Higher-order SPOP assembly reveals a basis for cancer mutant dysregulation.

The speckle-type POZ protein (SPOP) functions in the Cullin3-RING ubiquitin ligase (CRL3) as a receptor for the recognition of substrates involved in cell growth, survival, and signaling. SPOP mutations have been attributed to the development of many types of cancers, including prostate and endometrial cancers. Prostate cancer mutations localize in the substrate-binding site of the substrate recognition (MATH) domain and reduce or prevent binding. However, most endometrial cancer mutations are dispersed in seemingly inconspicuous solvent-exposed regions of SPOP, offering no clear basis for their cancer-causing and peculiar gain-of-function properties. Herein, we present the first structure of SPOP in its oligomeric form, uncovering several new interfaces important for SPOP self-assembly and normal function. Given that many previously unaccounted-for cancer mutations are localized in these newly identified interfaces, we uncover molecular mechanisms underlying dysregulation of SPOP function, with effects ranging from gross structural changes to enhanced self-association, and heightened stability and activity.

Multi-Institutional Outcomes of Dorsal Onlay Buccal Mucosal Graft Urethroplasty in Patients With Postprostatectomy, Postradiation Anastomotic Stenosis.

PURPOSE: The treatment of urethral stenosis after a combination of prostatectomy and radiation therapy for prostate cancer is understudied. We evaluate the clinical and patient-related outcomes after dorsal onlay buccal mucosal graft urethroplasty (D-BMGU) in men who underwent prostatectomy and radiation therapy. MATERIALS AND METHODS: A multi-institutional, retrospective review of men with vesicourethral anastomotic stenosis or bulbomembranous urethral stricture disease after radical prostatectomy and radiation therapy from 8 institutions between 2013 to 2021 was performed. The primary outcomes were stenosis recurrence and development of de novo stress urinary incontinence. Secondary outcomes were surgical complications, changes in voiding, and patient-reported satisfaction. RESULTS: Forty-five men were treated with D-BMGU for stenosis following prostatectomy and radiation. There was a total of 7 recurrences. Median follow-up in patients without recurrence was 21 months (IQR 12-24). There were no incidents of de novo incontinence, 28 patients were incontinent pre- and postoperatively, and of the 6 patients managed with suprapubic catheter preoperatively, 4 were continent after repair. Following repair, men had significant improvement in postvoid residual, uroflow, International Prostate Symptom Score, and International Prostate Symptom Score quality-of-life domain. Overall satisfaction was +2 or better in 86.6% of men on the Global Response Assessment. CONCLUSIONS: D-BMGU is a safe, feasible, and effective technique in patients with urethral stenosis after a combination of prostatectomy and radiation therapy. Although our findings suggest this technique may result in lower rates of de novo urinary incontinence compared to conventional urethral transection and excision techniques, head-to-head comparisons are needed.

Estimating the potential public health impact of fibre enrichment: a UK modelling study.

For improving human health, reformulation can be a tool as it allows individuals to consume products of choice while reducing intake of less desirable nutrients, such as sugars and fats, and potentially increasing intake of beneficial nutrients such as fibre. The potential effects of reformulating foods with increased fibre on diet and health need to be better understood. The objective of this statistical modelling study was to understand how fibre enrichment can affect the diet and health of consumers. The UK National Diet and Nutrition Survey datasets from 2014 to 2015 and 2015 to 2016 were utilised to evaluate intakes of fibre and kilocalories with a dietary intake model. Foods and beverages eligible for fibre enrichment were identified (n 915) based on EU legislation for fibre content claims. Those people who meet dietary reference values and fibre enrichment health outcomes such as weight, CVD and type 2 diabetes risk reductions were quantified pre- and post-fibre reformulation via Reynolds et al., D'Agostino et al. and QDiabetes algorithms, respectively. The fibre enrichment intervention showed a mean fibre intake of 19·9 g/d in the UK, signifying a 2·2 g/d increase from baseline. Modelling suggested that 5·9 % of subjects could achieve a weight reduction, 72·2 % a reduction in cardiovascular risk and 71·7 % a reduced risk of type 2 diabetes with fibre fortification (all Ps ≤ 0·05). This study gives a good overview of the potential public health benefits of reformulating food products using a straightforward enrichment scenario.

Characterizing the Effects of Explosive Ordnance Disposal Operations on the Human Body While Wearing Heavy Personal Protective Equipment.

OBJECTIVE: To provide a comprehensive characterization of explosive ordnance disposal (EOD) personal protective equipment (PPE) by evaluating its effects on the human body, specifically the poses, tasks, and conditions under which EOD operations are performed. BACKGROUND: EOD PPE is designed to protect technicians from a blast. The required features of protection make EOD PPE heavy, bulky, poorly ventilated, and difficult to maneuver in. It is not clear how the EOD PPE wearer physiologically adapts to maintain physical and cognitive performance during EOD operations. METHOD: Fourteen participants performed EOD operations including mobility and inspection tasks with and without EOD PPE. Physiological measurement and kinematic data recording were used to record human physiological responses and performance. RESULTS: All physiological measures were significantly higher during the mobility and the inspection tasks when EOD PPE was worn. Participants spent significantly more time to complete the mobility tasks, whereas mixed results were found in the inspection tasks. Higher back muscle activations were seen in participants who performed object manipulation while wearing EOD PPE. CONCLUSION: EOD operations while wearing EOD PPE pose significant physical stress on the human body. The wearer's mobility is impacted by EOD PPE, resulting in decreased speed and higher muscle activations. APPLICATION: The testing and evaluation methodology in this study can be used to benchmark future EOD PPE designs. Identifying hazards posed by EOD PPE lays the groundwork for developing mitigation plans, such as exoskeletons, to reduce physical and cognitive stress caused by EOD PPE on the wearers without compromising their operational performance.

A multi-institutional critical assessment of dorsal onlay urethroplasty for post-radiation urethral stenosis.

PURPOSE: To critically evaluate a multi-institutional patient cohort undergoing Dorsal-Onlay Buccal Mucosal Graft Urethroplasty (D-BMGU) for recurrent post-radiation posterior urethral stenosis. METHODS: Retrospective multi-institutional review of patients with posterior urethral stenosis from 10 institutions between 2010-2019 was performed. Patients with at least 1-year follow-up were assessed. Patient demographics, stenosis characteristics, peri-operative outcomes, and post-operative clinical and patient-reported outcomes were analyzed. The primary outcomes were stenosis recurrence and de-novo stress urinary incontinence (SUI). Secondary outcomes were changes in voiding, sexual function, and patient-reported satisfaction. RESULTS: Seventy-nine men with post-radiation urethral stenosis treated with D-BMGU met inclusion criteria. Median age and stenosis length were 72 years, (IQR 66-75), and 3.0 cm (IQR 2.5-4 cm), respectively. Radiation modalities included: 36 (45.6%) external beam radiotherapy (EBRT), 13 (16.5%) brachytherapy (BT), 10 (12.7%) combination EBRT/BT, and 20 (25.3%) EBRT/radical prostatectomy. At a median follow-up of 21 months (IQR 13-40), 14 patients (17.7%) had stenosis recurrence. Among 37 preoperatively-continent patients, 3 men (8.1%) developed de-novo SUI following dorsal onlay urethroplasty. Of 29 patients with preoperative SUI all but one remained incontinent post-operatively (96.6%). Following repair, patients experienced significant improvement in PVR (92.5 to 26 cc, p = 0.001) and Uroflow (4.6 to 15.9 cc/s, p = 0.001), and high overall satisfaction, with 91.9% reporting a GRA of + 2 or better). CONCLUSION: Dorsal onlay buccal mucosa graft urethroplasty is a safe and feasible technique in patients with post-radiation posterior urethral stenosis. This non-transecting approach may confer low rates of de-novo SUI. Further research is needed to compare this technique with excisional urethroplasty.

Identification of catalytically distinct arylalkylamine N-acetyltransferase splicoforms from Tribolium castaneum.

The assumption that structural or sequential homology between enzymes implies functional homology is a common misconception. Through in-depth structural and kinetic analysis, we are now beginning to understand the minute differences in primary structure that can alter the function of an enzyme completely. Alternative splicing is one method for which the activity of an enzyme can be controlled, simply by altering its length. Arylalkylamine N-acetyltransferase A (AANATA) in D. melanogaster, which catalyzes the N-acetylation of biogenic amines, has multiple splicoforms - alternatively spliced enzyme isoforms - with differing tissue distribution. As demonstrated here, AANAT1 from Tribolium castaneum is another such enzyme with multiple splicoforms. A screening assay was developed and utilized to determine that, despite only a 35 amino acid truncation, the shortened form of TcAANAT1 is a more active form of the enzyme. This implies regulation of enzyme metabolic activity via alternative splicing.

Transurethral ventral buccal mucosa graft inlay for treatment of distal urethral strictures: international multi-institutional experience.

PURPOSE: To critically evaluate a multi-institutional patient cohort undergoing single-stage distal urethral repair using a novel transurethral buccal mucosa graft inlay urethroplasty technique (TBMGI). METHODS: A retrospective multi-institutional review of consecutive patients with fossa navicularis (FN) strictures treated with a single-stage TBMGI technique at 12 institutions from March 2014-March 2018 was performed. Patient demographics, stricture characteristics, clinical and patient-reported outcomes were analyzed. The primary outcomes were stricture recurrence and complications. Secondary outcomes were change in maximum urinary flow rate (Qmax), PVR, and changes in IPSS, SHIM and global response assessment (GRA) questionnaire responses. Descriptive statistical analysis was used for evaluation of outcomes. RESULTS: Sixty-eight men met inclusion criteria. Median age and stricture length were 60 years (IQR 48-69) and 2 cm (IQR 2-3), respectively. Most common stricture etiology was lichen sclerosus (34%). Median operative time and EBL were 72 min (IQR 50-120) and 20 mL (IQR 10-43), respectively. Fifty-seven men completed ≥ 12-month follow-up. At a median follow-up of 17 months (IQR 13-22), 54 patients (95%) remained stricture-free. Median Qmax improved from 5 to 18 mL/s (p < 0.0001), PVR 76-21 mL (p < 0.0001), and IPSS 15-5 (p < 0.0001); IPSS-QOL score: 5-1 (p < 0.0001). SHIM score did not significantly change following repair (median 22-21 p = 0.85). On GRA assessment, a majority of men reported "marked" (64%) or "moderate" (28%) overall improvement. No patient developed fistula, glanular dehiscence, graft necrosis or chordee. CONCLUSIONS: This novel minimally invasive transurethral urethroplasty technique is feasible and has demonstrated generalizable outcomes in a multi-institutional cohort with varying etiologies.

Bm-iAANAT3: Expression and characterization of a novel arylalkylamine N-acyltransferase from Bombyx mori.

The arylalkylamine N-acyltransferases (AANATs) are enzymes that catalyze the acyl-CoA-dependent formation of N-acylarylalkylamides: acyl-CoA + arylalkylamine → N-acylarylalkylamides + CoA-SH. Herein, we describe our study of a previously uncharacterized AANAT from Bombyx mori: Bm-iAANAT3. Bm-iAANAT3 catalyzes the direct formation of N-acylarylalkylamides and accepts a broad range of short-chain acyl-CoA thioesters and amines as substrates. Acyl-CoA thioesters possessing an acyl chain length >10 carbon atoms are not substrates for Bm-iAANAT3. We report that Bm-iAANAT3 is a "versatile generalist", most likely, functioning in amine acetylation - a reaction in amine inactivation/excretion, cuticle sclerotization, and melanism. We propose a kinetic and chemical mechanism for Bm-iAANAT3 that is consistent with our steady-state kinetic analysis, dead-end inhibition studies, determination of the pH-rate profiles, and site-directed mutagenesis of a catalytically important amino acid in Bm-iAANAT3. These mechanistic studies of Bm-iAANAT3 will foster the development of novel compounds targeted against this enzyme and other insect AANATs for the control of insect pests.

Disaster behavioral health: legal and ethical considerations in a rapidly changing field.

Disaster behavioral health is increasingly regarded as a central part of disaster preparedness, response and recovery. Legal and ethical issues have received relatively little attention and have sparked divergent opinions. Optimally, understanding and applying legal and ethical considerations requires an understanding of the evolution of the disaster behavioral health field and the context of disaster response and recovery. In addition, there are many legal and ethical questions identified for consideration, and many ways to approach reaching understanding and consensus. Traditionally, discussions of disaster behavioral health, including legal and ethical issues, have not included understanding decision making processes that occur in extreme circumstances. Models which interpret disaster response operations as complex adaptive systems are presented for consideration as useful tools for preparing mental health workers for effectively delivering services in acute disaster response environments.

Multiple vantage points on the mental health effects of mass shootings.

The phenomenon of mass shootings has emerged over the past 50 years. A high proportion of rampage shootings have occurred in the United States, and secondarily, in European nations with otherwise low firearm homicide rates; yet, paradoxically, shooting massacres are not prominent in the Latin American nations with the highest firearm homicide rates in the world. A review of the scientific literature from 2010 to early 2014 reveals that, at the individual level, mental health effects include psychological distress and clinically significant elevations in posttraumatic stress, depression, and anxiety symptoms in relation to the degree of physical exposure and social proximity to the shooting incident. Psychological repercussions extend to the surrounding affected community. In the aftermath of the deadliest mass shooting on record, Norway has been in the vanguard of intervention research focusing on rapid delivery of psychological support and services to survivors of the "Oslo Terror." Grounded on a detailed review of the clinical literature on the mental health effects of mass shootings, this paper also incorporates wide-ranging co-author expertise to delineate: 1) the patterning of mass shootings within the international context of firearm homicides, 2) the effects of shooting rampages on children and adolescents, 3) the psychological effects for wounded victims and the emergency healthcare personnel who care for them, 4) the disaster behavioral health considerations for preparedness and response, and 5) the media "framing" of mass shooting incidents in relation to the portrayal of mental health themes.

Towards near-term quantum simulation of materials.

Determining the ground and excited state properties of materials is considered one of the most promising applications of quantum computers. On near-term hardware, the limiting constraint on such simulations is the requisite circuit depths and qubit numbers, which currently lie well beyond near-term capabilities. Here we develop a quantum algorithm which reduces the estimated cost of material simulations. For example, we obtain a circuit depth improvement by up to 6 orders of magnitude for a Trotter layer of time-dynamics simulation in the transition-metal oxide SrVO3 compared with the best previous quantum algorithms. We achieve this by introducing a collection of connected techniques, including highly localised and physically compact representations of materials Hamiltonians in the Wannier basis, a hybrid fermion-to-qubit mapping, and an efficient circuit compiler. Combined together, these methods leverage locality of materials Hamiltonians and result in a design that generates quantum circuits with depth independent of the system's size. Although the requisite resources for the quantum simulation of materials are still beyond current hardware, our results show that realistic simulation of specific properties may be feasible without necessarily requiring fully scalable, fault-tolerant quantum computers, providing quantum algorithm design incorporates deeper understanding of the target materials and applications.

Modelling the public health benefits of fibre fortification in the Chinese population through food reformulation.

OBJECTIVES: Various studies have highlighted how consuming adequate dietary fibre (DF) foods could confer multiple potential health benefits to humans, though data suggested that the average intake of the population is below the recommendations. The aim of this study, which involved probabilistic, mathematical and statistical modelling, was to understand, for the first time, how fibre fortification in a broad array of food categories could impact the diet and health status of Chinese consumers. DESIGN: A simulation-based approach was used to examine the potential impact of fibre fortification. The China Health and Nutrition Survey dataset was used to evaluate intakes of DF together with a dietary intake mathematical model. Commercially manufactured foods and beverages eligible for fibre fortification were identified and a total of 296 food and beverages were selected for fibre fortification calculation. Foods and beverages eligible for fibre fortification and the concentration of fibre used at intervention were identified based on Chinese legislations and regulations of nutrition label claims. Populations who meet the dietary reference values of fibre fortification have their health outcomes such as weight, cardiovascular disease (CVD) and type 2 diabetes risk quantified prefibre and postfibre reformulation as per published studies. RESULTS: The simulated fibre fortification intervention model has shown that the mean DF intake increased by 13.28%, from 12.8 g/day of baseline to 14.5 g/day, leading to an increase of 48% (from 6.85% to 10.13%) and 54% (from 14.22% to 21.84%) of the adult and children population, respectively, achieving the recommended fibre guidelines. Additionally, 234 diabetes cases per day (85 340 cases per year) as well as 73 065 deaths secondary to CVD could also potentially be averted or delayed with the increase of DF intake via fibre fortification. CONCLUSIONS: This study provides a practical application implicating the potential public health benefits that could be achieved with food product reformulation.

Surgical management of lower urinary mesh perforation after mid-urethral polypropylene mesh sling: mesh excision, urinary tract reconstruction and concomitant pubovaginal sling with autologous rectus fascia.

INTRODUCTION AND HYPOTHESIS: We present our management of lower urinary tract (LUT) mesh perforation after mid-urethral polypropylene mesh sling using a novel combination of surgical techniques including total or near total mesh excision, urinary tract reconstruction, and concomitant pubovaginal sling with autologous rectus fascia in a single operation. METHODS: We retrospectively reviewed the medical records of 189 patients undergoing transvaginal removal of polypropylene mesh from the lower urinary tract or vagina. The focus of this study is 21 patients with LUT mesh perforation after mid-urethral polypropylene mesh sling. We excluded patients with LUT mesh perforation from prolapse kits (n = 4) or sutures (n = 11), or mesh that was removed because of isolated vaginal wall exposure without concomitant LUT perforation (n = 164). RESULTS: Twenty-one patients underwent surgical removal of mesh through a transvaginal approach or combined transvaginal/abdominal approaches. The location of the perforation was the urethra in 14 and the bladder in 7. The mean follow-up was 22 months. There were no major intraoperative complications. All patients had complete resolution of the mesh complication and the primary symptom. Of the patients with urethral perforation, continence was achieved in 10 out of 14 (71.5 %). Of the patients with bladder perforation, continence was achieved in all 7. CONCLUSIONS: Total or near total removal of lower urinary tract (LUT) mesh perforation after mid-urethral polypropylene mesh sling can completely resolve LUT mesh perforation in a single operation. A concomitant pubovaginal sling can be safely performed in efforts to treat existing SUI or avoid future surgery for SUI.

Secondary placement of adjustable continence therapy (ProACT™) using open perineal technique: Case report of ProACT placement in a man with a devastated urethra following pelvic trauma and multiple AUS erosions.

Adjustable continence therapy (ProACT) is an underutilized treatment option in men with stress urinary incontinence. The device is placed using a perineal percutaneous tunneled approach. We demonstrate a salvage technique for ProACT placement in a man with a devastated urethra following pelvic trauma and multiple artificial urinary sphincter (AUS) erosions who failed a tunneled approach. Our novel technique has utility in those at high risk for intra-operative trocar injury to the urinary tract with a tunneled approach. An open approach may also be a viable option in high-risk patients who have failed a conventional ProACT approach, male sling, or AUS.

Female urethroplasty with dorsal onlay buccal mucosal graft: a single institution experience.

PURPOSE: Female urethral stricture disease is frequently unrecognized or misdiagnosed, with controversy in the literature regarding the definition of strictures and approach to management. The purpose of this study is to report our institutional experience with female urethroplasty and add our experience to the growing body of research. METHODS: We performed a retrospective review of patients undergoing female urethroplasty with dorsal onlay BMG at the University of Colorado between March 2015 and December 2021 performed by two surgeons (BF and JO). The primary outcome measure was surgical success, defined as no stricture recurrence. The secondary outcome measure was the incidence of de novo urinary incontinence. RESULTS: 23 patients were included in our data analysis. The median duration of lower urinary tract symptoms prior to urethroplasty was 16 years. 87% had undergone previous dilations. At a median follow-up of 12.2 months (range 1-81 months), four patients required a secondary procedure for obstruction with an overall success rate of 83%. One patient developed de novo stress urinary incontinence and one patient developed urge urinary incontinence. Subgroup analysis was performed comparing the patients that developed stricture recurrence (N = 4) to those that did not (N = 19). Those with stricture recurrence had a longer duration of symptoms and more dilations prior to urethroplasty. CONCLUSION: Female urethroplasty with BMG is effective at treating female urethral stricture disease, with excellent outcomes at over a year of follow-up and minimal risk of stress incontinence postoperatively.

Weather factor impacts on commuting to work by bicycle.

OBJECTIVE: Quantify the impact of weather conditions on individual decisions to commute to work by bicycle among a diverse panel of adults who commute ≥2 miles each way. METHOD: Working adults (n=163) in a northern U.S. state reported transportation mode for four seven-day periods in 2009-2010 that maximized seasonal weather variations. Personal characteristics, trip to work distances, and commuting mode data were linked to location- and time-specific weather data and daylight hours. Analyses focused on effect of weather conditions on reports of commuting by bicycle. RESULTS: Participants were diverse in age, gender and bicycle use, but were relatively well-educated; they traveled to work by bicycle on 34.5% of the logged commuting days. Modeling indicated that the likelihood of bicycle commuting increased in the absence of rain (odds ratio=1.91; 95% confidence interval 1.42, 2.57) and with higher temperatures (1.03; 1.02, 1.04), and decreased with snow (0.90; 0.84, 0.98) and wind (0.95; 0.92, 0.97). Independent effects also were found for bicycle commuting distance, gender, and age, but not for daylight hours. CONCLUSION: Precipitation, temperature, wind and snow conditions had significant and substantial independent effects on the odds of travel to work by bicycle among a diverse panel of adult bicycle commuters.

Development and validation of the Italian version of the 15-item dispositional resilience scale.

Studies have shown that psychological hardiness is an important stress resilience resource for individuals. The 15-items Dispositional Resilience Scale (DRS-15) is a short, reliable and valid self-report instrument to measure hardiness that is not available in Italian. The present study was undertaken to create an Italian version of the DRS-15, and evaluate its psychometric properties and validity in the Italian context. An Italian version was produced using multiple independent bilingual translators. This version was administered to a non-clinical sample of adults (N=150), along with measure o psychological well-being (PWB-18) and health. A sub-sample (N = 66) completed the DRS-15 again one month later. Results showed good reliability in terms of internal consistency and test-retest stability. With regard to the subscale, stability was high for all three subscales, whereas two subscales (Commitment and Control) showed marginal internal consistency. DRS-15 total and subscales scores showed a theoretically meaningful pattern of correlations with PWB-18 subscales, supporting the validity of the Italian DRS. Also, multiple regression analysis revealed a correlation between DRS-15 scores and self-rated general health, even after controlling for age and sex. The new Italian DRS-15 provides a valid, reliable and easy to use tool fr assessing stress resilience in clinical and research settings.

Non-Transecting Urethroplasty for Bulbar Urethral Strictures-Narrative Review and Treatment Algorithm.

The bulbar urethra is the most common site of stricture disease for which urethroplasty remains standard of care. A decrease in trauma as an etiology in the developed world and concerns regarding sexual dysfunction related to transection of the corpus spongiosum have placed a renewed emphasis on non-transecting urethroplasty techniques. Here, we present our surgical algorithm with emphasis on non-transecting techniques for bulbar urethral stricture disease and review the current state of literature comparing transecting to non-transecting approaches in order to provide guidance to practitioners on patient selection, counseling, and technique.