Towards an atomistic understanding of polymorphism in molecular solids.

Understanding and controlling polymorphism in molecular solids is a major unsolved problem in crystal engineering. While the ability to calculate accurate lattice energies with atomistic modelling provides valuable insight into the associated energy scales, existing methods cannot connect energy differences to the delicate balances of intra- and intermolecular forces that ultimately determine polymorph stability ordering. We report herein a protocol for applying Quantum Chemical Topology (QCT) to study the key intra- and intermolecular interactions in molecular solids, which we use to compare the three known polymorphs of succinic acid including the recently-discovered γ form. QCT provides a rigorous partitioning of the total energy into contributions associated with topological atoms, and a quantitative and chemically intuitive description of the intra- and intermolecular interactions. The newly-proposed Relative Energy Gradient (REG) method ranks atomistic energy terms (steric, electrostatic and exchange) by their importance in constructing the total energy profile for a chemical process. We find that the conformation of the succinic acid molecule is governed by a balance of large and opposing electrostatic interactions, while the H-bond dimerisation is governed by a combination of electrostatics and sterics. In the solids, an atomistic energy balance emerges that governs the contraction, towards the equilibrium geometry, of a molecular cluster representing the bulk crystal. The protocol we put forward is as general as the capabilities of the underlying quantum-mechanical model and it can provide novel perspectives on polymorphism in a wide range of chemical systems.

Increasing frequency of gene copy number aberrations is associated with immunosuppression and predicts poor prognosis in gastric adenocarcinoma.

BACKGROUND: Patients with Epstein-Barr virus-positive gastric cancers or those with microsatellite instability appear to have a favourable prognosis. However, the prognostic value of the chromosomal status (chromosome-stable (CS) versus chromosomal instable (CIN)) remains unclear in gastric cancer. METHODS: Gene copy number aberrations (CNAs) were determined in 16 CIN-associated genes in a retrospective study including test and validation cohorts of patients with gastric cancer. Patients were stratified into CS (no CNA), CINlow (1-2 CNAs) or CINhigh (3 or more CNAs). The relationship between chromosomal status, clinicopathological variables, and overall survival (OS) was analysed. The relationship between chromosomal status, p53 expression, and tumour infiltrating immune cells was also assessed and validated externally. RESULTS: The test and validation cohorts included 206 and 748 patients, respectively. CINlow and CINhigh were seen in 35.0 and 15.0 per cent of patients, respectively, in the test cohort, and 48.5 and 20.7 per cent in the validation cohort. Patients with CINhigh gastric cancer had the poorest OS in the test and validation cohorts. In multivariable analysis, CINlow, CINhigh and pTNM stage III-IV (P < 0.001) were independently associated with poor OS. CIN was associated with high p53 expression and low immune cell infiltration. CONCLUSION: CIN may be a potential new prognostic biomarker independent of pTNM stage in gastric cancer. Patients with gastric cancer demonstrating CIN appear to be immunosuppressed, which might represent one of the underlying mechanisms explaining the poor survival and may help guide future therapeutic decisions.

Detecting fine and elaborate movements with piezo sensors provides non-invasive access to overlooked behavioral components.

Behavioral phenotyping devices have been successfully used to build ethograms, but many aspects of behavior remain out of reach of available phenotyping systems. We now report on a novel device, which consists in an open-field platform resting on highly sensitive piezoelectric (electromechanical) pressure-sensors, with which we could detect the slightest movements (up to individual heart beats during rest) from freely moving rats and mice. The combination with video recordings and signal analysis based on time-frequency decomposition, clustering, and machine learning algorithms provided non-invasive access to previously overlooked behavioral components. The detection of shaking/shivering provided an original readout of fear, distinct from but complementary to behavioral freezing. Analyzing the dynamics of momentum in locomotion and grooming allowed to identify the signature of gait and neurodevelopmental pathological phenotypes. We believe that this device represents a significant progress and offers new opportunities for the awaited advance of behavioral phenotyping.

Probing the polarity of spontaneous perisomatic GABAergic synaptic transmission in the mouse CA3 circuit in vivo.

The hypothesis that reversed, excitatory GABA may be involved in various brain pathologies, including epileptogenesis, is appealing but controversial because of the technical difficulty of probing endogenous GABAergic synaptic function in vivo. We overcome this challenge by non-invasive extracellular recording of neuronal firing responses to optogenetically evoked and spontaneously occurring inhibitory perisomatic GABAergic field potentials, generated by individual parvalbumin interneurons on their target pyramidal cells. Our direct probing of GABAergic transmission suggests a rather anecdotal participation of excitatory GABA in two specific models of epileptogenesis in the mouse CA3 circuit in vivo, even though this does not preclude its expression in other brain areas or pathological conditions. Our approach allows the detection of distinct alterations of inhibition during spontaneous activity in vivo, with high sensitivity. It represents a promising tool for the investigation of excitatory GABA in different pathological conditions that may affect the hippocampal circuit.

Spatial profiling of gastric cancer patient-matched primary and locoregional metastases reveals principles of tumour dissemination.

OBJECTIVE: Endoscopic mucosal biopsies of primary gastric cancers (GCs) are used to guide diagnosis, biomarker testing and treatment. Spatial intratumoural heterogeneity (ITH) may influence biopsy-derived information. We aimed to study ITH of primary GCs and matched lymph node metastasis (LNmet). DESIGN: GC resection samples were annotated to identify primary tumour superficial (PTsup), primary tumour deep (PTdeep) and LNmet subregions. For each subregion, we determined (1) transcriptomic profiles (NanoString 'PanCancer Progression Panel', 770 genes); (2) next-generation sequencing (NGS, 225 gastrointestinal cancer-related genes); (3) DNA copy number profiles by multiplex ligation-dependent probe amplification (MLPA, 16 genes); and (4) histomorphological phenotypes. RESULTS: NanoString profiling of 64 GCs revealed no differences between PTsup1 and PTsup2, while 43% of genes were differentially expressed between PTsup versus PTdeep and 38% in PTsup versus LNmet. Only 16% of genes were differently expressed between PTdeep and LNmet. Several genes with therapeutic potential (eg IGF1, PIK3CD and TGFB1) were overexpressed in LNmet and PTdeep compared with PTsup. NGS data revealed orthogonal support of NanoString results with 40% mutations present in PTdeep and/or LNmet, but not in PTsup. Conversely, only 6% of mutations were present in PTsup and were absent in PTdeep and LNmet. MLPA demonstrated significant ITH between subregions and progressive genomic changes from PTsup to PTdeep/LNmet. CONCLUSION: In GC, regional lymph node metastases are likely to originate from deeper subregions of the primary tumour. Future clinical trials of novel targeted therapies must consider assessment of deeper subregions of the primary tumour and/or metastases as several therapeutically relevant genes are only mutated, overexpressed or amplified in these regions.

Iliac Fossa Muscle Splitting Incision in Laparoscopic Donor Nephrectomy: A comparison With the Suprapubic Approach.

OBJECTIVE: To compare the outcomes of a transverse suprapubic incision with peritoneal access through the midline (SPM) and an iliac fossa muscle splitting (IFMS) incision for kidney retrieval during laparoscopic donor nephrectomy (LDN). MATERIAL AND METHODS: This observational retrospective comparative cohort study was performed using data from a prospectively maintained database to compare the outcomes of 2 different incisions (SPM n = 35 and IFMS n = 35) used for kidney retrieval during LDN. All incisions were infiltrated with local anesthesia at the time of closure. The primary outcome measure was postoperative analgesic requirements. Secondary outcome measures included donor complication rates and recipient outcomes. Selection bias was minimized by the study of 2 consecutive series of donors. RESULTS: Overall, 28 of the 70 (40%) of the total cohort were male. There was no difference between age (IFMS 49 ± 12 vs SPM 49 ± 11 years, P = .317), body mass index (IFMS 26.5 ± 3.9 vs SPM 25.9 ± 3.3 kg/m2, P = .493), and total postoperative opioid analgesic requirements (IFMS 213 ± 168 vs SPM 211 ± 168 mg, P = .807) between the 2 groups. The volume of local anesthetic infiltrated during wound closure was higher in the IFMS 0.470 ± 0.160 vs SPM 0.370 ± 0.234 mL/kg (P = .030) and associated with a reduction in postoperative opioid requirements (r = -0.511, P = .002). There were no major donor or recipient postoperative complications in either group and no difference in renal allograft function at 3-, 6-, 9-, or 12 months post-transplant. CONCLUSION: An iliac fossa muscle splitting incision is a straightforward and safe approach, providing a reasonable alternative to the more traditional and widely used suprapubic incision for kidney retrieval during LDN.

An Interacting Quantum Atoms (IQA) and Relative Energy Gradient (REG) Study of the Halogen Bond with Explicit Analysis of Electron Correlation.

Energy profiles of seven halogen-bonded complexes were analysed with the topological energy partitioning called Interacting Quantum Atoms (IQA) at MP4(SDQ)/6-31+G(2d,2p) level of theory. Explicit interatomic electron correlation energies are included in the analysis. Four complexes combine X2 (X = Cl or F) with HCN or NH3, while the remaining three combine ClF with HCN, NH3 or N2. Each complex was systematically deformed by translating the constituent molecules along its central axis linking X and N, and reoptimising its remaining geometry. The Relative Energy Gradient (REG) method (Theor. Chem. Acc. 2017, 136, 86) then computes which IQA energies most correlate with the total energy during the process of complex formation and further compression beyond the respective equilibrium geometries. It turns out that the covalent energy (i.e., exchange) of the halogen bond, X…N, itself drives the complex formation. When the complexes are compressed from their equilibrium to shorter X…N distance then the intra-atomic energy of N is in charge. When the REG analysis is restricted to electron correlation then the interatomic correlation energy between X and N again drives the complex formation, and the complex compression is best described by the destabilisation of the through-space correlation energy between N and the "outer" halogen.

Quantum chemical intensity determinations of overlapped gas phase infrared bands.

The largest source of experimental error in determining gas phase fundamental infrared intensities arises from the separation of overlapped bands. Quantum chemical calculations at the QCISD/cc-pVTZ and QCISD/aug-cc-pVTZ levels were carried out on four simple hydrocarbons and the fluoro- and chloromethanes with the aim of accurate overlapped band separation. Fundamental vibrational intensity results were compared with individual empirical intensity estimates reported for overlapped band systems. Root mean square differences of 3.7 km mol-1 are found between the experimental and QCISD/cc-pVTZ values for nine overlapped bands of the hydrocarbons and 11.8 km mol-1 for the QCISD/aug-cc-pVTZ values for 12 overlapped bands of the fluoro- and chloromethanes. These values correspond to 14% and 18% of the average hydrocarbon and halomethane intensity values. Previous experimental separation errors were estimated to be quite larger, between 20% and 50%. As quantum calculations are continuously being refined one can expect more accurate band separation results in the future.

Transobturator suburethral tape versus suburethral tape placement in female stress urinary incontinence / Cinta suburetral versus cinta transobsturatriz en el tratamiento de la incontinencia urinaria de esfuerzo femenina

ABSTRACT Introduction : The surgical management of stress urinary incontinence uses the transobturator tape (TOT) technique since 2006. We present a study applying the suburethral tape as a better alternative that does not require the TOT needle. Objective : To demonstrate the advantages of the suburethral tape placement technique over the transobturator tape technique in the surgical treatment of stress urinary incontinence. Methods : Observational comparative study using the non- invasive suburethral tape placement versus the transobturator tape technique. Results : Fifty patients were treated with TOT for stress urinary incontinence and other 50 patients were managed with suburethral tape placement (UTP) in the previous shift the same day or the preceding day. The TOT patients were 56 years old on average, and time of the procedure was 18 minutes on average. Complications included pain in the inguinal area (13 cases), mesh extrusion (2 cases), and suture dehiscence of anterior colporrhaphy, presence of left inguinoperineal granuloma due to mesh reaction and bruising in the left obturator area (one case of each). The 50 patients treated with UTP were 56 years old on average, operating time was 7 minutes on average, and there were no complications. The cost of the TOT kit was about US$ 1 000.00, and the suburethral tape cost was US$ 50.00. Conclusions : In this study of stress urinary incontinence treatment, the suburethral tape technique was safer than the transobturator tape technique and had a lower cost.

RESUMEN Introducción . Entre los tratamientos quirúrgicos de la incontinencia urinaria de esfuerzo se emplea la técnica de la cinta transobturatriz (TOT, por sus siglas en inglés) desde el 2006 hasta la actualidad. Se presenta un estudio con la aplicación de la cinta uretral (UTP, por sus siglas en inglés) como mejor alternativa al no usar la aguja del TOT. Objetivo . Demostrar las ventajas de la aplicación de la cinta suburetral versus la cinta transobturatriz en el tratamiento quirúrgico de la incontinencia urinaria de esfuerzo. Métodos . Estudio observacional, comparativo con la técnica no invasiva empleando cinta suburetral versus la técnica de la cinta transobturatriz. Resultados . Se evaluó 50 pacientes intervenidas con TOT, quienes precedieron un turno el mismo día o el día precedente a las pacientes operadas con la cinta uretral. El promedio de edad fue 56 años y el tiempo promedio del procedimiento fue 18 minutos. Las complicaciones consistieron en dolor en la zona inguinal (13 casos), extrusión de malla (2 casos) y, una de cada caso, dehiscencia de sutura de la colpoporrafia anterior, presencia de granuloma inguinoperineal izquierdo por reacción a la malla, hematoma en zona obturatriz izquierda. En los 50 casos tratados con cinta suburetral, el promedio de edad fue 56 años, el tiempo operatorio 7 minutos y no existió complicación alguna. El costo del kit de la TOT fue alrededor de US$ 1 000.00; la cinta suburetral costó US$ 50.00. Conclusiones . En la presente serie de manejo de la incontinencia urinaria de esfuerzo, la técnica de la cinta suburetral resultó más segura que la técnica de la cinta transobturatriz y fue de menor costo.

A FFLUX Water Model: Flexible, Polarizable and with a Multipolar Description of Electrostatics.

Key to progress in molecular simulation is the development of advanced models that go beyond the limitations of traditional force fields that employ a fixed, point charge-based description of electrostatics. Taking water as an example system, the FFLUX framework is shown capable of producing models that are flexible, polarizable and have a multipolar description of the electrostatics. The kriging machine-learning methods used in FFLUX are able to reproduce the intramolecular potential energy surface and multipole moments of a single water molecule with chemical accuracy using as few as 50 training configurations. Molecular dynamics simulations of water clusters (25-216 molecules) using the new FFLUX model reveal that incorporating charge-quadrupole, dipole-dipole, and quadrupole-charge interactions into the description of the electrostatics results in significant changes to the intermolecular structuring of the water molecules. © 2019 The Authors. Journal of Computational Chemistry published by Wiley Periodicals, Inc.

Atomic Partitioning of the MPn (n = 2, 3, 4) Dynamic Electron Correlation Energy by the Interacting Quantum Atoms Method: A Fast and Accurate Electrostatic Potential Integral Approach.

Recently, the quantum topological energy partitioning method called interacting quantum atoms (IQA) has been extended to MPn (n = 2, 3, 4) wave functions. This enables the extraction of chemical insight related to dynamic electron correlation. The large computational expense of the IQA-MPn approach is compensated by the advantages that IQA offers compared to older nontopological energy decomposition schemes. This expense is problematic in the construction of a machine learning training set to create kriging models for topological atoms. However, the algorithm presented here markedly accelerates the calculation of atomically partitioned electron correlation energies. Then again, the algorithm cannot calculate pairwise interatomic energies because it applies analytical integrals over whole space (rather than over atomic volumes). However, these pairwise energies are not needed in the quantum topological force field FFLUX, which only uses the energy of an atom interacting with all remaining atoms of the system that it is part of. Thus, it is now feasible to generate accurate and sizeable training sets at MPn level of theory. © 2019 The Authors. Journal of Computational Chemistry published by Wiley Periodicals, Inc.

Infrared Intensification and Hydrogen Bond Stabilization: Beyond Point Charges.

Infrared band intensification of the A-H bond stretching mode of A-H···B acid-base systems has long been known to be the most spectacular spectral change occurring on hydrogen bonding. A QTAIM/CCTDP model is reported here to quantitatively explain the electronic structure origins of intensification and investigate the correlation between experimental enthalpies of formation and infrared hydrogen bond stretching intensifications amply reported in the literature. Augmented correlation-consistent polarized triple-zeta quantum calculations at the MP2 level were performed on complexes with HF and HCl electron acceptors and HF, HCl, NH3, H2O, HCN, acetonitrile, formic acid, acetaldehyde, and formaldehyde electron donor molecules. The A-H stretching band intensities are calculated to be 3 to 40 times larger than their monomer values. Although the acidic hydrogen atomic charge is important for determining the intensities of HF complexes relative to HCl complexes with the same electron donor, they are not important for infrared intensifications occurring on hydrogen bond formation for a series of bases with a common acid. Charge transfers are found to be the most important factor resulting in the intensifications, but dipolar polarization effects are also significant for each series of complexes. A mechanism involving intra-acid and intermolecular electron transfers as well as atomic polarizations is proposed for understanding the intensifications. The calculated sums of the intermolecular electron transfer and acid dipolar polarization contributions to the dipole moment derivatives for each series of complexes are highly correlated with their enthalpies of formation and H-bond intensifications. This could be related to increasing electron transfer from base to acid that correlates with the calculated hydrogen bonding energies and may be a consequence of the A-H bond elongation on complex formation having amplitudes similar to those expected for the A-H vibration.

Correction to: KRAS status is related to histological phenotype in gastric cancer: results from a large multicentre study.

In the original publication of this article, Fig. 2 was published incorrectly. The correct Fig. 2 is given in this correction.

KRAS status is related to histological phenotype in gastric cancer: results from a large multicentre study.

BACKGROUND: Gastric cancer (GC) is histologically a very heterogeneous disease, and the temporal development of different histological phenotypes remains unclear. Recent studies in lung and ovarian cancer suggest that KRAS activation (KRASact) can influence histological phenotype. KRASact likely results from KRAS mutation (KRASmut) or KRAS amplification (KRASamp). The aim of the study was to investigate whether KRASmut and/or KRASamp are related to the histological phenotype in GC. METHODS: Digitized haematoxylin/eosin-stained slides from 1282 GC resection specimens were classified according to Japanese Gastric Cancer Association (JGCA) and the Lauren classification by at least two observers. The relationship between KRAS status, predominant histological phenotype and clinicopathological variables was assessed. RESULTS: KRASmut and KRASamp were found in 68 (5%) and 47 (7%) GCs, respectively. Within the KRASmut and KRASamp cases, the most frequent GC histological phenotype was moderately differentiated tubular 2 (tub2) type (KRASmut: n = 27, 40%; KRASamp: n = 21, 46%) or intestinal type (KRASmut: n = 41, 61%; KRASamp: n = 23, 50%). Comparing individual histological subtypes, mucinous carcinoma displayed the highest frequency of KRASmut (JGCA: n = 6, 12%, p = 0.012; Lauren: n = 6, 12%, p = 0.013), and KRASamp was more frequently found in poorly differentiated solid type (n = 12, 10%, p = 0.267) or indeterminate type (n = 12, 10%, p = 0.480) GC. 724 GCs (57%) had intratumour morphological heterogeneity. CONCLUSIONS: This is the largest GC study investigating KRAS status and histological phenotype. We identified a relationship between KRASmut and mucinous phenotype. The high level of intratumour morphological heterogeneity could reflect KRASmut heterogeneity, which may explain the failure of anti-EGFR therapy in GC.

Adhesional small bowel obstruction related to stapling device from previous laparoscopic inguinal hernia repair.

Small bowel obstruction (SBO) is common surgical presenting problem, accounting for roughly 15 000 laparotomies per year in the UK. However, SBO post laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair is uncommon with an estimated incidence of 0.2%-0.5%. The common causes for SBO post-TAPP include inadequate closure, port-site herniation and adhesions. Here, we present a case of adhesional SBO related to stapling device from previous laparoscopic inguinal hernia repair and review alternative methods for mesh fixation. This case reports a rare but life-threatening complication from a commonly performed day case procedure and highlights importance of adequate surgical technique when inserting foreign bodies intra-abdominally. The patient required an emergency laparotomy and small bowel resection, developed postoperative ileus which managed with a nasogastric tube, intravenous fluids and parenteral nutrition and was discharged 12 days postoperatively.

Dolichoectasia Presenting as Renal Artery Aneurysm in a Deceased Donor Kidney: A Case Report and Review of the Literature.

We describe a case of fusiform aneurysm of the renal artery on a background of dolichoectasia in a kidney recovered from a deceased donor. The donor, a 57-year-old female, had died of an extensive nonsurvivable subarachnoid hemorrhage. Fusiform aneurysms involving the main renal artery and its superior branch had extended into the hilum with insufficient accessible stump for safe reconstruction. Placement of a stent through an intraoperative radiologic intervention was not possible without compromising renal perfusion. Consequently, renal transplant did not proceed. Dolichoectasia is a condition associated with generalized weakness of the arterial vascular wall and may result in aneurysm formation. When the renal artery is involved, a safe reconstruction excising the aneurysmal segment may be considered before transplant of the kidney.

Decomposition of Møller-Plesset Energies within the Quantum Theory of Atoms-in-Molecules.

We discuss two main approaches to decompose the Møller-Plesset perturbation theory molecular energies into atomic contributions within the interacting quantum atoms (IQA) formalism, as implemented in the programs Morphy and AIMAll. For this purpose, the so-called intraatomic energies (also known as self-energies) of a representative set of 55 small molecules are compared with each other. The origin of the possible discrepancies between both approaches is analyzed, and linear models linking the two approaches are proposed for each atom type.

Repetitive Peripheral Sensory Stimulation and Upper Limb Performance in Stroke: A Systematic Review and Meta-analysis.

BACKGROUND: Enhancement of sensory input in the form of repetitive peripheral sensory stimulation (RPSS) can enhance excitability of the motor cortex and upper limb performance. OBJECTIVE: To perform a systematic review and meta-analysis of effects of RPSS compared with control stimulation on improvement of motor outcomes in the upper limb of subjects with stroke. METHODS: We searched studies published between 1948 and December 2017 and selected 5 studies that provided individual data and applied a specific paradigm of stimulation (trains of 1-ms pulses at 10 Hz, delivered at 1 Hz). Continuous data were analyzed with means and standard deviations of differences in performance before and after active or control interventions. Adverse events were also assessed. RESULTS: There was a statistically significant beneficial effect of RPSS on motor performance (standard mean difference between active and control RPSS, 0.67; 95% CI, 0.09-1.24; I2 = 65%). Only 1 study included subjects in the subacute phase after stroke. Subgroup analysis of studies that only included subjects in the chronic phase showed a significant effect (1.04; 95% CI, 0.66-1.42) with no heterogeneity. Significant results were obtained for outcomes of body structure and function as well as for outcomes of activity limitation according to the International Classification of Function, Disability and Health, when only studies that included subjects in the chronic phase were analyzed. No serious adverse events were reported. CONCLUSIONS: RPSS is a safe intervention with potential to become an adjuvant tool for upper extremity paresis rehabilitation in subjects with stroke in the chronic phase.

FTIR and dispersive gas phase fundamental infrared intensities of the fluorochloromethanes: Comparison with QCISD/cc-pVTZ results.

New experimental values of the fundamental infrared gas phase intensities of the fluorochloromethanes have been determined by integrating the areas of vibrational bands contained in the PNNL spectral library using homemade software. The root mean square differences of these values and averages of experimental values determined at lower resolution during the latter part of the 20th century is 26.6 km mol-1. All but one of the low resolution intensities are smaller than the PNNL values. The exception is the ν1,ν4 overlapped band intensity of CF3Cl that has a standard deviation of the low resolution values of ±112.5 km mol-1, larger than the observed difference of 102.5 km mol-1. The use of an augmented triple zeta basis set at the QCISD level results in an rms difference of only 8.4 km mol-1 for the fluoro- and chloromethane PNNL intensities, whereas a comparison of these with results at the QCISD/cc-pVTZ level produces an error twice as large, 16.2 km mol-1. As such these results suggest that future comparisons of theoretical intensities with experimental values should take into account integrated intensities that can be obtained from hundreds of spectra in the PNNL library. Furthermore, the intensity values obtained from the PNNL spectra confirm electronegativity model results previously reported based on the low resolution intensities.