Clinical variables associated with major adverse cardiac events following radical cystectomy.

Objectives: The objective of this study is to investigate the association between major adverse cardiac events (MACE) and clinical factors of patients undergoing radical cystectomy (RC) for bladder cancer. Materials and Methods: A retrospective analysis using the 2015-2020 National Surgical Quality Improvement Program database was performed on patients who underwent RC for bladder cancer. MACE was defined as any report of cerebrovascular accident, myocardial infarction, or thromboembolic events (pulmonary embolism or deep vein thrombosis). A multivariable-adjusted logistic regression was conducted to identify clinical predictors of postoperative MACE. Results: A total of 10 308 (84.2%) patients underwent RC with incontinent urinary diversion (iUD), and 1938 (15.8%) underwent RC with continent urinary diversion (cUD). A total of 629 (5.1%) patients recorded a MACE, and on the multivariable-adjusted logistic regression, it was shown that MACE was significantly associated with increased age (OR = 1.035, 95% CI: 1.024-1.046, p < 0.001), obesity (OR = 1.583, 95% CI: 1.266-1.978, p < 0.001), current smokers (OR = 1.386, 95% CI: 1.130-1.700, p = 0.002), congestive heart failure before surgery (OR = 1.991, 95% CI: 1.016-3.900; p = 0.045), hypertension (OR = 1.209, 95% CI: 1.016-1.453, p = 0.043), and increase the surgical time (per 10 min increase, OR = 1.010, 95% CI: 1.003-1.017, p = 0.009). We also report that increased age, obesity, and patients undergoing cUD (OR = 1.368, 95% CI: 1.040-1.798; p = 0.025) are associated with thromboembolic events. Conclusion: By considering the preoperative characteristics of patients, including age, obesity, smoking, congestive heart failure, and hypertension status, urologists may be able to decrease the incidence of MACE in patients undergoing RC. Urologists should aim for lower operative times as this was associated with a decreased risk of thromboembolic events.

Factors associated with urinary incontinence among Hispanic/Latina women in the United States: Findings from The Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

PURPOSE: To identify factors associated with urinary incontinence (UI) in women of various Hispanic/Latina backgrounds. MATERIALS AND METHODS: We analyzed data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a multicenter, community-based cohort study which includes a health-related questionnaire assessing presence and type of UI. Complex survey logistic regression analysis was used to assess the cross-sectional association of Hispanic/Latina backgrounds and other factors of UI. All estimates accounted for HCHS/SOL survey design. RESULTS: Of 5027 women, 33.4% answered "yes" to UI. Rates of any UI ranged from approximately 21.9% to 40.3% in women of Dominican and Puerto-Rican background, respectively. Any UI and UI subtypes were associated with age older than 65 years, increasing body mass index, smoking status, any alcohol use, parity ≥3, and postmenopausal status. After controlling for covariates and when compared with women of Mexican background, women of Dominican background were less likely to have any UI (OR = 0.42, 95% CI 0.30-0.57), as were women of Cuban (OR = 0.48, 95% CI 0.37-0.62), Puerto-Rican (OR = 0.79, 95% CI 0.62-1.0), and mixed (OR = 0.62, 95% CI 0.39-0.99) background; and women of every other background except for South American were less likely to have stress UI. In addition, women of Cuban (OR = 0.53, 95% CI 0.32-0.86) and mixed (OR = 0.38, 95% CI 0.16-0.87) background were less likely to have urge UI than women of Mexican background. CONCLUSIONS: Our study demonstrates differences in UI by Hispanic/Latina background, suggesting collective designation of Hispanics/Latinas as a single ethnic group does not adequately describe UI among this diverse group.

Racial disparity in the utilization of immunotherapy for advanced prostate cancer.

PURPOSE: To identify whether there was a disparity in the utilization of immunotherapy in the treatment of black patients with metastatic castration resistant prostate cancer (mCRPC). METHODS: Using the National Cancer Database, we identified patients between 2010- 2015 with likely minimally/asymptomatic mCRPC. We analyzed annual trends for chemotherapy and immunotherapy use and compared utilization by demographic and clinical features. Multivariable analysis was performed to determine predictors of receiving immunotherapy vs chemotherapy. RESULTS: We identified 1301 patients with likely mCRPC. The majority were non Hispanic White (NHW - 63 %) and 23 % were non-Hispanic Black (NHB). Overall, there was increased utilization of immunotherapy in mCRPC from 2010 onwards, with the peak occurring in 2014 (4.6 %). Chemotherapy use increased significantly, peaking in 2014 to 26.1 %. However, the increased utilization of immunotherapy in the mCRPC was mainly seen in White patients: from 50 % to 74.2 % of the cohort. Conversely, there was a decrease in utilization of immunotherapy among Black mCPRC patients: from 50 % to 25.8 %. On multivariable analysis, there was no statistically significant difference between treatment types by race. CONCLUSION: FDA approval of Sipuleucel-T for mCRPC led to increased utilization of immunotherapy shortly thereafter, but this was mainly noted in white patients. Black patients comparatively did not exhibit increased utilization of this novel agent after 2010. Further studies are necessary to help understand barriers to access to new treatment in mCRPC and eliminate the burden of disease in minority populations."

Optimum threshold of the 4Kscore for biopsy in men with negative or indeterminate multiparametric magnetic resonance imaging.

Objective: The study aims to identify the optimal 4Kscore thresholds to determine the need for a prostate biopsy when multiparametric magnetic resonance imaging (MRI) (mpMRI) is negative or indeterminate. Materials and methods: We analysed retrospective data from men in eight different institutions who underwent an mpMRI, 4Kscore and prostate biopsy for evaluation of prostate cancer. We selected men with a negative (PIRADS ≤2) or indeterminate (PIRADS 3) mpMRI. 4Kscore values were categorized into ranges of 1-7, 8-19, 20-32 and greater than 32. We evaluated the proportion of men with grade group 2 or higher (GG2+) cancer in groups defined by PIRADS and 4Kscore. We also evaluated the number of biopsies avoided and GG2+ cancer missed in each group reported depend on 4Kscore cutoff points. Results: Among 1111 men who had an mpMRI, 4Kscore and biopsy, 625 of them had PIRADS ≤3 on mpMRI: 374 negative (PIRADS ≤2) and 251 indeterminate (PIRADS 3). In men with a negative mpMRI, we found a 4Kscore cut-point of 33 resulted in an increased risk of GG2+ cancer on biopsy. In patients with an equivocal lesion on mpMRI, men with a 4Kscore cutoff ≥8 had a greater risk of GG2+ cancer on biopsy. Decision curve analysis supported the proposed cut-points in each mpMRI group. Conclusions: In men with negative and indeterminate mpMRI, we found the best 4Kscore threshold to determine the need for biopsy to be 33 and 8 respectively. Future prospective studies in independent populations are needed to confirm these findings.

Incidence and predictors of deep incisional and organ/space surgical site infection following radical cystectomy.

OBJECTIVE: To investigate clinical risk factors associated with postoperative deep incisional or organ/space surgical site infections (SSI) following radical cystectomy (RC) in a well characterized and large contemporary cohort. METHODS: We used the American College of Surgeons National Surgical Quality Improvement Program database to identify adult patients who underwent RC for bladder cancer between 2015 and 2020 (n = 13,081). We conducted multivariable-adjusted logistic regression and Cox adjusted proportional hazards regression analysis to identify clinical predictors of deep incisional or organ/space SSI in the 30-day postoperative-period following RC. RESULTS: Deep incisional or organ/space SSI risk increased with continent urinary diversion (HR = 1.61, 95% CI: 1.38-1.88; P < 0.001), obesity (HR = 1.60, 95% CI: 1.35-1.90; P < 0.001), diabetes mellitus (HR = 1.30, 95% CI: 1.13-1.51; P < 0.001), and being functionally dependent before surgery (HR = 2.09, 95% CI: 1.44-3.03; P < 0.001). CONCLUSIONS: Postoperative deep incisional or organ/space SSIs following RC occur more frequently in patients who were obese, diabetic, functionally dependent before surgery, and those who underwent continent urinary diversion. These findings may assist urologists in preoperative counseling, medical optimization, and choice of urinary diversion approach, as well as improved patient monitoring and identification of candidates for intervention postoperatively.

Endometrial carcinoma: association between mutational status, sites of metastasis, recurrence, and correlation with overall survival.

PURPOSE: To investigate the association between sites of endometrial carcinoma (EC) recurrence and metastases, mutational status, race, and overall survival (OS). METHODS: This single-center retrospective study evaluated patients with biopsy-proven EC that underwent genomic molecular testing between January 2015 and July 2021. Association between genomic profile and sites of metastases or recurrence was performed using Pearson's chi-squared or Fisher exact test. Survival curves for ethnicity and race, mutations, sites of metastases or recurrence were estimated using the Kaplan-Meier method. Univariable and multivariable Cox proportional hazard regression models were used. RESULTS: The study included 133 women [median age 64 years (IQR 57-69)]. The most common mutation was TP53 (65/105 patients, 62%). The most common site of metastasis was the peritoneum (35/43, 81%). The most common recurrence was in lymph nodes (34/75, 45%). Mutations of TP53 and PTEN were significantly associated with Black women (p = 0.048, p = 0.004, respectively). In the univariable Cox regression analyses, TP53 mutation and presence of recurrence or metastases to the peritoneum were associated with lower OS (HR 2.1; 95% CI 1.1, 4.3; p = 0.03/ HR 2.9; 95% CI 1.6, 5.4; p = 0.0004; respectively). On multivariable Cox proportional hazards model ER expression (HR 0.4; 95% CI 0.22, 0.91; p = 0.03), peritoneal recurrence or metastases (HR 3.55; 95% CI 1.67, 7.57; p = 0.001), and Black race (HR 2.2; 95% CI 1.1, 4.6; p = 0.03) were significant independent predictors of OS. CONCLUSIONS: The integration of EC mutational status and clinicopathological risk assessment demonstrated potential implications on the patterns of metastasis, recurrence, and OS.

Uterine serous carcinoma: assessing association between genomics and patterns of metastasis.

Background: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial carcinoma which has been increasing at alarming rates, particularly among Asian, Hispanic and Black women. USC has not been well characterized in terms of mutational status, pattern of metastases and survival. Objective: To investigate the association between sites of recurrence and metastases of USC, mutational status, race, and overall survival (OS). Methods: This single-center retrospective study evaluated patients with biopsy-proven USC that underwent genomic testing between January 2015 and July 2021. Association between genomic profile and sites of metastases or recurrence was performed using χ2 or Fisher's exact test. Survival curves for ethnicity and race, mutations, sites of metastasis/recurrence were estimated using the Kaplan-Meier method and compared with log-rank test. Cox proportional hazard regression models were used to examine the association between OS with age, race, ethnicity, mutational status, and sites of metastasis/recurrence. Statistical analyses were performed using SAS Software Version 9.4. Results: The study included 67 women (mean age 65.8 years, range 44-82) with 52 non-Hispanic women (78%) and 33 Black women (49%). The most common mutation was TP53 (55/58 women, 95%). The peritoneum was the most common site of metastasis (29/33, 88%) and recurrence (8/27, 30%). PR expression was more common in women with nodal metastases (p=0.02) and non-Hispanic women (p=0.01). ERBB2 alterations were more common in women with vaginal cuff recurrence (p=0.02), while PIK3CA mutation was more common in women with liver metastases (p=0.048). ARID1A mutation and presence of recurrence or metastases to the liver were associated with lower OS (Hazard Ratio (HR): 31.87; 95%CI: 3.21, 316.9; p<0.001 and HR: 5.66; 95%CI: 1.2, 26.79; p=0.01, respectively). In the bivariable Cox model, the presence of metastasis/recurrence to the liver and/or the peritoneum were both independent significant predictors of OS (HR: 9.8; 95%CI: 1.85-52.7; p=0.007 and HR: 2.7; 95%CI: 1.02-7.1; p=0.04, respectively). Conclusions: TP53 is often mutated in USC, which most commonly metastasize and recur in the peritoneum. OS was shorter in women with ARID1A mutations and with metastasis/recurrence to the liver. The presence of metastasis/recurrence to liver and/or peritoneum were independently associated with shorter OS.

Disease stage-dependent changes in brain levels and neuroprotective effects of neuroactive steroids in Parkinson's disease.

Neuroactive steroids are known neuroprotective agents and neurotransmitter regulators. We previously found that expression of the enzymes synthesizing 5α-dihydroprogesterone (5α-DHP), allopregnanolone (ALLO), and dehydroepiandrosterone sulfate (DHEAS) were reduced in the substantia nigra (SN) of Parkinson's Disease (PD) brain. Here, concentrations of a comprehensive panel of steroids were measured in human post-mortem brains of PD patients and controls. Gas chromatography-mass spectrometry (GC/MS) was used to measure steroid levels in SN (involved in early symptoms) and prefrontal cortex (PFC) (involved later in the disease) of five control (CTR) and nine PD donors, divided into two groups: PD4 (PD-Braak stages 1-4) and PD6 (PD-Braak stages 5-6). In SN, ALLO was increased in PD4 compared to CTR and 5α-DHP and ALLO levels were diminished in PD6 compared to PD4. The ALLO metabolite 3α5α20α-hexahydroprogesterone (3α5α20α-HHP) was higher in PD4 compared to CTR. In PFC, 3α5α20α-HHP was higher in PD4 compared to both CTR and PD6. The effects of 5α-DHP, ALLO and DHEAS were tested on human post-mortem brain slices of patients and controls in culture. RNA expression of genes involved in neuroprotection, neuroinflammation and neurotransmission was analysed after 5 days of incubation with each steroid. In PD6 slices, both 5α-DHP and ALLO induced an increase of the glutamate reuptake effector GLAST1, while 5α-DHP also increased gene expression of the neuroprotective TGFB. In CTR slices, ALLO caused reduced expression of IGF1 and GLS, while DHEAS reduced the expression of p75 and the anti-apoptotic molecule APAF1. Together these data suggest that a potentially protective upregulation of ALLO occurs at early stages of PD, followed by a downregulation of progesterone metabolites at later stages that may exacerbate the pathological changes, especially in SN. Neuroprotective effects of neurosteroids are thus dependent on the neuropathological stage of the disease.

Racial and socioeconomic disparities in cost and postoperative complications following sacrocolpopexy in a US National Inpatient Database.

PURPOSE: We sought to determine the association between socioeconomic factors, procedural costs, and postoperative complications among patients who underwent sacrocolpopexy. METHODS: The 2016-2017 US National Inpatient Sample from the Healthcare Cost and Utilization Project was used to identify females > 18 years of age with an ICD10 diagnosis code of apical prolapse who received open or laparoscopic/robotic sacrocolpopexy. We analyzed relationships between socioeconomic factors, procedural costs, and postoperative complications in these patients. Multivariate logistic and linear regressions were used to identify variables associated with increased complications and costs, respectively. RESULTS: We identified 4439 women who underwent sacrocolpopexy, of which 10.7% had complications. 34.6% of whites, 29.1% of Blacks, 29% of Hispanics, and 34% of Others underwent a laparoscopic/robotic procedure. Hispanic patients had the highest median charge associated with surgical admission for sacrocolpopexy at $51,768, followed by Other ($44,522), White ($43,471), and Black ($40,634) patients. Procedure being within an urban teaching hospital (+ $2602), laparoscopic/robotic (+ $6790), or in the West (+ $9729) were associated with a significantly higher median cost of surgical management. CONCLUSIONS: In women undergoing sacrocolpopexy, the protective factors against postoperative complications included private insurance status, a laparoscopic approach, and concurrent hysterectomy. Procedures held within an urban teaching hospital, conducted laparoscopically/robotically or in the West are associated with significantly higher costs of surgical management. Hispanic patients observe significantly higher procedure charges and costs, possibly resulting from the large number of this ethnic group living in the Western United States.

Using the EPAs to Evaluate the Clinical Experience of Medical Students.

Introduction: Although there are standardized assessments of medical students throughout medical school, the clinical experience of each student may vary widely. Currently, medical schools do not have a systematic method to ensure that students perform clinical skills during clinical clerkships. Our study used the Entrustable Professional Activities for Entering Residency (EPAs) framework to assess the ways in which medical students meaningfully participate in patient care at various clinical sites in each required clerkship and over time. Methods: Over the 2020-2021 academic year, 170 third-year medical students were asked to report the number of times they performed EPA-1 (gather history and perform physical examination), EPA-5 (document clinical encounter), and EPA-6 (provide oral presentation of clinical encounter) at the end of each required clinical rotation (emergency medicine, internal medicine, surgery, obstetrics/gynecology, pediatrics, neurology, psychiatry) at a single medical school. We used descriptive statistics and t tests to compare frequency of these EPAs by campus type, site type, clerkship, and time. Results: One thousand, two hundred sixty-one surveys met inclusion criteria. Students performed EPA-5 more often at an academic medical center, and EPA-1 more frequently in the outpatient setting. Students performed EPA-1 and EPA-6 most often during emergency medicine and EPA-5 most often during internal medicine. Performance of all three EPAs increased over time. Conclusion: This reporting system produced a robust data set that allowed for EPA performance comparisons by campus, site type, clerkship, and time. EPA performance varied by rotation, site type, clerkship, and time.

Inhibition of hypoxia-inducible factor-prolyl hydroxylation protects from cyclophosphamide-induced bladder injury and urinary dysfunction.

Disruption of the blood-urine barrier can result in acute or chronic inflammatory bladder injury. Activation of the oxygen-regulated hypoxia-inducible factor (HIF) pathway has been shown to protect mucosal membranes by increasing the expression of cytoprotective genes and by suppressing inflammation. The activity of HIF is controlled by prolyl hydroxylase domain (PHD) dioxygenases, which have been exploited as therapeutic targets for the treatment of anemia of chronic kidney disease. Here, we established a mouse model of acute cyclophosphamide (CYP)-induced blood-urine barrier disruption associated with inflammation and severe urinary dysfunction to investigate the HIF-PHD axis in inflammatory bladder injury. We found that systemic administration of dimethyloxalylglycine or molidustat, two small-molecule inhibitors of HIF-prolyl hydroxylases, profoundly mitigated CYP-induced bladder injury and inflammation as assessed by morphological analysis of transmural edema and urothelial integrity and by measuring tissue cytokine expression. Void spot analysis to examine bladder function quantitatively demonstrated that HIF-prolyl hydroxylase inhibitor administration normalized micturition patterns and protected against CYP-induced alteration of urinary frequency and micturition patterns. Our study highlights the therapeutic potential of HIF-activating small-molecule compounds for the prevention or therapy of bladder injury and urinary dysfunction due to blood-urine barrier disruption.NEW & NOTEWORTHY Disruption of the blood-urine barrier can result in acute or chronic inflammatory bladder injury. Here, we demonstrate that pharmacological inhibition of hypoxia-inducible factor (HIF)-prolyl hydroxylation prevented bladder injury and protected from urinary dysfunction in a mouse model of cyclophosphamide-induced disruption of the blood-urine barrier. Our study highlights a potential role for HIF-activating small-molecule compounds in the prevention or therapy of bladder injury and urinary dysfunction and provides a rationale for future clinical studies.

Neurofilament Light Chain Levels in Multiple Sclerosis Correlate With Lesions Containing Foamy Macrophages and With Acute Axonal Damage.

BACKGROUND AND OBJECTIVES: To investigate whether white matter lesion activity, acute axonal damage, and axonal density in MS associate with CSF neurofilament light chain (NfL) levels. METHODS: Of 101 brain donors with MS (n = 92 progressive MS, n = 9 relapsing-remitting MS), ventricular CSF was collected, and NfL levels were measured. White matter lesions were classified as active, mixed, inactive, or remyelinated, and microglia/macrophage morphology in active and mixed lesions was classified as ramified, ameboid, or foamy. In addition, axonal density and acute axonal damage were assessed using Bielschowsky and amyloid precursor protein (APP) (immune)histochemistry. RESULTS: CSF NfL measurements of donors with recent (<1 year) or clinically silent stroke were excluded. CSF NfL levels correlated negatively with disease duration (p = 6.9e-3, r = 0.31). In donors without atrophy, CSF NfL levels correlated positively with the proportion of active and mixed lesions containing foamy microglia/macrophages (p = 9.85e-10 and p = 1.75e-3, respectively), but not with those containing ramified microglia. CSF NfL correlated negatively with proportions of inactive (p = 5.66e-3) and remyelinated lesions (p = 0.03). In the normal appearing pyramid tract, axonal density negatively correlated with CSF NfL levels (Bielschowsky, p = 0.02, r = -0.31), and the presence of acute axonal damage in lesions was related to higher NfL levels (APP, p = 1.17e-6). The amount of acute axonal damage was higher in active lesions with foamy microglia/macrophages and in the rim of mixed lesions with foamy microglia/macrophages when compared with active lesions containing ramified microglia/macrophages (p = 4.6e-3 and p = 0.02, respectively), the center and border of mixed lesions containing ramified microglia/macrophages (center: p = 4.6e-3, border, p = 4.6e-3, and n.s., p = 4.6e-3, respectively), the center of mixed lesions containing foamy microglia/macrophages (p = 4.6e-3 and p = 0.02, respectively), inactive lesions (p = 4.6e-3 and p = 4.6e-3, respectively), and remyelinated lesions (p = 0.03 and p = 0.04, respectively). DISCUSSION: Our results demonstrated that active and mixed white matter MS lesions with foamy microglia show high acute axonal damage and correlate with elevated CSF NfL levels. Our data support the use of this biomarker to monitor inflammatory demyelinating lesion activity with axonal damage in MS.

PSA Testing in Men Receiving Testosterone Therapy With History of Prostate Cancer: A Matched Analysis of a Large Multi-Institutional Research Network.

OBJECTIVE: To investigate the frequency of prostate-specific antigen (PSA) testing in men receiving testosterone replacement therapy (TT) and with a history of prostate cancer (PCa). METHODS: We queried the TriNetX network database, a global health research network consisting of 65 million men in 44 large healthcare organizations, to investigate rates of PSA testing in 4 cohorts of men aged 55-69 with a history of PCa diagnosis and/or a prescription for any route or formulation of testosterone. We further stratified each cohort to evaluate PSA testing in men with previously treated (CPT 55,840, 55,866, 77,778, 77,385) or untreated PCa. All cohorts' PSA testing rates were compared against the "no PCa or TT" cohort by Chi-square test. RESULTS: A total of 4,525,259 men, aged 55-69, were included in our study. Following stratification into cohorts based on PCa or TT history, we found that 14.2% (P < .0001) of men without PCa or TT underwent PSA testing following an initial ambulatory visit. Among men without PCa who received TT, 33.6% (P < .0001) underwent testing. Unfortunately, only 53.2% (P < .0001) and 61.0% (P < .0001) of men receiving TT with previously untreated and treated PCa, respectively, had PSA testing. CONCLUSION: In contrast to current guidelines, a large proportion of men receiving TT and with a history of PCa did not undergo PSA testing. Further studies are necessary to better characterize reasons why PSA testing rates are low even in this high-risk cohort.

The naked truth: a comprehensive clarification and classification of current 'myths' in naked mole-rat biology.

The naked mole-rat (Heterocephalus glaber) has fascinated zoologists for at least half a century. It has also generated considerable biomedical interest not only because of its extraordinary longevity, but also because of unusual protective features (e.g. its tolerance of variable oxygen availability), which may be pertinent to several human disease states, including ischemia/reperfusion injury and neurodegeneration. A recent article entitled 'Surprisingly long survival of premature conclusions about naked mole-rat biology' described 28 'myths' which, those authors claimed, are a 'perpetuation of beautiful, but falsified, hypotheses' and impede our understanding of this enigmatic mammal. Here, we re-examine each of these 'myths' based on evidence published in the scientific literature. Following Braude et al., we argue that these 'myths' fall into four main categories: (i) 'myths' that would be better described as oversimplifications, some of which persist solely in the popular press; (ii) 'myths' that are based on incomplete understanding, where more evidence is clearly needed; (iii) 'myths' where the accumulation of evidence over the years has led to a revision in interpretation, but where there is no significant disagreement among scientists currently working in the field; (iv) 'myths' where there is a genuine difference in opinion among active researchers, based on alternative interpretations of the available evidence. The term 'myth' is particularly inappropriate when applied to competing, evidence-based hypotheses, which form part of the normal evolution of scientific knowledge. Here, we provide a comprehensive critical review of naked mole-rat biology and attempt to clarify some of these misconceptions.

The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity.

The regeneration-associated gene (RAG) expression program is activated in injured peripheral neurons after axotomy and enables long-distance axon re-growth. Over 1000 genes are regulated, and many transcription factors are upregulated or activated as part of this response. However, a detailed picture of how RAG expression is regulated is lacking. In particular, the transcriptional targets and specific functions of the various transcription factors are unclear. Jun was the first-regeneration-associated transcription factor identified and the first shown to be functionally important. Here we fully define the role of Jun in the RAG expression program in regenerating facial motor neurons. At 1, 4 and 14 days after axotomy, Jun upregulates 11, 23 and 44% of the RAG program, respectively. Jun functions relevant to regeneration include cytoskeleton production, metabolic functions and cell activation, and the downregulation of neurotransmission machinery. In silico analysis of promoter regions of Jun targets identifies stronger over-representation of AP1-like sites than CRE-like sites, although CRE sites were also over-represented in regions flanking AP1 sites. Strikingly, in motor neurons lacking Jun, an alternative SRF-dependent gene expression program is initiated after axotomy. The promoters of these newly expressed genes exhibit over-representation of CRE sites in regions near to SRF target sites. This alternative gene expression program includes plasticity-associated transcription factors and leads to an aberrant early increase in synapse density on motor neurons. Jun thus has the important function in the early phase after axotomy of pushing the injured neuron away from a plasticity response and towards a regenerative phenotype.

Malignant lymphomatous invasion of Meckel's cave: pathoanatomical considerations of the petrous apex.

Secondary central nervous system lymphoma is rare, occurring in up to 10% of non-Hodgkin's lymphoma patients and in 5% of diffuse large B-cell lymphoma patients. The prognosis is poor, even rarer is metastasis of large B-cell lymphomas into Meckel's cave and the trigeminal nerve roots. We describe a relapsing case of a large B-cell lymphoma that migrated into Meckel's cave, the mandibular branch of the trigeminal nerve and the adjacent cavernous sinus. We review petrous apex anatomy, review the literature of metastatic spread into Meckel's cave and analyse existing pathoanatomical studies that explain the conduits and barriers of tumour spread. Understanding this pathoanatomical relationship is critical for neurologists and neurosurgeons alike to effectively correlate patient signs and symptoms to intracranial pathology and identify origins and sites of metastatic dispersion in similar rare clinical scenarios.

Evaluating Patient Adherence to Routine and Symptom Indicated Colonoscopies During the COVID-19 Pandemic.

Background and aims The COVID-19 pandemic has led to significant changes in healthcare delivery. In response to these changes, patients have increasingly reduced healthcare utilization in several ways, such as medication compliance, cancer screenings, and routine wellness appointments. This study aims to quantify patient adherence rates to routine and symptom indicated colonoscopies during the COVID-19 and to assess patient medication compliance and utilization of healthcare facilities. Methods A cross-sectional study was performed at a single-center internal medicine clinic from January 2021 to April 2021. A 28-item survey was administered to patients to evaluate for adherence rates to routine and symptom indicated colonoscopies. Patients were also evaluated for rates of healthcare facility usage and medication compliance. Results Among 103 participants, 30.8% of patients who were due for routine colonoscopy either missed, refused, or rescheduled, while 16.7% of patients did so for symptom indicated colonoscopies. Nearly all respondents (94.2%) reported no change to medication compliance when compared to pre-COVID. A significant portion (36.9%) of patients reported missing a healthcare appointment at some point during the pandemic, and of the respondents who felt sick enough to visit the emergency department, 23.1% decided not to go. Conclusions During the COVID-19 pandemic, patients are deferring colorectal cancer surveillance, reducing the usage of acute care facilities, and missing routine healthcare appointments. It is important for providers to address the risks and benefits of delaying colorectal cancer screenings as well as identify physical and psychosocial barriers to patient utilization of both acute and chronic healthcare facilities. As COVID-19 restrictions inevitably continue to ease, medical providers should be aware of these potential lapses in cancer screenings and healthcare visits and be vigilant in catching patients up on their preventative health screenings.

Myeloneuropathy in the Setting of Hypocupremia: An Overview of Copper-Related Pathophysiology.

A posterior cord or dorsal column myelopathy due to neurosyphilis presenting as a tabetic gait is a classic neurological vignette and is taught to all medical students. Its clinical presentation is so graphic that its simulacrum with diseases other than neurosyphilis is labeled as pseudotabes. The latter can be seen with vitamin B12 deficiency as a subacute combined degeneration (SCD) of the spinal cord, another neurology classic. However, not all cases of pseudotabes are due to posterior cord myelopathy as some can arise with other deafferentation syndromes such as polyganglioneuropathies as seen with paraneoplastic syndromes, Sjogren's syndrome, idiopathic autoimmune diseases, and post-viral neuronopathies. A unique and interesting cause of pseudotabes is due to copper deficiency; copper being a metallic trace element that is fundamental to cellular life. Herein, we present a case of copper deficiency manifesting as pseudotabes and review the biochemical properties of copper and its effects on the nervous system.

Coordinated changes in the expression of Wnt pathway genes following human and rat peripheral nerve injury.

A human neuroma-in continuity (NIC), formed following a peripheral nerve lesion, impedes functional recovery. The molecular mechanisms that underlie the formation of a NIC are poorly understood. Here we show that the expression of multiple genes of the Wnt family, including Wnt5a, is changed in NIC tissue from patients that underwent reconstructive surgery. The role of Wnt ligands in NIC pathology and nerve regeneration is of interest because Wnt ligands are implicated in tissue regeneration, fibrosis, axon repulsion and guidance. The observations in NIC prompted us to investigate the expression of Wnt ligands in the injured rat sciatic nerve and in the dorsal root ganglia (DRG). In the injured nerve, four gene clusters were identified with temporal expression profiles corresponding to particular phases of the regeneration process. In the DRG up- and down regulation of certain Wnt receptors suggests that nerve injury has an impact on the responsiveness of injured sensory neurons to Wnt ligands in the nerve. Immunohistochemistry showed that Schwann cells in the NIC and in the injured nerve are the source of Wnt5a, whereas the Wnt5a receptor Ryk is expressed by axons traversing the NIC. Taken together, these observations suggest a central role for Wnt signalling in peripheral nerve regeneration.

Effect of Preoperative Weight Loss and Baseline Comorbidity on Short-Term Complications and Reoperations After Laparoscopic Roux-en-Y Gastric Bypass in 2,067 Patients.

PURPOSE: Decreasing popularity of Roux-en-Y gastric bypass (RYGB) in bariatric-metabolic surgery may be due to higher perceived peri-operative complications. There are few studies on whether preoperative weight loss can reduce complications or reoperations following RYGB. We investigated this using a standardised operative technique. MATERIALS AND METHODS: Retrospective single-centre study of RYGB from 2004 to 2019 using a prospective database. Preoperative behavioural management included intentional weight loss. Maximum preoperative weight, weight on the day of operation, and Obesity-Surgery Mortality Risk Score (OS-MRS) class were recorded. Short-term outcomes (post-operative stay, 30-day complication and reoperation rates) were analysed. RESULTS: In 2,067 RYGB patients (1,901 primary and 166 revisional), median preoperative total body weight loss (TWL) was 6.2% (IQR: 2.5-10.7%). The median age was 46 (interquartile range (IQR) 38-54) and 80.4% were female (n=1,661). For primary surgery, the median body mass index (BMI) was 47.6 kg/m2 (IQR: 43.1-53.3). Excluding the 100-procedure learning curve, the complication rate for primary cases was 4.4% and reoperation rate of 2.8% and one peri-operative mortality (0.06%). OS-MRS ≥2 (class B or C) predicted higher risk of complications (6.1%) compared to those with a score <2 (class A) (3.8%, p=0.021), but not reoperations. Five percent preoperative TWL did not decrease complications compared to <5% TWL. Patients with ≥10% TWL had greater baseline risk and had an increased risk of complications (6.6% vs 3.7%, p=0.017) and reoperations (4.5% vs 2.7%, p<0.001). CONCLUSIONS: RYGB performed using a standardised technique has low overall risk. The influence of preoperative weight loss on outcomes was inconsistent.