Translation variation across genetic backgrounds reveals a post-transcriptional buffering signature in yeast.

Gene expression is known to vary among individuals, and this variability can impact the phenotypic diversity observed in natural populations. While the transcriptome and proteome have been extensively studied, little is known about the translation process itself. Here, we therefore performed ribosome and transcriptomic profiling on a genetically and ecologically diverse set of natural isolates of the Saccharomyces cerevisiae yeast. Interestingly, we found that the Euclidean distances between each profile and the expression fold changes in each pairwise isolate comparison were higher at the transcriptomic level. This observation clearly indicates that the transcriptional variation observed in the different isolates is buffered through a phenomenon known as post-transcriptional buffering at the translation level. Furthermore, this phenomenon seemed to have a specific signature by preferentially affecting essential genes as well as genes involved in complex-forming proteins, and low transcribed genes. We also explored the translation of the S. cerevisiae pangenome and found that the accessory genes related to introgression events displayed similar transcription and translation levels as the core genome. By contrast, genes acquired through horizontal gene transfer events tended to be less efficiently translated. Together, our results highlight both the extent and signature of the post-transcriptional buffering.

Exploring the Clinical Use of Molecular Profiling of Intrahepatic Cholangiocarcinoma in a Comprehensive Multidisciplinary Clinic.

BACKGROUND: Molecular profiling of intrahepatic cholangiocarcinoma (ICC) can detect actionable molecular alterations and guide targeted therapies. We explore the clinical use of molecular profiling of ICC in our comprehensive multidisciplinary clinic. STUDY DESIGN: Patients with a tissue diagnosis of ICC seen between 2019 and 2023 were identified. A retrospective review was performed to identify their molecular profiles and targeted therapy. The association between the detection of actionable molecular alterations and overall survival (OS) from the first clinic visit date was studied. Patients with an OS of less than 2 months were excluded. RESULTS: Among 194 patients with ICC, 125 had molecular profiling. Actionable molecular alterations were detected in 56 (45%) patients, including microsatellite instability (n = 3), high tumor mutational burden (>10 muts/mb; n = 5), isocitrate dehydrogenase 1 and 2 mutations (n = 22 and 6, respectively), BRAF V600E mutations (n = 2), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha mutations (n = 7), breast cancer 1 and breast cancer 2 mutations (n = 5), mesenchymal epithelial transition amplification (n = 2), fibroblast growth factor receptor 2 and 3 fusions (n = 13), erb-b2 receptor tyrosine kinase 2 overexpression (n = 6), and receptor tyrosine kinase 1 fusion (n = 1). Twenty-one patients received targeted therapies during their treatment course. Survival analysis revealed that for 120 patients with molecular profiling, the detection of an actionable molecular alteration was associated with improved mean OS (34.1 vs 23.6 months, p = 0.008). Among 70 patients with nonmetastatic ICC, the detection of an actionable molecular alteration was associated with improved mean OS (32.1 vs 27.5 months, p = 0.02). CONCLUSIONS: Actionable molecular alterations were frequently observed in patients with ICC. Detection of actionable alterations was associated with improved OS. The role of targeted therapy needs further exploration in prospective multicenter studies.

Detecting Somatic Mutations for Well-Differentiated Pancreatic Neuroendocrine Tumors in Endoscopic Ultrasound-Guided Fine Needle Aspiration with Next-Generation Sequencing.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) exhibit heterogenous behavior, whereby some small tumors are aggressive with a propensity for metastasis. Detection of somatic mutations associated with aggressive biology may help with patient stratification and surgical decision-making in patients with well-differentiated PanNETs. Using next-generation sequencing (NGS), we investigated the feasibility of detecting somatic mutations in endoscopic ultrasound-guided, fine-needle aspiration (EUS-FNA) specimens and determining the mutational concordance between the EUS-FNA specimens and the primary tumors. METHODS: Thirty-eight patients with well-differentiated, nonfunctioning PanNETs were obtained from two tertiary referral centers. Patient demographic characteristics and tumor, clinicopathologic features were collected. Tissue from both the EUS-FNA specimen and the primary tumor was extracted from archival tissue blocks. NGS using a panel of ten genes was performed on both samples. RESULTS: In our series, the median age was 61.1 years. Tumors were predominantly left-sided (60.5%) and unifocal (94.7%). The median tumor size was 2.2 cm. NGS detected somatic mutations in 29% of primary tumors and 36.8% of EUS-FNA specimens. In primary tumors, DAXX/ATRX mutations were predominantly detected (63.6%). In EUS-FNA specimens, MEN1 mutations were predominantly detected (64.3%). Among non-wild-type specimens, mutational concordance was achieved in 31.6% of cases. In 11 patients with a detectable mutation in the primary tumor, a mutation was detected in the EUS-FNA specimen in 45.5% of cases, with a mutational concordance of 54.5%. CONCLUSIONS: NGS can detect somatic mutations in EUS-FNA specimens of well-differentiated PanNETs. Efforts to improve detection sensitivity and mutational concordance are required to overcome current technical limitations.

Does systemic steroid use affect the length of hospital stay for head and neck infections?

OBJECTIVE: The purpose of this study was to conduct a systematic review to perform a meta-analysis to investigate the outcomes of head and neck infections treated with systemic steroids. STUDY DESIGN: The protocol was registered to the International Prospective Register of Systematic Reviews on August 24, 2020. The studies were compiled using PubMed/Medline with a single reviewer from their inception until August 17, 2020. The studies were uploaded onto Convidence.org, and a repeat search was conducted and uploaded on August 17, 2021. Two independent reviewers (J.S. and S.H.) blinded to each other's assessments reviewed the title and/or abstract for inclusion. After a first pass, full-text reviews of the articles were assessed (J.S. and K.F.) for study inclusion. Data were extracted from the steroid (test) and nonsteroid (control) cohorts. RESULTS: The initial search of key terms yielded 2,711 studies. Titles and abstracts were reviewed, and only cohort and/or cross-sectional studies with the relevant study groups and the relevant outcomes were retrieved for the filtration system. The 2 reviewers reviewed 188 full-text studies, and 3 studies met the inclusion criteria. Although all 3 studies included the mean length of stay for the treatment and a control group, only 2 studies included the confidence interval, and only 1 included P values. Overall, the studies presented insufficient data to pool outcomes and ran a statistical analysis for meta-analysis. CONCLUSIONS: Steroid use reduced the length of stay in 2 studies and increased the length of stay in another larger study. Given the lack of data to perform a meta-analysis, more studies need to be conducted, with a prospective randomized control trial design being essential for guiding evidence-based practice regarding the use of steroids in head and neck infections.

Cancer-cell-derived sialylated IgG as a novel biomarker for predicting poor pathological response to neoadjuvant therapy and prognosis in pancreatic cancer.

BACKGROUND: Neoadjuvant therapy (NAT) is increasingly applied in pancreatic ductal adenocarcinoma (PDAC); however, accurate prediction of therapeutic response to NAT remains a pressing clinical challenge. Cancer-cell-derived sialylated immunoglobulin G (SIA-IgG) was previously identified as a prognostic biomarker in PDAC. This study aims to explore whether SIA-IgG expression in treatment-naïve fine needle aspirate (FNA) biopsy specimens could predict the pathological response (PR) to NAT for PDAC. METHODS: Endoscopic ultrasonography-guided FNA biopsy specimens prior to NAT were prospectively obtained from 72 patients with PDAC at the Johns Hopkins Hospital. SIA-IgG expression of PDAC specimens was assessed by immunohistochemistry. Associations between SIA-IgG expression and PR, as well as patient prognosis, were analyzed. A second cohort enrolling surgically resected primary tumor specimens from 79 patients with PDAC was used to validate the prognostic value of SIA-IgG expression. RESULTS: SIA-IgG was expressed in 58.3% of treatment-naïve FNA biopsies. Positive SIA-IgG expression at diagnosis was associated with unfavorable PR and can serve as an independent predictor of PR. The sensitivity and specificity of SIA-IgG expression in FNA specimens in predicting an unfavorable PR were 63.9% and 80.6%, respectively. Both positive SIA-IgG expression in treatment-naïve FNA specimens and high SIA-IgG expression in surgically resected primary tumor specimens were significantly associated with shorter survival. CONCLUSIONS: Assessment of SIA-IgG on FNA specimens prior to NAT may help predict PR for PDAC. Additionally, SIA-IgG expression in treatment-naïve FNA specimens and surgically resected primary tumor specimens were predictive of the prognosis for PDAC.

Delayed Aortic Valve Perforation Caused by Blunt Trauma.

Traumatic aortic regurgitation (AR) is a rare complication of blunt chest trauma. We described the case of a 35-year-old male who presented to our hospital with shortness of breath 7 years after sustaining blunt chest trauma associated with a motorcycle accident. Transthoracic and transesophageal echocardiogram detected severe AR with two separate jets. The patient was diagnosed with congestive heart failure due to severe AR, and surgical aortic valve replacement was performed. A large perforation of the right coronary cusp likely sustained during the initial blunt chest trauma injury was confirmed surgically. As AR caused by blunt chest trauma can gradually worsen, it is necessary to confirm if there is a history of trauma in patients with severe AR of unknown origin.

Tailoring Adjuvant Chemotherapy to Biologic Response Following Neoadjuvant Chemotherapy Impacts Overall Survival in Pancreatic Cancer.

BACKGROUND: The role of postoperative chemotherapy in patients with resected pancreatic cancer who receive neoadjuvant treatment is unknown. Clinicians use changes in CA19-9 and histopathologic scores to assess treatment response. We sought to investigate if CA19-9 normalization in response to NAT can help guide the need for postoperative treatment. METHODS: Patients with elevated baseline CA19-9 (CA19-9 > 37U/mL) who received NAT followed by surgery between 2011 and 2019 were retrospectively reviewed. Treatment response was determined by CA19-9 normalization following NAT and histopathologic scoring. The role of postoperative chemotherapy was analyzed in light of CA19-9 normalization and histopathologic response. RESULTS: We identified and included 345 patients. Following NAT, CA19-9 normalization was observed in 125 patients (36.2%). CA19-9 normalization was associated with a favorable histopathologic response (41.6% vs 23.2%, p < 0.001) and a lower ypT (p < 0.001) and ypN stage (p = 0.003). Receipt of adjuvant chemotherapy was associated with improved overall survival in patients in whom CA19-9 did not normalize following NAT (26.8 vs 16.4 months, p = 0.008). In patients who received 5FU-based NAT and in whom CA19-9 did not normalize, receipt of 5FU-based adjuvant chemotherapy was associated with improved OS (p = 0.014). CONCLUSION: CA19-9 normalization in response to NAT was associated with favorable outcomes and can serve as a biomarker for treatment response. In patients where CA19-9 did not normalize, receipt of postoperative chemotherapy was associated with improved OS. These patients also benefited from additional 5FU-based postoperative chemotherapy following 5FU-based NAT.

Opioid-Prescribing Patterns in Connecticut and New Jersey Following Third Molar Extractions.

OBJECTIVE: In recent years, opioid misuse has resulted in much scrutiny on providers' prescribing habits. The purpose of this study was to analyze prescribing habits in the context of third molar extractions as a model for promoting better postsurgical pain management. METHODS: This was a cross-sectional survey of oral maxillofacial surgeons in Connecticut and New Jersey. A total of 291 practitioners were contacted to complete an online survey using Qualtrics Research Services to determine prescribing habits following third molar extractions. RESULTS: The most common approach for postoperative analgesia was nonsteroidal anti-inflammatory drugs (NSAIDs) and an opioid/acetaminophen (APAP) combination as 2 separate prescriptions, reported by 36% of participants. The combination of hydrocodone/APAP was the most common opioid formulation, and an average of 10.93 ± 4.51 opioid pills were prescribed with a maximum of 20 pills reported. Most providers (79%) consistently provided patients with opioid information. Only 22% reported always checking opioid-monitoring programs; however, providers were more likely to check if prescribing more than ∼11 opioid pills (P = .0228). Most reported using dexamethasone (82%) and bupivacaine (56%) intraoperatively, while ketorolac was less common (15%). No association was found between the quantity of opioids prescribed and the use of intraoperative ketorolac, steroids, or bupivacaine (P > .05). CONCLUSION: There remains to be a universal standard for using opioids for postoperative pain management in dentistry. Providers should be mindful when prescribing opioids and consider using NSAIDs and APAP for baseline pain plus a separate opioid prescription for breakthrough pain. Additional focus on minimizing the quantity of opioids prescribed and self-reflecting on prescribing and practice habits to further reduce opioid-related complications is warranted.

Algebraic approach for subspace decomposition and clustering of neural activity.

We developed an approach to decompose neuronal signals into disjoint components, corresponding to task- or event-based epochs. This protocol describes how to project behavioral templates onto a low-dimensional subspace of neuronal responses to derive neuronal templates, then how to decompose and cluster neuronal responses using these derived templates. We outline these steps on complementary datasets of calcium imaging and spiking activity. Our approach relies on fundamental, linear algebraic principles and is adaptive to the temporal structure of the neural data. For complete details on the use and execution of this protocol, please refer to Adam et al. (2022).1.

Are we training oral and maxillofacial surgeons in minimally invasive cosmetic procedures?

OBJECTIVE: Oral and maxillofacial surgeons (OMS) are well trained in facial anatomy, but exposure to cosmetic procedures in residencies is inconsistent due to several factors, including the patient population, technique, and cost. The primary objective of the present study was to identify an association with exposure to treatment modality in residency with likelihood to perform these procedures in practice. STUDY DESIGN: This was a cross-sectional survey distributed to practicing OMS in the United States. Links to the online survey were distributed using communications from local, state, and regional OMS surgery societies. Information was gathered on clinical practice and training during and after residency. The study outcome was whether the respondent performed injectables (dermal fillers or neuromodulators) in their practice. RESULTS: A total of 150 responses were included in the study sample, and no responses were excluded. Only 42.7% of respondents reported performing injectables. Just 37% of respondents stated they had had an opportunity to perform these procedures as a resident, suggesting that 5.7% did not perform injectables until they started practice. Dual-degree training, additional fellowship training, and practical and didactic continuing education training were all associated with higher likelihoods of having an injectable practice. Injectable exposure in residency did not significantly affect the prevalence of having an injectable practice. CONCLUSIONS: OMS who performed injectables were more likely to seek additional forms of training outside of residency. Educators should reevaluate the way that they are approaching cosmetics procedures in residency.

Dynamic control of visually guided locomotion through corticosubthalamic projections.

Goal-directed locomotion requires control signals that propagate from higher order areas to regulate spinal mechanisms. The corticosubthalamic hyperdirect pathway offers a short route for cortical information to reach locomotor centers in the brainstem. We developed a task in which head-fixed mice run to a visual landmark and then stop and wait to collect the reward and examined the role of secondary motor cortex (M2) projections to the subthalamic nucleus (STN) in controlling locomotion. Our behavioral modeling, calcium imaging, and optogenetics manipulation results suggest that the M2-STN pathway can be recruited during visually guided locomotion to rapidly and precisely control the pedunculopontine nucleus (PPN) of the mesencephalic locomotor region through the basal ganglia. By capturing the physiological dynamics through a feedback control model and analyzing neuronal signals in M2, PPN, and STN, we find that the corticosubthalamic projections potentially control PPN activity by differentiating an M2 error signal to ensure fast input-output dynamics.

Clinical Trials in Hepatopancreatobiliary Surgery: Assessing Trial Characteristics, Early Discontinuation, Result Reporting, and Publication.

BACKGROUND: Hepatopancreaticobiliary (HPB) diseases carry high morbidity despite efforts aimed at their reduction. An assessment of their trial characteristics is paramount to determine trial design adequacy and highlight areas for improvement. As such, the aim of this study is to assess HPB surgery trial characteristics, summarize logistic, financial, and practical reasons behind early discontinuation, and propose potential interventions to prevent this in the future. METHODS: All clinical trials investigating HPB surgery registered on ClinicalTrials.gov from October 1st, 2007 (inclusive), to April 20th, 2021 (inclusive), were examined. Trial characteristics were collected including, but not limited to, study phase, duration, patient enrollment size, location, and study design. Peer-reviewed publications associated with the selected trials were also assessed to determine outcome reporting. RESULTS: A total of 1776 clinical trials conducted in 43 countries were identified, the majority of which were conducted in the USA. Of these trials, 32% were reported as "completed" whereas 12% were "discontinued." The most common cause of trial discontinuation was low accrual, which was reported in 37% of terminated studies. These resulted in 413 published studies. Most trials had multiple assignment, randomized, or open-label designs. Treatment was the most common study objective (73%) with pharmacological therapy being the most commonly studied intervention. CONCLUSIONS: The main reasons for early discontinuation of clinical trials in HPB surgery are poor patient recruitment and inadequate funding. Improved trial design, recruitment strategies and increased funding are needed to prevent trial discontinuation and increase publication rates of HPB surgery clinical trials.

Deep brain stimulation in the subthalamic nucleus for Parkinson's disease can restore dynamics of striatal networks.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in alleviating movement disability in patients with Parkinson's disease (PD). However, its therapeutic mechanism of action is unknown. The healthy striatum exhibits rich dynamics resulting from an interaction of beta, gamma, and theta oscillations. These rhythms are essential to selection and execution of motor programs, and their loss or exaggeration due to dopamine (DA) depletion in PD is a major source of behavioral deficits. Restoring the natural rhythms may then be instrumental in the therapeutic action of DBS. We develop a biophysical networked model of a BG pathway to study how abnormal beta oscillations can emerge throughout the BG in PD and how DBS can restore normal beta, gamma, and theta striatal rhythms. Our model incorporates STN projections to the striatum, long known but understudied, found to preferentially target fast-spiking interneurons (FSI). We find that DBS in STN can normalize striatal medium spiny neuron activity by recruiting FSI dynamics and restoring the inhibitory potency of FSIs observed in normal conditions. We also find that DBS allows the reexpression of gamma and theta rhythms, thought to be dependent on high DA levels and thus lost in PD, through cortical noise control. Our study highlights that DBS effects can go beyond regularizing BG output dynamics to restoring normal internal BG dynamics and the ability to regulate them. It also suggests how gamma and theta oscillations can be leveraged to supplement DBS treatment and enhance its effectiveness.

Factors Affecting Outcomes of Craniofacial Clinical Trials.

PURPOSE: This study aims to provide a cross-sectional view of craniofacial trials and to identify factors associated with completion, publication, and trial longevity. MATERIALS AND METHODS: This is a cross-sectional study of cleft and craniofacial clinical trials registered with ClinicalTrials.gov between September 1999 and April 2020. Predictor variables included funding source, trial design, trial location, number of recruitment sites, and investigator specialty.Study outcomes were completion status, publication status, and trial duration. Univariate comparisons and multivariate regression models were calculated for each outcome. RESULTS: The final sample included 179 clinical trials pertaining to craniofacial care. Nearly all trials were single-center (86.5%), and roughly half of trials were interventional (57.0%) or conducted in the United States (40.5%). No single specialty predominated, although plastic surgery (13.4%) was the most common investigator specialty. The completion rate was 82.7%, the publication rate was 40.8%, and the mean trial duration was 39.1 months. Interventional design (odds ratio = 0.30, P = 0.02) and United States location (odds ratio = 0.15, P < 0.01) were each independently associated with lower odds of trial completion. Trial longevity was independently associated with the National Institute of Health-funding (P < 0.01) and multicenter design (P < 0.01). CONCLUSIONS: Craniofacial trials are multidisciplinary and have a high rate of completion. Although most existing trials were conducted at only a single-center, multicenter efforts significantly increased trial longevity without compromising completion and publication rates. Given the diverse array of conditions and lines of inquiry that compose craniofacial care, it is reassuring that collaboration did not negatively affect trial outcomes.