Case report: Salivary duct carcinoma in a patient with a germline CDH1 pathogenic variant - expanding the spectrum of hereditary cancer predisposition syndromes.

Introduction: Recently, an entity known as salivary duct carcinoma with rhabdoid features (SDC-RF) has been associated with somatic CDH1 mutations. Here we present the first known case report of conventional SDC occurring in the setting of a germline CDH1 pathogenic variant accompanied by a somatic loss of heterozygosity at the CDH1 locus. Case discussion: A 67-year-old man presented with chest and back pain and was found to have osteolytic lesions in the sternum and lumbar spine. Vertebral bone biopsies were positive for metastatic carcinoma of unknown primary. A molecular profiling assay consisting of both whole-exome next-generation sequencing (NGS) as well as immunohistochemistry (IHC) for select clinically-relevant proteins performed on the bone biopsy suggested a triple-negative (ER/PR/ERBB2 negative, by IHC), androgen receptor (AR IHC) positive tumor profile. Additionally, the assay uncovered a coding mutation in the CDH1 gene (c.1792C>T, p.R598*) with genomic loss of the second CDH1 allele. Germline testing returned positive for a heterozygous CDH1 pathogenic variant. PET-CT revealed a tumor in the neck suggestive of the primary malignancy consistent with that of salivary gland origin. The patient was initially treated with carboplatin and paclitaxel, then pembrolizumab, and finally with AR-directed therapy using leuprolide and enzalutamide. These treatments were not successful, and the patient eventually succumbed to his disease. Conclusion: Molecular testing revealed that our patient had bi-allelic inactivation of the CDH1 gene. We believe our patient developed a somatic mutation in addition to his preexisting germline CDH1 mutation that ultimately predisposed him to SDC. While previous studies have found somatic CDH1 pathogenic variants in SDC-RF, our patient was found to have a germline CDH1 pathogenic variant in the setting of conventional SDC, without rhabdoid features. This case provokes questions regarding tumor genetics and molecular profiling of SDC in patients with germline CDH1 pathogenic variants. Moreover, this case supports the notion that SDC may be the salivary counterpart of other malignancies associated with germline CDH1 pathogenic variants and may possibly expand the spectrum of tumors that arise in this familial cancer-predisposition syndrome.

Association of antibiotic exposure with residual cancer burden in HER2-negative early stage breast cancer.

Antibiotic exposure during immunotherapy (IO) has been shown to negatively affect clinical outcomes in various cancer types. The aim of this study was to evaluate whether antibiotic exposure in patients with high-risk early-stage HER2-negative breast cancer (BC) undergoing treatment with neoadjuvant pembrolizumab impacted residual cancer burden (RCB) and pathologic complete response (pCR) in the pembrolizumab-4 arm of the ISPY-2 clinical trial. Patients received pembrolizumab for four cycles concurrently with weekly paclitaxel for 12 weeks, followed by four cycles of doxorubicin plus cyclophosphamide every 2 or 3 weeks. Patients who received at least one dose of systemic antibiotics concurrently at the time of immunotherapy (IO) were included in the antibiotic exposure group (ATB+). All other participants were included in the control group (ATB-). RCB index and PCR rates were compared between the ATB+ and ATB- groups using t-tests and Chi-squared tests, and linear and logistic regression models, respectively. Sixty-six patients were included in the analysis. 18/66 (27%) patients were in the ATB+ group. Antibiotic use during IO was associated with a higher mean RCB index (1.80 ± 1.43 versus 1.08 ± 1.41) and a lower pCR rate (27.8% versus 52.1%). The association between antibiotic use and the RCB index remained significant in multivariable linear regression analysis (RCB index-coefficient 0.86, 95% CI 0.20-1.53, P = 0.01). Our findings suggest that concurrent antibiotic exposure during neoadjuvant pembrolizumab in HER2-negative early-stage BC is associated with higher RCB. Further validation in larger cohorts is needed to confirm these findings.

Estimating Muscle Mass Using D3-Creatine Dilution: A Narrative Review of Clinical Implications and Comparison With Other Methods.

BACKGROUND: The D3-creatine (D3-Cr) dilution method is of emerging interest for estimating total-body skeletal muscle mass. This review explores the association of muscle mass estimated via D3-Cr with various clinical outcomes and provides a summary of the literature comparing D3-Cr with other body composition techniques. METHODS: A literature search was conducted on PubMed/MEDLINE and Web of Science for studies using D3-Cr to measure muscle in adult populations (ie, ≥18 years old) from inception until September 2023. RESULTS: Out of the 23 included studies, 15 investigated the correlation between D3-Cr and clinical outcomes. More consistent associations were reported for mortality (100%, n = 2), mobility disability (100%; n = 5), falls and fractures (100%; n = 3), physical performance (63.3%; n = 11), muscle strength (44.4%; n = 9), and muscle composition (33.3%; n = 3). However, conflicting findings were also reported for such correlations. Among the 23 studies, 14 compared D3-Cr-estimated muscle with other body composition techniques, including magnetic resonance imaging (MRI) as a reference method. Strong and positive correlations were found between D3-Cr and MRI. Nonetheless, variations in muscle measurements were noted, with differences in D3-Cr values ranging from 0.62 kg lower to 13.47 kg higher compared to MRI. CONCLUSIONS: D3-Cr-estimated muscle mass may be a valuable predictor of clinical outcomes showing consistent associations with falls and fractures, mobility disability, and mortality. However, less consistent associations were found with muscle strength and composition, and physical performance. Although a strong correlation exists between D3-Cr-estimated muscle mass and MRI measurements, under- or overestimation may occur.

Outcomes and predictors of survival for tracheal cancer.

INTRODUCTION: Primary tracheal cancer is uncommon, with poor survival. While surgical resection is the mainstay of therapy, the role of chemotherapy and radiation is poorly defined. We aimed to study the impact of treatment modalities on survival. METHODS: Patients with primary tracheal cancer were identified from the National Cancer Database over 12 years, 2004-2015. Patient characteristics, tumor characteristics, treatment modalities, and survival were recorded. Factors associated with survival were assessed using Cox Regression. RESULTS: Of the 1726 patients identified, 59% were male, 83% White race, 62% had a comorbidity index of zero, median age 64 years, median tumor size 2.7 cm, and median survival was 28.5 months (89 months for patients undergoing surgical resection). Cox Regression for all patients found adenoid cystic carcinoma (ACC) (p < 0.001), radiation (p < 0.001), and surgical resection (p < 0.001) to be associated with improved survival, while increasing age (p < 0.001) decreased survival. For patients receiving resection, ACC (p < 0.001) was associated with improved survival, while increasing age (p < 0.001) and positive margins (p = 0.002) were associated with worse survival. For R0 resections, ACC (p < 0.001) was associated with improved survival, while increasing age (p < 0.001) decreased survival, with chemotherapy and radiation having no impact. For R1/2 resections, ACC (p < 0.001) and radiation (p < 0.001) were associated with improved survival, while increasing age (p < 0.001) decreased survival, with chemotherapy having no impact on survival. CONCLUSIONS: Primary tracheal cancer is highly lethal, with surgical resection leading to the best chance of survival. For patients undergoing resection, radiation provided survival benefits for R1/2 but not R0, while chemotherapy did not impact survival regardless of margin status.

Influence of menopausal status on physical function and performance: A cross-sectional study.

OBJECTIVE: To compare the physical function and performance in pre-, peri-, and postmenopausal women. STUDY DESIGN: A cross sectional study using convenience sampling method was conducted in 210 women categorized into premenopausal, perimenopausal, and postmenopausal. MAIN OUTCOME MEASURES: Flexibility, muscle strength, muscle endurance, cardiovascular endurance, static balance, dynamic balance, and gait speed. RESULTS: The mean age of the premenopausal, perimenopausal, and postmenopausal women was 46.55 ± 1.77, 49.54 ± 3.38 and 54.85 ± 3.77 years respectively. There is significant difference observed between premenopausal, perimenopausal, and postmenopausal women in muscle strength, upper limb endurance, lower limb endurance, static balance, dynamic balance, gait speed, and cardiovascular endurance (p < .05) using Kruskal Wallis test. There is no significant difference observed between the groups for flexibility (p > .05). CONCLUSION: It was observed that physical function and performance was impaired in postmenopausal women when compared to pre- and perimenopausal women. Hence, these components should be included during assessment which will provide a holistic and multimodal approach toward the understanding, planning and management of postmenopausal women in community settings.

Perturbations of immune landscape in COVID-19 associated mucormycosis.

BACKGROUND: A rise in secondary fungal infections during the COVID-19 pandemic necessitates a deeper understanding of the associated immunological perturbations. OBJECTIVES: To evaluate the clinical and immunological characteristics observed in patients with COVID-19 associated mucormycosis (CAM) infection. PATIENTS/ METHODS: Cases of mucormycosis with or post-COVID-19 infection were compared with cases of acute COVID-19 and convalescent COVID-19. Lymphocyte subsets, cytokines and other laboratory markers were compared between the groups. RESULTS: The frequency of proposed risk factors for CAM was diabetes mellitus (77%), recent history of steroid use (69%) and hypoxia during COVID-19 infection (52%). Iron metabolism was dysregulated in CAM patients with low TIBC and total iron. Further, CAM was accompanied with lymphopenia with drastic reduction in B cell counts; however, plasmablasts were not altered. Further, CAM patients had low immunoglobulin levels and antibodies specific to mucor peptide did not increase in CAM suggesting dysfunction in B-cell response. There was increase in activated effector cytotoxic CD8 T cells and NK cells in CAM compared with COVID-19 infection and healthy controls. Among T helper cells, Tregs were reduced and Th-1 frequency was increased in CAM compared with COVID-19 infection. A distinct cytokine signature was evident in CAM with increase in IL-1ß, IFN-γ, IL-6, IL-22, IL-17A, IL-10, IL-2, IL-8, IL-7, IL-21 and GM-CSF. CONCLUSION: This is the first study on immunophenotyping in CAM suggesting the need for long-term monitoring of B-cell function after SARS-CoV-2 in patients with dysregulated glycaemic control and the possible benefit of therapeutic supplementation with intravenous immunoglobulins in CAM.

Optimal time to thoracoscopy for trauma patients with retained hemothorax.

BACKGROUND: Retained hemothorax remains a common problem after thoracic trauma with associated morbidity and prolonged hospitalizations. The goal of this study was to examine the impact of time to video assisted thoracoscopic surgery (VATS) on pulmonary morbidity using a large, national data set. METHODS: Patients undergoing VATS for retained hemothorax within the first 14 days postinjury were identified from the Trauma Quality Improvement Program database over 5 years, ending in 2016. Demographics, mechanism, severity of injury, severity of shock, time to VATS, pulmonary morbidity, and mortality were recorded. Multivariable logistic regression analysis was performed to determine independent predictors of pulmonary morbidity. Youden's index was then used to identify the optimal time to VATS. RESULTS: From the Trauma Quality Improvement Program database, 3,546 patients were identified. Of these, 2,355 (66%) suffered blunt injury. The majority were male (81%) with a median age and Injury Severity Score of 46 and 16, respectively. The median time to VATS was 134 hours. Both pulmonary morbidity (13 vs 17%, P = .004) and hospital length of stay (9 vs 12 days, P < .0001) were significantly reduced in patients undergoing VATS before 3.9 days. Multivariable logistic regression identified VATS during the first 7 days as the only modifiable risk factor significantly associated with reduced pulmonary morbidity (odds ratio 0.52; 95% confidence interval 0.43-0.63, P < .0001). CONCLUSION: Patients undergoing VATS for retained hemothorax have significant morbidity and prolonged length of stay. VATS within the first week of admission results in fewer pulmonary complications and shorter length of stay. In fact, the optimal time to VATS was identified as 3.9 days and was the only modifiable risk factor associated with decreased pulmonary morbidity.

Distinct burst properties contribute to the functional diversity of thalamic nuclei.

Thalamic neurons fire spikes in two modes, burst and tonic. The function of burst firing is unclear, but the evidence suggests that bursts are more effective at activating cortical cells, and that postinhibition rebound bursting contributes to thalamocortical oscillations during sleep. Bursts are considered stereotyped signals; however, there is limited evidence regarding how burst properties compare across thalamic nuclei of different functional or anatomical organization. Here, we used whole-cell patch clamp recordings and compartmental modeling to investigate the properties of bursts in six sensory thalamic nuclei, to study the mechanisms that can lead to different burst properties, and to assess the implications of different burst properties for thalamocortical transmission and oscillatory functions. We found that bursts in higher-order cells on average had higher number of spikes and longer latency to the first spike. Additionally, burst features in first-order neurons were determined by sensory modality. Shifting the voltage-dependence and density of the T-channel conductance in a compartmental model replicates the burst properties from the intracellular recordings, pointing to molecular mechanisms that can generate burst diversity. Furthermore, the model predicts that bursts with higher number of spikes will drastically reduce the effectiveness of thalamocortical transmission. In addition, the latency to burst limited the rebound oscillatory frequency in modeled cells. These results demonstrate that burst properties vary according to the thalamocortical hierarchy and with sensory modality. The findings imply that, while in burst mode, thalamocortical transmission and firing frequency will be determined by the number of spikes and latency to burst.

Understanding gestational surrogacy in the United States: a primer for obstetricians and gynecologists.

As gestational surrogacy (a process by which intended parents contract with a woman to carry a fetus that the intended parents will raise) increases across the United States, it is imperative that obstetrician/gynecologists understand the unique nuances of caring for patients who are gestational surrogates. Gestational surrogacy offers a route to parenthood for individuals and families who may otherwise have limited options. Understanding surrogacy requires multiple ethical considerations about the potential medical and psychosocial effects on gestational surrogates as well as the families built through surrogacy. There is a dearth of research on the subject, particularly in the United States and other countries that practice compensated surrogacy. Here we seek to review the process of gestational surrogacy in the United States, including the legal landscape, current trends in gestational surrogacy use, and what is known about the medical and social effects of this process on all participants. We also aim to highlight the limitations of available data and to identify topics for future research to provide optimal evidence-based and just care for these patients.

Correlation Between Altmetric Score and Citations in Pediatric Surgery Core Journals.

BACKGROUND: The impact of a scientific article has traditionally been measured by the impact factor (IF) of the journal it is published in and the number of times it is cited. However, citations have a lag period before the true impact of an article can be determined. The Altmetric score has emerged as a measure of the digital dissemination of a scientific article across multiple platforms, including Tweets, Facebook likes, and other social and popular media mentions. We hypothesized that Altmetric score would correlate with citations and journal IF in pediatric surgery. METHODS: Using the previously identified 14 core journals of pediatric surgery, the top ten most-cited articles from each of these journals were identified for the year 2012, allowing for 5+ y of follow-up. For each article, we determined the number of times cited and the Altmetric score. For each journal, the 2012 IF and year in which the journal's Twitter account was established were determined. Bibliometric data were collected for the year 2015 to allow comparison of Altmetric scores across years. Descriptive statistics and Pearson's correlation coefficients were determined using the GraphPad PRISM software. RESULTS: Citation information for n = 140 articles from 2012 to 2015 was obtained. In 2012, articles were cited 56,159 times (median 192, range 21-5029), and the median Altmetric score was 8 (range 0-4261). Citations correlated strongly with journal IF (r = 0.82, P < 0.0001). Altmetric scores in 2012 showed weak positive correlation with citations (r = 0.1895, P = 0.0125) but did not correlate with IF (r = 0.0841, P = 0.1617). Altmetric scores in 2015 also showed weak positive correlation with citations (r = 0.238, P = 0.0023) but additionally weakly correlated with IF (r = 0.2027, P = 0.0082). Increasing age of a journal's Twitter account resulted in increasing correlation between Altmetric score and citations in both 2012 (r = 0.299, P = 0.169) and 2015 (r = 0.512, P = 0.037). Twitter was the primary social media contributor to Altmetric score in 2012 and 2015, with decreasing contribution from Facebook. CONCLUSIONS: This study is the first to link traditional bibliometric measures with newer measures of digital dissemination for publications in pediatric surgery. Although the Altmetric score of the top cited articles did not correlate with journal IF, it did weakly correlate with citations. Interestingly, this correlation was strongest for journals with well-established Twitter accounts, indicating that, over time, the Altmetric score may emerge as a tool to predict future citations. Currently, Altmetric and traditional bibliometric measures appear to have distinct but complementary roles in measuring dissemination and impact of scientific articles in pediatric surgery.

Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry.

Mu-opioid receptors (MORs) are the primary site of action of opioid drugs, both licit and illicit. Susceptibility to opioid addiction is associated with variants in the gene encoding the MOR, OPRM1 Varying with ethnicity, ∼25% of humans carry a single nucleotide polymorphism (SNP) in OPRM1 (A118G). This SNP produces a nonsynonymous amino acid substitution, replacing asparagine (N40) with aspartate (D40), and has been linked with an increased risk for drug addiction. While a murine model of human OPRM1 A118G (A112G in mouse) recapitulates most of the phenotypes reported in humans, the neuronal mechanisms underlying these phenotypes remain elusive. Here, we investigated the impact of A118G on opioid regulation of synaptic transmission in mesolimbic VTA dopaminergic neurons. Using electrophysiology, we showed that both inhibitory and excitatory inputs to VTA dopaminergic neurons projecting to the NAc medial shell were suppressed by the MOR agonists DAMGO and morphine, which caused a shift in the excitatory/inhibitory balance and an increased action potential firing rate. Mice carrying the 112G/G allele exhibited lower sensitivity to DAMGO and morphine compared with major allele carriers (112A/A). Paradoxically, DAMGO produced facilitatory effects on mEPSCs, which were mediated by presynaptic GABAB receptors. However, this was only prominent in homozygous major allele carriers, which could explain a stronger shift in action potential firing in 112A/A mice. This study provides a better understanding on the neurobiological mechanisms that may underlie risk of addiction development in carriers of the A118G SNP in OPRM1SIGNIFICANCE STATEMENT The pandemic of opioid drug abuse is associated with many socioeconomic burdens. The primary brain target of opioid drugs is the µ-opioid receptor (MOR), encoded by the OPRM1 gene, which is highly polymorphic in humans. Using a mouse model of the human OPRM1 A118G single nucleotide polymorphism (SNP) (A112G in mice), we demonstrated that MOR and GABAB signaling coordinate in regulating mesolimbic dopamine neuronal firing via presynaptic regulation. The A118G SNP affects MOR-mediated suppression of GABA and glutamate release, showing weaker efficacy of synaptic regulation by MORs. These results may shed light on whether MOR SNPs need to be considered for devising effective therapeutic interventions.

Crowders Steal Dihydrofolate Reductase Ligands through Quinary Interactions.

Dihydrofolate reductase (DHFR) reduces dihydrofolate (DHF) to tetrahydrofolate using NADPH as a cofactor. Due to its role in one carbon metabolism, chromosomal DHFR is the target of the antibacterial drug, trimethoprim. Resistance to trimethoprim has resulted in a type II DHFR that is not structurally related to the chromosomal enzyme target. Because of its metabolic significance, understanding DHFR kinetics and ligand binding behavior in more cell-like conditions, where the total macromolecule concentration can be as great as 300 mg/mL, is important. The progress-curve kinetics and ligand binding properties of the drug target (chromosomal E. coli DHFR) and the drug resistant (R67 DHFR) enzymes were studied in the presence of macromolecular cosolutes. There were varied effects on NADPH oxidation and binding to the two DHFRs, with some cosolutes increasing affinity and others weakening binding. However, DHF binding and reduction in both DHFRs decreased in the presence of all cosolutes. The decreased binding of ligands is mostly attributed to weak associations with the macromolecules, as opposed to crowder effects on the DHFRs. Computer simulations found weak, transient interactions for both ligands with several proteins. The net charge of protein cosolutes correlated with effects on NADP+ binding, with near neutral and positively charged proteins having more detrimental effects on binding. For DHF binding, effects correlated more with the size of binding pockets on the protein crowders. These nonspecific interactions between DHFR ligands and proteins predict that the in vivo efficiency of DHFRs may be much lower than expected from their in vitro rates.

Using Bradford's law of scattering to identify the core journals of pediatric surgery.

BACKGROUND: Bradford's law of scattering defines an exponentially diminishing return when extending a search for references in journals and can be used to identify the "core" journals in a field. The purpose of this study was to identify the core journals of pediatric surgery. METHODS: With Institutional Review Board approval, we developed bibliometric profiles for the top academically productive pediatric surgeons in the United States. These profiles included the total number of publications, journals in which those authors published their manuscripts, and identification of all articles cited by those surgeons, along with the journals those references were drawn from. Bradford's law of scattering was applied to identify the core journals of pediatric surgery. RESULTS: We identified n = 69 pediatric surgeons (10 ± 0.2 5-year h-index). These authors published 10,031 articles (145 ± 90 per surgeon), which were cited 250841 times (3635 ± 413 per surgeon). Pediatric surgeons' articles contained 199507 references (2891 ± 176 per surgeon). We analyzed 58,310 references (top 20 journals) cited by pediatric surgeons. Bradford's Law identified a single core journal for p = 3-10 zones, with P = 3, providing the best correlation between predicted and actual values (Rˆ2 = 0.9996). The core journal for pediatric surgery is Journal of Pediatric Surgery. CONCLUSIONS: We used Bradford's Law to identify the core journals of pediatric surgery. These core journals include the two leading pediatric surgery-specific journals and the highest impact factor journals in surgery (Annals of Surgery) and medicine (NEJM). These findings can help busy pediatric surgeons focus their reading to stay updated in a rapidly evolving field.

Using bibliometrics to analyze the state of academic productivity in US pediatric surgery training programs.

BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) Common Program Requirements state that faculty must establish and maintain an environment of inquiry and scholarship. Bibliometrics, the statistical analysis of written publications, assesses scientific productivity and impact. The goal of this study was to understand the state of scholarship at Pediatric Surgery training programs. METHODS: Following IRB approval, Scopus was used to generate bibliometric profiles for US Pediatric Surgery training programs and faculty. Statistical analyses were performed. RESULTS: Information was obtained for 430 surgeons (105 female) from 48 US training programs. The mean lifetime h-index/surgeon for programs was 14.4 +/- 4.7 (6 programs above 1 SD, 9 programs below 1 SD). The mean 5-yearh-index/surgeon for programs was 3.92 +/- 1.5 (7 programs above 1 SD, 8 programs below 1 SD). Programs accredited after 2000 had a lower lifetime h-index than those accredited before 2000 (p=0.0378). Female surgeons had a lower lifetime h-index (p<0.0001), 5-yearh-index (p=0.0049), and m-quotient (p<0.0001) compared to males. Mean lifetime h-index increased with academic rank (p<0.0001), with no gender differences beyond the assistant professor rank (p=NS). CONCLUSION: Variability was identified based on institution, gender, and rank. This information can be used for benchmarking the academic productivity of faculty and programs and as an adjunct in promotion/tenure decisions. TYPE OF STUDY: Original Research. LEVEL OF EVIDENCE: n/a.

Molecular modeling, docking and ADMET studies towards development of novel Disopyramide analogs for potential inhibition of human voltage gated sodium channel proteins.

The sodium "channelopathies" are the first among the ion channel diseases identified and have attracted widespread clinical and scientific interests. Human voltage gated sodium channels are sites of action of several antiarrhythmic drugs, local anesthetics and related antiepileptic drugs. The present study aims to optimize the activity of Disopyramide, by modification in its structures which may improve the drug action by reducing its side effects. Herein, we have selected Human voltage-gated sodium channel protein type 5 as a potent molecular target. Nearly eighty analogs of Disopyramide are designed and optimized. Thirty are selected for energy minimization using Discovery studio and the LigPrep 2.5. Prior to docking, the active sites of all the proteins are identified. The processing, optimization and minimization of all the proteins is done in Protein preparation wizard. The docking study is performed using the GLIDE. Finally top five ranked lead molecules with better dock scores are identified as having strong binding affinity to 2KAV protein than Disopyramide based on XP G scores. These five leads are further docked with other similar voltage gated sodium channel proteins (PDB IDs: 2KBI, 4DCK, 2L53 and 4DJC) and the best scoring analog with each protein is identified. Drug likeliness and comparative bioactivity analysis for all the analogs is done using QikProp 3.4. Results have shown that the top five lead molecules would have the potential to act as better drugs as compared to Disopyramide and would be of interest as promising starting point for designing compounds against various Sodium channelopathies.