Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.

Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn(-/-) microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn(-/-) mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.

Characterizing voiding experiences of men choosing seated and standing positions.

AIMS: Voiding positions and preferences in men are not well characterized. In this study, we aim to understand the interplay of voiding characteristics and their impact on voiding position. METHODS: We designed a 27-item survey to assess voiding characteristics and lower urinary tract symptoms (LUTS) severity in men seen in urology and other outpatient clinics. Participants included adult men patients and adult men accompanying patients at our institution's outpatient clinics. Data collected included demographics, International Prostate Symptom Score questionnaire, stream type (single, split, and dribble), voiding behavior, positional stream quality, and voiding bother. RESULTS: We received 195 completed surveys (80% response rate). Of men queried, 18% (35/195) preferred to sit while voiding. Overall, men who sit had a higher proportion of LUTS (66% [23/35] vs. 41% [66/160]; p = .01), more physical limitations affecting voiding choice (20% [7/35] vs. 3% [5/160]; (p = .001), and a lower desire to stand (6% [2/35] vs. 24% [38/160]; p = .02), compared to men who stand. Men who sit while voiding reported nearly double the amount of voiding associated bother (34% [12/35]) compared to men who stand (18% [28/160]; p = .04). Older aged men reported a similar rate of seated urination compared to younger men. The most common reasons to void seated included comfort and avoidance of spraying. CONCLUSIONS: Our findings discourage the use of anecdotal beliefs founded on generalizable characteristics, such as age and stream type, to infer a patient's voiding characteristics. Open dialog with patients regarding voiding preferences may garner important information regarding overall urologic health and better inform urologic care.

Pre-operative factors associated with the development of distal ureteral stump syndrome after upper pole heminephrectomy.

INTRODUCTION: For children with duplex systems and severe hydroureteronephrosis of the upper pole, heminephrectomy is one of many suitable treatments, particularly if there is no associated lower pole reflux. Distal ureteral stump syndrome (DSS) is a very difficult complication and manifests as stump empyema, urinary tract infection and/or vulvar discharge and can occur months to years later in 10-20 percent of patients. Secondary distal ureterectomy is an extremely difficult surgery due to inflammation and adhesions. To avoid DSS, distal ureterectomy at the time of heminephrectomy can be performed concurrently but carries a risk of lower pole ureter devascularization and injury. Current literature on DSS has shown associations with subtotal ureterectomy or long ureteral stumps. We hypothesized that there may be preoperative variables prior to heminephrectomy that are associated with the development of DSS. OBJECTIVE: Identify pre-operative risk factors for the development of DSS in pediatric patients who underwent upper pole heminephrectomy for duplex kidneys. STUDY METHODS: Retrospective analysis of pediatric patients who underwent upper pole heminephrectomy at single, academic institution from 1999 to 2021. Pre-operative patient age, gender, history, imaging, and lab results were extracted from patient charts to assess for factors that may predict the development of DSS. Patient groups with and without DSS were compared using Fischer's Exact Test. RESULTS: Five (14%) of 36 patients developed DSS and required secondary distal ureterectomy at a median time of 22 months (IQR 6-27) after heminephrectomy. The presence of ureteral debris (80% of DSS) on preoperative ultrasound (p < 0.001), reflux into the upper pole (p = 0.005), and mucus discharge (100% of DSS) (p < 0.001) prior to surgery were found to be significantly associated with those who developed DSS, compared to those who did not. These three pre-operative factors had high specificity (97-100%) and negative predictive value (94-97%). DISCUSSION: Substantial experience has shown that less than 20% of patients benefit from distal ureterectomy during upper heminephrectomy. Whether using an open or laparoscopic approach, selection of at-risk patients should lower operative time and avoid injury and devascularization of the lower pole ureter for most patients. CONCLUSION: The presence or absence of ureteral debris, mucus discharge and/or upper pole reflux prior to heminephrectomy may be useful guides in selecting which patients would benefit from concurrent distal ureterectomy and conversely which patients may safely avoid the additional dissection.

The Metastatic Risk of Renal Cell Carcinoma by Primary Tumor Size and Subtype.

Background: Current data on the association between tumor size, subtype, and metastases, and thresholds for intervention, for renal cell carcinoma (RCC), are largely based on single-center nephrectomy registries that may under-represent those presenting with metastatic disease. Objective: We sought to assess tumor size and histologic subtype in relation to metastatic status at presentation for patients with RCC. Design setting and participants: Using Surveillance, Epidemiology and End Results cancer registry data, we identified patients with a diagnosis of RCC made between 2004 and 2019, and a known size of primary tumor. We used nodal and metastatic TNM staging to assess metastatic disease at presentation. Outcome measurements and statistical analysis: We report the proportion of metastatic disease across varying tumor sizes for clear cell (ccRCC), papillary (pRCC), and chromophobe (chRCC) RCC. We also examine sarcomatoid RCC and RCC with sarcomatoid features (sarcRCC). Logistic regression models were used to model the likelihood of metastatic disease for each histologic subtype. Results and limitations: Of 181 096 RCC patients included, 23 829 had metastatic disease. For any RCC, metastatic rates of 3.6%, 13.1%, 30.3%, and 45.1% were observed for tumors ≤4, 4-≤7, 7-≤10, and >10 cm, respectively. Metastatic rates of chRCC were low at even large sizes, 11.0% at >10 cm. In contrast, sarcRCC had high metastatic rates at all sizes, 27.1% at ≤4 cm. Metastatic rates for ccRCC and pRCC increased steadily above 3 cm. For any RCC and each evaluated subtype, tumor size was found to be associated with metastatic disease on logistic regression (p < 0.001). Conclusions: The likelihood of a renal mass being metastatic varies greatly with both its subtype and size. We report higher likelihoods of metastatic disease across tumor sizes compared with what has been reported previously. These results may help clinicians pick appropriate thresholds for intervention and candidates for active surveillance. Patient summary: We find that the metastatic probability of renal cell carcinoma varies greatly with subtype and increases with tumor size.

Secondary Bladder Cancer After Prostate Cancer Treatment: An Age-matched Comparison Between Radiation and Surgery.

BACKGROUND: Secondary malignancy is a long-term risk of radiation. External beam radiation therapy (EBRT) for prostate cancer treatment has been associated with later development of bladder cancer and worse bladder cancer features. OBJECTIVE: We sought to provide an updated comparison of the long-term risk of bladder cancer after different localized prostate cancer treatments. DESIGN, SETTING, AND PARTICIPANTS: Using the Surveillance, Epidemiology, and End Results (SEER) cancer registry, we compared an age-matched subset of patients who underwent radical prostatectomy (RP) with those who underwent EBRT, brachytherapy (BT), EBRT + BT, and RP followed by EBRT (RPtoEBRT) between 2000 and 2018. Our final cohort included 261 609 patients with a median follow-up of 11.6 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Our primary outcomes were time to bladder cancer diagnosis, muscle-invasive bladder cancer diagnosis, and bladder cancer death. We used cause-specific hazard models considering death as a competing event. A similar analysis was performed on lung cancer, as a surrogate marker for smoking. We also compared proportions of variant histology, high-grade, and invasive disease among bladder cancers that occurred after radiation versus RP using chi-square testing. RESULTS AND LIMITATIONS: All radiation groups were associated with bladder cancer diagnosis; hazard ratios (HRs) were 1.72, 1.85, 1.80, and 1.53 for EBRT, BT, EBRT + BT, and RPtoEBRT, respectively, using RP as a referent (all p < 0.001). HRs for bladder cancer death were even higher: 2.39, 2.57, and 3.02 for EBRT, BT, and EBRT + BT, respectively (all p < 0.001), except for RPtoEBRT (HR 1.43, p = 0.28). Lung cancer diagnosis was also associated with radiation but at lower HRs-1.63, 1.32, 1.42, and 1.30 for EBRT, BT, EBRT + BT, and RPtoEBRT, respectively (all p < 0.001). There were a higher proportion of ≥T2, ≥T3, and sarcomatoid variant bladder cancers after radiation (all p < 0.01) CONCLUSIONS: The risk of developing and dying from bladder cancer is increased in patients treated with radiation compared with those treated with RP. The risk was similar for BT and EBRT. Bladder cancers after radiation are more likely to be sarcomatoid variant and present as muscle invasive. PATIENT SUMMARY: We observed the rates of bladder cancer after patients had undergone surgery or radiation for prostate cancer, and found higher rates of bladder cancer after radiation. We also observed that bladder cancers that occur after radiation tend to be more aggressive.

Morbidity and Mortality Caused by Noncompliance With California Hospital Licensure: Immediate Jeopardies in California Hospitals, 2007-2017.

OBJECTIVE: The California Department of Public Health investigates compliance with hospital licensure and issues an administrative penalty when there is an immediate jeopardy. Immediate jeopardies are situations in which a hospital's noncompliance of licensure requirements causes serious injury or death to patient. In this study, we critically examine immediate jeopardies between 2007 and 2017 in California. METHODS: All immediate jeopardies reported between 2007 and 2017 were abstracted for hospital, location, date, details of noncompliance, and patient's health outcome. RESULTS: Of 385 unique immediate jeopardies, 141 (36.6%) caused mortality, 120 (31.2%) caused morbidity, 96 (24.9%) led to a second surgery, 9 (2.3%) caused emotional trauma without physical trauma, and 19 (4.9%) were caught before patients were harmed. Immediate jeopardy categories included the following: surgical (34.2%), medication (18.9%), monitoring (14.2%), falls (7.8%), equipment (5.4%), procedural (5.4%), resuscitation (4.4%), suicide (3.9%), MD/RN miscommunication (3.4%), and abuse (2.3%). CONCLUSIONS: Noncompliance to hospital licensure causes significant morbidity and mortality. Statewide hospital licensure policies should focus on enacting standardized reporting requirements of immediate jeopardies into an Internet-based form that public health officials can regularly analyze to improve hospital safety.

Association of Bicycle-Related Genital Numbness and Female Sexual Dysfunction: Results From a Large, Multinational, Cross-Sectional Study.

INTRODUCTION: Cycling can lead to microtrauma due to increased perineal pressure, possibly contributing to genital numbness and sexual dysfunction in female cyclists. AIM: We aim to explore the associations between cycling characteristics, female genital numbness, and female sexual dysfunction. METHODS: We conducted a cross-sectional study on female cyclists and sexual wellness. Participants were recruited through Facebook® advertisements and online outreach at athletic clubs. Participants were asked about their cycling characteristics, genital numbness, and female sexual function using the Female Sexual Function Index (FSFI). Univariate and multivariable linear and logistic regression were used to assess risk factors for genital numbness and the association between genital numbness and the FSFI. OUTCOME MEASURES: The outcome measures were cycling characteristics, questions regarding numbness (intensity, duration, location), and the FSFI score. RESULTS: Eight-hundred and seventy-five women were included in the study. Total lifetime miles cycled, biking duration, frequency, distance, speed, and biking surface were not significantly associated with genital numbness. Higher handlebar height was associated with less numbness. The prevalence of sexual dysfunction in the cohort was 52%. Genital numbness was significantly associated with sexual dysfunction (OR: 1.43, 95% CI: 1.05 - 1.95). Sub-group analysis for location of numbness demonstrated significant increase in risk for sexual dysfunction in cyclists who described numbness aro`und the perineum (OR: 2.72, 95% CI: 1.05 - 7.02) and the vulva (OR: 1.55, 95% CI: 1.13 - 2.13). There was also a significant increase in the risk of sexual dysfunction in cyclists who reported a longer duration of numbness (OR: 6.58, 95% CI: 2.27 - 19.07). CONCLUSIONS: Genital numbness is common in women who cycle and is associated with increased risk of FSD and lower average sexual response scores on FSFI. Lui H, Mmonu N, Awad MA, et al. Association of Bicycle-Related Genital Numbness and Female Sexual Dysfunction: Results From a Large, Multinational, Cross-Sectional Study. Sex Med 2021;9:100365.

Rates of Serious Surgical Errors in California and Plans to Prevent Recurrence.

Importance: Despite widespread recognition and known harms, serious surgical errors, known as surgical never events, endure. The California Department of Public Health (CDPH) has developed an oversight system to capture never events and a platform for process improvement that has not yet been critically appraised. Objectives: To examine surgical never events occurring in hospitals in California and summarize recommendations to prevent future events. Design, Setting, and Participants: This cross-sectional study identified 386 CDPH hospital administrative penalty reports, of which 142 were ascribable to never events occurring during surgery. These never events were identified and summarized from January 1, 2007, to December 31, 2017. A directed qualitative approach was used to analyze CDPH-mandated corrective steps to reduce future errors in this multicenter study of all accredited hospitals in California. Inclusion of surgical never event records was based on definitions established by the US Department of Health and Human Services National Quality Forum. Data analysis was performed from January 1, 2019, to November 30, 2020. Exposures: Never events include death or disability of an American Society of Anesthesiologists class I patient, wrong site or wrong surgery, retained foreign objects, burns, equipment failure leading to intraoperative injury, nonapproved experimental procedures, insufficient surgeon presence or privileges, or fall from the operating room table. Main Outcomes and Measures: Incident rates, consequences, and improvement plans to prevent additional never events were outcomes of interest. Results: A total of 142 never events were reported to the CDPH (1 per 200 000 operations). Annual surgical volume for hospitals with events was 9203 vs 3251 cases for hospitals without events (P < .001). A total of 94 of 142 events (66.2%) were retained foreign objects ranging from Kocher clamps to drain sponges. Wrong site or patient surgery accounted for 22 events (15.5%), surgical burns for 11 (7.7%), and other for 15 (10.6%). Other included insufficient surgeon presence, equipment failure, or falls in the operating room. Improvement plans included 18 unique categories of recommendations from regulators, many focusing on proper use of checklists. Regulators mandated a mean (SD) of 13 (7) corrective actions in the improvement plans. Policy adherence monitoring (119 [90.2%]), revision of existing policy (84 [63.6%]), and education regarding policy (83 [62.9%]) were common action items, whereas disciplinary action toward staff was rare (11 [8.3%]). Conclusions and Relevance: Surgical never events are a rare issue in California. Numerous strategies have evolved to reduce errors, many involving the thorough and proper use of intraoperative checklists.

Design and development of referrals automation, a SMART on FHIR solution to improve patient access to specialty care.

BACKGROUND: Referring patients to specialty care is an inefficient and error-prone process. Gaps in the referral process lead to delays in patients' access to care, negative patient experience, worse health outcomes, and increased operational costs. While implementation of standards-based electronic referral options can alleviate some of these inefficiencies, many referrals to tertiary and quaternary care centers continue to be sent via fax. OBJECTIVE: We describe the design process and architecture for a software application that has been developed and deployed to optimize the referrals intake process by automating the processing and digitization of incoming specialty referral faxes, extracting key data elements and integrating them into the electronic health record (EHR), and organizing referrals. METHODS: A human-centered design approach was used to identify and describe the inefficiencies in the external referral process at our large, urban tertiary care center. Referrals Automation, an application to convert referral faxes to digital referrals in the EHR, was conceptualized based on key stakeholder interviews and time and motion studies. This application was designed using Substitutable Medical Applications and Reusable Technologies (SMART) and Fast Healthcare Interoperability Resource (FHIR) platforms to allow for adaptability into other healthcare organizations. RESULTS: Referrals Automation software was developed as a healthcare information technology solution to streamline the fax to referral process. The application was implemented into several specialty clinics. Metrics were built-in to the applications to evaluate and guide the further iteration of these features. CONCLUSIONS: Referrals Automation will enhance the referrals process by further streamlining and organizing the patient referral process.

Use of GoFundMe® to crowdfund complementary and alternative medicine treatments for cancer.

PURPOSE: Complementary and alternative medicine (CAM) use is common amongst cancer patients. However, there is growing concern about its safety and efficacy. Online crowdfunding campaigns represent a unique avenue to understand the cancer patient's perspective for using CAM or declining conventional cancer therapy (CCT). METHODS: Five hundred GoFundMe campaigns from 2012 to 2019 detailing financial need for cancer treatment were randomly selected and reviewed for endorsement of CAM use, reasons for using CAM, and reasons for declining CCT. Descriptive statistics were used to compare patient and campaign characteristics between 250 CAM users and 250 non-CAM users. RESULTS: Compared to non-CAM users, CAM users were more likely to be female (70% vs. 54%, p < 0.01), to report more stage IV cancer (54% vs. 12%, p < 0.01), and to have a history of delayed, missed, or misdiagnosis (10% vs. 4%, p < 0.01). Reasons for using CAM include endorsing curative/therapeutic effects 212 (85%), pain/stress reduction 137 (55%), and dissatisfaction with current or past medical treatment options 105 (42%). 87 (35%) CAM users that declined CCT reported that they wanted to try to fight off cancer using CAM first 57 (61%), that CCT was too "toxic" to the body 39 (42%), and cancer was already too advanced, so that CCT would be futile or too aggressive 25 (27%). CONCLUSION: Cancer patients on GoFundMe using CAM highly value quality of life, comfort, and autonomy. Physicians should educate themselves on CAM to set realistic expectations and provide comprehensive counseling of the risks and benefits of CAM usage to patients who choose to use CAM to either augment or completely replace CCT.

ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects.

Autosomal dominant mutations of the RNA/DNA binding protein FUS are linked to familial amyotrophic lateral sclerosis (FALS); however, it is not clear how FUS mutations cause neurodegeneration. Using transgenic mice expressing a common FALS-associated FUS mutation (FUS-R521C mice), we found that mutant FUS proteins formed a stable complex with WT FUS proteins and interfered with the normal interactions between FUS and histone deacetylase 1 (HDAC1). Consequently, FUS-R521C mice exhibited evidence of DNA damage as well as profound dendritic and synaptic phenotypes in brain and spinal cord. To provide insights into these defects, we screened neural genes for nucleotide oxidation and identified brain-derived neurotrophic factor (Bdnf) as a target of FUS-R521C-associated DNA damage and RNA splicing defects in mice. Compared with WT FUS, mutant FUS-R521C proteins formed a more stable complex with Bdnf RNA in electrophoretic mobility shift assays. Stabilization of the FUS/Bdnf RNA complex contributed to Bdnf splicing defects and impaired BDNF signaling through receptor TrkB. Exogenous BDNF only partially restored dendrite phenotype in FUS-R521C neurons, suggesting that BDNF-independent mechanisms may contribute to the defects in these neurons. Indeed, RNA-seq analyses of FUS-R521C spinal cords revealed additional transcription and splicing defects in genes that regulate dendritic growth and synaptic functions. Together, our results provide insight into how gain-of-function FUS mutations affect critical neuronal functions.