Is Barbed Better? Evaluation of Triclosan-Coated Barbed Suture on Wound Complications Following Emergency Laparotomy.

INTRODUCTION: Emergent laparotomy is associated with significant wound complications including surgical site infections (SSI) and fascial dehiscence (FD). Triclosan-coated barbed suture (TCB) for fascial closure has been shown to reduce local complications but primarily in elective settings. We sought to evaluate the effect of TCB emergency laparotomy fascial closure on major wound complications. METHODS: Adult patients undergoing emergency laparotomy were prospectively evaluated over 1-year. Patients were grouped into TCB vs polydioxanone (PDS) for fascial closure. Subanalysis was performed on patients undergoing single-stage laparotomy. Primary outcomes were SSI and FD. Multivariate analysis identified independent factors associated with SSI and FD. RESULTS: Of the 206 laparotomies, 73 (35%) were closed with TCB and 133 (65%) were closed with PDS. Trauma was the reason for laparotomy in 73% of cases; damage control laparotomy (DCL) was performed in 27% of cases. The overall rate of SSI and FD was 18% and 10%, respectively. Operative strategy was similar between groups, including DCL, wound vac use, skin closure, and blood products. SSI events trended lower with TCB vs PDS closure (11% vs. 21%; p = .07), and FD was significantly lower with TCB versus PDS (4% vs. 14%; p < .05, Fig 1). Subanalysis of trauma and non-trauma cases showed no difference in SSI or FD. Multivariable analysis found that TCB decreased the likelihood of FD (OR .07; p < .05, Fig 2) following emergency laparotomy. Increased odds of FD were seen in DCL (OR 3.1; p < 0.05). CONCLUSIONS: Emergency laparotomy fascial closure with TCB showed significantly decreased rates of FD compared to closure with PDS, and a strong trend toward lower SSI events. TCB was independently associated with decreased FD rates after emergency laparotomy.

Simulated outcomes for durotomy repair in minimally invasive spine surgery.

Minimally invasive spine surgery (MISS) is increasingly performed using endoscopic and microscopic visualization, and the captured video can be used for surgical education and development of predictive artificial intelligence (AI) models. Video datasets depicting adverse event management are also valuable, as predictive models not exposed to adverse events may exhibit poor performance when these occur. Given that no dedicated spine surgery video datasets for AI model development are publicly available, we introduce Simulated Outcomes for Durotomy Repair in Minimally Invasive Spine Surgery (SOSpine). A validated MISS cadaveric dural repair simulator was used to educate neurosurgery residents, and surgical microscope video recordings were paired with outcome data. Objects including durotomy, needle, grasper, needle driver, and nerve hook were then annotated. Altogether, SOSpine contains 15,698 frames with 53,238 annotations and associated durotomy repair outcomes. For validation, an AI model was fine-tuned on SOSpine video and detected surgical instruments with a mean average precision of 0.77. In summary, SOSpine depicts spine surgeons managing a common complication, providing opportunities to develop surgical AI models.

Prevalence of active cytomegalovirus infection at diagnosis of ovarian cancer and during chemotherapy and subsequent changes in cognitive functioning.

PURPOSE: One of the most frequently reported effects of cancer and its treatments is cancer-related cognitive impairment (CRCI). Viral infections may affect inflammation and immune function and therefore may influence patient symptoms, including CRCI. The goal of this study was to describe the prevalence of cytomegalovirus (CMV) infections at diagnosis, during, and after chemotherapy in individuals with ovarian cancer and explore CMV infection at diagnosis with cancer-related cognitive impairment (CRCI) following chemotherapy. METHODS: We recruited adults newly diagnosed with ovarian, primary peritoneal or fallopian tube cancer at a single academic cancer center into two prospective studies. In Study 1 (N = 71), participants provided blood samples at diagnosis. In Study 2 (N = 18), participants provided blood samples and completed symptom surveys before, during and after front-line adjuvant chemotherapy. Serum CMV DNA levels were assessed using digital PCR; >100 copies/mL of serum was considered positive for active CMV infection (CMV+). CRCI was measured using the Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog) questionnaire. Changes in FACT-Cog scores were compared by CMV status at diagnosis using t-tests at each time point. RESULTS: At diagnosis, 29.2% were CMV+ (28.2% in Study 1, 33.3% in Study 2). Following three cycles of chemotherapy (Study 2), CMV positivity rose to 60.0% and then back down to 31.3% after chemotherapy. We observed significant differences in CRCI following chemotherapy by CMV status at diagnosis. CONCLUSION: Our data suggest that active CMV infection is common among patients undergoing treatment for ovarian cancer and may contribute to symptoms of CRCI.

Genetic counseling processes and strategies for racially and ethnically diverse populations: A systematic review.

Genetic counseling outcomes are influenced by the processes and strategies used by counselors, yet little is known about how these strategies directly impact patients and populations. In particular, tailoring genetic counseling consultations to best meet the needs of cultural, racial, and ethnically diverse populations has been explored. This review aims to identify genetic counseling strategies tailored for a diversity of racial and ethnic populations with the goal to find ways to improve genetic counseling outcomes. Medline, Cochrane CENTRAL, Embase, PsychInfo, and CINAHL databases were searched for original research articles published in English that employed genetic counseling processes and strategies to improve genetic counseling outcomes, specifically for participants from ethnically or racially diverse populations. A review of 5300 titles and abstracts resulted in the identification of 36 articles that met the inclusion criteria. Three themes emerged: (1) community involvement in culturally tailoring genetic counseling, (2) creation and use of culturally tailored resources, and (3) modifications to the genetic counseling process. The effectiveness of genetic counseling strategies could not be evaluated due to lack of consistent outcome measures in the articles. The involvement of diverse ethnic and racial populations in developing inclusive genetic counseling tools and practices will help the profession provide better patient care in the future. More research connecting genetic counseling processes and outcomes will help to assess how well these modified approaches meet the needs of diverse populations.

Stable isotope synthesis of glycine transporter 1 inhibitor Iclepertin (BI 425809) and its major metabolites.

Stable isotope labeled Iclepertin (BI 425809, 1) and its major metabolites are needed as internal standards in bioanalytical studies. BI 425809 consists of two main building blocks, 5-methylsulfonyl-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]benzoic acid (2) and 3-[(1R,5R)-3-azabicyclo[3.1.0]hexan-5-yl]-5-(trifluoromethyl)isoxazole (3) linked to each other via an amide bond. We used fluoro[13 C6 ]benzene as the starting material in the preparation of [13 C6 ]-2. This intermediate was then employed to access carbon 13 labeled Iclepertin ([13 C6 ]-1) and other metabolites. The major metabolite BI 761036 (6), which resulted from cytochrome P450 oxidation and amide hydrolysis of BI 425809, was prepared labeled with carbon 13 and nitrogen 15 via two synthetic routes. In the first route, diethyl [13 C3 ]malonate, [13 C]methyl iodide, and hydroxyl[15 N]amine were used to provide [13 C4 ,15 N]-BI 761036 ([13 C4 ,15 N]-6a) in 13 steps in 6% overall yield, whereas in the second route, [13 C3 ]propargyl alcohol, potassium [13 C]cyanide, and [15 N]ammonia were used to furnish [13 C4 ,15 N]-BI 761036 ([13 C4 ,15 N]-6b) in 11 steps in 1% overall yield. The detailed stable isotope synthesis of 1 and its major metabolites is described.

Carbon 14 and stable isotope synthesis of two potent and selective phosphodiesterase type 4 inhibitors.

(R)-2-(4-(Benzo[d]oxazol-2-yl)piperazin-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (1) and (R)-2-(4-(4-chlorophenoxy)piperidin-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (2) are two potent and selective inhibitors of phosphodiesterase type 4 (PDE4). In this manuscript, we report the detailed synthesis of these two compounds labeled with carbon 14 and with stable isotopes. The core (R)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide is common in both inhibitors. In the radioactive synthesis, the carbon 14 atom was introduced in the benzoxazole moiety using [14 C]carbon disulfide to obtain [14 C]-1 in five steps at a 55% overall yield. [14 C]Urea was used to incorporate the carbon 14 atom in two steps in the dihydrothieno[3,2-d]pyrimidine intermediate, which was then transformed in four more steps to [14 C]-2 at a 30% overall yield. Both compounds were isolated with specific activities higher than 54 mCi/mmol, radio- and chemical-purities higher than 99%, and with excellent enantiomeric excess. In the stable isotope synthesis, [2 H8 ]piperazine was used to prepare [2 H8 ]-1 in three steps in 72% overall yield, while [13 C6 ]phenol was used to prepare [13 C6 ]-2 in four steps in 18% overall yield.

Carbon 14 synthesis of glycine transporter 1 inhibitor Iclepertin (BI 425809) and its major metabolites.

Carbon 14 labeled Iclepertin (BI 425809, 1) and its major metabolites were needed for ADME and several other studies necessary for the advancement of this drug candidate in clinical trials. Iclepertin is composed of two main chemical blocks, (R)-5-(methylsulfonyl)-2-([1,1,1-trifluoropropan-2-yl]oxy)benzoic acid (2), and 3-[(1R,5R)-3-azabicyclo[3.1.0]hexan-5-yl]-5-(trifluoromethyl)isoxazole (3) linked to each other via an amide bond. In the first synthesis of carbon 14 labeled 1, 2-fluorobenzoic acid, carboxyl-14 C was converted to [14 C]-2 in three steps and then coupled to 3 to provide [14 C]-1a in 45% overall yield. In the second synthesis, [14 C]-3 was prepared in six radioactive steps and coupled to the acid 2 to furnish [14 C]-1b in 20% overall yield. Both synthetic routes provided [14 C]-1a and [14 C]-1b with specific activities higher than 53 mCi/mmol and radiochemical, chemical, and enantiomeric purities above 98%. Two major metabolites of 1, BI 761036 and BI 758790, were also prepared labeled with carbon 14 using intermediates already available from the synthesis of [14 C]-1.

Synthesis of BI 894416 and BI 1342561, two potent and selective spleen tyrosine kinase inhibitors, labeled with carbon 14 and with deuterium.

(R)-4-((R)-1-((6-(1-[tert-butyl]-1H-pyrazol-4-yl)-2-methyl-2H-pyrazolo[3,4-d]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (BI 894416, 1) and (R)-4-((R)-1-((6-(1-[tert-butyl]-1H-pyrazol-4-yl)-2,3-dimethyl-2H-indazol-4-yl)oxy)ethyl)pyrrolidin-2-one (BI 1342561, 2) are two new potent and selective spleen tyrosine kinase inhibitors developed to treat severe asthma. Both compounds have similar structures and they differ only in the bicyclic moiety 2-methyl-2H-pyrazolo[4,3-c]pyridine in 1 versus 2,3-dimethyl-2H-indazole in 2. In the carbon 14 synthesis, 1-(1-[tert-butyl]-1H-pyrazol-4-yl)ethan-1-one-1-14 C ([14 C]-8) was prepared from the cyanation of 4-bromopyrazole using zinc [14 C]cyanide followed by methyl lithium addition on the nitrile group. The enolate of [14 C]-8 was then used to access these two bicyclic moieties via pyrano-pyrazoles [14 C]-11 and [14 C]-12, which were further transformed in few more steps to [14 C]-(1) and [14 C]-2. Both inhibitors contain a tert-butyl group. Introducing tert-butyl-d9 will not only provide internal standards for bioanalytical studies, but it is also expected to slow down the metabolism of these two compounds. Most of the metabolites of compound 1, for example, are the result of tert-butyl oxidation, like alcohol 3, acid 4, and the further N-demethylation of 4 to 5. The detailed preparation of these deuterium-labeled metabolites is also described.

Synthesis of beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors BI 1147560 and BI 1181181 labeled with carbon-14 and deuterium.

The generation of amyloid beta peptides that aggregate in the brain is believed to play a major role in Alzheimer's disease. In theory, the inhibition of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), which catalyzes the initial rate-limiting step in amyloid beta production, may slow or stop Alzheimer's disease. Herein, we report the preparation of two potent BACE1 inhibitors, BI 1147560 (1) and BI 1181181 (2), labeled with carbon-14 and with deuterium. The use of advanced key chiral intermediates like 3 and 5 shortened the carbon-14 syntheses of these two compounds to five and six steps, respectively, and helped in preparing them with very high chemical purity and enantiomeric excess without deviating from the process chemistry route. For the deuterium synthesis, oxetan-3-ylmethanamine [2 H6 ]-7 and 2-fluoro-2-methylpropan-1-amine [2 H6 ]-9 were prepared then used with the chiral intermediate 5 to furnish deuterium labeled 1 and 2, respectively.

Safety, tolerability, and pharmacokinetics of single and multiple ascending Oral doses of DA-8010 in healthy subjects: First-in-human phase I study.

This study assessed the safety, tolerability, and pharmacokinetics of single and multiple oral doses of DA-8010, a muscarinic M3 receptor antagonist, in healthy subjects. This was a randomized, double-blind, placebo-controlled, ascending single (Part A: 1, 2.5, 5, 20, and 40 mg QD fasted and 10 mg QD fasted and fed) and multiple doses (Part B: 5, 10, and 20 mg QD from Days 1 to 7 fasted), sequential-group study. Safety data were analyzed descriptively, time to maximum plasma concentration (tmax ) nonparametrically, and pharmacokinetic parameters using power and mixed models and ANOVA. Of 109 subjects randomized (Part A = 69 and Part B = 40; each part consisted a female group), 31 (44.9%) in Part A and 29 (72.5%) in Part B experienced treatment-emergent adverse events (TEAEs) in a dose-related manner. Common drug-related TEAEs in Part A and B were dizziness (8.7% and 15.0%), headache (5.8% and 12.5%) and blurred vision (8.7% and 20%). One male (20 mg) and one female (10 mg) from Part B discontinued the study due to a confusional state, and nausea and vomiting. Irrespective of sex, DA-8010 was steadily absorbed following single and multiple doses in the fasted state with increased systemic exposure in a dose-proportional manner with maximum plasma concentration occurring at a median tmax between 4.0 and 6.0 h. A high-fat meal increased systemic exposure. DA-8010 was safe, well tolerated, and well absorbed at lower doses and moderately tolerated at higher doses without any notable effects of food and sex.

Rapid manufacturing of micro-drilling devices using FFF-type 3D printing technology.

Micro-drilling devices with different blade shapes were fabricated with a rapid and facile manufacturing process using three-dimensional (3D) printing technology. The 3D-printed casting mold was utilized to customize the continuous shape of the blades without the need for expensive manufacturing tools. A computational fluid dynamics simulation was performed to estimate the pressure differences (fluidic resistance) around each rotating device in a flowing stream. Three types of blades (i.e., 45°, 0°, and helical type) were manufactured and compared to a device without blades (i.e., plain type). As a result, the device with the 45° blades exhibited the best drilling performance. At a rotational speed of 1000 rpm, the average drilling depth of the device with the 45° blades to penetrate artificial thrombus for 90 s was 3.64 mm, which was ~ 2.4 times longer than that of helical blades (1.51 mm). This study demonstrates the feasibility of using 3D printing to fabricate microscale drilling devices with sharp blades for various applications, such as in vivo microsurgery and clogged water supply tube maintenance.

Modeling and application of anisotropic hyperelasticity of PDMS polymers with surface patterns obtained by additive manufacturing technology.

Polydimethylsiloxane (PDMS) polymer has been widely used in the biomedical fields because of its bio-compatibility, being used as sensors, medical equipment and tissue implants. The present study aims to synthesize and characterize micro lane-type surface patterns of PDMS polymers and evaluate their effects on mechanical properties for various applications in the bio-engineering field. Fabrication of surface patterns is achieved using fused filament fabrication in additive manufacturing, and the mechanical properties of the polymer specimens with the surface patterns are measured using tensile test. The surface patterns are rotated at different angles and changed into different shapes to change the anisotropic material properties of the PDMS specimens. This is achieved by changing the raster angles and modifying the fused filament paths during the additive manufacturing process. In addition, the application of the printed pattern to medical soft robot is presented. Owing to the anisotropic material properties, in-plane and out-of-plane actuation can be realized by attaching polymer patches with different lane-type surface patterns. The results of this study support the implementation of additive manufacturing for the rapid manufacture of scalable structures with anisotropic material properties for various applications.

Comparisons of emotional health by diagnosis among women with early stage gynecological cancers.

OBJECTIVE: To assess self-reported emotional health in a cohort of women with early stage gynecologic cancers and to explore differences based on primary cancer type. METHODS: We analyzed survey data from a cohort study of gynecological cancer patients treated at an academic cancer center. Measures of emotional health included cancer-related quality of life, distress, depression, anxiety, posttraumatic stress disorder (PTSD), and posttraumatic growth. Univariate and multivariate linear regression models examined differences in emotional health measures by primary cancer site. Potential confounders considered for inclusion in the final models were age, stage, education, income, partner status, treatment status, and race. RESULTS: 242 patients with early stage disease completed the survey. Patients with cervical and vaginal/vulvar cancers reported greater cancer-related distress, anxiety and PTSD symptoms. Patients with endometrial cancer reported the lowest posttraumatic growth scores, which remained statistically significant after adjustment for demographic and clinical differences. No significant differences in cancer-related quality of life were observed among individuals with different primary cancer sites CONCLUSIONS: These data suggest patients with early-stage gynecologic cancer face different psychosocial sequelae based on primary cancer site, though underlying clinical and sociodemographic factors may play a significant role in this observed relationship. Further research is needed to assess poorer emotional health among individuals with vaginal/vulvar cancers and the lower posttraumatic growth among patients with endometrial cancer as posttraumatic growth is considered a potentially beneficial psychosocial outcome of cancer.

Blockade of translationally controlled tumor protein attenuated the aggressiveness of fibroblast-like synoviocytes and ameliorated collagen-induced arthritis.

Histamine releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses, but the role of HRF/TCTP in rheumatoid arthritis (RA) remains undefined. In this study, we explored the pathogenic significance of HRF/TCTP and evaluated the therapeutic effects of HRF/TCTP blockade in RA. HRF/TCTP transgenic (TG) and knockdown (KD) mice with collagen-induced arthritis (CIA) were used to determine the experimental phenotypes of RA. HRF/TCTP levels in the sera of RA patients were measured and compared to those from patients with osteoarthritis (OA), ankylosing spondylitis, Behçet's disease, and healthy controls. HRF/TCTP expression was also assessed in the synovium and fibroblast-like synoviocytes (FLSs) obtained from RA or OA patients. Finally, we assessed the effects of HRF/TCTP and dimerized HRF/TCTP-binding peptide-2 (dTBP2), an HRF/TCTP inhibitor, in RA-FLSs and CIA mice. Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were increased in HRF/TCTP TG mice and decreased in KD mice compared to wild-type littermates. HRF/TCTP levels in the sera, synovial fluid, synovium, and FLSs were higher in patients with RA than in control groups. Serum levels of HRF/TCTP correlated well with RA disease activity. The tumor-like aggressiveness of RA-FLSs was exacerbated by HRF/TCTP stimulation and ameliorated by dTBP2 treatment. dTBP2 exerted protective and therapeutic effects in CIA mice and had no detrimental effects in a murine tuberculosis model. Our results indicate that HRF/TCTP is a novel biomarker and therapeutic target for the diagnosis and treatment of RA.

Adult adoptees and their use of direct-to-consumer genetic testing: Searching for family, searching for health.

Use of direct-to-consumer genetic testing (DTC-GT) is rapidly growing in the United States. Yet little is known about how specific populations like domestic and intercountry adoptees use DTC-GT. Adoptees often have little to no biological family history, which may affect how they use DTC-GT. This study aimed to examine adult adoptees' motivations to pursue DTC-GT, experiences completing a test, and reasons for not completing one. An online survey consisting of 41 closed-ended questions was distributed to domestic and intercountry adult adoptees in a snowball convenience method addressing seven areas: (a) demographics and adoption experience, (b) family health history, (c) familiarity with DTC-GT, (d) actual DTC-GT experience, (e) hypothetical DTC-GT experience, (f) health results, and (g) satisfaction with DTC-GT. Descriptive statistics were performed on participant demographics and adoption characteristics, and chi-squared and Fisher's exact tests compared demographics and adoption characteristics by familiarity with DTC-GT and completion of DTC-GT. A total of 117 adoptees met criteria and completed the survey. Adoptees were motivated to use DTC-GT to search for biological family (83.0%), verify race and ethnicity (72.3%), and find out where ancestors came from (66.0%). Most participants completed DTC-GT (80.3%); completion was significantly associated with searching for biological relatives (p < 0.01) and with older age (p = 0.05). For those who received health information (59.6%), 44.4% of participants reported talking with a health provider. Adoptees are using DTC-GT to search for biological relatives, confirm their ethnicity and ancestry, and gain information about their health. Genetic counselors and health professionals should be prepared to address DTC-GT with adoptees as nearly half discussed their results with providers; findings from this study provide insight into how this unique population uses DTC-GT, and the possibility of patient-centered, tailored care for adopted patients who do not have family health history.

Sustainability Challenges and Opportunities in Oligonucleotide Manufacturing.

With a renewed and growing interest in therapeutic oligonucleotides across the pharmaceutical industry, pressure is increasing on drug developers to take more seriously the sustainability ramifications of this modality. With 12 oligonucleotide drugs reaching the market to date and hundreds more in clinical trials and preclinical development, the current state of the art in oligonucleotide production poses a waste and cost burden to manufacturers. Legacy technologies make use of large volumes of hazardous reagents and solvents, as well as energy-intensive processes in synthesis, purification, and isolation. In 2016, the American Chemical Society (ACS) Green Chemistry Institute Pharmaceutical Roundtable (GCIPR) identified the development of greener processes for oligonucleotide Active Pharmaceutical Ingredients (APIs) as a critical unmet need. As a result, the Roundtable formed a focus team with the remit of identifying green chemistry and engineering improvements that would make oligonucleotide production more sustainable. In this Perspective, we summarize the present challenges in oligonucleotide synthesis, purification, and isolation; highlight potential solutions; and encourage synergies between academia; contract research, development and manufacturing organizations; and the pharmaceutical industry. A critical part of our assessment includes Process Mass Intensity (PMI) data from multiple companies to provide preliminary baseline metrics for current oligonucleotide manufacturing processes.

Hidden among the hidden: Transracially adopted Korean American adults raising multiracial children.

The parenting practices of both transracially adopted Korean American adults and multiracial families are often overlooked in developmental science, yet are important to address, given that the majority of Korean adoptees are now adults with families of their own and given rapid increases in the multiracial population. This qualitative study examined the cultural socialization beliefs and practices among transracially adopted Korean Americans who are parents of multiracial Asian-White children. Drawing upon interviews with 31 Korean adoptee parents (29 female; Mage = 41.26), we identified four themes that capture parents' understanding of their children's multiracial identities, how that understanding subsequently shapes their cultural socialization practices, and how parents' socialization beliefs and practices vary by developmental stage. These themes described the ways that parents' cultural socialization practices were shaped by their children's phenotypes, parents' understanding of their children's multiracial identities, geographic location, and the multiracial family context. This study also demonstrated how multiracial couples in our sample engaged in cultural socialization together. Results suggest that Korean adoptee parents largely acknowledged their children's multiracial identities through labels, but primarily socialized children as monoracial minorities. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Community Assessment of the Predictability of Cancer Protein and Phosphoprotein Levels from Genomics and Transcriptomics.

Cancer is driven by genomic alterations, but the processes causing this disease are largely performed by proteins. However, proteins are harder and more expensive to measure than genes and transcripts. To catalyze developments of methods to infer protein levels from other omics measurements, we leveraged crowdsourcing via the NCI-CPTAC DREAM proteogenomic challenge. We asked for methods to predict protein and phosphorylation levels from genomic and transcriptomic data in cancer patients. The best performance was achieved by an ensemble of models, including as predictors transcript level of the corresponding genes, interaction between genes, conservation across tumor types, and phosphosite proximity for phosphorylation prediction. Proteins from metabolic pathways and complexes were the best and worst predicted, respectively. The performance of even the best-performing model was modest, suggesting that many proteins are strongly regulated through translational control and degradation. Our results set a reference for the limitations of computational inference in proteogenomics. A record of this paper's transparent peer review process is included in the Supplemental Information.

Sulfone-Mediated SNAr Reaction as a Powerful Tool for the Synthesis of 4-Quinolinyl Ethers and More-Application to the Synthesis of HCV NS3/4a Protease Inhibitor BI 201420.

An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive SNAr reaction of 4-quinolinyl sulfones with a range of structurally diversified 1°, 2°, and 3° alcohols with a wide substrate scope and high yields. By adapting this methodology, a convergent synthesis of a complex target of HCV NS3/4a protease inhibitor BI 201420 was accomplished.

Cancer-Related Distress: Revisiting the Utility of the National Comprehensive Cancer Network Distress Thermometer Problem List in Women With Gynecologic Cancers.

PURPOSE: The Distress Thermometer (DT) includes a measure of cancer-related distress and a list of self-reported problems. This study evaluated the utility of the DT problem list in identifying concerns most associated with distress and poorer quality of life (QOL) in survivors of gynecologic cancer. METHODS: Demographic, clinical, psychosocial functioning, and DT data were described among 355 women participating in a gynecologic cancer cohort. Problems from the DT list were ranked by prevalence, distress, and QOL. Logistic regression models explored factors associated with problems that were common (≥ 25% prevalence) and associated with distress and QOL. RESULTS: The average age of participants was 59.9 years (standard deviation [SD], 10.8 years). Most participants were non-Hispanic white (97%) and had ovarian (44%) or uterine (42%) cancer. The mean DT score was 2.7 (SD, 2.7); participants reported a mean of 7.3 problems (SD, 5.9 problems). The most common problems were fatigue (53.6%), worry (49.9%), and tingling (46.3%); least common problems were childcare (2.1%), fevers (2.1%), and substance abuse (1.1%). Report of some common problems, including tingling, sleep, memory, skin issues, and appearance, was not associated with large differences in distress or QOL. In contrast, some rarer problems such as childcare, treatment decisions, eating, housing, nausea, and bathing/dressing were associated with worse distress or QOL. Younger age, lower income, and chemotherapy were risk factors across common problems that were associated with worse distress or QOL (fatigue, nervousness, sadness, fears, and pain). CONCLUSION: The DT problem list did not easily identify concerns most associated with distress and low QOL in patients with gynecologic cancer. Adaptations that enable patients to report their most distressing concerns would enhance clinical utility of this commonly used tool.