Miracle-dz/UniFAR-FTUs huggingface dataset:
Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition

Purpose: Although KRAS represents the most commonly mutated oncogene, it has long been considered an “undruggable” target. Novel covalent inhibitors selective for the KRASG12C mutation offer the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS–MAPK pathway have been hampered by adaptive feedback, which drives pathway reactivation and resistance. Experimental Design: A panel of KRASG12C cell lines were treated with the KRASG12C inhibitors ARS-1620 and AMG 510 to assess effects on signaling and viability. Isoform-specific pulldown of activated GTP-bound RAS was performed to evaluate effects on the activity of specific RAS isoforms over time following treatment. RTK inhibitors, SHP2 inhibitors, and MEK/ERK inhibitors were assessed in combination with KRASG12C inhibitors in vitro and in vivo as potential strategies to overcome resistance and enhance efficacy. Results: We observed rapid adaptive RAS pathway feedback reactivation following KRASG12C inhibition in the majority of KRASG12C models, driven by RTK-mediated activation of wild-type RAS, which cannot be inhibited by G12C-specific inhibitors. Importantly, multiple RTKs can mediate feedback, with no single RTK appearing critical across all KRASG12C models. However, coinhibition of SHP2, which mediates signaling from multiple RTKs to RAS, abrogated feedback reactivation more universally, and combined KRASG12C/SHP2 inhibition drove sustained RAS pathway suppression and improved efficacy in vitro and in vivo. Conclusions: These data identify feedback reactivation of wild-type RAS as a key mechanism of adaptive resistance to KRASG12C inhibitors and highlight the potential importance of vertical inhibition strategies to enhance the clinical efficacy of KRASG12C inhibitors. See related commentary by Yaeger and Solit, p. 1538
Metformin and risk of Alzheimer's disease among community-dwelling people with diabetes: a national case-control study.

CONTEXT Type 2 diabetes has been linked with an increased risk of Alzheimer's disease (AD). Studies on the association between metformin use and AD have reported conflicting results. OBJECTIVE To investigate whether metformin use modifies the association between diabetes and incident, clinically verified AD. DESIGN Nested case-control study. SETTING All community dwelling people in Finland. PARTICIPANTS Cases were all community-dwelling Finns with AD diagnosed between 2005-2011 and with diabetes diagnosed ≥3 years before AD (n=9862). Cases were matched with up to 2 control persons by age, sex and diabetes duration (n=19550). MAIN OUTCOME MEASURE Cumulative metformin exposure was determined from reimbursed dispensings over a 10-16 year period. Adjusted odds ratios (aORs) were calculated using conditional logistic regression to estimate associations, with adjustment for potential confounders. RESULTS 7225 (73.3%) cases and 14528 (74.3%) controls received metformin at least once. Metformin use (ever use) was not associated with incident AD (aOR 0.99, 95% CI 0.94-1.05). The adjusted odds of AD were lower among people dispensed metformin for ≥10 years (aOR 0.85, 95% CI 0.76-0.95), those dispensed cumulative defined daily doses (DDDs) of <1825-3650 (aOR 0.91, 95% CI 0.84-0.98) and >3650 DDDs (aOR 0.77, 95% CI 0.67-0.88), and among persons dispensed an average of 2g metformin daily (aOR 0.89, 95% CI 0.82-0.96). CONCLUSION In this large national sample we found no evidence that metformin use increases the risk of AD. Conversely, long-term and high-dose metformin use was associated with a lower risk of incident AD in older people with diabetes.
Orofacial muscles may be affected in early stages of Becker muscular dystrophy: A preliminary study

Dysphagia is reported in patients with Duchenne or Becker muscular dystrophy. Our clinical experience suggests that, compared with Duchenne patients, impaired mastication and swallowing occur early in Becker patients relative to their skeletal muscle involvement. The aim of this study was to assess dysphagia in Duchenne and Becker patients in relation to ambulatory capacity.
A Combined Linkage and GWAS Analysis Identifies QTLs Linked to Soybean Seed Protein and Oil Content

Soybean is an excellent source of vegetable protein and edible oil. Understanding the genetic basis of protein and oil content will improve the breeding programs for soybean. Linkage analysis and genome-wide association study (GWAS) tools were combined to detect quantitative trait loci (QTL) that are associated with protein and oil content in soybean. Three hundred and eight recombinant inbred lines (RILs) containing 3454 single nucleotide polymorphism (SNP) markers and 200 soybean accessions, including 94,462 SNPs and indels, were applied to identify QTL intervals and significant SNP loci. Intervals on chromosomes 1, 15, and 20 were correlated with both traits, and QTL qPro15-1, qPro20-1, and qOil5-1 reproducibly correlated with large phenotypic variations. SNP loci on chromosome 20 that overlapped with qPro20-1 were reproducibly connected to both traits by GWAS (p < 10−4). Twenty-five candidate genes with putative roles in protein and/or oil metabolisms within two regions (qPro15-1, qPro20-1) were identified, and eight of these genes showed differential expressions in parent lines during late reproductive growth stages, consistent with a role in controlling protein and oil content. The new well-defined QTL should significantly improve molecular breeding programs, and the identified candidate genes may help elucidate the mechanisms of protein and oil biosynthesis.
Return to Work and Sport After Proximal Tibial Osteotomy and the Effects of Opening Versus Closing Wedge Techniques on Adverse Outcomes: A Systematic Review and Meta-analysis

Background: Although many studies have reported successful functional outcomes after proximal tibial osteotomy (PTO), a paucity of literature has sought to quantify outcomes and current rates of return to sport (RTS) and return to work (RTW) after PTO. Purpose: To (1) determine current rates of RTS and RTW after PTO and (2) quantify the incidence of complications and conversion to total knee arthroplasty (TKA) after PTO for all patients as well as those undergoing opening and closing wedge PTO. Study Design: Systematic review and meta-analysis; Level of evidence, 4. Methods: The Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed (2008-2019), EMBASE (2008-2019), and MEDLINE (2008-2019) databases were queried. Data pertaining to article information, patient demographics, surgical techniques, rates of complication and conversion to TKA, patient-reported outcome scores, RTS, and RTW were extracted. Data were synthesized, and a random effects meta-analysis of proportions using continuity correction methods was performed to determine the proportion of patients receiving opening and closing wedge PTO who experienced adverse events. Results: The review and meta-analysis included 33 studies involving 1914 patients who underwent PTO with a weighted mean ± SD age of 50.3 ± 9.9 years and body mass index of 26.9 ± 2.3 kg/m2. The pooled RTS and RTW rates were 75.7% (range, 55%-100%) in 814 patients and 80.8% (range, 41%-100%) in 505 patients, respectively. The pooled TKA rate was 12.5% (range, 0%-35.7%) at a mean of 70.6 months and the pooled complication rate was 11.1% (range, 0%-28.6%). The overall random pooled summary estimate of the proportion of patients who underwent opening wedge PTO and subsequently converted to TKA was 2.0% (95% CI, 1.0%-4.0%; I2 = 63.65) at a mean of 43.4 ± 31.9 months and who experienced a complication was 6.0% (95% CI, 3.0%-9.0%; I2 = 87.10%). For closing wedge PTO, the proportion of patients who converted to TKA was 5.0% (95% CI, 1.0%-9.0%; I2 = 93.1%) and experienced a complication was 2.0% (95% CI, 1.0%-3.0%; I2 = 90.0%). Only 53.8% of studies that referenced RTS provided postoperative RTS rates, and 80% of studies that referenced RTW provided RTW rates. Only 1 study defined RTS criteria, no studies defined RTW criteria, and 31 different outcome measures were reported across all studies. Conclusion: Patients undergoing PTO for osteoarthritis, cartilage defects, and symptomatic malalignment of the knee experience high rates of RTS and RTW. These patients also experience low rates of complications and conversion to TKA, regardless of opening or closing wedge technique. Significant heterogeneity exists with regard to criteria used to define RTS and RTW and patient-reported outcome measures used to assess clinical and functional improvements after PTO.
Quantitative Trait Module-Based Genetic Analysis of Alzheimer’s Disease

The pathological features of Alzheimer’s Disease (AD) first appear in the medial temporal lobe and then in other brain structures with the development of the disease. In this work, we investigated the association between genetic loci and subcortical structure volumes of AD on 393 samples in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Brain subcortical structures were clustered into modules using Pearson’s correlation coefficient of volumes across all samples. Module volumes were used as quantitative traits to identify not only the main effect loci but also the interactive effect loci for each module. Thirty-five subcortical structures were clustered into five modules, each corresponding to a particular brain structure/area, including the limbic system (module I), the corpus callosum (module II), thalamus–cerebellum–brainstem–pallidum (module III), the basal ganglia neostriatum (module IV), and the ventricular system (module V). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results indicate that the gene annotations of the five modules were distinct, with few overlaps between different modules. We identified several main effect loci and interactive effect loci for each module. All these loci are related to the function of module structures and basic biological processes such as material transport and signal transduction.
Gallbladder Retrieval From Epigastric Versus Umbilical Port in Laparoscopic Cholecystectomy: A PRISMA-Compliant Meta-Analysis

Purpose. To date, no evidence supports the retrieval of the gallbladder through a specific trocar site, and this choice is left to surgeons’ preference. The aim of this meta-analysis was to investigate the influence of the trocar site used to extract the gallbladder on postoperative outcomes. Methods. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a literature search of PubMed, Google Scholar, Cochrane Library, and EMBASE databases was performed. Terms used were: (“gallbladder” OR “cholecystectomy”) AND “umbilical” AND (“epigastric” OR “subxiphoid”). Randomized trials comparing the gallbladder retrieval from different trocar sites were considered for further analysis. Results. Literature search revealed 145 articles, of which 7 matched inclusion criteria and reported adequate data about postoperative pain, operative time, port-site infections, and hernias. A total of 876 patients were included, and the gallbladder was extracted through epigastric or umbilical trocar site in 441 and in 435 patients, respectively. A statistically significant difference among groups was noted in terms of postoperative pain at 1, 6, 12, and 24 hours in favor of the umbilical trocar site (P < .001). No significant differences were noted in postoperative hernia and infection rate, nor in terms of operative time. Conclusions. This meta-analysis shows a statistically significant reduction in terms of postoperative pain at 1, 6, 12, and 24 hours after surgery when the gallbladder is extracted through the umbilical port. Retrieval time, infections, and hernias rate implicate no contraindication for the choice of a specific trocar site to extract specimens. Despite limitations of this study, the umbilical trocar should be favored as the first choice to retrieve the gallbladder.
Generativity and other buffers of death awareness in first responders

ABSTRACT Background and Objectives: Anxiety buffer disruption theory (ABDT) predicts that posttraumatic stress reactions occur when buffers of awareness of death, such as meaning in life, self-esteem, and social intimacy, fail to suppress overwhelming death-anxiety. In this study, we hypothesized that generativity may also serve as an effective buffer of awareness of death and posttraumatic stress disorder (PTSD). Design: The present study investigated the presence of anxiety buffering disruption in first responders with a spectrum of posttraumatic stress via a mediation path model of self-report measures of PTSD symptoms, anxiety buffer variables, and death-thought accessibility. Methods: To investigate the role of anxiety buffering in PTSD, a sample of 986 first responders completed self-report measures of PTSD symptoms and anxiety buffer variables in randomized order, and a death-thought accessibility measure following random assignment to mortality salience (n = 290) or control (n = 302) conditioning. Results and Conclusion: Results of structural equation modeling indicated PTSD symptoms have a small relation to increased awareness of death whereas anxiety buffering variables did not mediate the relation between PTSD symptoms and awareness of death. Nonetheless, generativity and meaning in life, self-esteem, and social support were significant predictors of lower levels of PTSD.
Inlay graft of acellular dermal matrix to prevent incisional dehiscence after radiotherapy in prosthetic breast reconstruction

Background As the indications for postmastectomy radiotherapy expand, innovative solutions are required to reduce operative complications and reconstructive failure after prosthetic breast reconstruction. In this study, we investigated the effectiveness of acellular dermal matrix (ADM) inlay grafts in preventing postoperative wound dehiscence of irradiated breasts in the context of prosthetic breast reconstruction. Methods A retrospective analysis was conducted of 45 patients who received two-stage prosthetic reconstruction and radiotherapy following mastectomy. An ADM graft was placed beneath the incisional site during the second-stage operation in 19 patients using marionette sutures, whereas the control group did not receive the ADM reinforcement. Patient demographics and complications such as wound dehiscence, capsular contracture, peri-prosthetic infection, cellulitis, and seroma were compared between the two groups. Results During an average follow-up period of 37.1 months, wound dehiscence occurred significantly less often in the ADM-reinforced closure group (0%) than in the non-ADM group (23.1%) (P=0.032). There was no significant difference between the two groups in relation to other complications, such as capsular contracture, postoperative infection, or seroma. Conclusions The ADM inlay graft is a simple and easily reproducible technique for preventing incisional dehiscence in the setting of radiotherapy after prosthetic breast reconstruction. The ADM graft serves as a buttress to offload tension during healing and provides a mechanical barrier against pathogens. Application of this technique may serve to reduce complications in prosthetic breast reconstruction after radiotherapy.
A New Scoring System for the Assessment of Neonatal Abstinence Syndrome

Abstract Objective This study aimed to evaluate the concordance of a new scoring system for neonatal abstinence syndrome (NAS) and NAS scores to the traditional Modified Finnegan Neonatal Abstinence Scoring Tool (M-FNAST) score. The NAS score is based on the physiology of withdrawal, with equal emphasis on behavior, and neurological signs. Study Design The NAS scores for a control group of 202 healthy, term neonates were compared with those for 45 term neonates with NAS. The NAS and M-FNAST scores obtained simultaneously in 45 term neonates with NAS were compared using correlation, linear regression, and receiver operating characteristic curve analysis to determine the validity, reliability, and specificity of the NAS scores. Results The association between the NAS and M-FNAST scores was high (Spearman's correlation, 83%; linear regression, 83%), with an area under the curve of the NAS score of 1.00 (p < 0.01). A cut-off NAS score ≥4 identified NAS neonates with a sensitivity of 100% and specificity of 96%. The values of intraclass correlation, interrater agreement, and Cronbach's α were 0.63, 0.88, and 0.63, respectively. Conclusion The new NAS scoring system is valid, reliable, physiologically based, and correlates closely with the M-FNAST score. The NAS scores may require further validation before its use in clinical practice.
Tumor suppressor properties of the small C-terminal domain phosphatases in non-small cell lung cancer

Abstract Non-Small Cell Lung Cancer (NSCLC) is responsible for the majority of deaths caused by cancer. Small C-terminal domain (CTD) phosphatases (SCP), CTDSP1, CTDSP2 and CTDSPL (CTDSPs) belong to SCP/CTDSP subfamily and are involved in many vital cellular processes and tumorigenesis. High similarity of their structures suggests similar functions. However their role in NSCLC remains insufficiently understood. For the first time we revealed the suppressor function of CTDSPs leading to a significant growth slowdown and senescence of A549 lung adenocarcinoma (ADC) cells in vitro. Their tumor-suppressive activity can be realized through increasing the proportion of the active form of Rb protein dephosphorylated at Ser807/811, Ser780, and Ser795 (P<0.05) thereby negatively regulating cancer cell proliferation. Moreover, we observed that a frequent (84%, 39/46) and highly concordant (Spearman’s rank correlation coefficient (rs) = 0.53–0.62, P≤0.01) down-regulation of CTDSPs and RB1 is characteristic of primary NSCLC samples (n=46). A clear difference in their mRNA levels was found between lung ADCs with and without lymph node metastases, but not in squamous cell carcinomas (SCCs) (P≤0.05). Based on The Cancer Genome Atlas (TCGA) data and the results obtained using the CrossHub tool, we suggest that the well-known oncogenic cluster miR-96/182/183 could be a common expression regulator of CTDSPs. Indeed, according to our qPCR, the expression of CTDSPs negatively correlates with these miRs, but positively correlates with their intronic miR-26a/b. Our results reflect functional association of CTDSP1, CTDSP2, and CTDSPL, expand knowledge about their suppressor properties through Rb dephosphorylation and provide new insights into the regulation of NSCLC growth.
Prescriber Education Interventions to Optimize Opioid Prescribing in Acute Care: A Systematic Review.

BACKGROUND Opioid medications are frequently used effectively for analgesia in acute settings, however, they are associated with dependence and addiction, and were implicated in 47,600 American fatalities in 2017. Evidence suggests that despite guidelines and professional body recommendations, acute prescribing remains highly variable. Educational interventions targeting prescribers have potential to optimize prescribing in-line with evidence-based best practice. OBJECTIVES To identify the objective impacts of education interventions on opioid prescribing in the acute care setting. STUDY DESIGN A systematic literature review. SETTING The electronic databases MEDLINE, Embase, and Cochrane for works published until December 31, 2018. Bibliographies of relevant studies and the gray literature were also searched. METHODS Databases were searched for interventional studies (clinical trials and pre- and poststudies). Studies describing an educational intervention delivered to clinicians and reporting at least one objective measure of opioid use in the acute care setting were included. Studies reporting only subjective outcomes and those focused on chronic pain or set in primary care were excluded. Two reviewers (RB, TB) extracted data and assessed the quality of included studies using the Downs and Black Tool. RESULTS Nine studies met inclusion criteria; all used pre- and postdesigns. Three studies described stand-alone education, and the others described multifaceted interventions. All 9 interventions significantly reduced at least one of the following: high-risk agent use including meperidine use by up to 71%; total or daily dosage of opioids at discharge, including median morphine milligram equivalence (MME) from 90 mg to 45 mg per patient; and quantity of medications such as oxycodone supplied to patients, halved in one study from 6,170 expected to 2,932 supplied tablets. No increase in pain complaints or prescription refill requests were reported in those studies assessing these outcomes. The longest study examined prescribing 15 months after education delivery, reporting sustained practice changes. LIMITATIONS Overall study quality was fair to poor. Significant heterogeneity in settings, patient groups, methodologies, and outcomes prevented pooled quantitative analysis. No studies examined all available opioid agents or formulations. CONCLUSIONS These findings support prescriber education as an effective strategy to reduce opioid use and optimize prescribing in acute settings. Further research, particularly high quality randomized studies, describing the impact of education on all available opioid formulations and total MME is required. Reviewing the existing literature has offered useful models that can be implemented to improve care with opioid prescribing in acute settings. KEY WORDS Opioids, education, physician education, prescriber education, opioid education, opioid prescribing, systematic review, prescriptions, prevention.
Radiofrequency Thermocoagulation Through Foramen Rotundum Versus Foramen Ovale for the Treatment of V2 Trigeminal Neuralgia.

BACKGROUND Percutaneous radiofrequency thermocoagulation through the foramen rotundum (FR) is a new approach for the treatment of V2 trigeminal neuralgia (TN). OBJECTIVES This study aimed to compare the efficacy and safety of the FR approach with that of the foramen ovale (FO) approach. STUDY DESIGN Nonrandomized controlled clinical trial. SETTING The study was conducted at Huaian Hospital of Huaian City, Huaian, China. METHODS From July 2014 to December 2016, 80 consecutive patients with V2 TN were prospectively assigned into the FO group (n = 40) or the FR group (n = 40). All radiofrequency thermocoagulation procedures were performed under the guidance of digital subtraction angiography (DSA). Patients in the FO group were treated with Gasserian ganglion ablation through the Hartel approach. Patients in the FR group received ablation of the maxillary nerve at the internal opening of the FR. Facial pain was evaluated using the Visual Analog Scale preoperatively and postoperatively at 1 week, 6 months, and 1 year. RESULTS All surgical procedures were successfully completed using DSA guidance. The FR group had no facial pain at postoperative 1 week, 6 months, and 1 year. The facial fain was not relieved in 4 patients of the FO group. They were treated with radiofrequency thermocoagulation of the maxillary nerve through the FR and maintained painless at postoperative 1 week, 6 months, and 1 year. At postoperative 1 year, another 3 patients relapsed in the FO group. The incidences of facial numbness and swelling did not differ significantly between the 2 groups (all P > 0.05). There was no postoperative corneal involvement or masticatory weakness in the FR group. However, corneal involvement and masticatory weakness occurred postoperatively in 22 (55%) patients and 31 (77.5%) patients in the FO group. The FR group had significantly shorter operation time than the FO group (19.3 ± 5.9 vs. 32.7 ± 8.7 minutes; P < 0.05). LIMITATIONS We were unable to avoid the V1 and V3 branches, despite multiple adjustments of the needed position in 35 of the 40 patients in this group. CONCLUSIONS For the treatment of V2 TN, thermocoagulation of the maxillary nerve through the FR had better efficacy and fewer complications in comparison with the Gasserian ganglion ablation through the FO. KEY WORDS Neuralgia, pain, radiology, facial pain.