Western diet consumption impairs memory function via dysregulated hippocampus acetylcholine signaling.

Western diet (WD) consumption during early life developmental periods is associated with impaired memory function, particularly for hippocampus (HPC)-dependent processes. We developed an early life WD rodent model associated with long-lasting HPC dysfunction to investigate the neurobiological mechanisms mediating these effects. Rats received either a cafeteria-style WD (ad libitum access to various high-fat/high-sugar foods; CAF) or standard healthy chow (CTL) during the juvenile and adolescent stages (postnatal days 26-56). Behavioral and metabolic assessments were performed both before and after a healthy diet intervention period beginning at early adulthood. Results revealed HPC-dependent contextual episodic memory impairments in CAF rats that persisted despite the healthy diet intervention. Given that dysregulated HPC acetylcholine (ACh) signaling is associated with memory impairments in humans and animal models, we examined protein markers of ACh tone in the dorsal HPC (HPCd) in CAF and CTL rats. Results revealed significantly lower protein levels of vesicular ACh transporter in the HPCd of CAF vs. CTL rats, indicating chronically reduced ACh tone. Using intensity-based ACh sensing fluorescent reporter (iAChSnFr) in vivo fiber photometry targeting the HPCd, we next revealed that ACh release during object-contextual novelty recognition was highly predictive of memory performance and was disrupted in CAF vs. CTL rats. Neuropharmacological results showed that alpha 7 nicotinic ACh receptor agonist infusion in the HPCd during training rescued memory deficits in CAF rats. Overall, these findings reveal a functional connection linking early life WD intake with long-lasting dysregulation of HPC ACh signaling, thereby identifying an underlying mechanism for WD-associated memory impairments.

Validation of Distinct Bladder Pain Phenotypes Utilizing the MAPP Research Network Cohort.

INTRODUCTION AND HYPOTHESIS: As interstitial cystitis/bladder pain syndrome (IC/BPS) likely represents multiple pathophysiologies, we sought to validate three clinical phenotypes of IC/BPS patients in a large, multi-center cohort using unsupervised machine learning (ML) analysis. METHODS: Using the female Genitourinary Pain Index and O'Leary-Sant Indices, k-means unsupervised clustering was utilized to define symptomatic phenotypes in 130 premenopausal IC/BPS participants recruited through the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research network. Patient-reported symptoms were directly compared between MAPP ML-derived phenotypic clusters to previously defined phenotypes from a single center (SC) cohort. RESULTS: Unsupervised ML categorized IC/BPS participants into three phenotypes with distinct pain and urinary symptom patterns: myofascial pain, non-urologic pelvic pain, and bladder-specific pain. Defining characteristics included presence of myofascial pain or trigger points on examination for myofascial pain patients (p = 0.003) and bladder pain/burning for bladder-specific pain patients (p < 0.001). The three phenotypes were derived using only 11 features (fGUPI subscales and ICSI/ICPI items), in contrast to 49 items required previously. Despite substantial reduction in classification features, unsupervised ML independently generated similar symptomatic clusters in the MAPP cohort with equivalent symptomatic patterns and physical examination findings as the SC cohort. CONCLUSIONS: The reproducible identification of IC/BPS phenotypes, distinguishing bladder-specific pain from myofascial and genital pain, using independent ML analysis of a multicenter database suggests these phenotypes reflect true pathophysiologic differences in IC/BPS patients.

Ventral hippocampus neurons encode meal-related memory.

The ability to encode and retrieve meal-related information is critical to efficiently guide energy acquisition and consumption, yet the underlying neural processes remain elusive. Here we reveal that ventral hippocampus (HPCv) neuronal activity dynamically elevates during meal consumption and this response is highly predictive of subsequent performance in a foraging-related spatial memory task. Targeted recombination-mediated ablation of HPCv meal-responsive neurons impairs foraging-related spatial memory without influencing food motivation, anxiety-like behavior, or escape-mediated spatial memory. These HPCv meal-responsive neurons project to the lateral hypothalamic area (LHA) and single-nucleus RNA sequencing and in situ hybridization analyses indicate they are enriched in serotonin 2a receptors (5HT2aR). Either chemogenetic silencing of HPCv-to-LHA projections or intra-HPCv 5HT2aR antagonist yielded foraging-related spatial memory deficits, as well as alterations in caloric intake and the temporal sequence of spontaneous meal consumption. Collective results identify a population of HPCv neurons that dynamically respond to eating to encode meal-related memories.

Safety and Immunogenicity of Live Viral Vaccines in a Multicenter Cohort of Pediatric Transplant Recipients.

Importance: Live vaccines (measles-mumps-rubella [MMR] and varicella-zoster virus [VZV]) have not been recommended after solid organ transplant due to concern for inciting vaccine strain infection in an immunocompromised host. However, the rates of measles, mumps, and varicella are rising nationally and internationally, leaving susceptible immunocompromised children at risk for life-threating conditions. Objective: To determine the safety and immunogenicity of live vaccines in pediatric liver and kidney transplant recipients. Design, Setting, and Participants: This cohort study included select pediatric liver and kidney transplant recipients who had not completed their primary MMR and VZV vaccine series and/or who displayed nonprotective serum antibody levels at enrollment between January 1, 2002, and February 28, 2023. Eligibility for live vaccine was determined by individual US pediatric solid organ transplant center protocols. Exposures: Exposure was defined as receipt of a posttransplant live vaccine. Transplant recipients received 1 to 3 doses of MMR vaccine and/or 1 to 3 doses of VZV vaccine. Main Outcome and Measure: Safety data were collected following each vaccination, and antibody levels were obtained at 0 to 3 months and 1 year following vaccination. Comparisons were performed using Mann-Whitney U test, and factors associated with development of postvaccination protective antibodies were explored using univariate analysis. Results: The cohort included 281 children (270 [96%] liver, 9 [3%] kidney, 2 [1%] liver-kidney recipients) from 18 centers. The median time from transplant to enrollment was 6.3 years (IQR, 3.4-11.1 years). The median age at first posttransplant vaccine was 8.9 years (IQR, 4.7-13.8 years). A total of 202 of 275 (73%) children were receiving low-level monotherapy immunosuppression at the time of vaccination. The majority of children developed protective antibodies following vaccination (107 of 149 [72%] varicella, 130 of 152 [86%] measles, 100 of 120 [83%] mumps, and 124 of 125 [99%] rubella). One year post vaccination, the majority of children who initially mounted protective antibodies maintained this protection (34 of 44 [77%] varicella, 45 of 49 [92%] measles, 35 of 42 [83%] mumps, 51 of 54 [94%] rubella). Five children developed clinical varicella, all of which resolved within 1 week. There were no cases of measles or rubella and no episodes of graft rejection within 1 month of vaccination. There was no association between antibody response and immunosuppression level at the time of vaccination. Conclusions and Relevance: The findings suggest that live vaccinations may be safe and immunogenic after solid organ transplant in select pediatric recipients and can offer protection against circulating measles, mumps, and varicella.

Western diet consumption impairs memory function via dysregulated hippocampus acetylcholine signaling.

Western diet (WD) consumption during development yields long-lasting memory impairments, yet the underlying neurobiological mechanisms remain elusive. Here we developed an early life WD rodent model to evaluate whether dysregulated hippocampus (HPC) acetylcholine (ACh) signaling, a pathology associated with memory impairment in human dementia, is causally-related to WD-induced cognitive impairment. Rats received a cafeteria-style WD (access to various high-fat/high-sugar foods; CAF) or healthy chow (CTL) during the juvenile and adolescent periods (postnatal days 26-56). Behavioral, metabolic, and microbiome assessments were performed both before and after a 30-day healthy diet intervention beginning at early adulthood. Results revealed CAF-induced HPC-dependent contextual episodic memory impairments that persisted despite healthy diet intervention, whereas CAF was not associated with long-term changes in body weight, body composition, glucose tolerance, anxiety-like behavior, or gut microbiome. HPC immunoblot analyses after the healthy diet intervention identified reduced levels of vesicular ACh transporter in CAF vs. CTL rats, indicative of chronically reduced HPC ACh tone. To determine whether these changes were functionally related to memory impairments, we evaluated temporal HPC ACh binding via ACh-sensing fluorescent reporter in vivo fiber photometry during memory testing, as well as whether the memory impairments could be rescued pharmacologically. Results revealed dynamic HPC ACh binding during object-contextual novelty recognition was highly predictive of memory performance and was disrupted in CAF vs. CTL rats. Further, HPC alpha-7 nicotinic receptor agonist infusion during consolidation rescued memory deficits in CAF rats. Overall, these findings identify dysregulated HPC ACh signaling as a mechanism underlying early life WD-associated memory impairments.

Defining Mastectomy Skin Flap Necrosis: A Systematic Review of the Literature and a Call for Standardization.

BACKGROUND: Mastectomy skin flap necrosis following breast reconstruction may lead to wound dehiscence, infection, implant exposure, and reconstructive failure. The absence of a standardized definition for it has led to variation in estimated incidence, from as low as 2 percent to greater than 40 percent. The authors systematically reviewed the literature on mastectomy skin flap necrosis to characterize existing definitions and provide a framework for future classification. METHODS: A systematic review of the PubMed and Cochrane databases identified studies reporting a discrete definition of mastectomy skin flap necrosis and corresponding outcomes in breast reconstruction. Provided definitions were extracted, categorized, and comparatively analyzed. RESULTS: Fifty-nine studies met inclusion criteria, with a combined total of 14,368 patients and 18,920 breasts. Thirty-four studies (57.6 percent) reported mastectomy skin flap necrosis solely as a function of total breasts, and 11 (18.6 percent) reported mastectomy skin flap necrosis solely as a function of total patients. Only 14 studies (23.7 percent) provided two separate rates. The overall rate of mastectomy skin flap necrosis was 10.4 percent (range, 2.3 to 41.2 percent) and 15.3 percent (range, 4.7 to 39.0 percent), when reported per breast or per patient, respectively. Studies were categorized by mastectomy skin flap necrosis definition, including intervention (n = 33), depth (n = 20), area (n = 4), and timing (n = 2). Mastectomy skin flap necrosis rates were highest in studies defining necrosis by depth (15.1 percent), followed by intervention (9.6 percent), timing (6.4 percent), and area (6.3 percent). Necrosis rates among studies defining mastectomy skin flap necrosis by intervention, depth, and area were found to be statistically different (p < 0.001). CONCLUSIONS: Reported mastectomy skin flap necrosis definitions and outcomes vary significantly in the existing literature. For accurate characterization and quantification, a clear, simplified, consensus definition must be adopted.

Optimizing patient selection for cytoreductive nephrectomy based on outcomes in the contemporary era of systemic therapy.

BACKGROUND: The management of metastatic renal cell carcinoma (mRCC) has evolved rapidly, and results from the Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques (CARMENA) trial bring into question the utility of cytoreductive nephrectomy (CN). The objective of this study was to examine overall survival (OS) and identify risk factors associated with patients less likely to benefit from CN in the targeted therapy era. METHODS: Patients with mRCC undergoing CN from 2005 to 2017 were identified. Kaplan-Meier methods and Cox proportional hazards regression analyses were used to assess OS and risk-stratify patients, respectively, on the basis of preoperative clinical and laboratory data. RESULTS: Six hundred eight patients were eligible with a median follow-up of 29.4 months. Ninety-five percent of the patients had an Eastern Cooperative Oncology Group performance status less than or equal to 1, and 70% had a single site of metastatic disease. In a multivariable analysis, risk factors significantly associated with decreased OS included systemic symptoms at diagnosis, retroperitoneal and supradiaphragmatic lymphadenopathy, bone metastasis, clinical T4 disease, a hemoglobin level less than the lower limit of normal (LLN), a serum albumin level less than the LLN, a serum lactate dehydrogenase level greater than the upper limit of normal, and a neutrophil/lymphocyte ratio greater than or equal to 4. Patients were stratified into 3 risk groups: low (fewer than 2 risk factors), intermediate (2-3 risk factors), and high (more than 3 risk factors). These groups had median OS of 58.9 months (95% confidence interval [CI], 44.3-66.6 months), 30.6 months (95% CI, 27.0-35.0 months), and 19.2 months (95% CI, 13.9-22.6 months), respectively (P < .0001). The median time to postoperative systemic therapy was 45 days (interquartile range, 30-90 days). CONCLUSIONS: Patients with more than 3 risk factors did not seem to benefit from CN. Importantly, OS in this group was equivalent to, if not higher than, OS for patients in the CN plus sunitinib arm of CARMENA, and this raises the possibility that a well-selected population might benefit from CN.

Enhanced recovery after surgery (ERAS) pathways in breast reconstruction: systematic review and meta-analysis of the literature.

PURPOSE: Enhanced recovery after surgery (ERAS) pathways are increasingly promoted in post-mastectomy reconstruction, with several articles reporting their benefits and safety. This meta-analysis appraises the evidence for ERAS pathways in breast reconstruction. METHODS: A systematic search of Medline, EMBASE, and Cochrane databases was performed to identify reports of ERAS protocols in post-mastectomy breast reconstruction. Two reviewers screened studies using predetermined inclusion criteria. Studies evaluated at least one of the following end-points of interest: length of stay (LOS), opioid use, or major complications. Risk of bias was assessed for each study. Meta-analysis was performed via a mixed-effects model to compare outcomes for ERAS versus traditional standard of care. Surgical techniques were assessed through subgroup analysis. RESULTS: A total of 260 articles were identified; 9 (3.46%) met inclusion criteria with a total of 1191 patients. Most studies had "fair" methodological quality and incomplete implementation of ERAS society recommendations was noted. Autologous flaps comprised the majority of cases. In autologous breast reconstruction, ERAS significantly reduces opioid use [Mean difference (MD) = - 183.96, 95% CI - 340.27 to 27.64, p = 0.02) and LOS (MD) = - 1.58, 95% CI - 1.99 to 1.18, p < 0.00001] versus traditional care. There is no significant difference in the incidence of complications (major complications, readmission, hematoma, and infection). CONCLUSION: ERAS pathways significantly reduce opioid use and length of hospital stay following autologous breast reconstruction without increasing complication rates. This is salient given the current US healthcare climate of rising expenditures and an opioid crisis.

Renal cell carcinoma and pathologic nodal disease: Implications for American Joint Committee on Cancer staging.

BACKGROUND: Lymph node (LN) metastases are associated with poor outcomes for patients with renal cell carcinoma (RCC). This study compared the survival outcomes of patients with stage III, node-positive disease (pT123 N1 M0 ) and patients with stage III, node-negative disease (pT3 N0 M0 ). METHODS: A database of 4652 patients with RCC of any histological subtype treated with surgery at The University of Texas MD Anderson Cancer Center from 1993 to 2012 was retrospectively assessed. A total of 115 patients with pT123 N1 M0 disease, 274 patients with pT3 N0 M0 disease, and 523 patients with pT123 N0/x M1 disease were included. Overall survival (OS) and cancer-specific survival (CSS) were estimated and compared between each cohort. RESULTS: Median OS and CSS times were significantly better for pT3 N0 M0 patients than pT123 N1 M0 patients (OS, 10.2 vs 2.4 years, P < .0001; CSS, not reached vs 2.8 years, P < .0001). Similar median OS and CSS times were noted for pT123 N1 M0 and pT123 N0/x M1 patients (OS, 2.4 vs 2.4 years; P = .62; CSS, 2.8 vs 2.4 years; P = .10). In a multivariate analysis, tumor grade (hazard ratio [HR] for OS, 2.47; P < .0001; HR for CSS, 2.99; P < .0001) and pathologic LN involvement (HR for OS, 2.44; P < .0001; HR for CSS, 2.85; P < .0001) were associated with worse OS and CSS. CONCLUSIONS: Among RCC patients classified with stage III disease, those with pT123 N1 M0 disease had significantly worse survival than those with pT3 N0 M0 disease. OS and CSS were similar for patients with pT123 N1 M0 disease and patients with pT123 N0/x M1 disease (stage IV). If validated, these findings suggest that RCC patients with nodal disease should be reclassified as having stage IV disease.

Intraoperative Conversion From Partial to Radical Nephrectomy: Incidence, Predictive Factors, and Outcomes.

OBJECTIVE: To evaluate preoperative and intraoperative predictors of conversion to radical nephrectomy (RN) in a cohort of patients undergoing a planned partial nephrectomy (PN) for renal cell carcinoma (RCC). METHODS: A single-center, retrospective review was conducted using our PN database that includes patients who were scheduled to undergo PN (regardless of the approach) but were converted to RN between August 1990 and December 2016. Reasons for conversion were collected from the operative report. Patient demographics and perioperative variables were compared with the successful PN group. Univariate and multivariate logistic regression analyses were conducted to assess predictors of conversion. RESULTS: A total of 1857 patients were scheduled to undergo PN. Of these patients, 90 (5%) were converted to RN. The multivariate model showed that larger tumor size (odds ratio [OR] = 1.20, P = .040), higher RENAL nephrometry score (OR = 1.41, P = .001), hilar tumor or renal sinus invasion (OR = 2.80, P = .004), laparoscopic PN (OR = 7.34, P <.001), intraoperative bleeding (OR = 19.62, P <.001), positive surgical margin (OR = 31.85, P <.001), and advanced pathologic tumor-stage (T3 or T4) (OR = 7.29, P <.001) were associated with increased odds of intraoperative conversion to RN. CONCLUSION: The rate of conversion to RN was low in patients who were scheduled to undergo PN in this series. Larger tumor size with increasing complexity, hilar tumor location or renal sinus invasion, locally advanced tumors, laparoscopic PN but not robotic PN, bleeding complication, and positive surgical margin were associated with intraoperative conversion from scheduled PN to RN.

Oncologic outcomes of patients with positive surgical margin after partial nephrectomy: a 25-year single institution experience.

PURPOSE: To evaluate oncologic outcomes and management of patients with microscopic positive surgical margin (PSM) after partial nephrectomy (PN) for renal cell carcinoma (RCC). METHODS: We reviewed our database to identify patients who underwent PN between 1990 and 2015 for RCC and had PSM on final pathology. A 1:3 matching was performed to a negative surgical margin (NSM) cohort. Kaplan-Meier method and log-rank test were used to estimate survival and differences in outcomes, respectively. Cox proportional hazards models were conducted to estimate the Hazards ratio. RESULTS: A total of 2297 patients underwent PN at our institution, of which 1863 (81%) had RCC. Microscopic PSM was found in 34 (1.8%) RCC patients who were matched to 100 patients with NSM. Of these 34 patients, local recurrence (n = 4), distant kidney recurrences (n = 4), and metastases (n = 5) developed during a median follow-up of 62 months. Bilateral tumors/tumors in a solitary kidney (n = 12/13, 92%), and multifocal tumors (n = 7/13, 54%) were found in patients who developed recurrence/metastasis. PSM patients were at a higher risk of shorter overall survival (p = 0.001), local recurrence-free survival (p = 0.003), distant recurrence-free survival (p = 0.032) and metastasis-free survival (p = 0.018). There was statistically significant association between PSM and bilateral tumors, prior treated RCC at presentation and higher nephrometry score in multivariable model. CONCLUSIONS: There was a low rate of microscopic PSM in our large cohort of patients undergoing PN despite tumor complexity. Higher nephrometry score, bilateral tumors, and prior treated RCC independently predicted PSM which showed worse survival, recurrence and metastasis compared to patients with NSM.

Trained and dedicated staff appears to be the main factor in decreasing anxiety and improving overall satisfaction during urodynamic testing: A prospective, randomized trial.

INTRODUCTION: We sought to determine whether listening to patient-selected music during urodynamic study (UDS) reduced pain and anxiety while increasing overall patient satisfaction and willingness to repeat the procedure. METHODS: Fifty-one (51) patients who underwent UDS from March to July 2014 were randomized into two groups: Group 1 with patient-selected music during the procedure (n=27) and Group 2 without music (n=24). Standard multichannel filling cystometry was performed. Anxiety was self-assessed using the State Trait Anxiety Inventory, while overall pain, satisfaction, and willingness to undergo the procedure again were self-measured using a visual analogue scale. RESULTS: Demographic characteristics and reasons for testing were similar between the two groups. The state score for Groups 1 and 2 were 27.04 and 29.5, respectively (p=0.3225) and 31.78 and 33.86, respectively (p=0.4970) for the trait score. The mean pain scores were 1.04 and 1.57, respectively (p=0.2047); the mean satisfaction scores were 0.65 and 0.52, respectively (p=0.8169); and the scores for willingness to undergo the procedure again were 0.77 and 0.74, respectively (p=0.9442). While there were no significant differences between the two groups in anxiety and satisfaction scores, pain, and willingness to undergo the procedure again, both groups commented on the nurse as the most important factor in their overall comfort. CONCLUSIONS: Music during UDS did not appear to lower pain and anxiety, nor increase overall satisfaction and willingness to repeat the procedure. The most important aspect in alleviating patients' pain and anxiety was the person actually performing the testing, highlighting the importance of having trained and dedicated staff.