% at T0, 13.5% at T1 and 11.5% at T2. At T0, one subject showed nephrocalcinosis. In the study population, a statistically significant difference was found for 17-OHP [T0: 11.1 (3.0-25.1) ng/mL; T1: 7.1 (1.8-19.9) ng/mL; T2: 5.9 (2.0-20.0) ng/mL, p < 0.005], and Δ4-androstenedione [T0: 0.9 (0.3-2.5) ng/mL; T1: 0.3 (0.3-1.1) ng/mL; T2: 0.5 (0.3-1.5) ng/mL, p < 0.005] which both decreased over the follow up time. No statistically significant difference among metabolic markers was found in the group of the subjects with nephrolithiasis, even if 17-OHP, DHEAS and Δ4-androstenedione levels showed a tendency towards a reduction from T0 to T2. Principal component analysis (PCA) was performed to study possible hidden patterns of associations/correlations between variables, and to assess the trend of them during the time. PCA revealed a decrease in the amount of the variables 17-OHP, Δ4-androstenedione, and ACTH that occurred during follow-up, which was also observed in subjects showing nephrolithiasis., Conclusions: our data demonstrated that children affected with 21-OHD can be at risk of developing nephrolithiasis. Additional studies are needed to clarify the pathogenesis and other possible risk factors for this condition, and to establish if regular screening of kidney ultrasound in these patients can be indicated., (© 2024. The Author(s).)

Competing Interests: Disclosures None.

Objective: Zonular dialysis (ZD), referred to as the presence of a deficient zonular support for the lenticular capsule, might be the result of several causes and be detected only at the time of cataract surgery. The aim of this study was to evaluate pre-, intra-, and postoperative features of eyes with ZD regardless of the etiology detected during cataract surgery., Methods: A single-centre retrospective observational cohort study was performed at Moorfields Eye Hospital (NHS Foundation Trust, London, U.K.) to identify patients who underwent cataract surgery whose procedure was intraoperatively described as being complicated by ZD between January 1, 2014, and August 22, 2019. Patient characteristics, intraoperative clinical findings, visual and refractive outcomes, and postoperative complications were recorded., Results: ZD was identified intraoperatively in 447 eyes. In most cases (213 of 223; 96.8%), patients underwent a phacoemulsification procedure, not requiring any conversion to intracapsular or extracapsular extraction technique. Intraoperative complications increased to 46.2% (103 of 223), with no significant correlation with ZD width. Capsular tension rings (CTRs) were implanted in 43.4% of patients (97 of 223). The use of CTRs correlated with better postoperative visual and refractive outcomes., Conclusions: ZD is a serious complication of cataract surgery requiring prompt intraoperative diagnosis and proper management. While it tends to worsen cataract surgery outcomes, the implantation of CTRs during the surgical procedure seems to be associated with better postoperative visual and refractive results., (Copyright © 2022 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Background: Blue-yellow axis dyschromatopsia is well-known in Autosomal Dominant Optic Atrophy (ADOA) patients, but there were no data on the correlation between retinal structure and short-wavelength automated perimetry (SWAP) values in this pathology. Methods: In this cross-sectional case-control study, we assessed the correlation between best corrected visual acuity (BCVA), standard automated perimetry (SAP), SWAP, and optical coherence tomography (OCT) parameters of 9 ADOA patients compared with healthy controls. Correlation analysis was performed between BCVA, mean deviation, pattern standard deviation (PSD), and fovea sensitivity (FS) values and the OCT thickness of each retinal layer and the peripapillary retinal nerve fiber layer (pRNFL). Results: The following significant and strong correlations were found: between BCVA and ganglion cell layer (GCL) and the global (G) pRNFL thicknesses; between SAP FS and GCL and the G-pRNFL thicknesses; between SWAP PSD and total retina, GCL, inner plexiform layer, inner nuclear layer, inner retinal layer and the temporal pRNFL thicknesses. We found a constant shorter duration of the SITA-SWAP compared with the SITA-STANDARD strategy. Conclusions: SWAP, SAP, and BCVA values provided relevant clinical information about retinal involvement in our ADOA patients. The perimetric functional parameters that seemed to correlate better with structure involvement were FS on SAP and PSD on SWAP.

In the exploration of chiral solvating agents (CSAs) for nuclear magnetic resonance (NMR) spectroscopy designed for the chiral analysis of amino acid derivatives, notable advancements have been made with thiourea-CSAs. 1-TU , derived from 2-[(1 R )-1-aminoethyl]phenol and benzoyl isothiocyanate, is effective in the enantiodifferentiation of N -3,5-dinitrobenzoyl ( N -DNB) amino acids. In order to broaden the application of 1-TU for configurational assignment, enantiomerically enriched N -DNB amino acids were analyzed via NMR. A robust correlation was established between the relative position of specific 1 H and 13 C NMR resonances of the enantiomers in the presence of 1-TU . 1,4-Diazabicyclo[2.2.2]octane (DABCO) was selected for the complete solubilization of amino acid substrates. Notably, the para and ortho protons of the N -DNB moiety displayed higher frequency shifts for the ( R )-enantiomers as opposed to the ( S )-enantiomers. This trend was consistently observed in the 13 C NMR spectra for quaternary carbons bonded to NO 2 groups. Conversely, an inverse correlation was noted for quaternary carbon resonances of the carboxyl moiety, amide carbonyl, and methine carbon at the chiral center. This observed trend aligns with the interaction mechanism previously reported for the same chiral auxiliary. The configurational correlation can be effectively exploited under conditions of high dilution or, significantly, under sub-stoichiometric conditions.

Competing Interests: Competing interests: None declared.

Purpose: The aim of this study was to delineate the personality traits of patients affected by keratoconus (KC) compared with a group of nonkeratoconic controls matched in age and sex., Methods: In this prospective interventional case-control study, 60 consecutive subjects (30 KC cases and 30 healthy controls), aged 18 to 30, were enrolled at the time of their first encounter at the ophthalmology unit of the Fondazione Policlinico "Tor Vergata", Roma. After completing the ophthalmic evaluation, participants were asked to respond to the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25). A complete psychiatric assessment was performed, including the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (SCID-5); the Symptom Check List-90-Revised (SCL-90); the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Modified (TEMPS-M); and the NEO Five-Factor Inventory (NEO-FFI)., Results: Cases had lower quality of life than controls, as demonstrated by lower scores in all NEI VFQ-25 subdomains. Nine patients with KC (30.0%) were diagnosed by the SCID-5 with at least 1 cluster C personality disorder, resulting in a 9-fold increased risk compared with controls. Moreover, keratoconic patients showed a more pronounced psychosomatic symptomatology (SCL-90) and a characteristic neurotic temperament (TEMPS-M and NEO-FFI)., Conclusions: Our results support the hypothesis that subjects with KC feature dysfunctional coping mechanisms and personality traits, which might already be present at the first clinical encounter. Ophthalmologists should question the mental and emotional status of patients with KC and be especially careful in managing these patients., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

In this work, the peels of red and blonde oranges as well as lemons were efficiently (5.75-9.65% yield) extracted by hydroalcoholic solution with ultrasound assistance and employed as active molecule sources in the preparation of functional gummies. Antioxidant performances of the hydroalcoholic extracts were characterized by colorimetric assays, whereas LC-HRMS analyses identified the main bioactive compounds (phenolic acids and flavonoids). The highest scavenging activity was recorded for lemon extract in an aqueous environment (IC 50 = 0.081 mg mL -1 ). An ecofriendly grafting procedure was performed to anchor polyphenols to gelatin chains, providing macromolecular systems characterized by thermal analysis and antioxidant properties. Scavenger abilities (IC 50 = 0.201-0.454 mg mL -1 ) allowed the employment of the conjugates as functional ingredients in the preparation of gummies with remarkable antioxidant and rheological properties over time (14 days). These findings confirmed the possible employment of highly polluting wastes as valuable sources of bioactive compounds for functional gummies preparation.

Soon after the outset of the Coronavirus Disease 2019 (COVID-19) pandemic (March-April 2020), formulations of the old antimalarial racemic drug hydroxychloroquine (HCQ) sulfate were authorized by the U.S. Food and Drug Administration (FDA) for emergency treatment of hospitalized patients with COVID-19. A call for the chiral switch of HCQ to the single enantiomer (S)-(+)-HCQ for treating the disease followed. The above authorizations were later withdrawn. Angiotensin-converting enzyme 2 (ACE2) has been recognized to be the forward receptor of SARS-CoV-2, the virus responsible for COVID-19. The objective of the present study was to evaluate the chiral distinction in the potential preferential binding of the HCQ enantiomers to ACE2, as a basis for its future drug repurposing, using high-field solution Nuclear Magnetic Resonance (NMR) spectroscopy. Proton selective spin-lattice relaxation rates were measured for selected diagnostic nuclei; in particular, protons belonging to the quinoline ring proved to be the most affected by the presence of the protein, for both (S)-(+)-HCQ and (R)-(-)-HCQ enantiomers. An increase in mono-selective relaxation rates was observed for both enantiomers. A significant difference in the magnitude of the increase was detected for all protons investigated, up to a 5-fold and an 8-fold increase in the case of (R)-(-)-HCQ and (S)-(+)-HCQ, respectively. Furthermore, comparison between the normalized mono-selective relaxation rates of the two HCQ enantiomers in their binary mixtures with ACE2 pointed out a certain preference for the (S)-(+)-HCQ enantiomer over (R)-(-)-HCQ in the interaction with ACE2. The findings form the basis for a future application of the drug repurposing/chiral-switch combination strategy to racemic HCQ in previously reported indications for hydroxychloroquine treatment and in the search for new indications in which ACE2 receptors are involved., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cinnamic acid and its derivatives represent attractive building blocks for the development of pharmacological tools. A series of piperoniloyl and cinnamoyl-based amides (6-9 a-f) have been synthesized and assayed against a wide panel of colorectal cancer (CRC) cells, with the aim of finding promising anticancer agents. Among all twenty-four synthesized molecules, 7a, 7e-f, 9c, and 9f displayed the best antiproliferative activity. The induced G1 cell cycle arrest and the increase in apoptotic cell death was seen in FACS analysis and western Blotting in the colon tumor cell lines HCT116, SW480, LoVo, and HT29, but not in the nontumor cell line HCEC. In particular, 9f overcame the resistance of HT29 cells, which have a mutant p53 and BRAF. Furthermore, 9f, amide of piperonilic acid with the 3,4-dichlorobenzyl substituent upregulated p21, which is involved in cell cycle arrest as well as in apoptosis induction. Cinnamic acid derivatives might be potential anticancer compounds, useful for the development of promising anti-CRC agents., (© 2023 The Authors. Chemical Biology & Drug Design published by John Wiley & Sons Ltd.)

In meta-analysis literature, there are several checklists describing the procedures necessary to evaluate studies from a qualitative point of view, whereas preliminary quantitative and statistical investigations on the "combinability" of trials have been neglected. Covariate balance is an important prerequisite to conduct meta-analysis. We propose a method to identify unbalanced trials with respect to a set of covariates, in presence of covariate imbalance, namely when the randomized controlled trials generate a meta-sample that cannot satisfy the requisite of randomization/combinability in meta-analysis. The method is able to identify the unbalanced trials, through four stages aimed at achieving combinability. The studies responsible for the imbalance are identified, and then they can be eliminated. The proposed procedure is simple and relies on the combined Anderson-Darling test applied to the Empirical Cumulative Distribution Functions of both experimental and control meta-arms. To illustrate the method in practice, two datasets from well-known meta-analyses in the literature are used., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Attanasio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chimeric antigen receptor (CAR) T cell therapy targeting CD-19 has revolutionized the treatment of refractory B-cell malignancies. However, patients undergoing this therapy face an increased risk of infections due to compromised immune function, lymphodepleting chemotherapy, hospitalization, and therapy-related complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. Patients with systemic corticosteroid use, low immunoglobulin levels, and severe CRS, are at higher risk of infection. This review article highlights the spectrum of infections encountered in CAR T cell therapy, including bacterial, viral, and fungal infections. Following consensus guidelines for vaccination and immunoglobulin replacement is recommended. Clear criteria for antibiotic usage and vaccinating household members against respiratory viruses are crucial. Understanding the risk factors, spectrum of infections, and implementing appropriate prophylactic measures are essential to optimize outcomes in patients undergoing CAR T cell therapy. By prioritizing infection prevention strategies, healthcare professionals can effectively improve patient care., (©The Author 2023. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

Nearly 60,000 major lower extremity amputations (AKA/BKA) are performed annually in the United States. We created a simple risk score for predicting ambulation at 1 year following AKA/BKA. We queried the Vascular Quality Initiative amputation database for patients who underwent above-knee (AKA) or below-knee (BKA) amputation (2013-2018). The primary endpoint was ambulation at 1 year either independently or with assistance. The cohort was divided into 80% derivation and 20% validation. Using the derivation set, a multivariable model identified preoperatively available independent predictors of 1 year ambulation and an integer-based risk-score was created. Scores were calculated to assign patients to risk groups-low, medium, or high chance of being ambulatory at 1 year. Internal validation was performed by applying the risk score to the validation set. Of 8725 AKA/BKA, 2055 met inclusion criteria-excluded: 2644 nonambulatory prior to amputation, 3753 missing 1-year follow-up ambulatory status. The majority-n = 1366, 66% were BKAs. The indications were CLTI; 47%, ischemic tissue loss; 9%, ischemic rest pain; 35%, infection/neuropathic; 9%, acute limb ischemia. Ambulation at 1 year was higher for BKA than AKA: 67%, versus 50%, p < .0001. In the final prediction model, contralateral BKA/AKA was the strongest predictor of nonambulation. The score provided reasonable discrimination (C-statistic = 0.65) and was well calibrated (Hosmer-Lemeshow p = .24). Sixty-two percent of patients who were ambulatory preoperatively remained ambulatory at 1 year. An integer-based risk score can stratify patients according to chance of ambulation at 1 year after major amputation and may be useful for preoperative patient counseling and selection., (Copyright © 2023 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: To provide a comprehensive review of the incidence, risk factors, and management of early complications after deep anterior lamellar keratoplasty (DALK), Descemet stripping automated keratoplasty (DSAEK), and Descemet membrane endothelial keratoplasty (DMEK)., Methods: A literature review of complications, that can occur from the time of the transplant up to 1 month after the transplant procedure, was conducted. Case reports and case series were included in the review., Results: Complications in the earliest postoperative days following anterior and posterior lamellar keratoplasty have shown to affect graft survival. These complications include, but are not limited to, double anterior chamber, sclerokeratitis endothelial graft detachment, acute glaucoma, fluid misdirection syndrome, donor-transmitted and recurrent infection, and Uretts-Zavalia syndrome., Conclusion: It is essential for surgeons and clinicians to not only be aware of these complications but also know how to manage them to minimize their impact on long-term transplant survival and visual outcomes., (© 2023. The Author(s).)

The main aim of this systematic review and meta-analysis was to evaluate the safety and efficacy profile of immediate sequential bilateral cataract surgery (ISBCS) compared with delayed sequential bilateral cataract surgery (DSBCS). MEDLINE Ovid, EMBASE, and CENTRAL databases were searched. Outcome measures were postoperative visual acuity, postoperative spherical equivalent (refractive outcome), endophthalmitis, corneal edema, pseudophakic macular edema, and posterior capsule rupture (PCR). 13 articles met criteria for final inclusion. A total of 11 068 622 participants (18 802 043 eyes) were included. No statistically significant differences between ISBCS and DSBCS were identified in all the postoperative outcomes evaluated. However, a higher risk for PCR was identified in the ISBCS group from the pooled analysis of nonrandomized studies (risk ratio, 1.34, 95% CI, 1.08-1.67, P = .0081). In our view, the ISBCS approach has an acceptable safety-efficacy profile, comparable with DSBCS. Future investigations are warranted, with a focus on the analysis of risk factors for surgical complications, patient-reported outcome-measures, and cost effectiveness., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of ASCRS and ESCRS.)

Wound-healing delay is one of the major problems of type 2 diabetes, representing also a clinical emergency in non-healing chronic wounds. Natural antioxidants show interesting wound-healing properties, including those extracted from waste derived from olive oil production. Olive mill wastewater is one of the main by-products of the olive oil-making process, and it is rich in high-value secondary metabolites, mainly hydroxytyrosol. We proposed an eco-friendly extraction method, employing both ultrasound-assisted and Soxhlet techniques and ethanol as a solvent, to recover valuable molecules from Roggianella cv ( Olea europea L.) olive mill wastewater, which was further entrapped in a pectin polymer via an enzymatic reaction using porcine pancreatic lipase. Pectin, in combination with other substances, promoted and accelerated wound healing and demonstrated good potential to produce a biomedical conjugate for wound treatment. The antioxidant activity of the extracts and conjugate were evaluated against lipophilic (IC 50 equal to 0.152 mg mL -1 ) and hydrophilic (IC 50 equal to 0.0371 mg mL -1 ) radical species as well as the in vitro cytotoxicity via NRU, h-CLAT, and a wound-healing scratch assay and assessment. The pectin conjugate did not exert hemolytic effects on the peripheral blood, demonstrating interesting wound-healing properties due to its ability to stimulate cell proliferation in a dose-dependent manner.

Topoisomerases are ubiquitous enzymes in the human body, particularly involved in cancer development and progression. Topoisomerase I (topoI) performs DNA relaxation reactions by "controlled rotation" rather than by "strand passage." The inhibition of topoI has become a useful strategy to control cancer cell proliferation. Nowadays, different compounds have undergone clinical trials, but the search for new molecular entities is necessary and benefits from medicinal chemistry efforts. Pyrrole-based compounds emerged as promising antiproliferative agents, with particular interest in breast cancer therapy and topoI inhibition. Starting from these observations and based on the scaffold-hopping approach, we developed a small library of 1-(2-aminophenyl)pyrrole-based amides (7a-f) as new anticancer agents. Tested on a panel of cancer cell lines, 7a-f displayed the most interesting profile in MDA-MB-231 cells, where the most active compounds, 7d-f, were able to induce death by apoptosis. Direct enzymatic assays and docking simulations on the topoI active site (PDB: 1A35) revealed the inhibitory activity and potential binding site for the newly developed 1-(2-aminophenyl)pyrrole-based amides., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

Purpose: The aim of this study was to report the first case of successful use of corneal collagen cross-linking (CXL) to halt the progression of keratoconus in a patient with concurrent iridocorneal endothelial (ICE) syndrome., Methods: A 30-year-old White man was referred to our subspecialty corneal clinic for further investigation of right corectopia. The patient was asymptomatic and was otherwise fit. Slit-lamp examination revealed a right oval-shaped pupil decentered superiorly, a transillumination defect at the 5-o'clock position, minimal gutta-like changes in the corneal endothelium, and few inferior peripheral anterior synechiae. Dilated fundoscopy was normal in both eyes, with healthy optic discs, maculae, and peripheral retinae. Specular microscopy and slit-lamp findings suggested ICE syndrome. Subsequent investigation with corneal tomography showed progressive signs of inferior corneal ectasia with steepening, and thinning in the right eye, consistent with keratoconus. The left eye was unremarkable., Results: Epithelium-off accelerated corneal CXL was performed in the affected eye. Early post-CXL follow-up (1 week) was unremarkable, and further follow-ups were arranged at 3, 6, 12, and 24 months, respectively. In subsequent reviews, the patient's vision and corneal tomography findings were stable., Conclusions: We describe the first case of corneal CXL for progressive keratoconus with ICE syndrome. co-existing keratoconus and ICE syndrome can occur, and corneal cross-linking was used successfully in this case to halt keratoconus progression. However, further studies will need to establish the impact of epithelium-off corneal cross-linking, especially in more severely affected eyes., Competing Interests: Conflicts of interest statement: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Nuclear magnetic resonance (NMR) spectroscopy is an analytical technique largely applied in the analysis of discrimination processes involving enantiomeric substrates and chiral agents, which can interact with the analyte either via covalent bonding or via formation of diastereomeric solvates. However, enantiodiscrimination has been observed, in some cases, even in the absence of any additional chiral selector. The reasons behind this phenomenon must be found in the capability of some chiral substrates to interact with themselves by forming diastereomeric solvates in solution that can generate nonequivalences in the NMR spectra of enantiomerically enriched mixtures. As a result, differentiation of enantiomers is observed, thus allowing the quantification of the enantiomeric composition of the mixture under investigation. The tendency of certain substrates to self-aggregate and to generate diastereomeric adducts in solution can be defined as Self-Induced Diastereomeric Anisochrony (SIDA), but other acronyms have been used to refer to this phenomenon. In the present work, an overview of SIDA processes investigated via NMR spectroscopy will be provided, with a particular emphasis on the nature of the substrates involved, on the interaction mechanisms at the basis of the phenomenon, and on theoretical treatments proposed in the literature to explain them., Competing Interests: The authors declare no conflicts of interest.

Introduction: The success of keratoplasty strongly depends on the health status of the transplanted endothelial cells. Donor corneal tissues are routinely screened for endothelial damage before shipment; however, surgical teams have currently no means of assessing the overall viability of corneal endothelium immediately prior to transplantation. The aim of this study is to validate a preoperative method of evaluating the endothelial health of donor corneal tissues, to assess the proportion of tissues deemed suitable for transplantation by the surgeons and to prospectively record the clinical outcomes of a cohort of patients undergoing keratoplasty in relation to preoperatively defined endothelial viability., Methods and Analysis: In this multicentre cohort study, consecutive patients undergoing keratoplasty (perforating keratoplasty, Descemet stripping automated endothelial keratoplasty (DSAEK), ultra-thin DSAEK (UT-DSAEK) or Descemet membrane endothelial keratoplasty) will be enrolled and followed-up for 1 year. Before transplantation, the endothelial viability of the donor corneal tissue will be evaluated preoperatively through trypan blue staining and custom image analysis to estimate the overall percentage of trypan blue-positive areas (TBPAs), a proxy of endothelial damage. Functional and structural outcomes at the end of the follow-up will be correlated with preoperatively assessed TBPA values., Ethics and Dissemination: The protocol will be reviewed by the ethical committees of participating centres, with the sponsor centre issuing the final definitive approval. The results will be disseminated on ClinicalTrials.gov, at national and international conferences, by partner patient groups and in open access, peer-reviewed journals., Trial Registration Number: NCT05847387., Competing Interests: Competing interests: YZ, SK and VR are editors of BMJ Open Ophthalmology., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Understanding how injuries occur (inciting circumstances) is useful for developing etiological hypotheses and prevention strategies. The aims of this study were 1) to evaluate the feasibility of a method combining video and Global Positioning System data to estimate the speed and acceleration of activities leading to injuries and 2) to use this method to analyse the inciting circumstances leading to non-contact injuries., Design: Retrospective descriptive study., Methods: Injury inciting circumstances from 46 elite players over three seasons were analysed from video recordings and from external load measures collected through Catapult Vector S7 Global Positioning System., Results: In total 34 non-contact injuries were analysed. Sixteen out of the seventeen hamstring injuries occurred when players were running for (median and interquartile range) 16.75 m (8.42-26.65 m) and achieved a peak speed of 29.28 km·h -1 (26.61-31.13 km·h -1 ) which corresponded to 87.55 % of players' maximal speed (78.5 %-89.75 %). Of the three adductor injuries, one occurred whilst the player was decelerating without the ball, one occurred whilst the player was accelerating and controlling the ball at knee level, and one occurred whilst the player was performing an instep kick. Two quadriceps injuries occurred whilst the players were kicking either whilst walking or running., Conclusions: From the preliminary results reported in this study most hamstring injuries occurred when players ran >25 km·h -1 and above 80 % of their maximal speed. This study suggests that this novel approach can allow a detailed and standardised analysis of injury inciting circumstances., Competing Interests: Declaration of interest statement The authors declare that they have no financial or other interests in the products or distribution of the products included in this study., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A comprehensive examination of the sport-specific activities and circumstances being performed at the time of injury is important to hypothesise mechanisms, develop prevention strategies and inform future investigations. Results reported in the literature are inconsistent because inciting activities are reported using different classifications. Hence the aim was to develop a standardised system for the reporting of inciting circumstances., Methods: The system was developed using a modified Nominal Group Technique. The initial panel included 12 sports practitioners and researchers from four continents with respectively ≥ 5 years of experience working in professional football and/or conducting injury research. The process consisted of six phases: idea generation, two surveys, one online meeting and two confirmations. For answers to the closed questions, consensus was deemed achieved if ≥ 70% of respondents agreed. Open-ended answers were qualitatively analysed and then introduced in subsequent phases., Results: Ten panellists completed the study. The risk of attrition bias was low. The developed system includes a comprehensive range of inciting circumstances across five domains: contact type, ball situation, physical activity, session details, contextual information. The system also distinguishes between a core set (essential reporting) and an optional set. The panel deemed all the domains to be important and easy to use both in football and in research environments., Conclusion: A system to classify inciting circumstances in football was developed. Given the extent of reporting inconsistency of inciting circumstances in the available literature, this can be used while further studies evaluate its reliability., (© 2023. The Author(s).)

Objective: The purpose of the study is to assess body hydration in patients with posterior vitreous detachment (PVD) by bioelectrical impedance analysis (BIA). PVD, one of the most common eye diseases, is associated in both research and the collective image with reduced daily water intake, but this finding is not supported by strong evidence in the literature., Patients and Methods: Based on Spectral Domain Optical Coherence Tomography (SD-OCT) evaluation, different PVD stages are identified: absent posterior vitreous detachment, partial posterior vitreous detachment (P-PVD), or complete posterior vitreous detachment (C-PVD). BIA is a simple, non-invasive bedside method used to assess body composition. Patients underwent BIA and completed a floaters symptoms. 30 patients were enrolled and divided into two groups according to the degree of vitreous detachment, in P-PVD (n=12) and C-PVD (n=18). Patients underwent BIA and completed a floaters symptoms questionnaire. BIA measured the Resistance (R), Reactance (Xc), Phase Angle (PhA), Total Body Water (TBW), Extracellular Water (ECW), Fat Mass (FM), Fat-Free Mass (FFM), and Body Cell Mass Index (BCMI). Finally, patients received a test to assess adherence to the Mediterranean diet (Mediterranean Diet Test Score, MDTS) with the addition of daily water intake., Results: Relevant data were obtained from the BIA evaluation: the values of R and Xc were lower in the P-PVD group than C-PVD group (respectively 417.08±58.12 Ω vs. 476.94±51.29 Ω p=0.006 and 41.33±8.23 Ω vs. 50.61±7.98 Ω p=0.004). Instead, patients in the P-PVD group reported higher values of TBW and ECW than C-PVD group (respectively 44.13±7.57 L vs. 37.96±6.27 L p=0.021 and 21.03±4.06 L vs. 17.24±2.63 L p=0.004)., Conclusions: In the present study, we reported a significant correlation between vitreous pathology and anthropometric and BIA measurements.

Objective: To evaluate (i) the prevalence and association of euthyroid sick syndrome (ESS) [decreased FT3 and/or FT4 and normal/decreased TSH] with severity indexes of type 1 diabetes mellitus (T1DM) onset such as diabetic ketoacidosis (DKA) and kidney damage [acute kidney injury (AKI) based on KDIGO criteria, acute tubular necrosis (ATN), renal tubular damage (RTD)], (ii) relationship between clinical/metabolic parameters at T1DM onset and thyroid hormones, and (iii) ESS as a prognostic indicator of delayed recovery from kidney damage., Methods: A total of 161 children with T1DM onset were included. RTD was defined by abnormal urinary beta-2-microglobulin and/or neutrophil gelatinase-associated lipocalin (NGAL) and/or tubular reabsorption of phosphate <85% and/or fractional excretion of Na>2%. ATN was defined by RTD+AKI., Results: Of 161 participants, 60 (37.3%) presented ESS. It was more prevalent in case of more severe T1DM presentation both in terms of metabolic derangement (DKA) and kidney function impairment (AKI, RTD and ATN). Only ATN, however, was associated with ESS at adjusted analysis. FT3 inversely correlated with serum triglycerides and creatinine, and urinary calcium/creatinine ratio and NGAL. Participants with euthyroidism showed earlier recovery from AKI than those with ESS. ESS spontaneously disappeared., Conclusions: ESS is associated with T1DM onset severity and spontaneously disappears. ESS delayed the recovery from AKI., Impact: This is the first longitudinal study describing in detail the relationship between clinical/metabolic factors at type 1 diabetes mellitus (T1DM) onset and thyroid hormones, with particular attention to the relationship between diabetic ketoacidosis (DKA)-related kidney function impairment and euthyroid sick syndrome (ESS). Participants with more severe T1DM onset presentation both in terms of metabolic derangement and kidney function impairment had an increased prevalence of ESS. Children with ESS had a slower recovery from acute kidney injury compared with those without ESS. ESS spontaneously disappeared in all participants., (© 2023. The Author(s).)

Purpose: Lax eyelid condition (LEC) and floppy eyelid syndrome (FES) represent two distinct conditions which have been associated with several ocular and systemic comorbidities. The main aim of this systematic review and meta-analysis is to explore the available literature to estimate the prevalence rate of LEC and FES in obstructive sleep apnea (OSA)., Methods: The protocol of this systematic review and meta-analysis has been registered in PROSPERO. Four electronic databases (PubMed/MEDLINE, Google Scholar, Cochrane Library, Web of Science) were searched from inception to December 24, 2021. A random intercept logistic regression model was carried out for the analysis of overall proportions. Odds ratio and mean difference were reported as measures of the effect size in the presence of binary and continuous outcomes, respectively. The estimated numbers of LEC/FES patients in OSA were calculated by multiplying the prevalence rate determined by our random-effects model and the corresponding Benjafield et al.'s population prospect., Results: We included 11 studies comprising 1225 OSA patients of whom 431 and 153 affected by LEC and FES, respectively. Our model estimated a pooled prevalence rate for LEC and FES in OSA patients of 40.2% (95%CI: 28.6-53.1%) and of 22.4% (95%CI: 13.8-34.2%), respectively. The number of LEC/FES affected individuals among OSA patients is expected to peak up to 376 and to 210 million, respectively. OSA patients appeared to have a 3.4 (95%CI: 2.2-5.2) and a 3.0 (95%CI: 1.7-5.5) increased risk of developing LEC and FES than the healthy counterpart., Conclusion: Prevalence of LEC and FES is higher in OSA-affected patients compared to controls. More studies are warranted to investigate the mechanisms leading to the development of LEC and/or FES in OSA patients, as well as the feasibility of the adoption of these clinical findings as screening tools for OSA., (© 2022. The Author(s).)

Purpose: We aimed to investigate a cohort of female and male patients with idiopathic central precocious puberty (CPP), negative for Makorin Ring Finger Protein 3 (MKRN3) defect, by molecular screening for Delta-like 1 homolog (DLK1) defects. DLK1 is an imprinted gene, whose mutations have been described as a rare cause of CPP in girls and adult women with precocious menarche, obesity and metabolic derangement., Methods: We enrolled 14 girls with familial CPP and 13 boys with familial or sporadic CPP from multiple academic hospital centers. Gene sequencing of DLK1 gene was performed. Circulating levels of DLK1 were measured and clinical and biochemical characteristics were described in those with DLK1 defects., Results: A novel heterozygous mutation in DLK1, c.288&#95;289insC (p.Cys97Leufs*16), was identified in a male proband, his sister and their father. Age at onset of puberty was in line with previous reports in the girl and 8 years in the boy. The father with untreated CPP showed short stature. No metabolic derangement was present in the father except hypercholesterolemia. Undetectable Dlk1 serum levels indicated the complete lack of protein production in the three affected patients., Conclusion: A DLK1 defect has been identified for the first time in a boy, underscoring the importance of genetic testing in males with idiopathic or sporadic CPP. The short stature reported by his untreated father suggests the need for timely diagnosis and treatment of subjects with DLK1 defects., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

We describe an in silico -guided rational drug design and the synthesis of the suggested ligands, aimed at improving the TRPV1-ligand binding properties and the potency of N -(4-hydroxy-3-methoxybenzyl)-4-(thiophen-2-yl) butanamide I , a previously identified TRPV1 agonist. The docking experiments followed by molecular dynamics simulations and thermodynamic analysis led the drug design toward both the introduction of a lipophilic iodine and a flat pyridine/benzene at position 5 of the thiophene nucleus. Most of the synthesized compounds showed high TRPV1 efficacy and potency as well as selectivity. The molecular modeling analysis highlighted crucial hydrophobic interactions between Leu547 and the iodo-thiophene nucleus, as in amide 2a , or between Phe543 and the pyridinyl moiety, as in 3a . In the biological evaluation, both compounds showed protective properties against oxidative stress-induced ROS formation in human keratinocytes. Additionally, while 2a showed neuroprotective effects in both neurons and rat brain slices, 3a exhibited potent antinociceptive effect in vivo. .

Topic: To provide standardized confidence limits of the transient pattern electroretinogram (tPERG) P50 and N95 and steady state pattern electroretinogram (ssPERG) amplitudes in normal controls as compared to ocular hypertension (OHT), glaucoma suspect (GS), or early manifest glaucoma (EMG) eyes., Clinical Relevance: The identification of standardized confidence limits in the context of pattern electroretinogram (PERG) might overcome the high intrinsic variability of the measure, and it might lead to a more intuitive understanding of the results as well as to an easier comparison of data from multiple tests, sites, and operators., Methods: The study protocol was prospectively registered on the International Prospective Register of Systematic Reviews (ID: CRD42022370032). A literature search was conducted on PubMed, Web of Science, and Scopus. Studies comparing PERG raw data in normal control eyes as compared to OHT, GS, or EMG were included. The risk of bias was assessed using the National Institute for Health and Clinical Excellence quality assessment tool. The main outcome was the P50, N95, and ssPERG amplitude difference between the control and the study groups' eyes. The standardized mean difference was calculated as a measure of the effect size for the primary outcome. A subanalysis was conducted based on the type of electrodes adopted for the PERG measurements (invasive vs. noninvasive)., Results: Of the 4580 eligible papers, only 23 were included (1754 eyes). Statistically significant amplitude differences were found in the P50, N95, and ssPERG amplitudes between normal controls and OHT, GS, and EMG eyes. The highest standardized mean difference values were observed in the ssPERG amplitude in all 3 sets of comparison. The subanalysis did not reveal any statistically significant differences between invasive and noninvasive recording strategies., Conclusions: The use of standardized values as the main outcome measures in the context of the PERG data analysis is a valid approach, normalizing several confounding factors which have affected the clinical utility of PERG both for individual patients and in clinical trials. Steady state PERG apparently better discriminates diseased eyes compared to tPERG. The adoption of skin-active electrodes is able to adequately discriminate between healthy and diseased statuses., Financial Disclosures: Proprietary or commercial disclosure may be found after the references., (© 2023 by the American Academy of Ophthalmology.)