Total Copper and Labile Bound Copper Fraction as a Selective and Sensitive Tool in the Evaluation of Wilson Disease.

BACKGROUND: A dual filtration-based method for determination of serum labile bound copper (LBC) and LBC fraction (LBC/total copper) was developed. Reduced total copper, elevated LBC, and elevated LBC fraction have been reported in Wilson disease (WD). METHODS: To evaluate the diagnostic performance of these markers, samples were obtained from 21 WD treatment-naïve (WD-TN, no WD treatment or <28 days of treatment) patients, 46 WD standard-of-care-treated (WD-SOC) patients, along with 246 patients representing other potential disorders of copper status. These were then compared to 213 reference interval population patients. RESULTS: Receiver operating characteristic curves for the reference population vs WD-TN yielded areas under the curve for total copper, LBC, and LBC fraction, of 0.99, 0.81, and 0.98, respectively. Using Youden cutoffs, sensitivity/specificity for WD-TN was 95%/97% for total copper, 71%/85% for LBC, and 95%/94% for LBC fraction. LBC values, but not total copper and LBC fraction, differed substantially between WD-TN and WD-SOC cohorts.We propose a dual model wherein total copper and LBC fraction results must agree to be classified as a "positive" or "negative" result for WD. This correctly classified 19/21 WD-TN patients as positive, and 194/213 reference interval patients as negative. The remaining "indeterminate" patients (representing approximately 9% of the reference and the WD-TN populations) exhibited conflicting total copper and LBC fraction results. When indeterminate results are excluded, this model exhibited apparent 100% sensitivity/specificity. CONCLUSIONS: Agreement of total serum copper and LBC fraction classification may constitute an effective "rule-in" and "rule-out" assessment for WD-TN patients.

Exploring Differences in Four Types of Online Activities Across Individuals with and without Problematic Smartphone Use.

Studies on problematic online activities commonly focus on one type of online activity, such as social media. However, individuals often use their Smartphones for more than one online activity. This study examined four types of online activities (social networking, gaming, information acquisition, and short-form video viewing). Based on a combinatory assessment of problematic smartphone use and hours spent online, two groups were created from a larger sample (N = 642): a problematic smartphone user group (PSU; N = 230; F = 72%; Age = 24.99 ± 6.60) and a non-problematic smart phone user group (NPSU; N = 87; F = 62%; Age = 30.49 ± 10.22). As compared to the NPSU group, the PSU group engaged in more social networking, gaming, information acquisition, and short-form video seeing. The PSU group also scored higher on psychological distress, sleep disturbance, fear of missing out, metacognitions about Smartphone use (MSU), desire thinking (DT), and lower on satisfaction with life and cognitive reappraisal. Regression analyses were employed to probe correlates of each online activity among the PSU and NPSU groups. The findings are discussed in light of the metacognitive model of addictive behaviors and future directions are provided concerning the challenges of distinguishing individuals for problematic Internet-related behaviors.

Patient-Reported Outcome Measures Show No Relevant Change Between 1-year and 2-year Follow-Up Following Treatment for Anterior Shoulder Instability: a Systematic Review.

PURPOSE: The primary aim of this study was to compare patient-reported outcome measures (PROMs) at 1-year and 2-year follow-up following treatment for anterior shoulder instability. METHODS: Randomized controlled trials and prospective studies that evaluated and reported PROMs following a capsulolabral repair (with or without remplissage), bone augmentation or non-operative treatment to treat anterior shoulder instability at both 1-year and 2-year follow-up were included. PROMs were compared between 1-year and 2-year follow-up, forest plots with mean difference were created to compare baseline, 1-year and 2-year follow-up and scatterplots were created to visualize clinical improvement over time. RESULTS: Fourteen studies, comprising 923 patients, with level of evidence I and II were included. Nine PROMs, of which predominantly the Western Ontario Shoulder Instability Index (WOSI; 11 studies; 79%), were evaluated. Minimal to no statistically significant change in WOSI, Oxford Shoulder Instability Score (OSIS), American Shoulder and Elbow Surgeons (ASES), Subjective Shoulder Value (SSV), Simple Shoulder Test (SST), Disabilities of Arm, Shoulder, and Hand (DASH), Quick DASH, Single Assessment Numeric Evaluation (SANE) or Visual Analogue Scale (VAS) was observed between 1-year and 2-year follow-up. Pooling of the WOSI, OSIS, ASES and SANE demonstrated improvement from baseline to 1-year follow-up and minimal to no change between 1-year and 2-year follow-up. Scatterplots of the WOSI and ASES demonstrated the most improvement within 6 months and no clear improvement after 1-year follow-up. Recurrence rates increased with time but varied between studies. CONCLUSION: In contrast to recurrence rates which have been shown to increase with time, minimal to no statistically significant change was observed for any of the included PROMs between 1-year and 2-year follow-up. This finding questions whether it is necessary to evaluate PROMs in long term follow-up of patients following shoulder stabilization treatment. LEVEL OF EVIDENCE: Level II, systematic review of Level I - II studies.

Association between Early Airway Intervention in the Pre-Hospital setting and Outcomes in Out of Hospital Cardiac Arrest Patients: a post-hoc analysis of the Target Temperature Management-2 (TTM2) trial.

INTRODUCTION: Airway management is a critical component of out-of-hospital cardiac arrest (OHCA) resuscitation. The primary aim of this study was to describe pre-hospital airway management in adult patients post-OHCA. Secondary aims were to investigate whether tracheal intubation (TI) versus use of supraglottic airway device (SGA) was associated with patients' outcomes, including ventilator-free days within 26 days of randomization, 6 months neurological outcome and mortality. METHODS: Secondary analysis of the Target Temperature Management-2 (TTM2) trial conducted in 13 countries, including adult patients with OHCA and return of spontaneous circulation, with data available on pre-hospital airway management. A multivariate logistic regression model with backward stepwise selection was employed to assess whether TI versus SGA was associated with outcomes. RESULTS: Of the 1900 TTM2 trial patients, 1702 patients (89.5%) were included, with a mean age of 64 years (Standard Deviation, SD=13.53); 79.1% were males. Pre-hospital airway management was SGA in 484 (28.4%), and TI in 1218 (71.6%) patients. At hospital admission, 87.8% of patients with SGA and 98.5% with TI were mechanically ventilated (p<0.001). In the multivariate analysis, TI in comparison with SGA was not independently associated with an increase in ventilator-free days within 26 days of randomization, improved neurological outcomes, or decreased mortality. The hazard ratio for mortality with TI vs. SGA was 1.06, 95%Confidence Interval (CI) 0.88-1.28, p=0.54. CONCLUSIONS: In the multicentre randomized TTM2-trial including patients with OHCA, most patients received prehospital endotracheal intubation to manage their airway. The choice of pre-hospital airway device was not independently associated with patient clinical outcomes. TRIAL REGISTRATION NUMBER: NCT02908308.

Assessing the suitability of a one-time sampling event for close-kin mark-recapture: A caribou case study.

Abundance estimation is frequently an objective of conservation and monitoring initiatives for threatened and other managed populations. While abundance estimation via capture-mark-recapture or spatially explicit capture-recapture is now common, such approaches are logistically challenging and expensive for species such as boreal caribou (Rangifer tarandus), which inhabit remote regions, are widely dispersed, and exist at low densities. Fortunately, the recently developed 'close-kin mark-recapture' (CKMR) framework, which uses the number of kin pairs obtained within a sample to generate an abundance estimate, eliminates the need for multiple sampling events. As a result, some caribou managers are interested in using this method to generate an abundance estimate from a single, non-invasive sampling event for caribou populations. We conducted a simulation study using realistic boreal caribou demographic rates and population sizes to assess how population size and the proportion of the population surveyed impact the accuracy and precision of single-survey CKMR-based abundance estimates. Our results indicated that abundance estimates were biased and highly imprecise when very small proportions of the population were sampled, regardless of the population size. However, the larger the population size, the smaller the required proportion of the population surveyed to generate both accurate and reasonably precise estimates. Additionally, we also present a case study in which we used the CKMR framework to generate annual female abundance estimates for a small caribou population in Jasper National Park, Alberta, Canada, from 2006 to 2015 and compared them to existing published capture-mark-recapture-based estimates. Both the accuracy and precision of the annual CKMR-based abundance estimates varied across years and were sensitive to the proportion of pairwise kinship comparisons which yielded a mother-offspring pair. Taken together, our study demonstrates that it is possible to generate CKMR-based abundance estimates from a single sampling event for small caribou populations, so long as a sufficient sampling intensity can be achieved.

Assessing ecological responses of exposure to the pyrethroid insecticide lambda-cyhalothrin in sub-tropical freshwater ecosystems.

Pyrethroid insecticides are widely detected in aquatic ecosystems due to their extensive use in agriculture and horticulture, which could pose a potential risk to aquatic non-target organisms. While previous ecotoxicological studies have been conducted mainly with standard tests and local species under temperate conditions, scarce information is available on the effects of pyrethroid insecticides on communities and ecosystems under (sub-)tropical conditions. A single application of lambda-cyhalothrin at concentrations of 0, 9, 30, and 100 ng/L was evaluated in outdoor mesocosms under sub-tropical conditions. Lambda-cyhalothrin was found to dissipate rapidly in the water column, with only 11 % and 7 % of the remaining dose measured at 1 and 3 days after application, respectively. Lambda-cyhalothrin concentrations disappeared considerably faster from the water compartment compared to temperate conditions. Consistent decreases in abundance were observed for Lecane lunaris at the medium and higher treatments (NOEC = 9 ng/L) and at the highest treatment (NOEC = 30 ng/L) for Keratella tropica. On the contrary, two taxa belonging to Cladocera (i.e., Ceriodaphnia sp. and Diaphanosoma sp.) showed the most prominent increase in abundance related to the lambda-cyhalothrin treatments. At the community level, a consistent no observed effect concentrations (NOECs) of 9 ng/L could be calculated for the zooplankton community. A marginal significant overall treatment related effect was observed for the macroinvertebrate community. The results of species sensitivity distribution (SSD) analysis based on results of acute toxicity experiments conducted alongside the mesocosm experiment and obtained from the literature indicated that macroinvertebrates from temperate regions may be generally more sensitive than their counterparts in (sub-)tropical regions. Overall, these findings suggest that environmentally relevant concentrations of the pyrethroid insecticide lambda-cyhalothrin may lead to different ecological outcomes in freshwater ecosystems in the (sub-)tropics relative to temperate regions.

Decreased dust particles amplify the cloud cooling effect by regulating cloud ice formation over the Tibetan Plateau.

Ice-nucleating particles (INPs) can initiate cloud ice formation, influencing cloud radiative effects (CRE) and climate. However, the knowledge of INP sources, concentrations, and their impact on CRE over the Tibetan Plateau (TP)-a highly climate-sensitive region-remains largely hypothetical. Here, we integrated data from multisource satellite observations and snowpack samples collected from five glaciers to demonstrate that dust particles constitute primary INP sources over the TP. The springtime dust influxes lead to seasonally elevated ice concentrations in mixed-phase clouds. Furthermore, the decadal reduction in dustiness from 2007 to 2019 results in decreased springtime dust INPs, thereby amplifying the cooling effect of clouds over the TP, with a 1.98 ± 0.39-watt per square meter reduction in surface net CRE corresponding to a 0.01 decrease in dust optical depth. Our findings elucidate previously unidentified pathways of climate feedback from an atmospheric INP perspective, especially highlighting the crucial role of dust in aerosol-cloud interactions.

Unraveling the phenotypic states of human innate-like T cells: Comparative insights with conventional T cells and mouse models.

The "innate-like" T cell compartment, known as Tinn, represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity. We explore the transcriptional landscape of Tinn compared to conventional T cells (Tconv) in the human thymus and blood using single-cell RNA sequencing (scRNA-seq) and flow cytometry. In human blood, the majority of Tinn cells share an effector program driven by specific transcription factors, distinct from those governing Tconv cells. Conversely, only a fraction of thymic Tinn cells displays an effector phenotype, while others share transcriptional features with developing Tconv cells, indicating potential divergent developmental pathways. Unlike the mouse, human Tinn cells do not differentiate into multiple effector subsets but develop a mixed type 1/type 17 effector potential. Cross-species analysis uncovers species-specific distinctions, including the absence of type 2 Tinn cells in humans, which implies distinct immune regulatory mechanisms across species.

Calibrating acceleration transmitters to quantify the seasonal energetic costs of activity in lake trout.

Bioenergetics models are powerful tools used to address a range of questions in fish biology. However, these models are rarely informed by free-swimming activity data, introducing error. To quantify the costs of activity in free-swimming fish, calibrations produced from standardized laboratory trials can be applied to estimate energy expenditure from sensor data for specific tags and species. Using swim tunnel respirometry, we calibrated acceleration sensor-equipped transmitting tags to estimate the aerobic metabolic rates (MO2) of lake trout (Salvelinus namaycush) at three environmentally relevant temperatures. Aerobic and swim performance were also assessed. Like other calibrations, we found strong relationships between MO2 and acceleration or swimming speed, and jackknife validations and data simulations suggest that our models accurately predict metabolic costs of activity in adult lake trout (~5% algebraic error and ~20% absolute error). Aerobic and swim performance metrics were similar to those reported in other studies, but their critical swimming speed was lower than expected. Additionally, lake trout exhibited a wide aerobic scope, suggesting that the avoidance of waters ≥15°C may be related to selection for optimal growing temperatures. The ability to quantify the free-swimming energetic costs of activity will advance our understanding of lake trout ecology and may yield improvements to bioenergetics model.

The Groundswell Community Surf Therapy Intervention for At-Risk Women and Changes in Body Acceptance, Resilience, and Emotional Regulation.

Background: Surf therapy combines physical activity with social support to provide a healing environment. Objective: This exploratory pre-to post-intervention study examined the effects of a novel surf therapy program for women who experienced abuse, trauma, and/or mental illness on emotional regulation, resilience, body acceptance, and gratitude. Methods: Twenty-seven women (ages 25 to 54; mean 36.32 + SD 7.79) participated in an 8-week Groundswell Surf Therapy Program held in four different coastal cities in California. Standardized self-report questionnaires were administered prior to and following the therapy program, including the Body Acceptance Scale, the Connor-Davidson Resilience Scale (CD-RISC), the Affective Style Questionnaire, and the Gratitude Questionnaire-Six-Item Form (GQ-6) in a pre-post study design. Data were analyzed by repeated measures analysis of variance (ANOVA). Results: Body acceptance [P < 0.001; partial Eta squared = 0.472] and resilience were increased [P = 0.005; partial Eta squared = 0.319] following the surf therapy intervention. Emotional regulation was examined according to three subscales, with the adjust [P < 0.001; partial Eta squared = 0.397] and tolerate [P < 0.001; partial Eta squared = 0.299] subscales increasing following the intervention, and the conceal subscale [P = 0.459; partial Eta squared = 0.031] remaining unchanged. Gratitude scores were unchanged [P = 0.425; partial Eta squared = 0.026]. Conclusion: A surf therapy program rooted in somatic and trauma-informed models was associated with improved resilience, emotional regulation, and body acceptance in at-risk women.

Ohnut vs waitlist control for the self-management of endometriosis-associated deep dyspareunia: a pilot randomized controlled trial.

Background: Deep dyspareunia affects 50% of people with endometriosis. The Ohnut is a set of interlocking rings that fit over the penis/insertive object. One or more rings can be used to limit insertion depth and reduce deep dyspareunia. Aim: We conducted a pilot, parallel, open-label randomized controlled trial (RCT) to investigate the feasibility of the study design and the acceptability and preliminary efficacy of the Ohnut. Method: Participants were recruited from a tertiary center for endometriosis. Eligibility criteria were surgically confirmed endometriosis, age 19-49 years, monogamous sexual relationship with a partner willing to participate in the study, and no comorbid superficial dyspareunia, anxiety, or depression. Couples were randomized into an intervention group or a waitlist control group using a 1:1 allocation ratio. All couples had sex as normal during weeks 1 to 4 (baseline period), and couples in the intervention group used the Ohnut with sex during weeks 5 to 10 (intervention period) while controls had sex as normal. Patient participants used daily diaries to record sexual activity and deep dyspareunia score (0-10) for the 10-week study. Intervention group participants completed an acceptability questionnaire at the end of the study. Outcomes: The primary outcomes were feasibility of the study and acceptability of the Ohnut. We also assessed differences in deep dyspareunia scores in the participants who used the Ohnut compared to the control participants who did not. Results: We recruited approximately 5 couples per month of active recruitment. Of 864 potentially eligible participants, we successfully contacted 44.7% (n = 386), of whom 8.0% (n = 31) consented, 64.8% (n = 250) were ineligible, and 27.2% (n = 105) declined. Thirty-one couples were randomly assigned to the intervention or control group, and 17 couples completed the study. Intervention group couples used the Ohnut for an average of 72.4% (32.7%) of sexual encounters during the intervention period. The mean acceptability index score for the Ohnut was 0.83 (0.078) among patients and 0.83 (0.049) among partners (index between 0 and 1). After controlling for baseline deep dyspareunia, there was a significant difference in the intervention period mean deep dyspareunia scores between the control and intervention group (4.69 (2.44) vs 2.46 (1.82), P = .012). Clinical Implications: We identified preliminary evidence for the acceptability and efficacy of the Ohnut among both patients and partners, suggesting that the Ohnut may be a useful stand-alone or adjuvant management tool for endometriosis-associated deep dyspareunia. Strengths and Limitations: Strengths of this study were the "real-world" use of the Ohnut and data collection from both patients and partners. Limitations of the study design included the strict eligibility criteria that affected feasibility and generalizability. Conclusion: This pilot RCT indicated that the Ohnut may be an acceptable and effective intervention to reduce endometriosis-associated deep dyspareunia. We identified opportunities to improve design for a larger RCT. Clinical Trial Registration: This clinical trial was registered with clinicaltrials.gov (#NCT04370444).

Case Report: A rare presentation of rapidly progressive moyamoya disease refractory to unilateral surgical revascularization.

Moyamoya disease (MMD) is a chronic, occlusive cerebrovasculopathy typified by progressive steno-occlusive disease of the intracranial internal carotid arteries (ICAs) and their proximal branches. Moyamoya syndrome (MMS) categorizes patients with characteristic MMD plus associated conditions. As such, the most usual presentations are those that occur with cerebral ischemia, specifically transient ischemic attack, acute ischemic stroke, and seizures. Hemorrhagic stroke, headaches, and migraines can also occur secondary to the compensatory growth of fragile collateral vessels propagated by chronic cerebral ischemia. While the pathophysiology of MMD is unknown, there remain numerous clinical associations including radiation therapy to the brain, inherited genetic syndromes, hematologic disorders, and autoimmune conditions. We describe the case of a 31-year-old woman who presented with recurrent ischemic cerebral infarcts secondary to rapidly progressive, bilateral MMD despite undergoing early unilateral surgical revascularization with direct arterial bypass. She had numerous metabolic conditions and rapidly decompensated, ultimately passing away despite intensive and aggressive interventions. The present case highlights that progression of moyamoya disease to bilateral involvement can occur very rapidly, within a mere 6 weeks, a phenomenon which has not been documented in the literature to our knowledge.

Follicular DNA Damage and Pesticide Exposure Among Latinx Children in Rural and Urban Communities.

The intersectional risks of children in United States immigrant communities include environmental exposures. Pesticide exposures and their biological outcomes are not well characterized in this population group. We assessed pesticide exposure and related these exposures to DNA double-strand breaks (DSBs) in Latinx children from rural, farmworker families (FW; N = 30) and from urban, non-farmworker families (NFW; N = 15) living in North Carolina. DSBs were quantified in hair follicular cells by immunostaining of 53BP1, and exposure to 72 pesticides and pesticide degradation products were determined using silicone wristbands. Cholinesterase activity was measured in blood samples. DSB frequencies were higher in FW compared to NFW children. Seasonal effects were detected in the FW group, with highest DNA damage levels in April-June and lowest levels in October-November. Acetylcholinesterase depression had the same seasonality and correlated with follicular DNA damage. Organophosphate pesticides were more frequently detected in FW than in NFW children. Participants with organophosphate detections had increased follicular DNA damage compared to participants without organophosphate detection. Follicular DNA damage did not correlate with organochlorine or pyrethroid detections and was not associated with the total number of pesticides detected in the wristbands. These results point to rural disparities in pesticide exposures and their outcomes in children from vulnerable immigrant communities. They suggest that among the different classes of pesticides, organophosphates have the strongest genotoxic effects. Assessing pesticide exposures and their consequences at the individual level is key to environmental surveillance programs. To this end, the minimally invasive combined approach used here is particularly well suited for children. Supplementary Information: The online version contains supplementary material available at 10.1007/s12403-023-00609-1.

Efficient generation of human NOTCH ligand-expressing haemogenic endothelial cells as infrastructure for in vitro haematopoiesis and lymphopoiesis.

Arterial endothelial cells (AECs) are the founder cells for intraembryonic haematopoiesis. Here, we report a method for the efficient generation of human haemogenic DLL4+ AECs from pluripotent stem cells (PSC). Time-series single-cell RNA-sequencing reveals the dynamic evolution of haematopoiesis and lymphopoiesis, generating cell types with counterparts present in early human embryos, including stages marked by the pre-haematopoietic stem cell genes MECOM/EVI1, MLLT3 and SPINK2. DLL4+ AECs robustly support lymphoid differentiation, without the requirement for exogenous NOTCH ligands. Using this system, we find IL7 acts as a morphogenic factor determining the fate choice between the T and innate lymphoid lineages and also plays a role in regulating the relative expression level of RAG1. Moreover, we document a developmental pathway by which human RAG1+ lymphoid precursors give rise to the natural killer cell lineage. Our study describes an efficient method for producing lymphoid progenitors, providing insights into their endothelial and haematopoietic ontogeny, and establishing a platform to investigate the development of the human blood system.

Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.

Repeat expansions in FGF14 cause autosomal dominant late-onset cerebellar ataxia (SCA27B) with estimated pathogenic thresholds of 250 (incomplete penetrance) and 300 AAG repeats (full penetrance), but the sequence of pathogenic and non-pathogenic expansions remains unexplored. Here, we demonstrate that STRling and ExpansionHunter accurately detect FGF14 expansions from short-read genome data using outlier approaches. By combining long-range PCR and nanopore sequencing in 169 patients with cerebellar ataxia and 802 controls, we compare FGF14 expansion alleles, including interruptions and flanking regions. Uninterrupted AAG expansions are significantly enriched in patients with ataxia from a lower threshold (180-200 repeats) than previously reported based on expansion size alone. Conversely, AAGGAG hexameric expansions are equally frequent in patients and controls. Distinct 5' flanking regions, interruptions and pre-repeat sequences correlate with repeat size. Furthermore, pure AAG (pathogenic) and AAGGAG (non-pathogenic) repeats form different secondary structures. Regardless of expansion size, SCA27B is a recognizable clinical entity characterized by frequent episodic ataxia and downbeat nystagmus, similar to the presentation observed in a family with a previously unreported nonsense variant (SCA27A). Overall, this study suggests that SCA27B is a major overlooked cause of adult-onset ataxia, accounting for 23-31% of unsolved patients. We strongly recommend re-evaluating pathogenic thresholds and integrating expansion sequencing into the molecular diagnostic process.

Discovery and Optimization of N-Heteroaryl Indazole LRRK2 Inhibitors.

Inhibition of leucine-rich repeat kinase 2 is a genetically supported mechanism for the treatment of Parkinson's disease. We previously disclosed the discovery of an indazole series lead that demonstrated both safety and translational risks. The safety risks were hypothesized to be of unknown origin, so structural diversity in subsequent chemical matter was prioritized. The translational risks were identified due to a low brain Kpu,u in nonhuman primate studies, which raised concern over the use of an established peripheral biomarker as a surrogate for central target engagement. Given these challenges, the team sought to leverage structure- and property-based drug design and expanded efflux transporter profiling to identify structurally distinct leads with enhanced CNS drug-likeness. Herein, we describe the discovery of a "reinvented" indazole series with improved physicochemical properties and efflux transporter profiles while maintaining excellent potency and off-target kinase selectivity, which resulted in advanced lead, compound 23.

Common comorbidity indices fail to predict short-term postoperative outcomes following male urethroplasty.

PURPOSE: To evaluate whether commonly used comorbidity indices [Charlson Comorbidity Index (CCI), Van Walraven Index (VWI), and modified frailty index (mFI)] predict postoperative readmissions and complications after urethroplasty. METHODS: Patients undergoing urethroplasty for urethral stricture from the State Inpatient Database and State Ambulatory Surgery and Services Database for Florida (2010-2015) and California (2010-2011) were identified. We calculated CCI, VWI, and mFI scores for each patient. We extracted the following adverse outcomes: 30 day ER services, 30 day inpatient readmissions, and 90 day Clavien-Dindo III-V complications. We constructed receiver operating characteristic (ROC) curves and compared area under the curve (AUC), using the VWI as the reference index. RESULTS: We identified 908 urethroplasty patients. Among these patients, 11.5% (n = 104) of patients had a complication, with 4.8% (n = 44) specifically having 30-day ER services, 6.2% (n = 56) having 30 day readmissions, and 9.0% (n = 82) having 90-day Clavien-Dindo III-V complications. ROC curves demonstrated poor predictive performances for all four indices as no index achieved an AUC > 0.70. The indices performed similarly poorly but the mFI-DX was particularly poor at predicting 90 day Clavien-Dindo III-V complications (AUC = 0.49; 95% CI 0.43-0.55; p < 0.01). CONCLUSIONS: The CCI, VWI, and mFI have poor ability to identify patients who had an adverse event after urethroplasty. Our results support the need for a urology-specific comorbidity index to better identify at-risk patients undergoing urethroplasty.

Conserved signaling modules regulate filamentous growth in fungi: a model for eukaryotic cell differentiation.

Eukaryotic organisms are composed of different cell types with defined shapes and functions. Specific cell types are produced by the process of cell differentiation, which is regulated by signal transduction pathways. Signaling pathways regulate cell differentiation by sensing cues and controlling the expression of target genes whose products generate cell types with specific attributes. In studying how cells differentiate, fungi have proved valuable models because of their ease of genetic manipulation and striking cell morphologies. Many fungal species undergo filamentous growth-a specialized growth pattern where cells produce elongated tube-like projections. Filamentous growth promotes expansion into new environments, including invasion into plant and animal hosts by fungal pathogens. The same signaling pathways that regulate filamentous growth in fungi also control cell differentiation throughout eukaryotes and include highly conserved mitogen-activated protein kinase (MAPK) pathways, which is the focus of this review. In many fungal species, mucin-type sensors regulate MAPK pathways to control filamentous growth in response to diverse stimuli. Once activated, MAPK pathways reorganize cell polarity, induce changes in cell adhesion, and promote the secretion of degradative enzymes that mediate access to new environments. However, MAPK pathway regulation is complicated because related pathways can share components with each other yet induce unique responses (i.e. signal specificity). In addition, MAPK pathways function in highly integrated networks with other regulatory pathways (i.e. signal integration). Here, we discuss signal specificity and integration in several yeast models (mainly Saccharomyces cerevisiae and Candida albicans) by focusing on the filamentation MAPK pathway. Because of the strong evolutionary ties between species, a deeper understanding of the regulation of filamentous growth in established models and increasingly diverse fungal species can reveal fundamentally new mechanisms underlying eukaryotic cell differentiation.