Oxidation of Alcohols in Continuous Flow with a Solid Phase Hypervalent Iodine Catalyst.

One of the most useful transformations in the synthetic chemist arsenal is the oxidation of alcohols to their corresponding carbonyl congeners. Despite its seemingly straightforward nature, this transformative reaction predominantly relies on the use of metals or hazardous reagents, making these processes highly unsustainable. To address this challenge, we have developed a sustainable metal-free method for the oxidation of alcohols in continuous flow. Using a solid phase hypervalent iodine catalyst and nBu4HSO5 as a phase transfer catalyst and co-oxidant, primary and secondary alcohols were selectively oxidized to the corresponding carbonyl motifs. This operationally simple continuous-flow set-up is highly robust (15 cycles run without significant catalyst leaching or loss of reaction efficiency), uses green solvents, such as acetonitrile or acetic acid, and is readily scalable.

Modular synthesis of congested ß2,2-amino acids via the merger of photocatalysis and oxidative functionalisations.

A two-step protocol for the modular synthesis of ß2- and α-quaternary ß2,2-amino acid derivatives is reported. The key steps are a photocatalytic hydroalkylation reaction, followed by an oxidative functionalisation to access N-protected ß-amino acids, esters, and amides. This strategy can be effectively scaled up via continuous-flow technology.

Characterization of mismatch-repair/microsatellite instability-discordant endometrial cancers.

BACKGROUND: Mismatch-repair (MMR)/microsatellite instability (MSI) status has therapeutic implications in endometrial cancer (EC). The authors evaluated the concordance of testing and factors contributing to MMR expression heterogeneity. METHODS: Six hundred sixty-six ECs were characterized using immunohistochemistry (IHC), MSI testing, and mut-L homolog 1 (MLH1) methylation. Select samples underwent whole-transcriptome analysis and next-generation sequencing. MMR expression of metastatic/recurrent sites was evaluated. RESULTS: MSI testing identified 27.3% of cases as MSI-high (n = 182), MMR IHC identified 25.1% cases as MMR-deficient (n = 167), and 3.8% of cases (n = 25) demonstrated discordant results. A review of IHC staining explained discordant results in 18 cases, revealing subclonal loss of MLH1/Pms 1 homolog 2 (PMS2) (n = 10) and heterogeneous MMR IHC (mut-S homolog 6 [MSH6], n = 7; MLH1/PMS2, n = 1). MSH6-associated Lynch syndrome was diagnosed in three of six cases with heterogeneous expression. Subclonal or heterogeneous cases had a 38.9% recurrence rate (compared with 16.7% in complete MMR-deficient cases and 9% in MMR-proficient cases) and had abnormal MMR IHC results in all metastatic recurrent sites (n = 7). Tumors with subclonal MLH1/PMS2 demonstrated 74 differentially expressed genes (determined using digital spatial transcriptomics) when stratified by MLH1 expression, including many associated with epithelial-mesenchymal transition. CONCLUSIONS: Subclonal/heterogeneous MMR IHC cases showed epigenetic loss in 66.7%, germline mutations in 16.7%, and somatic mutations in 16.7%. MMR IHC reported as intact/deficient missed 21% of cases of Lynch syndrome. EC with subclonal/heterogeneous MMR expression demonstrated a high recurrence rate, and metastatic/recurrent sites were MMR-deficient. Transcriptional analysis indicated an increased risk for migration/metastasis, suggesting that clonal MMR deficiency may be a driver for tumor aggressiveness. Reporting MMR IHC only as intact/deficient, without reporting subclonal and heterogeneous staining, misses opportunities for biomarker-directed therapy. PLAIN LANGUAGE SUMMARY: Endometrial cancer is the most common gynecologic cancer, and 20%-40% of tumors have a defect in DNA proofreading known as mismatch-repair (MMR) deficiency. These results can be used to guide therapy. Tests for this defect can yield differing results, revealing heterogeneous (mixed) proofreading capabilities. Tumors with discordant testing results and mixed MMR findings can have germline or somatic defects in MMR genes. Cells with deficient DNA proofreading in tumors with mixed MMR findings have DNA expression profiles linked to more aggressive characteristics and cancer spread. These MMR-deficient cells may drive tumor behavior and the risk of spreading cancer.

Intraluminal tumor cells and prognostic accuracy of endometrial cancer stage criteria: A multi-institution study.

OBJECTIVE: Endometrial cancer stage is a strong prognostic factor; however, the current stage classification does not incorporate transtubal spread as determined by intraluminal tumor cells (ILTCs). We examined relationships between ILTCs and survival outcomes according to histological subtype and stage and examined whether identification of ILTCs improves prognostic accuracy of endometrial cancer staging. METHODS: We conducted a retrospective cohort study of women diagnosed with endometrial cancer at five academic hospitals between 2007 and 2012. Pathologists determined ILTC presence (no vs. yes) and location (free in lumen vs. attached to epithelial surface) based on pathology review of hematoxylin and eosin-stained sections of fallopian tubes. Associations between ILTCs with time to recurrence (TTR) and overall survival (OS) were examined with Cox proportional hazards models adjusted for other prognostic factors. Model discrimination metrics were used to assess the addition of ILTCs to stage for prediction of 5-year TTR and OS. RESULTS: In the overall study population (N = 1303), ILTCs were not independently associated with TTR (HR = 0.95, 95% CI = 0.69-1.32) or OS (HR = 0.97, 95% CI = 0.72-1.31). Among 805 women with stage I disease, ILTCs were independently associated with worse TTR (HR = 2.31, 95% CI = 1.06-5.05) and OS (HR = 2.16, 95% CI = 1.14-4.11). Upstaging early-stage cases with ILTCs present did not increase model discrimination. CONCLUSION: While our data do not suggest that endometrial cancer staging guidelines should be revised to include ILTCs, associations between ILTCs and reduced survival observed among stage I cases suggest this tumor feature holds clinical relevance for subgroups of endometrial cancer patients.

Stereochemistry in All Its Shapes and Forms: The 56th Bürgenstock Conference.

Acknowledging the crucial role of stereochemistry in fields as diverse as total synthesis, synthetic methodology, spectroscopy, and the study of the origin of life, the 56th SCS Conference on Stereochemistry, better known as the BÃ1/4rgenstock Conference, brought together a diverse range of chemistry expertise in Brunnen, Switzerland.

IL-18 discriminates highly frequent hepatitis E virus positive from negative blood donors in Mexico.

INTRODUCTION AND OBJECTIVES: Hepatitis E virus (HEV) is not routinely screened in blood banks in low- and middle-income countries, and no specific biomarkers of exposure to this virus have yet been identified. We aimed to identify HEV seropositivity and detect virus RNA among blood donors from Mexico to further correlate risk factors related to infection and levels of interleukin-18 (IL-18) and interferon-gamma (IFN-γ) as potential biomarkers. MATERIALS AND METHODS: This cross-sectional, single-center study included 691 serum samples of blood donors obtained in 2019. Anti-HEV IgG and IgM antibodies were detected in sera and the viral genome was screened in pooled samples. A statistical comparison of risk factors for infection, demographic and clinical features was performed; IL-18 and IFN- Î³ values were tested in sera. RESULTS: Of all the individuals, 9.4% were positive for anti-HEV antibodies and viral RNA detection was confirmed in one of the pools positive for anti-HEV. From the analysis of risk factors, age and having pets were statistically significant for anti-HEV antibody detection. Seropositive samples showed significantly higher IL-18 concentrations relative to samples from seronegative donors. Interestingly, IL-18 values were similar when HEV seropositive samples were compared to samples from clinically acute previously confirmed HEV patients. CONCLUSIONS: Our findings highlight the need to follow up on HEV in blood banks in Mexico and underscore that IL-18 could represent a biomarker of HEV exposure.

Modular Synthesis of Polar Spirocyclic Scaffolds Enabled by Radical Chemistry.

Herein, we report a highly modular strategy to access spirocyclic scaffolds from abundant starting materials, i.e., cyclic ketones and α-amino or oxamic acids. The sequence proceeds through a straightforward Knoevenagel condensation, followed by a domino Giese-type reaction/base-mediated cyclization process, to deliver a broad scope of polar spirocyclic scaffolds in good to excellent yields. The products can be readily diversified, thus increasing the versatility of our method to gain rapid access to libraries of potential druglike molecules.

Tissue factor as a novel diagnostic target for early detection of ovarian cancer using ultrasound microbubbles.

INTRODUCTION: Ovarian cancer (OC) is the deadliest gynecologic malignancy, with an overall 5-year survival rate of less than 30%. The existing paradigm for OC detection involves a serum marker, CA125, and ultrasound examination, neither of which is sufficiently specific for OC. This study addresses this deficiency through the use of a targeted ultrasound microbubble directed against tissue factor (TF). METHODS: TF expression was examined in both OC cell lines and patient-derived tumor samples via western blotting and IHC. In vivo microbubble ultrasound imaging was analyzed using high grade serous ovarian carcinoma orthotopic mouse models. RESULTS: While TF expression has previously been described on angiogenic, tumor-associated vascular endothelial cells (VECs) of several tumor types, this is first study to show TF expression on both murine and patient-derived ovarian tumor-associated VECs. Biotinylated anti-TF antibody was conjugated to streptavidin-coated microbubbles and in vitro binding assays were performed to assess the binding efficacy of these agents. TF-targeted microbubbles successfully bound to TF-expressing OC cells, as well as an in vitro model of angiogenic endothelium. In vivo, these microbubbles bound to the tumor-associated VECs of a clinically relevant orthotopic OC mouse model. CONCLUSION: Development of a TF-targeted microbubble capable of successfully detecting ovarian tumor neovasculature could have significant implications towards increasing the number of early-stage OC diagnoses. This preclinical study shows potential for translation to clinical use, which could ultimately help increase the number of early OC detections and decrease the mortality associated with this disease.

Glassy cell carcinoma of the cervix: Findings from a combined National Cancer Database analysis and single institution review of treatment patterns and outcomes.

OBJECTIVES: To describe stage, treatment patterns, and survival for glassy cell carcinoma of the cervix (GCCC), a poorly understood rare tumor. METHODS: Clinical data and survival were compared between GCCC and more common histologic types using the National Cancer Database (NCDB) from 2004 to 2017. A retrospective review of GCCC cases at our institution from 2012 to 2020 was simultaneously performed with staging updated according to 2018 FIGO staging. Descriptive statistics and survival analyses were performed, and outcomes compared to historical references. RESULTS: 143/89,001 (0.16%) NCDB cervical cancer cases were GCCC. Compared to other histologies, GCCC cases were younger, with 74.8% diagnosed before age 50. Stage distribution was similar. Stage I cases were less commonly treated with surgery alone (19/69, 27%). 79.4% of locally advanced (stage II-IVA) cases were treated with definitive chemoradiation. GCCC demonstrated worse OS for early-stage and locally-advanced disease. No survival differences were observed for patients with stage IVB disease. Our institutional review identified 14 GCCC cases. Median age at diagnosis was 34 years. All nine early-stage cases underwent radical hysterectomy. Adjuvant radiation was given for cases meeting Sedlis criteria (4/9, 44%). All five advanced stage cases were stage IIIC and received definitive chemoradiation. Recurrence rate was 0% (0/9) for early-stage and 60% (3/5) for advanced-stage cases. 3-year PFS was 100% for early-stage and 40% for advanced-stage. 3-year OS was 100% for early-stage and 60% for advanced-stage GCCC. CONCLUSIONS: GCCC presents at earlier ages than other cervical cancer histologic types. Although NCDB showed worse OS, our more contemporary institutional review, which incorporates updated staging and newer treatment modalities found outcomes more similar to historical references of more common histologic subtypes.

Factores pronósticos de muerte por neumonía adquirida en la comunidad en los pacientes con enfermedad pulmonar obstructiva crónica

Introducción: la prevención y tratamiento inmediato de las enfermedades infecciosas y en particular la neumonía adquirida en la comunidad (NAC), son indispensable para mejorar el pronóstico, en pacientes con enfermedad pulmonar obstructiva crónica (EPOC). Objetivo: evaluar la capacidad de un modelo basado en factores pronóstico para predecir el riego de morir por neumonía adquirida en la comunidad en los pacientes con enfermedad pulmonar obstructiva crónica. Métodos: se realizó un estudio analítico de cohorte en pacientes con diagnóstico de enfermedad pulmonar obstructiva crónica y neumonía adquirida en la comunidad ingresados en el hospital Carlos Manuel de Céspedes, en el periodo comprendido desde el1rode enero de 2019 al 31 de diciembre de 2020. Resultados: con el modelo de regresión logística se encontró que el choque fue el factor más importante al elevar a más de 18 veces el mencionado riesgo (OR= 18,84; IC= 3,26 a 24,61; p= 0,000), seguido de la neumonía multilobar (OR= 14,55; IC= 8,80 a 21,43; p = 0,019) y de la disfunción orgánica reversible (OR= 8,01; IC= 1,25 a 51,17; p = 0,009). La calibración y la discriminación del modelo quedó demostrado por los valores de la prueba de Hosmer-Lemeshow (p= 0,419) y el área bajo la curva características operativas receptor (0,952; p= 0,000) respectivamente. Conclusiones: con los valores obtenidos por el modelo de regresión logística se podrá estimar el riesgo de morir, al mostrar adecuada calibración y capacidad discriminativa.

Introduction: the prevention and immediate treatment of infectious diseases and in particular community-acquired pneumonia (CAP), are essential to improve the prognosis in patients with chronic obstructive pulmonary disease (COPD). Objective: to evaluate the ability of a model based on prognostic factors to predict the risk of dying from community-acquired pneumonia in patients with chronic obstructive pulmonary disease. Methods: an analytical cohort study was conducted in patients diagnosed with chronic obstructive pulmonary disease and community-acquired pneumonia admitted to the Carlos Manuel de Céspedes hospital, in the period from January 1, 2019 to December 31, 2020. Results: with the logistic regression model it was found that shock was the most important factor, raising the aforementioned risk to more than 18 times (OR= 18.84; CI= 3.26 to 24.61; p= 0.000), followed by multilobar pneumonia (OR= 14.55; CI= 8.80 to 21.43; p = 0.019) and reversible organ dysfunction (OR = 8.01; CI= 1.25 to 51.17; p = 0.009). The calibration and discrimination of the model was demonstrated by the values of the Hosmer-Lemeshow test (p = 0.419) and the area under the curve receiver operating characteristics (0.952; p = 0.000) respectively. Conclusions: with the values obtained by the logistic regression model, it will be possible to estimate the risk of dying, showing adequate calibration and discriminative capacity.

Introdução: a prevenção e o tratamento imediato das doenças infecciosas e, em particular, da pneumonia adquirida na comunidade (PAC), são essenciais para melhorar o prognóstico em pacientes com doença pulmonar obstrutiva crônica (DPOC). Objetivo: avaliar a capacidade de um modelo baseado em fatores prognósticos em predizer o risco de morte por pneumonia adquirida na comunidade em pacientes com doença pulmonar obstrutiva crônica. Métodos: foi realizado um estudo de coorte analítico em pacientes com diagnóstico de doença pulmonar obstrutiva crônica e pneumonia adquirida na comunidade internados no hospital Carlos Manuel de Céspedes, no período de 1º de janeiro de 2019 a 31 de dezembro de 2020. Resultados: com o modelo de regressão logística verificou-se que o choque foi o fator mais importante, elevando o risco supracitado para mais de 18 vezes (OR= 18,84; IC= 3,26 a 24,61; p= 0,000), seguida de pneumonia multilobar (OR= 14,55; IC= 8,80 a 21,43; p = 0,019) e disfunção orgânica reversível (OR = 8,01; IC= 1,25 a 51,17; p = 0,009). A calibração e discriminação do modelo foram demonstradas pelos valores do teste de Hosmer-Lemeshow (p = 0,419) e pelas características operacionais do receptor da área sob a curva (0,952; p = 0,000), respectivamente. Conclusões: com os valores obtidos pelo modelo de regressão logística, será possível estimar o risco de morrer, apresentando adequada calibração e capacidade discriminativa.

Neumomediastino secundario a efecto Macklin: a propósito de un caso / Pneumomediastinum secondary to Macklin effect: a case report

RESUMEN Introducción: el neumomediastino es la presencia de aire en el espacio mediastinal procedente de bronquios, alvéolos o de una ruptura esofágica, que viaja a través de las vainas vasculares y los planos tisulares hacia el espacio mediastinal; puede ser categorizado como espontáneo, traumático o secundario. Objetivo: describir un paciente con neumomediastino secundario al efecto Macklin. Caso clínico: se trata de un paciente masculino de 32 años sin antecedentes médicos, que acude a urgencias refiriendo tos seca, dolor de garganta, dolor al ingerir alimentos, malestar general, dolores articulares a predominio de rodillas y espalda baja y fiebre de 39°C acompañada de escalofríos. El día posterior a su ingreso, tras un acceso de tos, presenta de forma súbita aumento de volumen del cuello y porción superior del tórax, acompañado de dolor en dicha zona, dificultad para respirar y hablar. Al examen en este momento se constata aumento de volumen y crepitación en cuello, fosa supraclavicular, y porción anterosuperior y posterosuperior del tórax (enfisema subcutáneo) así como estertores roncos y sibilantes diseminados en ambos campos pulmonares. Se realiza radiografía de tórax de urgencia que muestra signos sugestivos de enfisema subcutáneo y neumomediastino. Se solicita valoración por servicio de cirugía General y otorrino, los cuales sugieren tratamiento conservador. Conlusiones: el neumomediastino es una enfermedad poco frecuente y benigna, sus características clínicas son dolor torácico y enfisema subcutáneo luego de un acceso de tos y evoluciona de forma satisfactoria entre dos y 15 días.

ABSTRACT Introduction: pneumomediastinum is the presence of air in the mediastinal space coming from bronchi, alveoli or esophageal rupture, which travels through vascular sheaths and tissue planes to the mediastinal space; it can be categorized as spontaneous, traumatic or secondary. Objective: to describe a patient with pneumomediastinum secondary to the Macklin effect. Case report: a 32-year-old male patient with no medical history came to the emergency room with a dry cough, sore throat, pain when eating and general malaise, joint pain predominantly in the knees and lower back, and fever of 39°C with chills. The day after his admission, after an attack of coughing, he suddenly presented an increase in volume of the neck and upper chest, accompanied by pain in this area, difficulty in breathing and speaking. On examination at this time, there was an increase in volume and crepitus in the neck, supraclavicular fossa, and anterosuperior and posterosuperior portion of the thorax (subcutaneous emphysema) as well as hoarse and wheezing rales disseminated in both lung fields. An emergency chest X-ray was performed showing signs suggestive of subcutaneous emphysema and pneumomediastinum. An evaluation by the General Surgery and Otorhinolaryngology Departments was requested, which suggested conservative treatment. Conclusions: pneumomediastinum is a rare and benign disease, its clinical characteristics are chest pain and subcutaneous emphysema after a coughing fit and it evolves satisfactorily between 2 and 15 days.

Photocatalysis in the Life Science Industry.

In the pursuit of new pharmaceuticals and agrochemicals, chemists in the life science industry require access to mild and robust synthetic methodologies to systematically modify chemical structures, explore novel chemical space, and enable efficient synthesis. In this context, photocatalysis has emerged as a powerful technology for the synthesis of complex and often highly functionalized molecules. This Review aims to summarize the published contributions to the field from the life science industry, including research from industrial-academic partnerships. An overview of the synthetic methodologies developed and strategic applications in chemical synthesis, including peptide functionalization, isotope labeling, and both DNA-encoded and traditional library synthesis, is provided, along with a summary of the state-of-the-art in photoreactor technology and the effective upscaling of photocatalytic reactions.

Determinants of Surgical Approach and Survival Among Women with Endometrial Carcinoma.

STUDY OBJECTIVE: To investigate determinants of surgical approach among women with endometrial carcinoma (EC) and associations between surgical approach and overall survival (OS). DESIGN: Retrospective cohort. SETTING: The National Cancer Database, 2010 to 2015. PATIENTS: A total of 140 470 patients with histologically confirmed EC who underwent hysterectomy. INTERVENTIONS: Patients were grouped according to surgical approach. MEASUREMENTS AND MAIN RESULTS: A total of 140 470 patients with EC were included. Robotic-assisted laparoscopy (RAL) was the most common surgical approach (48.8%), followed by laparotomy (33.6%) and traditional laparoscopy (17.6%). Use of RAL increased over the study period, and the percentages of cases managed by laparotomy decreased. Older women, those with insurance, residing in ZIP codes with lower proportions of individuals who did not graduate from high school, and those treated at noncommunity cancer programs were less likely to undergo laparotomy than RAL, and non-white women, those diagnosed with high-grade histology, and those with advanced-stage EC were more likely to undergo laparotomy than RAL. Compared with RAL, all other surgical approaches were associated with worse OS (laparotomy: hazard ratio 1.21; 95% confidence interval, 1.18-1.25; traditional laparoscopy: hazard ratio 1.06; 95% confidence interval, 1.02-1.09). Significant effect modification of the surgical approach and OS relationship according to age, race, histology, stage, and adjuvant treatment was observed. CONCLUSION: RAL increased in frequency over the study period and was associated with improved OS, supporting the continued use of RAL for EC management.

Mollusk death assemblages in 210Pb-dated marine sediment cores reveal recent biotic changes in the Gulf of Guanahacabibes, NW Cuba.

We investigated stratigraphic changes in mollusk death assemblages and geochemistry in sediment cores from four seagrass beds and one unvegetated site in the Gulf of Guanahacabibes (GG), NW Cuba. There was a transition from mangrove to seagrass beds, associated with sea level rise ∼6000 years ago. Sediment accumulation rates during the last century showed a general rise, but increased sharply after ∼1980, likely because of human activities. The GG displayed overall high mollusk γ-diversity, and our estimate of 189 species is biased toward the low end. High ß-diversity was driven by inter-site differences in grain size, vegetation cover, and nutrient input. Spatial heterogeneity within the basin influenced downcore abundance and diversity metrics, highlighting the influence of local drivers. Herbivorous gastropods dominated in seagrass beds and suspension feeder bivalves were dominant on sandy bottom. In the top parts of cores, species richness declined at two sites that were subject to high, human-mediated bulk sedimentation rates and eutrophication. Conservation measures are needed to preserve this hotspot of marine diversity.

Endometrial Cancer: Who Lives, Who Dies, Can We Improve Their Story?

BACKGROUND: Endometrial cancer (EC) is the most common gynecologic cancer in the U.S. The objective of this cohort study was to characterize the clinical and pathologic features that are associated with endometrial cancer-specific death for women cared for at a single National Cancer Institute-designated comprehensive cancer center. PATIENTS, MATERIALS, AND METHODS: This is a retrospective cohort from 2014 to 2017 including all women who had a hysterectomy for EC. Charts were reviewed for clinical and pathologic data, focusing on survival outcomes. RESULTS: Seven hundred seventy-one patients with EC underwent hysterectomy with 760 informative for outcomes. Seventy-six (10%) deaths were related to their EC; 62 women died from recurrent EC. Nonendometrioid histology and advanced stage were predictors of recurrence and EC death. Among patients with endometrioid ECs, mismatch repair status was significantly associated with EC-specific survival (relative risk = 4.8; 95% confidence interval, 2.3-10.3; p < .0001). Most patients with EC who recurred died of their disease 62/83 (74.7%). Nearly half of the patients that recurred (27/62) had no additional therapy at the time of recurrence. Overall survival was significantly longer for those women who had additional treatment at the time of recurrence; however, the improvement in overall survival with therapy at recurrence was largely attributable to effects in those women who were adjuvant therapy naïve. CONCLUSION: Although there is benefit of treatment at the time of recurrence for treatment-naïve women; only approximately half of patients were able to receive therapy. There is an urgent need for continued efforts for more effective EC therapy in both the front-line and recurrent setting as well as early identification of cancer diagnosis and recurrence. IMPLICATIONS FOR PRACTICE: Approximately 10% of patients died of their endometrial cancer. Most deaths were from recurrent disease; however, almost 20% of endometrial cancer deaths were within 120 days of surgery. Although treatment at the time of recurrence improves overall survival, only approximately half of patients will receive therapy at the time of recurrence. Traditional prognostic features like histology and stage remain important to predict risk of recurrence, and newer biomarkers, such as mismatch repair status, may improve risk stratification and targeted therapy. There remains an urgent need for improved therapy and early detection of diagnosis and recurrence.

Synthesis of γ-Oxo-α-amino Acids via Radical Acylation with Carboxylic Acids.

Herein we present a highly efficient, light-mediated, deoxygenative protocol to access γ-oxo-α-amino acid derivatives. This radical methodology employs photoredox catalysis, in combination with triphenylphosphine, to generate acyl radicals from readily available (hetero)aromatic and vinylic carboxylic acids. This approach allows for the straightforward synthesis of γ-oxo-α-amino acids bearing a wide range of functional groups (e.g., Cl, CN, furan, thiophene, Bpin) in synthetically useful yields (∼60% average yield). To further highlight the utility of the methodology, several deprotection and derivatization reactions were carried out.

Cardiac Structure and Function Is Associated With Hemispatial Neglect Severity.

Background: Hemispatial neglect is a debilitating consequence of right hemispheric ischemic stroke (RIS), with evidence that patient-level factors influence neglect severity. Study objective: Determine if cardiac function is associated with presence and severity of neglect, independent of infarct size. Methods: Two hundred and eighteen non-demented, RIS with cerebral MRI and echocardiography who completed ≥1 of 4 tests evaluating neglect were included. Age- and sex- adjusted Z-scores defined neglect with severity categorized as no neglect, neglect on one or neglect on ≥2 tests. The dependent variable was presence of neglect (multivariable logistic regression), or neglect severity (multinomial logistic regression). The association with left ventricular (LV) structure/function (independent variable) was evaluated using separate nested adjustment models. Results: Patients were on average 61 yo (21-95), female (50%), black (53%), with an ejection fraction of 60% (IQR 20-75%). Fifty eight (27%) had neglect. Each 1 cm increase in LV systolic diameter was associated with a higher relative risk of having neglect on two tests compared to those with no neglect (RRR = 1.83, 95% CI 1.01-3.32), but not after adjusting for education and DWI volume (RRR = 1.68, 95% CI 0.89-3.19). Per 1 cm increase in left atrial (LA) diameter, the relative risk of having neglect on 2 tests vs. no neglect was over two times higher (95% CI 1.04-4.77), but lost significance in the final model (RRR = 1.73, 95% CI 0.76-3.94). Conclusions: We found an association between markers of diastolic dysfunction (enlarging LV, compensatory enlarging LA) and severity of neglect, suggesting that cardiac structure, and function affects not only lesion volume, but also the functional consequences of infarct volume.

Differences in linguistic cohesion within the first year following right and left hemisphere lesions.

BACKGROUND: Characterizing productive language deficits following lesions to the right (RH) or left hemispheres (LH) is valuable in identifying appropriate therapeutic goals. While damage to the LH classically is associated with deficits in language, RH lesions also result in changed communication beyond prosody due to cognitive-linguistic effects. Cohesion, reference to introduced content across sentences within discourse, relies on a listener's clear and unambiguous understanding that a reference has occurred. To date, we are not aware of any prior work that has compared patterns of cohesive strategy between RH and LH lesioned individuals with cohesion deficits. AIMS: The purpose of the present study is to determine whether individuals with communication deficits following RH and LH lesions differ in the inclusion and clarity of cohesive markers. METHODS & PROCEDURES: Seventy-six RH samples and 145 LH samples were used for comparison of cohesion performance in a Cookie Theft picture description task. Cohesive ties were assessed following the protocol outlined in Liles and Coelho (1998). It was hypothesized that individuals with LH lesions would present a different pattern of cohesion behaviour than RH lesioned individuals when considered both acutely and chronically. OUTCOMES & RESULTS: Overall, samples from LH and RH groups did not differ in word counts or cohesive marker usage. However, the patterns of markers they chose to employ were different. LH samples used conjunctions and personal pronouns more frequently and used lexical cohesive markers less frequently than RH samples. Acutely, patterns of cohesive marker use between LH and RH samples were more similar. Chronically, LH samples contained more personal pronouns and the differences in lexical cohesive markers remained unchanged. When cohesion was unsuccessful, LH and RH damage were associated with different patterns of error. LH samples tended to omit information needed to clarify the intended referent, resulting in incomplete cohesion errors. RH samples tended to sustain breakdowns in cohesion from sentence to sentence, not resolving incorrectly chosen pronouns or ambiguities left in their samples. CONCLUSIONS: LH and RH lesions resulted in differing patterns of chosen cohesive markers and errors when cohesion was unsuccessful. This was particularly true in lexical cohesion, which has been far less studied than closed-class cohesive markers like referential pronouns. It was also noted that cohesive behavior did not appear to "recover" for either group, suggesting spontaneous recovery is minimal and present strategies for language therapy may not effectively address this linguistic function.

Double somatic mismatch repair gene pathogenic variants as common as Lynch syndrome among endometrial cancer patients.

OBJECTIVE: Lynch syndrome is the most common cause of inherited endometrial cancer, attributable to germline pathogenic variants (PV) in mismatch repair (MMR) genes. Tumor microsatellite instability (MSI-high) and MMR IHC abnormalities are characteristics of Lynch syndrome. Double somatic MMR gene PV also cause MSI-high endometrial cancers. The aim of this study was to determine the relative frequency of Lynch syndrome and double somatic MMR PV. METHODS: 341 endometrial cancer patients enrolled in the Ohio Colorectal Cancer Prevention Initiative at The Ohio State University Comprehensive Cancer Center from 1/1/13-12/31/16. All tumors underwent immunohistochemical (IHC) staining for the four MMR proteins, MSI testing, and MLH1 methylation testing if the tumor was MMR-deficient (dMMR). Germline genetic testing for Lynch syndrome was undertaken for all cases with dMMR tumors lacking MLH1 methylation. Tumor sequencing followed if a germline MMR gene PV was not identified. RESULTS: Twenty-seven percent (91/341) of tumors were either MSI-high or had abnormal IHC indicating dMMR. As expected, most dMMR tumors had MLH1 methylation; (69, 75.8% of the dMMR cases; 20.2% of total). Among the 22 (6.5%) cases with dMMR not explained by methylation, 10 (2.9% of total) were found to have Lynch syndrome (6 MSH6, 3 MSH2, 1 PMS2). Double somatic MMR PV accounted for the remaining 12 dMMR cases (3.5% of total). CONCLUSIONS: Since double somatic MMR gene PV are as common as Lynch syndrome among endometrial cancer patients, paired tumor and germline testing for patients with non-methylated dMMR tumor may be the most efficient approach for LS screening.