Trillions of bacteria reside within our gastrointestinal tract, ideally forming a mutually beneficial relationship between us. However, persistent changes in diet and lifestyle in the western diet and lifestyle contribute to a damaging of the gut microbiota-host symbiosis leading to diseases such as obesity and irritable bowel syndrome. Many symptoms and comorbidities associated with these diseases stem from dysfunctional signaling in peripheral neurons. Our peripheral nervous system (PNS) is comprised of a variety of sensory, autonomic, and enteric neurons which coordinate key homeostatic functions such as gastrointestinal motility, digestion, immunity, feeding behavior, glucose and lipid homeostasis, and more. The composition and signaling of bacteria in our gut dramatically influences how our peripheral neurons regulate these functions, and we are just beginning to uncover the molecular mechanisms mediating this communication. In this review, we cover the general anatomy and function of the PNS, and then we discuss how the molecules secreted or stimulated by gut microbes signal through the PNS to alter host development and physiology. Finally, we discuss how leveraging the power of our gut microbes on peripheral nervous system signaling may offer effective therapies to counteract the rise in chronic diseases crippling the western world.
Prior to the recommended age for population-based breast cancer screening by mammography, which ranges from 40−50 years depending on guidelines, the main way to identify higher risk women for earlier breast cancer (BC) screening to improve outcomes and discuss targeted chemoprevention is through specific clinical guidelines which are largely based on family history of breast cancer and known mutations in breast cancer susceptibility genes. The annual percent change (APC) in early-onset BC continues to rise, with the higher early-onset cancer burden and mortality continuing to be seen in non-Hispanic black (NHB) women compared to non-Hispanic white (NHW) women. Coupled with the increasing incidence overall as well as the lower percent of BC family history reported in NHB women compared with that of NHW women means that continued reliance on guidelines to identify women for genetic screening and initiation of early BC screening based largely on family history could lead to even greater BC health inequities. The similarity in the prevalence of mutations in key BC susceptibility genes between NHB and NHW women contrasts sharply to the differences in age-specific incidence rates between NHB and NHW women, supporting that there must be environmental modifiers that are contributing to the increased incidence in NHB women. This reality further argues for identifying NHB women early in adulthood through genetic testing who may benefit from tailored BC risk-reduction programs and early BC screening.
Background Prior research indicates that at least 35% of Alzheimer’s disease and related dementia risk may be amenable to prevention. Subjective cognitive decline is often the first indication of preclinical dementia, with the risk of subsequent Alzheimer’s disease in such individuals being greater in women than men. We wished to understand how modifiable factors are associated with subjective cognitive decline, and whether differences exist by sex. Methods Data were collected from men and women (45 years and older) who completed the U.S. Behavioral Risk Factor Surveillance System Cognitive Decline Module (2015–2018), n = 216,838. We calculated population-attributable fractions for subjective cognitive decline, stratified by sex, of the following factors: limited education, deafness, social isolation, depression, smoking, physical inactivity, obesity, hypertension, and diabetes. Our models were adjusted for age, race, income, employment, marital and Veteran status, and accounted for communality among risk factors. Results The final study sample included more women (53.7%) than men, but both had a similar prevalence of subjective cognitive decline (10.6% of women versus 11.2% of men). Women and men had nearly equivalent overall population-attributable fractions to explain subjective cognitive decline (39.7% for women versus 41.3% for men). The top three contributing risk factors were social isolation, depression, and hypertension, which explained three-quarters of the overall population-attributable fraction. Conclusions While we did not identify any differences in modifiable factors between men and women contributing to subjective cognitive decline, other factors including reproductive or endocrinological health history or biological factors that interact with sex to modify risk warrant further research.
The epigenetic changes associated with melanoma progression to advanced and metastatic stages are still poorly understood. To shed light on the CpG methylation dynamics during melanoma development, we analyzed the methylome profiles of a four-stage cell line model of melanoma progression: non-tumorigenic melanocytes (melan-a), premalignant melanocytes (4C), non-metastatic melanoma cells (4C11−), and metastatic melanoma cells (4C11+). We identified 540 hypo- and 37 hypermethylated gene promoters that together characterized a malignancy signature, and 646 hypo- and 520 hypermethylated promoters that distinguished a metastasis signature. Differentially methylated genes from these signatures were correlated with overall survival using TCGA-SKCM methylation data. Moreover, multivariate Cox analyses with LASSO regularization identified panels of 33 and 31 CpGs, respectively, from the malignancy and metastasis signatures that predicted poor survival. We found a concordant relationship between DNA methylation and transcriptional levels for genes from the malignancy ( Pyroxd2 and Ptgfrn ) and metastasis ( Arnt2 , Igfbp4 and Ptprf ) signatures, which were both also correlated with melanoma prognosis. Altogether, this study reveals novel CpGs methylation markers associated with malignancy and metastasis that collectively could improve the survival prediction of melanoma patients.
Multiple myeloma (MM) treatment regimens have vastly improved since the introduction of immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies; however, MM is considered an incurable disease due to inevitable relapse and acquired drug resistance. Understanding the molecular mechanism by which drug resistance is acquired will help create novel strategies to prevent relapse and help develop novel therapeutics to treat relapsed/refractory (RR)-MM patients. Currently, only homozygous deletion/mutation of TP53 gene due to “double-hits” on Chromosome 17p region is consistently associated with a poor prognosis. The exciting discovery of XPO1 overexpression and mislocalization of its cargos in the RR-MM cells has led to a novel treatment options. Clinical studies have demonstrated that the XPO1 inhibitor selinexor can restore sensitivity of RR-MM to PIs and dexamethasone. We will elaborate on the problems of MM treatment strategies and discuss the mechanism and challenges of using XPO1 inhibitors in RR-MM therapies while deliberating potential solutions.
The COVID-19 pandemic has impacted families in a variety of ways with much being written on the potential impact of sheltering in place and quarantining on intimate partner violence and parent-to-child abuse. One area that has received scant attention is that of physical and emotional sibling violence. While physical and emotional sibling violence is a predominant form of family violence, discussion of violence between siblings in the time of COVID-19 has not received the attention it warrants. This article examines the potential for family stress to place siblings at risk for engaging in physical and emotional sibling violence and how this is exacerbated in the time of COVID-19. Also discussed is the the connection between physical and emotional sibling violence and other forms of family violence including intimate partner violence and parent-to-child abuse and neglect which underwrites the need to place physical and emotional sibling violence on the radar of practitioners, policy makers, and researchers. Finally, implications for practice, policy, and research on physical and emotional sibling violence in the context of COVID-19 are discussed.
Background Functional dyspepsia (FD) is a chronic disorder of the upper gastrointestinal tract that currently lacks substantially effective therapy options. Aims To evaluate the feasibility and potential impact on FD symptoms and well-being of a fully automated gut-directed hypnosis intervention delivered via audio recordings. Methods FD patients were enrolled at a single medical center and given access to a password-protected website where they completed 7 bi-weekly audio-recorded hypnosis sessions over a 3-month period. Study questionnaires including the Patient assessment of upper gastrointestinal symptom severity index, Short-Form Nepean Dyspepsia Index, the Visceral Sensitivity Index, and the Brief Symptom Inventory (BSI-18) were completed online pre-treatment, mid-treatment, post-treatment and at 3-month follow-up. Results Of 23 enrolled patients (18 females; mean age = 38 years), 96% completed the entire treatment program and 3-month follow-up. Intention-to-treat analyses showed significant improvement at both end of treatment and 3-month follow-up in dyspepsia severity and quality of life, as well as in gut-specific anxiety and psychological distress. 68% of treatment completers reported that their FD symptoms were improved. Improvement in FD severity was significantly positively correlated with baseline PAGI-SYM total scores and BSI Global Severity Index scores. Conclusions The fully automated hypnosis audio treatment program, which requires no therapist or clinician involvement, demonstrated excellent feasibility and resulted in significant improvement in FD symptoms, quality of life and emotional well-being. The results indicate that the intervention has high potential as adjunctive therapy for FD and warrants further investigation in a randomized controlled trial.
Purpose To evaluate the diagnostic accuracy of a deep learning (DL) algorithm predicting hemodynamically significant coronary artery disease (CAD) by using a rest dataset of myocardial computed tomography perfusion (CTP) as compared to invasive evaluation. Methods One hundred and twelve consecutive symptomatic patients scheduled for clinically indicated invasive coronary angiography (ICA) underwent CCTA plus static stress CTP and ICA with invasive fractional flow reserve (FFR) for stenoses ranging between 30 and 80%. Subsequently, a DL algorithm for the prediction of significant CAD by using the rest dataset (CTP-DLrest) and stress dataset (CTP-DLstress) was developed. The diagnostic accuracy for identification of significant CAD using CCTA, CCTA + CTP stress, CCTA + CTP-DLrest, and CCTA + CTP-DLstress was measured and compared. The time of analysis for CTP stress, CTP-DLrest, and CTP-DLStress was recorded. Results Patient-specific sensitivity, specificity, NPV, PPV, accuracy, and area under the curve (AUC) of CCTA alone and CCTA + CTPStress were 100%, 33%, 100%, 54%, 63%, 67% and 86%, 89%, 89%, 86%, 88%, 87%, respectively. Patient-specific sensitivity, specificity, NPV, PPV, accuracy, and AUC of CCTA + DLrest and CCTA + DLstress were 100%, 72%, 100%, 74%, 84%, 96% and 93%, 83%, 94%, 81%, 88%, 98%, respectively. All CCTA + CTP stress, CCTA + CTP-DLRest, and CCTA + CTP-DLStress significantly improved detection of hemodynamically significant CAD compared to CCTA alone (p < 0.01). Time of CTP-DL was significantly lower as compared to human analysis (39.2 ± 3.2 vs. 379.6 ± 68.0 s, p < 0.001). Conclusion Evaluation of myocardial ischemia using a DL approach on rest CTP datasets is feasible and accurate. This approach may be a useful gatekeeper prior to CTP stress..
The ten–eleven translocation (TET) family of dioxygenases consists of three members, TET1, TET2, and TET3. All three TET enzymes have Fe⁺² and α-ketoglutarate (α-KG)-dependent dioxygenase activities, catalyzing the 1st step of DNA demethylation by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and further oxidize 5hmC to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Gene knockout studies demonstrated that all three TET proteins are involved in the regulation of fetal organ generation during embryonic development and normal tissue generation postnatally. TET proteins play such roles by regulating the expression of key differentiation and fate-determining genes via (1) enzymatic activity-dependent DNA methylation of the promoters and enhancers of target genes; and (2) enzymatic activity-independent regulation of histone modification. Interacting partner proteins and post-translational regulatory mechanisms regulate the activities of TET proteins. Mutations and dysregulation of TET proteins are involved in the pathogenesis of human diseases, specifically cancers. Here, we summarize the research on the interaction partners and post-translational modifications of TET proteins. We also discuss the molecular mechanisms by which these partner proteins and modifications regulate TET functioning and target gene expression. Such information will help in the design of medications useful for targeted therapy of TET-mutant-related diseases.
Background: Current studies evaluating outcomes for open, laparoscopic, and robotic inguinal hernia repair, in general, include small numbers of robotic cases and are not powered to allow a direct comparison of the 3 approaches to repair. Study design: We queried the Veterans Affairs Surgical Quality Improvement Program Database to identify patients undergoing initial elective inguinal hernia repair between 2013 and 2017. Propensity score matching and multivariable logistic regression were used to make risk-adjusted assessments of association between surgical approach and outcome. Results: A total of 39,358 patients underwent initial elective inguinal hernia repair; 32,881 (84%) underwent an open approach, 6,135 (16%) underwent a laparoscopic approach, and 342 (1%) underwent a robotic-assisted approach. Two hundred sixty-six (1%) patients had a recurrent repair performed during follow-up. On univariate comparison, patients undergoing a robotic-assisted approach had longer operative times for unilateral repair than those undergoing either an open or laparoscopic (73 ± 31 vs 74 ± 29 vs 107 ± 41 minutes; p < 0.001) approach. On multivariable logistic regression, patients with a higher BMI had an increased adjusted risk of a postoperative complication, but there was no association between surgical approach and complication rate. Three hundred forty-two patients undergoing robotic repair were 1:3:3 propensity score matched to 1,026 patients undergoing laparoscopic and 1,026 undergoing open repair. On comparison of matched cohorts, there were no statistical differences between approaches regarding recurrence (0.6% vs 0.8% vs 0.6%, p > 0.05) or complication rate (0.6% vs 1.2% vs 1.2%, p > 0.05). Conclusions: In patients undergoing initial elective inguinal hernia repair, rates of hernia recurrence are low independent of surgical approach. Both robotic and laparoscopic approaches demonstrate rates of early postoperative morbidity and recurrence similar to those for the open approach. The robotic approach is associated with longer operative time than either laparoscopic or open repair.
Background: Recent socioeconomic pressures in healthcare and work hour resections have limited opportunities for resident autonomy and independent decision-making. We sought to evaluate whether contemporary senior residents are being given the opportunity to operate independently and whether patient outcomes are affected when the attending is not directly involved in an operation. Study design: The VA Surgical Quality Improvement Program (VASQIP) Database was queried to identify patients undergoing elective laparoscopic cholecystectomy between 2004 and 2019. Cases were categorized as "attending" or "resident" depending on whether the attending surgeon was scrubbed. Cohorts were 1:1 propensity score-matched (PSM) for demographics, comorbidities, and facility case-mix. Clinical outcomes for matched cohorts were compared by standard methods. Results: There were 23,831 records for patients who underwent laparoscopic cholecystectomy; 20,568 (86%) performed with the attending scrubbed, and 3,263 (14%) without the attending scrubbed. Over time there was a significant decrease in the proportion of cases without the attending scrubbed, 18% in 2004-2009 to 13% in 2015-2019 (p < 0.001). On PSM, 3,263 patients undergoing laparoscopic cholecystectomy by the residents without the attending scrubbed were successfully matched (1:1) to cases with the attending scrubbed. On comparison of matched cohorts, procedures performed without the attending scrubbed were statistically longer (102 vs 98 minutes, p = 0.001) but with no difference in rates of postoperative complications (5% vs 5%, p = 0.9). Conclusion: In comparison with cases done with more direct attending involvement, residents perform laparoscopic cholecystectomies efficiently without increased complications. Over time, attendings are more frequently scrubbed for the operation.
There is acknowledgment that deployments can be stressful for military spouses; however, less is known about their experiences post-deployment. This qualitative study examined the post-deployment experiences of 16 female spouses, whose active duty Army husband had returned from deployment within the previous 2 years and who had a young child during the deployment. Spouses reported that the time surrounding their husbands’ return was one of the great transitions, often accompanied by stress. Most families were able to work through challenges and show positive adjustment over time. However, some spouses described severe post-deployment challenges marked by disconnect from their partners; three of these were spouses whose husbands had posttraumatic stress disorder. The findings address how spouses prepared for their husband’s return, their reunion experiences, the process of reintegrating their husband into family life, and individual changes in the partners post-deployment. Facilitators and challenges to adjustment were identified as potential targets for interventions.
The allosteric regulation of ADP–glucose pyrophosphorylase is critical for the biosynthesis of glycogen in bacteria and starch in plants. The enzyme from Agrobacterium tumefaciens is activated by fructose 6‐phosphate (Fru6P) and pyruvate (Pyr). The Pyr site has been recently found, but the site where Fru6P binds has remained unknown. We hypothesize that a sulfate ion previously found in the crystal structure reveals a part of the regulatory site mimicking the presence of the phosphoryl moiety of the activator Fru6P. Ser72 interacts with this sulfate ion and, if the hypothesis is correct, Ser72 would affect the interaction with Fru6P and activation of the enzyme. Here, we report structural, binding, and kinetic analysis of Ser72 mutants of the A. tumefaciens ADP‐glucose pyrophosphorylase. By X‐ray crystallography, we found that when Ser72 was replaced by Asp or Glu side chain carboxylates protruded into the sulfate‐binding pocket. They would present a strong steric and electrostatic hindrance to the phosphoryl moiety of Fru6P, while being remote from the Pyr site. In agreement, we found that Fru6P could not activate or bind to S72E or S72D mutants, whereas Pyr was still an effective activator. These mutants also blocked the binding of the inhibitor AMP. This could potentially have biotechnological importance in obtaining enzyme forms insensitive to inhibition. Other mutations in this position (Ala, Cys, and Trp) confirmed the importance of Ser72 in regulation. We propose that the ADP‐glucose pyrophosphorylase from A. tumefaciens have two distinct sites for Fru6P and Pyr working in tandem to regulate glycogen biosynthesis. PDB Code(s): 6V9A, 6V96 and 6V99;
Radiation therapy is an integral component of adjuvant therapy in women who undergo breast conservative surgery, decreasing the likelihood of tumor recurrence and extending survival. The likelihood of tumor recurrence is highest within a proximity of the lumpectomy cavity, which prompted the idea of partial breast irradiation in place of the usual standard-of-care treatment with external beam whole breast radiation therapy. Targeted intraoperative radiation therapy (TARGIT-A) is a multicenter trial initially developed in 1999 and designed as a randomized clinical trial comparing whole breast radiation therapy to risk-adapted intraoperative radiation therapy (IORT). TARGIT-A recruited its first patient in March 2000, with the study concluding in 2012. At a median follow-up of 8.6 years, the prepathology TARGIT-A trial noted results to be noninferior to external beam radiation therapy, with no statistically significant difference in ipsilateral breast tumor recurrence, mastectomy-free survival, distant disease-free survival, or breast cancer-specific mortality. These results are consistent with the majority of retrospective and prospective trials. Risk-adapted IORT, as performed in the prospective randomized TARGIT-A trial, gives level 1 evidence that this approach is a standard option in the treatment of breast cancer.
Thyroid cancer is a common endocrine carcinoma that occurs in the thyroid gland. Much effort has been invested in improving its diagnosis, and thyroidectomy remains the primary treatment method. A successful operation without unnecessary side injuries relies on an accurate preoperative diagnosis. Current human assessment of thyroid nodule malignancy is prone to errors and may not guarantee an accurate preoperative diagnosis. This study proposed a machine learning framework to predict thyroid nodule malignancy based on our collected novel clinical dataset. The ten-fold cross-validation, bootstrap analysis, and permutation predictor importance were applied to estimate and interpret the model performance under uncertainty. The comparison between model prediction and expert assessment shows the advantage of our framework over human judgment in predicting thyroid nodule malignancy. Our method is accurate, interpretable, and thus useable as additional evidence in the preoperative diagnosis of thyroid cancer.
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