Clinical outcomes of single blastocyst transfer with machine learning guided noninvasive chromosome screening grading system in infertile patients.

BACKGROUND: Prospective observational studies have demonstrated that the machine learning (ML) -guided noninvasive chromosome screening (NICS) grading system, which we called the noninvasive chromosome screening-artificial intelligence (NICS-AI) grading system, can be used embryo selection. The current prospective interventional clinical study was conducted to investigate whether this NICS-AI grading system can be used as a powerful tool for embryo selection. METHODS: Patients who visited our centre between October 2018 and December 2021 were recruited. Grade A and B embryos with a high probability of euploidy were transferred in the NICS group. The patients in the control group selected the embryos according to the traditional morphological grading. Finally, 90 patients in the NICS group and 161 patients in the control group were compared statistically for their clinical outcomes. RESULTS: In the NICS group, the clinical pregnancy rate (70.0% vs. 54.0%, p < 0.001), the ongoing pregnancy rate (58.9% vs. 44.7%, p = 0.001), and the live birth rate (56.7% vs. 42.9%, p = 0.001) were significantly higher than those of the control group. When the female was ≥ 35 years old, the clinical pregnancy rate (67.7% vs. 32.1%, p < 0.001), ongoing pregnancy rate (56.5% vs. 25.0%, p = 0.001), and live birth rate (54.8% vs. 25.0%, p = 0.001) in the NICS group were significantly higher than those of the control group. Regardless of whether the patients had a previous record of early spontaneous abortion or not, the live birth rate of the NICS group was higher than that of the control group (61.0% vs. 46.9%; 57.9% vs. 34.8%; 33.3% vs. 0%) but the differences were not statistically significant. CONCLUSIONS: NICS-AI was able to improve embryo utilisation rate, and the live birth rate, especially for those ≥ 35 years old, with transfer of Grade A embryos being preferred, followed by Grade B embryos. NICS-AI can be used as an effective tool for embryo selection in the future.

Tricyclic 1,4-Diphosphinines: Local vs. Global Aromaticity.

1D and 2D NICS π . zz SOM ${{{\rm { NICS}}}_{{\rm { {\rm \pi}{}}}{\rm { .zz}}}^{{\rm { SOM}}}}$ (Sigma only model) calculations were performed on recently established tricyclic 1,4-diphosphinines as well as related benzene and pyrazine derivatives. The study was extended to evaluate the effect of the fused rings on the overall aromatic properties with a special focus on functional groups such as carbenes. The effect of non-aromatic heterocycles on the local ring current of the central ring is small, while aromatic heterocycles (e. g. NHC, imidazolium) lead to a global aromaticity. A higher sulfur content of the adjacent five-membered rings reduces the central ring current. The comparison to related tricyclic benzene and pyrazine derivatives showed that the 1,4-diphosphinine systems resemble more closely the situation in the benzene derivatives than the pyrazines. The effect of charged systems was studied using bis(TTF)-fused 1,4-diphosphinines and, according to NICS π . zz SOM ${{{\rm { NICS}}}_{{\rm { {\rm \pi}{}}}{\rm { .zz}}}^{{\rm { SOM}}}}$ values, the neutral form doesn't possess significant aromaticity but the tetracation resembles the global aromatic situation observed for other heterocycles in this study.

Principal Singlet Fission Properties Of Twisted Acenes.

Acenes, especially tetracene derivatives, are used as singlet fission materials. The recent synthesis of Dodecaphenyl tetracene (showing end-to-end twist angles of 96-98 degrees) and twisted anthracene derivatives show that the synthesis of twisted linear oligoacenes is possible. Energy calculations and NICS-X-scan studies predict that twisted acenes may be better singlet fission materials compared to their planar analogues.

Comparison of Various Theoretical Measures of Aromaticity within Monosubstituted Benzene.

The effects of monosubstitution on the aromaticity of benzene are assessed using a number of different quantitative schemes. The ability of the mobile π-electrons to respond to an external magnetic field is evaluated using several variants of the NICS scheme which calculate the shielding of points along the axis perpendicular to the molecule. Another class of measures is related to the drive toward the uniformity of C-C bond lengths and strengths. Several energetic quantities are devised to approximate an aromatic stabilization energy and the tendency of the molecule to maintain planarity. There is a lack of consistency in that the various measures of aromaticity lead to differing conclusions as to the effects of substituents on the aromaticity of the ring.

Comparison of Antiaromatic Properties in a Series of Structurally Isomeric Naphthothiophene-Fused s-Indacenes.

Fusion of aromatic subunits to stabilize an antiaromatic core allows the isolation and study of otherwise unstable paratropic systems. A complete study of a series of six naphthothiophene-fused s-indacene isomers is herein described. Additionally, the structural modifications resulted in increased π-π overlap in the solid state, which was further explored through changing the sterically blocking mesityl group to (triisopropylsilyl)ethynyl in three derivatives. The computed antiaromaticity of the six isomers is compared to the observed physical properties, such as NMR chemical shift, UV-vis, and CV data. We find that the calculations predict the most antiaromatic isomer and give a general estimation of the relative degree of paratropicity for the remaining isomers, when compared to the experimental results.

Rare Spin Avoided σ-σ Diradical Planar Tetracoordinate Boron Cluster: A Proto-Star for Planar Pentacoordination.

We report a global planar star-like cluster B3 Li3 featuring three planar tetracoordinate boron centres with a rare spin avoided σ-σ diradical character. The cluster was found to be stable towards dissociation into different fragments. The spin density was found to be localized solely on the three boron atoms in the molecular plane. This spin avoided σ-σ diradical character leads to the extension of the coordination number to yield a neutral B3 Li3 H3 and a cationic B3 Li3 H3 + cluster with three planar pentacoordinate boron centres in their global minimum structures. The planar geometry of the aninonic B3 Li3 H3 - cluster is slightly higher in energy. The planar global clusters were found to maintain planarity in their ligand protected benzene bound complexes, B3 Li3 (Bz)3 , B3 Li3 H3 (Bz)3 and B3 Li3 H3 (Bz)3 + with high ligand dissociation energies offering candidature for experimental detection.

Nucleus Independent Chemical Shift (NICS) at Small Distances from the Molecular Plane: The Effect of Electron Density.

When close to the molecular plane, the behavior of nucleus independent chemical shift (NICS) as a function of the distance from the molecular plane deviates from its behavior at larger distances. By using a dense grid of NICS-probes (BQs) it is shown that, when close to the molecular plane, maximal (absolute) NICS values are obtained above the atoms. These maxima move towards the center as the grid is elevated until the (absolute) maximum NICS is obtained at the center and stay there when the grid is further elevated. It is shown that this behavior is a result of the current density, which is influenced by the electron density, according to the Biot-Savart law, which, in turn, causes the induced magnetic field measured by the NICS. It is thus concluded that if magnetic aromaticity is studied, the NICS calculations should be carried out at a large enough distance so that only the π-ring current affects the NICS. At distances ≥2 Å, NICS(r)π,zz =A+B*Cr . Using non-linear correlation for obtaining A, B and C and extrapolate to NICS(1)π,zz and NICS(1.7)π,zz is recommended as measures for aromaticity.

Legal Firearm Sales at State Level and Rates of Violent Crime, Property Crime, and Homicides.

INTRODUCTION: The effects of firearm sales and legislation on crime and violence are intensely debated, with multiple studies yielding differing results. We hypothesized that increased lawful firearm sales would not be associated with the rates of crime and homicide when studied using a robust statistical method. METHODS: National and state rates of crime and homicide during 1999-2015 were obtained from the United States Department of Justice and the Centers for Disease Control and Prevention. National Instant Criminal Background Check System background checks were used as a surrogate for lawful firearm sales. A general multiple linear regression model using log event rates was used to assess the effect of firearm sales on crime and homicide rates. Additional modeling was then performed on a state basis using an autoregressive correlation structure with generalized estimating equation estimates for standard errors to adjust for the interdependence of variables year to year within a particular state. RESULTS: Nationally, all crime rates except the Centers for Disease Control and Prevention-designated firearm homicides decreased as firearm sales increased over the study period. Using a naive national model, increases in firearm sales were associated with significant decreases in multiple crime categories. However, a more robust analysis using generalized estimating equation estimates on state-level data demonstrated increases in firearms sales were not associated with changes in any crime variables examined. CONCLUSIONS: Robust analysis does not identify an association between increased lawful firearm sales and rates of crime or homicide. Based on this, it is unclear if efforts to limit lawful firearm sales would have any effect on rates of crime, homicide, or injuries from violence committed with firearms.

On Integral INICS Aromaticity of Pyridodiazepine Constitutional Isomers and Tautomers.

The structure, energetics, and aromaticity of c.a. 100 constitutional isomers and tautomers of pyrido[m,n]diazepines (m = 1, 2; n = 2, 3, 4, 5; m ≠ n) were studied at the B3LYP/cc-pVTZ level. The pyrido[1,3]diazepines appear the most, while pyrido[2,4]diazepines are the least stable (ca. 26 kcal/mol). In the pyrido[1,n]diazepine group (n = 2-5), the [1,5] isomers are higher in energy by ca. 4.5 kcal/mol and the [1,4] ones by ca. 7 kcal/mol, and the pyrido[1,2]diazepines are the least stable (ca. 20 kcal/mol). All the most stable pyrido[1,n]diazepines have N-atoms near the ring's junction bond but on opposite sites. The most stable [2,n]-forms are also those with the pyridine ring N6-atom near the junction bond. Surprisingly, for the [1,2]-, [1,3]-, and [1,4]-isomer condensation types of pyridine and diazepine rings, the same N9 > N7 > N6 > N8 stability pattern obeys. The stability remains similar in a water medium simulated with the Polarizable Continuum Model of the solvent and is conserved when calculated using the CAM-B3LYP or BHandHlyp functionals. The ring's aromaticity in the pyridine[m,n]diazepines was established based on the integral INICS index resulting from the NICSzz-scan curves' integration. The integral INICS index is physically justified through its relation to the ringcurrent as demonstrated by Berger, R.J.F., et al. Phys. Chem. Chem. Phys. 2022, 24, 624. The six-membered pyrido rings have negative INICSZZ indices and can be aromatic only if they are not protonated at the N-atom. All protonated pyrido and seven-membered rings exhibit meaningful positive INICSZZ values and can be assigned as antiaromatic. However, some non-protonated pyrido rings also have substantial positive INICSZZ indices and are antiaromatic. A weak linear correlation (R2 = 0.72) between the INICSZZ values of the pyridine I(6) and diazepine I(7) rings exists and is a consequence of the communication between the π-electron systems of the two rings. The juxtaposition of the INICS descriptor of the six- and seven-membered rings and diverse electron density parameters at the Ring Critical Points (RCP) revealed good correlations only with the Electrostatic Potentials from the electrons and nuclei (ESPe and ESPn). The relationships with other RCP parameters like electron density and its Laplacian, total energy, and the Hamiltonian form of kinetic energy density were split into two parts: one nearly constant for the six-membered rings and one linearly correlating for the seven-membered rings. Thus, most of the electron density parameters at the RCP of the six-membered rings of pyridodiazepines practically do not change with the diazepine type and the labile proton position. In contrast, those of the seven-membered rings display aromaticity changes in the antiaromatic diazepine with its ring structural modifications.

Clinical application of noninvasive chromosomal screening for elective single-blastocyst transfer in frozen-thawed cycles.

BACKGROUND: The objective of this study was to explore the clinical application of noninvasive chromosomal screening (NICS) for elective single-blastocyst transfer (eSBT) in frozen-thawed cycles. METHODS: This study retrospectively analysed the data of 212 frozen-thawed single-blastocyst transfers performed in our centre from January 2019 to July 2019. The frozen embryos were selected based on morphological grades and placed in preincubation for 6 h after warming. Then spent microdroplet culture media of frozen-thawed blastocysts were harvested and subjected to NICS. The clinical outcomes were evaluated and further stratified analysis were performed, especially different fertilization approaches. RESULTS: The clinical pregnancy, ongoing pregnancy, and live birth rates in the euploidy group were significantly higher than those in the aneuploidy group (56.2% versus 29.4%) but were nonsignificantly different from those in the chaotic abnormal/NA embryos group (56.2% versus 60.4%). Compared with day6 (D6) blastocysts, D5 blastocysts had a nonsignificantly different euploidy rate (40.4% versus 48.1%, P = 0.320) but significantly increased clinical pregnancy (57.7% versus 22.2%, P < 0.001), ongoing pregnancy (48.1% versus 14.8%, P < 0.001), and live birth rates (48.1% versus 13.0%, P < 0.001). The percentage of chaotic abnormal/NA embryos group was significantly higher among D5 embryos than among D6 embryos (30.1% versus 11.1%, P = 0.006). The percentage of aneuploid embryos was higher among the embryos with lower morphological quality(21.5% among 'good' embryos versus 34.6% among 'fair' embryos versus 46.0% among 'poor' embryos, P = 0.013); correspondingly, the overall clinical pregnancy, ongoing pregnancy and live birth rate rates showed similar declines. CONCLUSIONS: NICS combined with morphological assessment is an effective tool to guide frozen-thawed SBT. The optimal embryo for SBT is a 'euploid embryo with good morphology', followed sequentially by a 'chaotic abnormal/NA embryo with good morphology', 'euploid embryo with fair morphology', and 'chaotic abnormal/NA embryo with fair morphology'.

Controlling Tautomerization in Pyridine-Fused Phosphorus-Nitrogen Heterocycles.

Inclusion of a second nitrogen atom in the aromatic core of phosphorus-nitrogen (PN) heterocycles results in unexpected tautomerization to a nonaromatic form. This tautomerization, initially observed in the solid state through X-ray crystallography, is also explained by computational analysis. We prepared an electron deficient analogue (2 e) with a fluorine on the pyridine ring and showed that the weakly basic pyridine resisted tautomerization, providing key insights to why the transformation occurs. To study the difference in solution vs. solid-state heterocycles, alkylated analogues that lock in the quinoidal tautomer were synthesized and their different 1 H NMR and UV/Vis spectra studied. Ultimately, we determined that all heterocycles are the aromatic tautomer in solution and all but 2 e switch to the quinoidal tautomer in the solid state. Better understanding of this transformation and under what circumstances it occurs suggest future use in a switchable on/off hydrogen-bond-directed receptor that can be tuned for complementary hydrogen bonding.

Dimorpholinoacetylene and Its Use for the Synthesis of Tetraaminocyclobutadiene Species.

The new diaminoacetylene (DAA) dimorpholinoacetylene (3) was prepared from 1,1-dimorpholinoethene (1) by bromination to form the dibromoketene aminal 2, which upon lithiation afforded 3 through a Fritsch-Buttenberg-Wiechell rearrangement. Heating 3 at elevated temperatures resulted in a complete conversion into the dimer 1,1,2,4-tetramorpholino-1-buten-3-yne (4), which was used for the synthesis of four-membered cyclic bent allene (CBA) transition-metal complexes of the type [(CBA)MLn ] (5-7; MLn =AuCl, RhCl(COD), RhCl(CO)2 ; CBA=1,3,4,4-tetramorpholino-1,2-cyclobutadiene; COD=1,5-cyclooctadiene). The reaction of 3 with tetraethylammonium bromide gave 1,2,3,4-tetramorpholinocyclobutenylium bromide (8), which reacted with bromine to form 1,2,3,4-tetra(morpholino)cyclobutenediylium bis(tribromide) (9). Compound 9 represents the first fully characterized compound containing a tetraaminocyclobutadiene dication and displays a nearly planar C4 N4 core as shown by X-ray diffraction analysis. Detailed quantum chemical calculations were performed to assess the aromaticity of tetraaminocyclubutadiene dications by employing the Nucleus Independent Chemical Shift (NICS) method and current density analysis.

Spherical Aromaticity of Tetrahedral Pnictogens Through Off-Nucleus Isotropic Magnetic Shielding.

This work revealed the spherical aromaticity of some inorganic E4 cages and their protonated E4 H+ ions (E=N, P, As, Sb, and Bi). For this purpose, we employed several evaluations like (0D-1D) nucleus independent chemical shift (NICS), multidimensional (2D-3D) off-nucleus isotropic shielding σiso (r), and natural bond orbital (NBO) analysis. The magnetic calculations involved gauge-including atomic orbitals (GIAO) with two density functionals B3LYP and WB97XD, and basis sets of Jorge-ATZP, 6-311+G(d,p), and Lanl2DZp. The Jorge-ATZP basis set showed the best consistency. Our findings disclosed non-classical aromatic characters in the above molecules, which decreased from N to Bi cages. Also, the results showed more aromaticity in E4 than E4 H+ . The NBO analysis attributed the aromaticity in the above molecules to the residual density of the overlapping σ-bonding orbitals. So, the aromaticity in these molecules is unlike the classical aromaticity that is associated with electron delocalization. Scanning 1D σiso (r) variation along E-E bonds indicated a lowering in the shielding trend from N to Bi cages. The 3D results showed a similar decrease in the relative volumetric diffusion of the magnetic activity, whereas the volumetric ratio of V1ppm /V2ppm is almost constant for all the E4 cages.

A Planar Five-Membered Aromatic Ring Stabilized by Only Two π-Electrons.

Many chemicals known today are partially or fully aromatic, since a ring framework experiences additional stabilization through the delocalization of π-electrons. While aromatic rings with equal numbers of π-electrons and ring atoms such as benzene are particularly stable, those with the minimally required two π-electrons are very rare and yet remain limited to three- and four-membered rings if not stabilized in the coordination sphere of heavy metals. Here we report the facile synthesis of a dipotassium cyclopentagallene, a unique example of a five-membered aromatic ring stabilized by only two π-electrons. Single-crystal X-ray diffraction revealed a planar Ga5 ring with almost equal gallium-gallium bond lengths, which together with computational and spectroscopic data confirm its aromatic character. Our results prove that aromatic stabilization goes far beyond what has previously been assumed as minimum π-electron count in a five-atom ring fragment.

Analysis of Non-innocence of Phosphaquinodimethane Ligands when Charge and Aromaticity Come into Play.

Several phosphaquinodimethanes and their M(CO)5 complexes (M=Cr, Mo, W) and model derivatives have been theoretically investigated regarding the quest of non-innocence. Computed structural and electronic properties of the P-Me/NH2 substituted phosphaquinodimethanes and tungsten complexes revealed an interesting non-innocent ligand behaviour for the radical anion complexes with distonic ion character and a strong rearomatization of the middle phenyl ring. The latter was further probed taking also geometric aromaticity (HOMA) and quinoid distortion parameters (HOMQc) into account, as well as NICS(1). Furthermore, the effect of the P-substitution was investigated for real (or plausible) complexes and their free ligands focusing on the resulting aromaticity at the middle phenyl ring and vertical one-electron redox processes. The best picture of ligand engagement in redox changes was provided by representing NICS(1) values versus HOMA and the new geometric distortion parameter HOMQc8.

Prediction of Spin Density, Baird-Antiaromaticity, and Singlet-Triplet Energy Gap in Triplet-State Polybenzenoid Systems from Simple Structural Motifs.

Triplet-state aromaticity has been recently proposed as a strategy for designing functional organic electronic compounds, many of which are polycyclic aromatic systems. However, in many cases, the aromatic nature of the triplet state cannot be easily predicted. Moreover, it is often unclear how specific structural manipulations affect the electronic properties of the excited-state compounds. Herein, the relationship between the structure of polybenzenoid hydrocarbons (PBHs) and their spin-density distribution and aromatic character in the first triplet excited state is studied. Although a direct link is not immediately visible, classifying the PBHs according to their annulation sequence reveals regularities. Based on these, a set of guidelines is defined to qualitatively predict the location of spin and paratropicity and the singlet-triplet energy gap in larger PBHs, using only their smaller tri- and tetracyclic components, and subsequently tested on larger systems.

Nucleus-Independent Chemical Shift (NICS) as a Criterion for the Design of New Antifungal Benzofuranones.

The assertion made by Wu et al. that aromaticity may have considerable implications for molecular design motivated us to use nucleus-independent chemical shifts (NICS) as an aromaticity criterion to evaluate the antifungal activity of two series of indol-4-ones. A linear regression analysis of NICS and antifungal activity showed that both tested variables were significantly related (p < 0.05); when aromaticity increased, the antifungal activity decreased for series I and increased for series II. To verify the validity of the obtained equations, a new set of 44 benzofuran-4-ones was designed by replacing the nitrogen atom of the five-membered ring with oxygen in indol-4-ones. The NICS(0) and NICS(1) of benzofuran-4-ones were calculated and used to predict their biological activities using the previous equations. A set of 10 benzofuran-4-ones was synthesized and tested in eight human pathogenic fungi, showing the validity of the equations. The minimum inhibitory concentration (MIC) in yeasts was 31.25 µg·mL-1 for Candida glabrata, Candida krusei and Candida guilliermondii with compounds 15-32, 15-15 and 15-1. The MIC for filamentous fungi was 1.95 µg·mL-1 for Aspergillus niger for compounds 15-1, 15-33 and 15-34. The results obtained support the use of NICS in the molecular design of compounds with antifungal activity.

Interplay Between Planar and Spherical Aromaticity: Shielding Cone Behavior in Dual Planar-Planar, Planar-Spherical and Spherical-Spherical Aromatics.

The shielding cone concept is one of the most characteristic aspects of planar aromatic species. Herein, we explored how two neighbor aromatic moieties behave as dual planar-planar, planar-spherical, and spherical-spherical species given by biphenyl, [PhCB11 H11 ]- , and [CB11 H11 ]2 2- , respectively. Our results show two separate aromatic regimes given by Clar's sextet and spherical aromatic states, with independent shielding cones sharing shielding regions of moderate strength, which can be extended for networks involving multiple independent aromatic states.

NICS-XY-Scan Predictions of Local, Semi-Global, and Global Ring Currents in Annulated Pentalene and s-Indacene Cores Compared to First-Principles Current Density Maps.

The magnetic response of a set of 20 molecules, their dications and their dianions has been studied by the NICS-XY method, and the results have been compared with first principles current density maps. The molecules have been built from pentalene and s-indacene by single and double annulation of cyclobutadiene, benzene and benzocyclobutadiene in an alternate fashion on both sides of the molecules. The prediction of tropicities obtained by the NICS-XY method are overall consistent with the current density maps. A literal code, developed to give a compact description of the tropicities of currents flowing around rings and bonds cut by the scan trajectory shows that, in most cases, the NICS-XY method leads to an exact match with the current density analyses. Mismatches are generally due to small circulations out of the scan trajectory, and they do not correspond to misinterpretations of the overall tropicities. The dataset provides several cases where the prediction of the overall antiaromatic/aromatic response by the 4n/4n+2 count of π electrons fails.

Non-conventional Hydrogen Bonding and Aromaticity: A Systematic Study on Model Nucleobases and Their Solvated Clusters.

The conceptual development of aromaticity is essential to rationalize and understand the structure and behavior of aromatic heterocycles. This work addresses for the first time, the interconnection between aromaticity and sulfur/selenium centered hydrogen bonds (S/SeCHBs) involved in representative heterocycle models of canonical nucleobases (2-Pyridone; 2PY) and its sulfur (2-Thiopyridone; 2TPY) and selenium (2-Selenopyridone; 2SePY) analogs. The nucleus-independent chemical shift (NICS) and gauge induced magnetic current density (GIMIC) values suggested significant reduction of aromaticity upon replacement of exocyclic carbonyl oxygen with sulfur and selenium. However, we observed two-fold (57 %) and three-fold (80 %) enhancement in the aromaticity for 2TPY dimer, and 2SePY dimer, respectively which are connected through S/SeCHBs. Aromaticity enhancement was also noticed in 1 : 1 H-bonded complexes (heterodimers), micro hydrated clusters and for bulk hydration. It is expected that exocyclic S and Se incorporation into heterocycles without compromising aromatic loss would definitely reinforce to design new supramolecular building blocks via S/SeCH-bonded complexes.