A comparison of methods to harmonize cortical thickness measurements across scanners and sites.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Deep eutectic solvent mediated synthesis of 3,4-dihydropyrimidin-2(1H)-ones and evaluation of biological activities targeting neurodegenerative disorders.

Substitution of hazardous and often harmful organic solvents with "green" and "sustainable" alternative reaction media is always desirous. Ionic liquids (IL) have emerged as valuable and versatile liquids that can replace most organic solvents in a variety of syntheses. However, recently new types of low melting mixtures termed as Deep Eutectic Solvents (DES) have been utilized in organic syntheses. DES are non-volatile in nature, have sufficient thermal stability, and also have the ability to be recycled and reused. Hence DES have been used as alternative reaction media to perform different organic reactions. The availability of green, inexpensive and easy to handle alternative solvents for organic synthesis is still scarce, hence our interest in DES mediated syntheses. Herein we have investigated Biginelli reaction in different DES for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Monoamine oxidases and cholinesterases are important drug targets for the treatment of various neurological disorders such as Alzheimer's disease, Parkinson's disease, depression and anxiety. The compounds synthesized herein were evaluated for their inhibitory potential against these enzymes. Some of the compounds were found to be highly potent and selective inhibitors. Compounds 1 h and 1c were the most active monoamine oxidase A (MAO A) (IC50 = 0.31 ± 0.11 µM) and monoamine oxidase B (MAO B) (IC50 = 0.34 ± 0.04 µM) inhibitors respectively. All compounds were selective AChE inhibitors and did not inhibit BChE (<29% inhibition). Compound 1 k (IC50 = 0.13 ± 0.09 µM) was the most active AChE inhibitor.

Development of a formative feedback tool for transanal total mesorectal excision.

INTRODUCTION: Transanal total mesorectal excision (TaTME) is a novel procedure in the treatment of rectal cancer. Current training models for TaTME suggest a period of proctored cases, but no structured feedback tool exists to guide operators during the learning phase. The objective of this study therefore was to develop a formative feedback tool for the critical steps of the transanal portion of TaTME. METHODS: A two-round Delphi study by TaTME experts was conducted to determine the items to be included in the formative feedback tool. Participants rated each step from a prepared list using a Likert scale from 1 (Not relevant) to 5 (Very relevant) with the option to suggest additional steps. Responses to the first round were presented in the second round, where participants rated the revised list of steps. Consensus was defined as > 80% of participants rating the step as 4 or 5 (out of 5). Items were combined when appropriate to avoid redundancy. Rating anchors describing performance (on a 5-point scale) were then developed for each step. The final tool was recirculated and participants rated the finished product on its feasibility and usefulness. RESULTS: Twenty-six TaTME experts were contacted for participation. Fifteen experts (58%) participated in the first round of the study, and eleven (42%) participated in the second round. The majority (14, 93%) had completed fellowship training in colorectal surgery. The first round of the Delphi study contained 34 items, and 32 items met inclusion criteria after the second round. Redundant items were combined into 15 items that comprised the final tool. Out of eight respondents to the feasibility survey, all believed the feedback tool enhances the feedback of learners and would use it for training purposes if available. CONCLUSION: This work describes the development of a novel consensus-based formative feedback tool specific to TaTME.

Design, Synthesis, and Biological Evaluation of Novel Dihydropyridine and Pyridine Analogs as Potent Human Tissue Nonspecific Alkaline Phosphatase Inhibitors with Anticancer Activity: ROS and DNA Damage-Induced Apoptosis.

Small molecules with nitrogen-containing scaffolds have gained much attention due to their biological importance in the development of new anticancer agents. The present paper reports the synthesis of a library of new dihydropyridine and pyridine analogs with diverse pharmacophores. All compounds were tested against the human tissue nonspecific alkaline phosphatase (h-TNAP) enzyme. Most of the compounds showed excellent enzyme inhibition against h-TNAP, having IC50 values ranging from 0.49 ± 0.025 to 8.8 ± 0.53 µM, which is multi-fold higher than that of the standard inhibitor (levamisole = 22.65 ± 1.60 µM) of the h-TNAP enzyme. Furthermore, an MTT assay was carried out to evaluate cytotoxicity against the HeLa and MCF-7 cancer cell lines. Among the analogs, the most potent dihydropyridine-based compound 4d was selected to investigate pro-apoptotic behavior. The further analysis demonstrated that compound 4d played a significant role in inducing apoptosis through multiple mechanisms, including overproduction of reactive oxygen species, mitochondrial dysfunction, DNA damaging, and arrest of the cell cycle at the G1 phase by inhibiting CDK4/6. The apoptosis-inducing effect of compound 4d was studied through staining agents, microscopic, and flow cytometry techniques. Detailed structure-activity relationship (SAR) and molecular docking studies were carried out to identify the core structural features responsible for inhibiting the enzymatic activity of the h-TNAP enzyme. Moreover, fluorescence emission studies corroborated the binding interaction of compound 4d with DNA through a fluorescence titration experiment.

Formulation and assessment of controlled release tablets of famotidine by using eudragit RL 100 polymer.

Controlled release in drug release kinetics denotes reproducibility and predictability, implying that drug release from delivery devices follows a kinetically predictable and repeatable rate profile from dose to dose. In the current study controlled release tablets of famotidine were prepared by direct compression technique using Eudragit RL 100 polymer. Four different formulations of controlled release tablets of famotidine as (F1, F2, F3 and F4) were prepared by adding different drug to polymer ratio. The pre compression and the post compression of the formulation, characteristics were compared. All results obtained were within the specified standard limits. FTIR studies showed that both the drug and the polymer were compatible. In vitro dissolution study were conducted by Method II (Paddle Method) in phosphate buffer (pH 7.4), at 100rpm. Power law kinetic model was applied for drug release mechanism. The difference similarity of the dissolution profile was determined. The formulation F1 and F2 were released 97 and 96 % in 24 hours and other formulations F3 and F4 were released subsequently 93% and 90% in 24 hours. The results showed that incorporation of Eudragit RL 100 in the formulation of controlled release tablets prolong the drug release rates for 24 hours. The release mechanism was Non-Fickian diffusion mechanism. It was deducted from the current study that the Eudragit RL 100 can be efficiently incorporated in the formulation of controlled release dosage forms with predictable kinetics.

Readmission for Treatment Failure After Nonoperative Management of Acute Diverticulitis: A Nationwide Readmissions Database Analysis.

BACKGROUND: The true incidence of, and risk factors for, readmission for treatment failure after nonoperative management of acute diverticulitis remain poorly understood. OBJECTIVE: The purpose of this study was to describe the incidence and risk factors for readmission for treatment failure after nonoperative management of acute diverticulitis using a large national database. DESIGN: This was a retrospective cohort study. SETTINGS: A representative sample of admissions and discharges from hospitals in the United States captured in the National Readmissions Database were included. PATIENTS: Adult patients (age ≥18 y) admitted with a primary diagnostic of colonic diverticulitis between 2010 and 2015 and who were managed nonoperatively and discharged from hospital alive were included. INTERVENTIONS: Study intervention included nonoperative management, consisting of medical therapy with or without percutaneous drainage. MAIN OUTCOME MEASURES: Readmission for treatment failure (defined as a nonelective readmission for diverticulitis within 90 d of discharge), complicated treatment failure (defined as a treatment failure with complicated diverticulitis), and time-to-treatment failure were measured. RESULTS: In total, 201,384 patients were included. The overall incidence of readmission for treatment failure was 6.6%. Treatment failure was significantly higher among patients with an index episode of acute complicated diverticulitis compared with acute uncomplicated diverticulitis (12.5% vs 5.7%; p < 0.001). The median time-to-readmission for treatment failure was 21.0 days (range, 20.4-21.6 d), and 85% of all readmissions occurred within 60 days of discharge. On multiple logistic regression, factors independently associated with readmission for treatment failure were an index admission of complicated diverticulitis (OR = 2.06 (95% CI, 1.97-2.16)), disposition on discharge (against medical advice: OR = 1.92 (95% CI, 1.66-2.20); home health care arrangements: OR = 1.24 (95% CI, 1.16-1.33)), and immunosuppression (OR = 1.42 (95% CI, 1.28-1.57)), among others. Risk factors for a complicated treatment failure were also described, after an index episode of complicated and uncomplicated diverticulitis. LIMITATIONS: The study was limited by residual confounding from missing covariates and its observational study design. CONCLUSIONS: The incidence of readmission for treatment failure after an episode of diverticulitis managed nonoperatively is 6.6%, and an index episode of complicated diverticulitis is the strongest risk factor for treatment failure. See Video Abstract at http://links.lww.com/DCR/B92. REINGRESO POR FRACASO DEL TRATAMIENTO DESPUÉS DEL TRATAMIENTO NO QUIRÚRGICO DE LA DIVERTICULITIS AGUDA: UN ANÁLISIS DE LA BASE DE DATOS DE REINGRESOS A NIVEL NACIONAL: La verdadera incidencia y los factores de riesgo para el reingreso por fracaso del tratamiento después de manejo no quirúrgico de la diverticulitis aguda siguen siendo mal definidos.Definir la incidencia y los factores de riesgo de reingreso por fracaso del tratamiento no quirúrgico de la diverticulitis aguda utilizando una base de datos nacional.Estudio de cohorte retrospectivo.Una muestra representativa de ingresos y egresos de hospitales en los Estados Unidos capturados en la base de datos nacional de reingresos hospitalarios.Pacientes adultos (≥18 años) ingresados con un diagnóstico primario de diverticulitis colónica entre 2010-2015, y que fueron tratados de forma no operativa y dados de alta del hospital vivos.Manejo no quirúrgico, que consiste en terapia médica con o sin drenaje percutáneo.Reingreso por fracaso del tratamiento (definido como un reingreso no electivo por diverticulitis dentro de los 90 días despues de ser dados de alta), fracaso del tratamiento complicado (definido como un fracaso del tratamiento con diverticulitis complicada) y el tiempo hasta el tratamiento en casos fracasaados.201.384 pacientes incluidos en total. La incidencia global de reingreso por fracaso del tratamiento fue del 6,6%. El fracaso del tratamiento fue significativamente mayor entre los pacientes con un episodio índice de diverticulitis aguda complicada en comparación con la diverticulitis aguda no complicada (12.5% vs. 5.7%, p <0.001). La mediana del tiempo hasta el reingreso por fracaso del tratamiento fue de 21.0 (20.4 - 21.6) días, y el 85% de todos los reingresos ocurrieron dentro de los 60 días posteriores a ser dados de alta. En la regresión logística múltiple, los factores asociados independientemente con el reingreso por fracaso del tratamiento fueron un índice de admisión de diverticulitis complicada (OR 2.06, IC 95% 1.97-2.16), disposición (de alta en contra del consejo médico: OR 1.92, IC 95% 1.66-2.2; atención médica domiciliaria: OR 1.24, IC 95% 1.16-1.33) e inmunosupresión (OR 1.42, IC 95% 1.28-1.57), entre otros. Los factores de riesgo para un fracaso del tratamiento complicado también se describieron, respectivamente, después de un episodio índice de diverticulitis complicada y no complicada.Covariables faltantes y diseño de estudio observacional.La incidencia de reingreso por fracaso del tratamiento después de un episodio de diverticulitis manejado de forma no operativa es del 6,6%, y un episodio índice de diverticulitis complicada es el factor de riesgo más fuerte para el fracaso del tratamiento. Consulte Video Resumen en http://links.lww.com/DCR/B92. (Traducción-Dr. Adrian E. Ortega).

Altered Cortical Brain Structure and Increased Risk for Disease Seen Decades After Perinatal Exposure to Maternal Smoking: A Study of 9000 Adults in the UK Biobank.

Secondhand smoke exposure is a major public health risk that is especially harmful to the developing brain, but it is unclear if early exposure affects brain structure during middle age and older adulthood. Here we analyzed brain MRI data from the UK Biobank in a population-based sample of individuals (ages 44-80) who were exposed (n = 2510) or unexposed (n = 6079) to smoking around birth. We used robust statistical models, including quantile regressions, to test the effect of perinatal smoke exposure (PSE) on cortical surface area (SA), thickness, and subcortical volumes. We hypothesized that PSE would be associated with cortical disruption in primary sensory areas compared to unexposed (PSE-) adults. After adjusting for multiple comparisons, SA was significantly lower in the pericalcarine (PCAL), inferior parietal (IPL), and regions of the temporal and frontal cortex of PSE+ adults; these abnormalities were associated with increased risk for several diseases, including circulatory and endocrine conditions. Sensitivity analyses conducted in a hold-out group of healthy participants (exposed, n = 109, unexposed, n = 315) replicated the effect of PSE on SA in the PCAL and IPL. Collectively our results show a negative, long term effect of PSE on sensory cortices that may increase risk for disease later in life.

Are right-sided colectomies for neoplastic disease at increased risk of primary postoperative ileus compared to left-sided colectomies? A coarsened exact matched analysis.

INTRODUCTION: The objective of this study was to determine whether right-sided colectomies (RC) were associated with a higher incidence of primary postoperative ileus (pPOI) compared to left-sided colectomies (LC). METHODS: Patients who underwent elective colectomy for neoplastic disease between 2012 and 2016 were identified using the American College of Surgeons National Surgical Quality Improvement Program database. RC and LC were defined as having an ileocolic or colocolic/colorectal anastomosis, respectively. Coarsened Exact Matching (CEM) was used to balance the two groups (1:1) on important confounders. The association between type of colectomy and pPOI, defined as POI in the absence of intra-abdominal sepsis, was then assessed in a multiple logistic regression analysis of the matched data. RESULTS: Of 40,636 patients who underwent a colectomy for neoplastic disease, 15,231 underwent a RC and 25,405 a LC. After CEM, 12,949 matched patients remained in each group, and all important confounders were well balanced. The incidence of pPOI was higher in the RC group (11.5% vs. 8.8%, p < 0.001). On multiple logistic regression, RC was associated with a 35% higher odds of developing pPOI compared to LC (OR 1.35, 95% CI 1.25-1.47). RC was also associated with increased risk for NSQIP-defined major morbidity (OR 1.10, 95% CI 1.01-1.20), 30-day readmission (OR 1.16, 95% CI 1.06-1.27), and increased length of stay (ß = 0.16 days, 95% CI 0.11-0.22). CONCLUSION: pPOI is more common after RC than LC. Future research should aim at better understanding the pathophysiology behind this increased risk and identifying interventions to mitigate pPOI in this population.

Eco-friendly green synthesis of silver nanoparticles and their potential applications as antioxidant and anticancer agents.

Eco-friendly green synthesis of nanoparticles using medicinal plants gained immense importance due to its potential therapeutic uses. In the current study, silver nanoparticles (AgNPs) were synthesized using water extract of Jurinea dolomiaea leaf and root at room temperature. MTT assay was used to study anticancer potential of AgNPs against cervical cancer cell line (HeLa), breast cancer cell lines (MCF-7), and mouse embryonic fibroblast (NIH-3 T3) cell line for toxicity evaluation. The antioxidant potential was evaluated using stable DPPH radicals. In addition, the apoptotic nuclear changes prompted by AgNPs in more susceptible HeLa cells were observed using fluorescence microscope through DAPI and PI staining. Physiochemical properties of biosynthesized AgNPs were characterized using various techniques. AgNPs were formed in very short time and UV-vis spectra showed characteristic absorption peak of AgNPs. SEM and TEM showed spherical shape of AgNPs and XRD revealed their crystalline nature. EDX analysis revealed high percentage of silver in green synthesized AgNPs. FTIR analysis indicated involvement of secondary metabolites in fabrication of AgNPs. In vitro cytotoxic and antioxidant study revealed that herb and biosynthesized AgNPs exhibited significant dose-dependent and time-dependent anticancer and antioxidant potential. Furthermore, study on normal cell line and microscopic analysis of apoptosis revealed that AgNPs exhibited good safety profile as compared to cisplatin and induces significant apoptosis effect. Based on the current findings, it is strongly believe that use of J. dolomiaea offers large scale production of biocompatible AgNPs that can be used as alternative anticancer agents against cancer cell lines tested.

Safeguarding Culture in the Catholic Church of England and Wales in the Twenty-First Century: An Examination of Progress.

In the wake of reported scandals of child sexual abuse by Roman catholic priests in mainstream media in the 1980s/1990s and conviction of Catholic priests on similar charges in England and Wales, Lord Nolan was invited by the Archbishop of Westminster in 2000 to undertake a review of child safeguarding policies of the Catholic Church of England and Wales since 1994, known as the Nolan Report. The Nolan Report led to the establishment of the first Catholic Office for protection of children (COPCA) which remained operative from 2001-2007 before being later modified in light of the Cumberlege Review (2007) as the National Child Safeguarding Commission (NCSC) and the Catholic Safeguarding Advisory service (CSAS) since 2008 which continue to operate till today. This article conducts a hermeneutical analysis of the Nolan Report, the Cumberlege Report, the annual reports of COPCA and the National Catholic Safeguarding Commission from 2007 till 2017. Wider academic literature on the subject is included in order to critically examine the performance of these child safeguarding structures developed to prevent and control clerical sexual abuse and to evaluate the utility of the child protection measures in place within the Catholic Church of England and Wales, since 2001.

Why the Focus of Clerical Child Sexual Abuse has Largely Remained on the Catholic Church amongst Other Non-Catholic Christian Denominations and Religions.

The current study considers reasons for the consistent focus of academic research and mainstream media on clerical child sexual abuse (cCSA) largely within the Roman Catholic Church, seeming to ignore cCSA in other Christian denominations and religions. This study includes an analysis of traditional mainstream media and case reports on cCSA in non-Catholic churches and other religious faiths. The authors highlight the inadequacy of research and identify a wide range of gaps in this so far neglected area. Commonalities of cCSA and institutional responses are identified across denominations and religions, and reasons for the apparent over focus on the Catholic Church are discussed. The mains potential reasons identified were: (a) the centralized nature of the Church's universal organizational stature and management structure; (b) the anti-Catholic political and media bias in Protestant-dominated developed countries; (c) secular legal systems with access to powerful lawyers and insurance companies to locate responsibility at organizational level in order to seek compensation and finally; (d) the organized institutional power exercisable by respective bishops to silence victims. Future research needs to move beyond analysis of existing academic literature, press, and case review reports to comparative empirical studies across denominations and religions.

Magnetic resonance spectroscopy of fiber tracts in children with traumatic brain injury: A combined MRS - Diffusion MRI study.

Traumatic brain injury can cause extensive damage to the white matter (WM) of the brain. These disruptions can be especially damaging in children, whose brains are still maturing. Diffusion magnetic resonance imaging (dMRI) is the most commonly used method to assess WM organization, but it has limited resolution to differentiate causes of WM disruption. Magnetic resonance spectroscopy (MRS) yields spectra showing the levels of neurometabolites that can indicate neuronal/axonal health, inflammation, membrane proliferation/turnover, and other cellular processes that are on-going post-injury. Previous analyses on this dataset revealed a significant division within the msTBI patient group, based on interhemispheric transfer time (IHTT); one subgroup of patients (TBI-normal) showed evidence of recovery over time, while the other showed continuing degeneration (TBI-slow). We combined dMRI with MRS to better understand WM disruptions in children with moderate-severe traumatic brain injury (msTBI). Tracts with poorer WM organization, as shown by lower FA and higher MD and RD, also showed lower N-acetylaspartate (NAA), a marker of neuronal and axonal health and myelination. We did not find lower NAA in tracts with normal WM organization. Choline, a marker of inflammation, membrane turnover, or gliosis, did not show such associations. We further show that multi-modal imaging can improve outcome prediction over a single modality, as well as over earlier cognitive function measures. Our results suggest that demyelination plays an important role in WM disruption post-injury in a subgroup of msTBI children and indicate the utility of multi-modal imaging.

The Roman Catholic Church: A Centuries Old History of Awareness of Clerical Child Sexual Abuse (from the First to the 19th Century).

Debates in international forums and in mainstream media on the role, responsibility, liability, and response of ecclesiastical authorities of the Roman Catholic Church (RCC) toward clerical child sexual abuse (cCSA) fail to take into account the historical roots and awareness of the problem. Reports also fail to mention the historic organizational laws RCC developed over centuries. In contrast, RCC documents evidence that the Catholic Church not only carried century's old history of cCSA, but also repeatedly condemned cCSA by successive papal authorities, organizational laws, and institutional management mechanisms. During the first millennium, however, church laws remained confined to the bookshelves and were not converted into appropriate management policies and infrastructural models. This was largely due to the absence of a central administrative organizational structure, which developed later in the 12th century, following the Second Council of Lateran (1139) when the Papacy asserted its authority to establish administrative control over the organizational church. It was only then that management policies started to be framed and institutional structures enacted to deal more appropriately with cCSA from the 14th to 20th centuries. Despite this, RCC developed a culture of secrecy using clandestine organizational management models and institutional laws prescribed in 1568, 1622, 1741, 1866, 1922, and 1962 which aimed to manage cCSA. The current study traces reported cCSA as far back as the first century and critically examines the organizational laws, and institutional policies developed by RCC to address clerical sexual misconduct up to the end of the 19th century.

Critique of the Vatican's Role in Recent Child Protection Practice: A Brief Report.

The current report aims to clarify the practices and implicit intentions of the Holy See in addressing child sexual abuse (CSA) by clerics in the twenty-first century. Church investigation reports, United Nations reports, press coverage, and academic literature were explored to understand the relationship between Church intention and practice. Various types of literature highlight the Roman Catholic Church (RCC) as an organization that is self-referential and self-defensive, with the implicit aim of protecting the reputation of RCC at the expense of children. Organizational responses are seen as promoting the protection of perpetrating clerics, resulting in the spread of CSA by clergy nationally and globally. Recommendations are made for the introduction of modern-day management practices in RCC, filtered through a faithful understanding of gospel principles. The authors suggest that the United Nations may be an important vehicle for fostering leverage for change in RCC child protection practice.

MRI uncovers disrupted hippocampal microstructure that underlies memory impairments after early-life adversity.

Memory and related cognitive functions are progressively impaired in a subgroup of individuals experiencing childhood adversity and stress. However, it is not possible to identify vulnerable individuals early, a crucial step for intervention. In this study, high-resolution magnetic resonance imaging (MRI) and intra-hippocampal diffusion tensor imaging (DTI) were employed to examine for structural signatures of cognitive adolescent vulnerabilities in a rodent model of early-life adversity. These methods were complemented by neuroanatomical and functional assessments of hippocampal network integrity during adolescence, adulthood and middle-age. The high-resolution MRI identified selective loss of dorsal hippocampal volume, and intra-hippocampal DTI uncovered disruption of dendritic structure, consistent with disrupted local connectivity, already during late adolescence in adversity-experiencing rats. Memory deteriorated over time, and stunting of hippocampal dendritic trees was apparent on neuroanatomical analyses. Thus, disrupted hippocampal neuronal structure and connectivity, associated with cognitive impairments, are detectable via non-invasive imaging modalities in rats experiencing early-life adversity. These high-resolution imaging approaches may constitute promising tools for prediction and assessment of at-risk individuals in the clinic. © 2016 Wiley Periodicals, Inc.

Pyrazole derivatives of pyridine and naphthyridine as proapoptotic agents in cervical and breast cancer cells.

Cancer is one of the leading causes of death worldwide. The increasing prevalence and resistance to chemotherapy is responsible for driving the search of novel molecules to combat this disease. In search of novel compounds with pro-apoptotic potential, pyrazolo-pyridine and pyrazolo-naphthyridine derivatives were investigated against cervical cancer (HeLa) and breast cancer (MCF-7) cells. The anti-proliferative activity was determined through the MTT assay. Potent compounds were then analyzed for their cytotoxic and apoptotic activity through a lactate dehydrogenase assay and fluorescence microscopy after propidium iodide and DAPI staining. Flow cytometry was used to determine cell cycle arrest in treated cells and pro-apoptotic effect was verified through measurement of mitochondrial membrane potential and activation of caspases. Compounds 5j and 5k were found to be most active against HeLa and MCF-7 cells, respectively. G0/G1 cell cycle arrest was observed in treated cancer cells. Morphological features of apoptosis were also confirmed, and an increased oxidative stress indicated the involvement of reactive oxygen species in apoptosis. The compound-DNA interaction studies demonstrated an intercalative mode of binding and the comet assay confirmed the DNA damaging effects. Finally, potent compounds demonstrated a decrease in mitochondrial membrane potential and increased levels of activated caspase-9 and -3/7 confirmed the induction of apoptosis in treated HeLa and MCF-7 cells. The present work concludes that the active compounds 5j and 5k may be used as lead candidates for the development of lead drug molecules against cervical and breast cancer.

Oral Antibiotic Bowel Preparation Prior to Urgent Colectomy Reduces Odds of Organ Space Surgical Site Infections: a NSQIP Propensity-Score Matched Study.

BACKGROUND: Preoperative administration of oral antibiotic bowel preparation (OABP) alone has been shown to reduce infectious outcomes in patients undergoing elective colectomy. However, it remains unclear if these benefits extend to the emergency setting. This is a retrospective, propensity-score matched study comparing 30-day perioperative morbidity between those who received OABP alone versus no preparation prior to urgent colectomy. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database, adults undergoing urgent colectomy from 2012 to 2019 were included. Those who were clinically obstructed or who received mechanical bowel preparation were excluded. Outcomes of interest included: surgical site infection (SSI), leak, ileus, and major morbidity. RESULTS: Of 24,559 patients meeting inclusion criteria, 878 (3.6%) received OABP prior to urgent colectomy. Prior to matching, those receiving no preparation were more likely to have higher ASA class, diabetes, hypertension, preoperative sepsis, open procedures, and a dirty wound classification. After matching, 1756 patients, remained with 878 in each arm. Preoperative characteristics were balanced on univariate analysis. Postoperatively, patients receiving OABP experienced decreased organ space SSI (11.2% vs. 15.5%, p = 0.009) and ileus (30.3% vs. 35.3%, p = 0.029), with no difference in leak rates (3.3% vs 3.3%, p = 1.000) or NSQIP major morbidity (47.4% vs. 49.9%, p = 0.316). On multivariate logistic regression, including propensity score, the reduction in organ space SSI associated with OABP persisted (OR 0.684, 95% CI 0.516-0.903). CONCLUSION: OABP prior to select urgent colectomies was associated with fewer organ space SSIs and may be considered when feasible.

A Novel Method of Quantifying the Choriocapillaris in Normal and Post-inflammatory Eyes.

OBJECTIVE: To assess the reliability and validity of gray level co-occurrence matrices (GLCM) in the quantification of choriocapillaris and describe GLCM features in normal and eyes with resolved acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and serpiginous choroiditis (SC). METHODS: In this, multicenter, reliability, validity and comparative study; OCTA was performed on eyes with resolved APMPPE and SC and normal individuals. CC texture classification, low flow area measurements and GLCM feature extraction were performed. RESULTS: A total of 13 normal, 8 APMPPE and 15 SC eyes were analyzed. All GLCM parameters demonstrated an excellent reliability. GLCM parameters were differently distributed across the three groups. Decision-tree based on the random forest predictive model provided an overall accuracy of 86% in classifying the three groups using GLCM features. CONCLUSION: These data demonstrated an excellent reliability and validity of GLCM features in quantifying the choriocapillaris in healthy and diseased eyes.

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium.

BACKGROUND: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). METHODS: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2-85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis-Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2-148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. RESULTS: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. CONCLUSIONS: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

In Vitro Anticancer Effects of Stilbene Derivatives: Mechanistic Studies on HeLa and MCF-7 Cells.

BACKGROUND AND OBJECTIVE: The growing prevalence of cancer and the resulting chemoresistance exert a huge burden on healthcare systems and impose a great challenge to public health around the world. In efforts to develop new chemotherapeutic agents for cancer treatment, a class of heterocyclic compounds i.e. triazine-based molecules were investigated as anticancer agents. MATERIALS AND METHODS: New triazine hybrids of stilbene were synthesized and evaluated as anticancer agents for cervical (HeLa) and breast (MCF-7) carcinoma cells. The compound (7e), sodium (E)-6,6'-(ethene-1,2- diyl)bis(3-((4-chloro-6-((3-luorophenyl)amino)-1,3,5-triazin-2-yl)amino)benzenesulfonate) was found to be most potent among synthesized derivatives and was explored further for detailed mechanistic studies. RESULTS: In a set comprised of twelve derivatives, compound 7e, sodium (E)-6,6'-(ethene-1,2-diyl)bis(3-((4- chloro-6-((3-luorophenyl)amino)-1,3,5-triazin-2-yl)amino)benzenesulfonate) was found most potent inhibitor for HeLa and MCF-7 cells. DISCUSSION: The present study has revealed that compound 7e may activate mitochondrial pathway of apoptosis in HeLa and MCF-7 cells which was assessed by DNA binding studies, estimation of the release of Lactate Dehydrogenase (LDH), fluorescence imaging, production of Reactive Oxygen Species (ROS) in cancer cells, analysis of cell cycle by flow cytometry, change in Mitochondrial Membrane Potential (MMP) and activation of caspase-9 and caspase-3. CONCLUSION: Compound 7e may serve as a lead in designing new anticancer compounds based on stilbene scaffold.