Transcriptome-wide association study and Mendelian randomization in pancreatic cancer identifies susceptibility genes and causal relationships with type 2 diabetes and venous thromboembolism.

BACKGROUND: Two important questions regarding the genetics of pancreatic adenocarcinoma (PDAC) are 1. Which germline genetic variants influence the incidence of this cancer; and 2. Whether PDAC causally predisposes to associated non-malignant phenotypes, such as type 2 diabetes (T2D) and venous thromboembolism (VTE). METHODS: In this study of 8803 patients with PDAC and 67,523 controls, we first performed a large-scale transcriptome-wide association study to investigate the association between genetically determined gene expression in normal pancreas tissue and PDAC risk. Secondly, we used Mendelian Randomization (MR) to analyse the causal relationships among PDAC, T2D (74,124 cases and 824,006 controls) and VTE (30,234 cases and 172,122 controls). FINDINGS: Sixteen genes showed an association with PDAC risk (FDR <0.10), including six genes not yet reported for PDAC risk (PPIP5K2, TFR2, HNF4G, LRRC10B, PRC1 and FBXL20) and ten previously reported genes (INHBA, SMC2, ABO, PDX1, MTMR6, ACOT2, PGAP3, STARD3, GSDMB, ADAM33). MR provided support for a causal effect of PDAC on T2D using genetic instruments in the HNF4G and PDX1 loci, and unidirectional causality of VTE on PDAC involving the ABO locus (OR 2.12, P < 1e-7). No evidence of a causal effect of PDAC on VTE was found. INTERPRETATION: These analyses identified candidate susceptibility genes and disease relationships for PDAC that warrant further investigation. HNF4G and PDX1 may induce PDAC-associated diabetes, whereas ABO may induce the causative effect of VTE on PDAC. FUNDING: National Institutes of Health (USA).

The Kidney Transplant: Maintaining Excellent Outcomes While Increasing Skills Acquisition.

OBJECTIVE/BACKGROUND: Kidney transplantation is a complex operation that incorporates multiple fundamental surgical techniques and is an excellent opportunity for surgical skill development during residency training. We hypothesized that increasing resident competency, measured as anastomosis time, could be demonstrated while maintaining high-quality surgical outcomes during the learning process. METHODS: We performed a retrospective cohort study of surgical resident involvement in kidney transplantation and recorded the anastomosis time. The study population comprised adult, single organ kidney transplants (n = 2052) at a large academic transplant center between 2006 and 2019. Descriptive statistics included frequencies, medians, and means. A mixed model of anastomosis time on number of procedures was fitted. Poisson models were fitted with outcomes of the number of patients with delayed graft function and number of patients that underwent reoperation postoperatively, with the exposure being number of kidney transplants performed by resident. RESULTS: Results from the mixed model suggest that as the number of times a resident performs the surgery increases, the time to conduct the operation decreases with statistical significance. The Poisson regression demonstrated no significant relationship between the operative volume of a resident and postoperative complications. CONCLUSION: This study demonstrated statistical evidence that with an increase in the number of renal transplantations performed by a surgical resident, anastomosis time decreased. It also demonstrated no significant relationship between number of kidney transplants performed by a resident and postoperative complications, suggesting that patient outcomes for this operation are not adversely affected by resident involvement.

Overlapping Surgeries From the Patient's Perspective.

INTRODUCTION: Overlapping surgery (OS) occurs when a single surgeon is concurrently caring for patients in multiple operating rooms (OR) but is present for all critical portions of each surgery. Although this is common practice, most studies have found public disapproval of OS. This study aims to better understand attitudes toward OS of patients who gave informed consent for OS. METHODS: Participant interviews covered topics including trust, OR personnel roles, and attitudes toward OS. Four representative transcripts were distributed among researchers for independent code identification. These were aggregated into a codebook, applied by two coders. Iterative and emergent thematic analyses were done. RESULTS: Twelve participants were interviewed to reach thematic saturation. Three themes shaped how participants felt about OS: trust in their surgeon, worries about OS, and understanding of OR personnel roles. Factors contributing to trust included personal research and the surgeon's experience. Frequently cited concerns were unpredictability of complications during operations and the surgeon's divided attention. Two participants inaccurately understood personnel roles, believing the surgeon did most or all the hands-on work while trainees were observers. Most participants felt a high or neutral level of comfort toward OS and indicated trust as the reason. CONCLUSIONS: In contrast to prior research, this study found that most participants had a neutral or positive view of OS. This suggests that a trusting relationship with their surgeon and informed consent are important factors in increasing comfort for OS. Participants who misunderstood OR roles felt less comfortable toward OS. This highlights an opportunity for patient education on trainee roles.

A meta-analysis examined the effect of intrawound vancomycin on surgical site wound infections in non-spinal neurosurgical operation.

To assess the impact of intrawound vancomycin on surgical site wound infections in non-spinal neurosurgical operations, we conducted a meta-analysis. A thorough review of the literature up to September 2022 showed that 4286 participants had a non-spinal neurosurgical operation at the start of the investigations; 1975 of them used intrawound vancomycin, while 2311 were control. Using dichotomous or contentious methods and a random or fixed-effect model, odds ratios (OR) and mean difference (MD) with 95% confidence intervals (CIs) were estimated to evaluate the impact of intrawound vancomycin on surgical site wound infections in non-spinal neurosurgical operation. The intrawound vancomycin had significantly lower surgical site wound infections (OR, 0.28; 95% CI, 0.19-0.40; P < .001) with low heterogeneity (I2 = 32%) compared with the control in non-spinal neurosurgical operation. The intrawound vancomycin had significantly lower surgical site wound infections compared with control in non-spinal neurosurgical operation. The low sample size of 2 out of 13 researches in the meta-analysis calls for care when analysing the results.

Sulfone as a Transient Activating Group in the Palladium-Catalyzed Asymmetric [4 + 3] Cycloaddition of Trimethylenemethane Enabling the Enantioselective Synthesis of Fused Azepines.

The palladium-catalyzed asymmetric [4 + 3] cycloaddition of a sulfonyl-trimethylenemethane (TMM) donor with azadienes furnished various sulfonyl-fused azepines with exclusive regioselectivities and excellent stereoselectivities (up to >20:1 dr, >99% ee) in high yields (up to 93%). Moreover, sulfone, serving as a transient activating group of the TMM species, can be easily removed from the cycloadducts to provide the structurally simple fused azepines with excellent enantioselectivities. This strategy demonstrates sulfonyl-TMM as an effective surrogate of naked TMM with high reactivity, exclusive regioselectivity, and excellent stereoselectivity.

Multivalue ethical framework for fair global allocation of a COVID-19 vaccine.

The urgent drive for vaccine development in the midst of the current COVID-19 pandemic has prompted public and private organisations to invest heavily in research and development of a COVID-19 vaccine. Organisations globally have affirmed the commitment of fair global access, but the means by which a successful vaccine can be mass produced and equitably distributed remains notably unanswered. Barriers for low-income countries include the inability to afford vaccines as well as inadequate resources to vaccinate, barriers that are exacerbated during a pandemic. Fair distribution of a pandemic vaccine is unlikely without a solid ethical framework for allocation. This piece analyses four allocation paradigms: ability to develop or purchase; reciprocity; ability to implement; and distributive justice, and synthesises their ethical considerations to develop an allocation model to fit the COVID-19 pandemic.

Alignment of Ethics Curricula in Medical Education: A Student Perspective.

Issue: Although there is consensus on the importance of including ethics in the medical school curriculum, there is wide variation in how this topic is taught. Recent literature also questions the effectiveness of current ethical teaching methods in changing student attitudes and future behavior. Furthermore, from the student perspective, there is a marked disconnect between the stated importance of and lack of effort in ethics courses. Evidence: Applying a student perspective of the hidden curriculum, as well as reviewing and applying insight from the available literature, we advocate for alignment of instructional design, content, and assessments. This article provides specific recommendations to increase student engagement in ethics courses and concludes by discussing whether a lack of engagement is attributable to intrinsic qualities of medical students in addition to pedagogical technique and educational setting and culture. Implications: This article has practical suggestions for medical educators to improve their ethics courses, leading to more well-rounded and thoughtful physicians.

Palladium-Catalyzed Asymmetric [4+3] Cyclization of Trimethylenemethane: Regio-, Diastereo-, and Enantioselective Construction of Benzofuro[3,2-b]azepine Skeletons.

The palladium-catalyzed asymmetric [4+3] cyclization of trimethylenemethane donors with benzofuran-derived azadienes furnishes chiral benzofuro[3,2-b]azepine frameworks in high yields (up to 98 %) with exclusive regioselectivities and excellent stereoselectivities (up to >20:1 d.r., >99 % ee). This catalytic asymmetric [4+3] cyclization of Pd-trimethylenemethane can enrich the arsenal of Pd-TMM reactions in organic synthesis. In addition, this strategy provides an alternative approach to chiral azepines by a transition-metal-catalyzed asymmetric [4+3] cyclization.

The Sooner the Better: High-Value Care Education in Medical School.

Over the last decade in the United States, a national emphasis on controlling health care costs has prompted the medical community to embrace the ideal of high-value care (HVC), with value defined as health outcomes achieved per dollar spent. Despite increasing recognition of its importance as a skill for the modern physician, the practice of HVC remains a relatively new concept. Integrating HVC into medical education has been heterogeneous at best, with the majority of current HVC education thus far implemented at the postgraduate level. The authors present the unique benefits of the earlier introduction of HVC training at the medical school level, including ease of standardization across programs, a synergy in learning the value of an intervention alongside its other innate qualities, and the establishment of a foundational HVC education to allow for specialty-specific value training during residency. In this Invited Commentary, the authors offer practical recommendations for the incorporation of HVC training into medical schools' curricula, with special attention to correlating specific education strategies with the preclerkship, clerkship, and elective years of medical school.

Stereoselective Synthesis of Pyrrolidines Containing a 3-Fluoro Quaternary Stereocenter via Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition.

A highly efficient asymmetric 1,3-dipolar cycloaddition of azomethine ylides to ß,ß-disubstituted ß-fluoroacrylates catalyzed by a chiral N,O-ligand/Cu(CH3CN)4BF4 system is reported, affording chiral densely substituted pyrrolidines with four contiguous stereocenters, including one fluorinated quaternary stereocenter at the 3-position, in good to excellent yields (up to 99%), with excellent levels of diastereo- and enantioselectivities (dr >20:1; ee up to 99%).

On-cartridge derivatisation using matrix solid phase dispersion for the determination of cyclamate in foods.

A novel method for determination of sodium cyclamate in foods was developed. In this method, a syringe was loaded with the homogeneous mixture of the sample, KMnO4 powder and silica dispersant and used as a matrix solid phase dispersion (MSPD) reactor. As the reactor was infiltrated with small amounts of concentrated HCl, cyclamate was converted to 2-chlorocyclohexanone quickly and effectively within 5 min and determined by HPLC on a reversed-phase column using UV detection at a wavelength of 310 nm. Comparing with the traditional derivatisation in solution, the better clean-up was provided using on-cartridge derivatisation of MSPD, and much time, labor, and expense were saved. The results showed good linearity (r2 = 0.9998) over the concentration range of 1-500 mg/L. The limit of detection (LOD) and limits of quantification (LOQ) of the cyclamate were 0.3 mg/L and 1 mg/L respectively. The recoveries ranged from 91.6% to 101.3% with the relative standard deviations (RSDs) in the range of 2.5%-4.3%.

Chiral N,O-Ligand/[Cu(OAc)2 ]-Catalyzed Asymmetric Construction of 4-Aminopyrrolidine Derivatives by 1,3-Dipolar Cycloaddition of Azomethine Ylides with α-Phthalimidoacrylates.

A protocol to access useful 4-aminopyrrolidine-2,4-dicarboxylate derivatives has been developed. A variety of chiral N,O-ligands derived from 2,3-dihydroimidazo[1,2-a]pyridine motifs have been evaluated in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides to α-phthalimidoacrylates. Reactions catalyzed by copper in combination with ligand 7-Cl-DHIPOH provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction. The reaction tolerates both ß-substituted and ß-unsubstituted α-phthalimidoacrylate as dipolarophiles, affording the corresponding quaternary 4-aminopyrrolidine cycloadducts with excellent diastereo- (>98:2 d.r.) and enantioselectivities (up to 97 % ee). Removal of the phthalimido protecting group can be accomplished by a simple NaBH4 reduction. Theoretical calculations employing DFT methods show this cycloaddition reaction is likely to proceed through a stepwise mechanism and the stereochemistry was also theoretically rationalized.

The copper-catalyzed asymmetric construction of a dispiropyrrolidine skeleton via 1,3-dipolar cycloaddition of azomethine ylides to α-alkylidene succinimides.

A highly efficient asymmetric 1,3-dipolar cycloaddition of azomethine ylides to α-alkylidene succinimides catalyzed by a novel chiral N,O-ligand/Cu(OAc)2 system is reported, affording dispiropyrrolidine derivatives with spiro quaternary stereogenic centers in good to excellent yields (up to 90%), excellent levels of diastereoselectivities (>20 : 1 dr) and enantioselectivities (up to 97% ee).

Catalytic asymmetric construction of quaternary α-amino acid containing pyrrolidines through 1,3-dipolar cycloaddition of azomethine ylides to α-aminoacrylates.

The first catalytic enantioselective 1,3-dipolar cycloaddition of azomethine ylides to α-aminoacrylate catalyzed by a AgOAc/ferrocenyl oxazolinylphosphine (FOXAP) system was developed, which exhibits excellent exo- and enantioselectivity (92-99 % ee). This process provides efficient access to useful 4-aminopyrrolidine-2,4-dicarboxylic acid (APDC)-like compounds containing a unique quaternary α-amino acid unit.

[Biotransformation by human intestinal flora and absorption-transportation characteristic in a model of Caco-2 cell monolayer of d-corydaline and tetrahydropalmatine].

OBJECTIVE: To study the biotransformation by human intestinal flora, and the absorption and transportation characteristic in a model of human colon adenocarcinoma cell lines (Caco-2 cell) monolayer of d-corydaline (CDL) and tetrahydropalmatine (THP). METHOD: CDL or THP was incubated with crude enzymes of human intestinal flora under the anaerobic environment and 37 degrees C conditions to transform CDL or THP. Caco-2 cell monolayer was used as an intestinal epithelial cell model for determination of the permeability of CDL or THP from apical side (AP side) to basolateral side (BL side) or from BL side to AP side. Transportation parameters and permeability coefficients (P(app)) were then calculated, and P(app) values were compared with the reported values for model compounds, propranolol as a well absorbed drug and atenolol as a poor absorbed drug. The concentration of CDL or THP was measured by HPLC coupled with photodiode array detector. RESULT: CDL or THP in the human intestinal flora incubation system did not happen biotransformation. In the Caco-2 cell monolayer model, the P(app) magnitudes of both CDL and THP were 1 x 10(-5) cm x s(-1) in the bi-directional transport, which were identical with propranolol. And their transports were concentration dependent between 0-180 min. CONCLUSION: Both CDL and THP may be stable in the human intestinal flora incubation system, and their absorption and transportation in the human Caco-2 cell monolayer model are mainly via passive diffusion mechanism.