Cofactor Selectivity in Methylmalonyl Coenzyme A Mutase, a Model Cobamide-Dependent Enzyme.

Cobamides, a uniquely diverse family of enzyme cofactors related to vitamin B12, are produced exclusively by bacteria and archaea but used in all domains of life. While it is widely accepted that cobamide-dependent organisms require specific cobamides for their metabolism, the biochemical mechanisms that make cobamides functionally distinct are largely unknown. Here, we examine the effects of cobamide structural variation on a model cobamide-dependent enzyme, methylmalonyl coenzyme A (CoA) mutase (MCM). The in vitro binding affinity of MCM for cobamides can be dramatically influenced by small changes in the structure of the lower ligand of the cobamide, and binding selectivity differs between bacterial orthologs of MCM. In contrast, variations in the lower ligand have minor effects on MCM catalysis. Bacterial growth assays demonstrate that cobamide requirements of MCM in vitro largely correlate with in vivo cobamide dependence. This result underscores the importance of enzyme selectivity in the cobamide-dependent physiology of bacteria.IMPORTANCE Cobamides, including vitamin B12, are enzyme cofactors used by organisms in all domains of life. Cobamides are structurally diverse, and microbial growth and metabolism vary based on cobamide structure. Understanding cobamide preference in microorganisms is important given that cobamides are widely used and appear to mediate microbial interactions in host-associated and aquatic environments. Until now, the biochemical basis for cobamide preferences was largely unknown. In this study, we analyzed the effects of the structural diversity of cobamides on a model cobamide-dependent enzyme, methylmalonyl-CoA mutase (MCM). We found that very small changes in cobamide structure could dramatically affect the binding affinity of cobamides to MCM. Strikingly, cobamide-dependent growth of a model bacterium, Sinorhizobium meliloti, largely correlated with the cofactor binding selectivity of S. meliloti MCM, emphasizing the importance of cobamide-dependent enzyme selectivity in bacterial growth and cobamide-mediated microbial interactions

How older men live with stress urinary incontinence: Patient experience and navigation to treatment

ObjectivesTo explore the context in which older men navigate treatment for stress urinary incontinence (SUI) following prostate surgery by characterizing lived experience of men with symptomatic SUI.Subjects/patients and methodsMixed method study using surveys and semistructured interviews to examine a cohort of men who underwent evaluation for treatment of postprostatectomy SUI.ResultsThirty-six men were interviewed after consultation for SUI and 31 had complete quantitative clinical data. Twenty-six underwent surgery and 10 chose no surgical intervention. In qualitative interviews, respondents experienced substantial decline in quality of life due to incontinence citing concerns associated with use of pads and worrying about incontinence. Most patients reported "workarounds"-efforts to mitigate or manage incontinence including Kegels, physical therapy, and garments. Participants also reported lifestyle changes including less strenuous physical activity, less sexual activity, and/or fewer social gatherings. Patients then described a "breaking point" where incontinence workarounds were no longer sufficient. After seeking evaluation, men described challenges in exploring treatment for SUI, including access to care and provider knowledge of treatment options.ConclusionIn a novel study of patients living with SUI a predictable lived experience was observed that culminated in a desire for change or "breaking point." In all men, this led to treatment-seeking behaviors and for many it led to SUI intervention. Despite effective treatments, patients continue to meet barriers gaining access to SUI evaluation and treatment

Recurrent Urinary Tract Infections are Associated With Frailty in Older Adults

ObjectiveTo understand the relationship between frailty, age, and recurrent urinary tract infections (rUTIs).Materials and methodsThe Timed Up and Go Test (TUGT), a measure of frailty, was administered to all adults aged ≥65 presenting to an academic nononcologic urology practice from December 2015 to January 2018. TUGT was categorized as fast (≤10 seconds), intermediate (11-14 seconds) or slow (≥15 seconds). The TUGT and other clinical data were abstracted from the medical record using direct queries supplemented with chart review. Logistic regression was used to determine the relationship between frailty, age, and the diagnosis of rUTIs in our clinic population.ResultsThere were 136 americans adults with and 2824 americans adults without a diagnosis of rUTIs. Individuals with rUTIs had slower TUGT times (13.8 ± 10.4 seconds compared to 10.8 ± 4.52 seconds, P <.01) and were more likely to be classified as slow, or "frail" (27.2% vs 10.8%). In multivariate analysis, slow TUGT times were associated with a diagnosis of rUTIs (adjusted OR 2.0, 95% CI 1.2-3.3), while age was not a statistically significant predictor of this diagnosis (adjusted OR 1.3, 95% CI 0.7-2.2 for aged ≥81 years).ConclusionOlder adults with a diagnosis of rUTIs are significantly more frail compared to those with other nononcologic urologic diagnoses. Frailty (adjusted for age), was significantly associated with rUTIs, while age (adjusted for frailty) was not. Furthermore, frailty (rather than age) may be important to consider when caring for and treating americans adults with rUTIs

Demographics and baseline care among newly transitioning adult congenital urology patients.

IntroductionIn 2017, UCSF established a formal Transitional Urology (TU) clinic co-run by pediatric and adult urology aimed at providing comprehensive urologic care for people progressing into adulthood with complex urologic histories.ObjectiveWe aim to describe baseline demographic and disease characteristics of this population, understand gaps in care, and gauge follow-through.Study designWe performed a retrospective chart review of all new patients in the TU clinic at UCSF from February 2017 through January 2019. After approval from an institutional review board, demographic and clinical data were collected from medical records.Results39 new patients were seen in UCSF's TU clinic during a 23-month period. Our cohort included 20 patients with spina bifida and neurogenic bladder, 5 with bladder exstrophy, 3 with disorders of sexual development (DSD), 5 with obstructive uropathy, 2 with cloacal anomalies, and 1 patient each with calcinuria, reflux nephropathy, prune belly syndrome, and urachal cyst. Mean age of patients was 26 years, 63% were male, 88% spoke English, and 70% had public insurance. Patients lived an average of 94 miles from the clinic and had a mean zipcode-based household income of $70,110. There was an average of 19 months between the initial TU visit and the most recent prior urology visit. The median time since last creatinine as well as last renal ultrasound was 9 months. 19 (54%) patients warranted a total of 28 referrals to other providers at their initial visit, and 42% of these were obtained within 6 months.DiscussionAccording to our demographic data, TU patients are likely to have public insurance, live far from the TU clinic, and come from low SES backgrounds. At initial presentation over half of patients warranted updated tests like creatinine and renal ultrasound. Furthermore, nearly two-thirds of patients required at least one referral to a different provider, suggesting a majority of these patients had unmet medical needs at the time of presentation to the TU clinic.ConclusionOur data indicate that new patients to the TU clinic often warrant additional workup, updated testing, and referrals to sub-specialty care as these needs are often unmet at the time of presentation. The etiology of this is unclear and it may be due to insurance difficulties, inability to identify an appropriate adult subspecialty provider or access to care issues. Further investigation into barriers to implementation of transitional care is needed to provide comprehensive management to this challenging patient population

The Timed Up and Go Test as a Measure of Frailty in Urologic Practice

ObjectiveTo evaluate the prevalence of frailty, a known predictor of poor outcomes, among patients presenting to an academic nononcologic urology practice and to examine whether frailty differs among patients who did and did not undergo urologic surgery.MethodsThe Timed Up and Go Test (TUGT), a parsimonious measure of frailty, was administered to patients ages ≥65. The TUGT, demographic data, urologic diagnoses, and procedural history were abstracted from the medical record into a prospective database. TUGT times were categorized as nonfrail (≤10 seconds), prefrail (11-14 seconds), and frail (≥15 seconds). These times were evaluated across age and urologic diagnoses and compared between patients who did and did not undergo urologic surgery using chi-square and t tests.ResultsThe TUGT was recorded for 78.9% of patient visits from December 2015 to May 2016. For 1089 patients, average age was 73.3 ± 6.3 years; average TUGT time was 11.6 ± 6.0 seconds; 30.0% were categorized as prefrail and 15.2% as frail. TUGT times increased with age, with 56.9% of patients age 86 and over categorized as frail. Times varied across diagnoses (highest average TUGT was 14.3 ± 11.9 seconds for patients with urinary tract infections); however, no difference existed between patients who did and did not undergo surgery (P = .94).ConclusionAmong our population, prefrailty and frailty were common, TUGT times increased with age and varied by urologic diagnosis, but did not differ between patients who did and did not undergo urologic surgery, presenting an opportunity to consider frailty in preoperative surgical decision making

Cofactor Selectivity in Methylmalonyl Coenzyme A Mutase, a Model Cobamide-Dependent Enzyme

Cobamides, including vitamin B12, are enzyme cofactors used by organisms in all domains of life. Cobamides are structurally diverse, and microbial growth and metabolism vary based on cobamide structure. Understanding cobamide preference in microorganisms is important given that cobamides are widely used and appear to mediate microbial interactions in host-associated and aquatic environments. Until now, the biochemical basis for cobamide preferences was largely unknown. In this study, we analyzed the effects of the structural diversity of cobamides on a model cobamide-dependent enzyme, methylmalonyl-CoA mutase (MCM). We found that very small changes in cobamide structure could dramatically affect the binding affinity of cobamides to MCM. Strikingly, cobamide-dependent growth of a model bacterium, Sinorhizobium meliloti, largely correlated with the cofactor binding selectivity of S. meliloti MCM, emphasizing the importance of cobamide-dependent enzyme selectivity in bacterial growth and cobamide-mediated microbial interactions.Cobamides, a uniquely diverse family of enzyme cofactors related to vitamin B12, are produced exclusively by bacteria and archaea but used in all domains of life. While it is widely accepted that cobamide-dependent organisms require specific cobamides for their metabolism, the biochemical mechanisms that make cobamides functionally distinct are largely unknown. Here, we examine the effects of cobamide structural variation on a model cobamide-dependent enzyme, methylmalonyl coenzyme A (CoA) mutase (MCM). The in vitro binding affinity of MCM for cobamides can be dramatically influenced by small changes in the structure of the lower ligand of the cobamide, and binding selectivity differs between bacterial orthologs of MCM. In contrast, variations in the lower ligand have minor effects on MCM catalysis. Bacterial growth assays demonstrate that cobamide requirements of MCM in vitro largely correlate with in vivo cobamide dependence. This result underscores the importance of enzyme selectivity in the cobamide-dependent physiology of bacteria

Cofactor Selectivity in Methylmalonyl Coenzyme A Mutase, a Model Cobamide-Dependent Enzyme.

Cobamides, a uniquely diverse family of enzyme cofactors related to vitamin B12, are produced exclusively by bacteria and archaea but used in all domains of life. While it is widely accepted that cobamide-dependent organisms require specific cobamides for their metabolism, the biochemical mechanisms that make cobamides functionally distinct are largely unknown. Here, we examine the effects of cobamide structural variation on a model cobamide-dependent enzyme, methylmalonyl coenzyme A (CoA) mutase (MCM). The in vitro binding affinity of MCM for cobamides can be dramatically influenced by small changes in the structure of the lower ligand of the cobamide, and binding selectivity differs between bacterial orthologs of MCM. In contrast, variations in the lower ligand have minor effects on MCM catalysis. Bacterial growth assays demonstrate that cobamide requirements of MCM in vitro largely correlate with in vivo cobamide dependence. This result underscores the importance of enzyme selectivity in the cobamide-dependent physiology of bacteria.IMPORTANCE Cobamides, including vitamin B12, are enzyme cofactors used by organisms in all domains of life. Cobamides are structurally diverse, and microbial growth and metabolism vary based on cobamide structure. Understanding cobamide preference in microorganisms is important given that cobamides are widely used and appear to mediate microbial interactions in host-associated and aquatic environments. Until now, the biochemical basis for cobamide preferences was largely unknown. In this study, we analyzed the effects of the structural diversity of cobamides on a model cobamide-dependent enzyme, methylmalonyl-CoA mutase (MCM). We found that very small changes in cobamide structure could dramatically affect the binding affinity of cobamides to MCM. Strikingly, cobamide-dependent growth of a model bacterium, Sinorhizobium meliloti, largely correlated with the cofactor binding selectivity of S. meliloti MCM, emphasizing the importance of cobamide-dependent enzyme selectivity in bacterial growth and cobamide-mediated microbial interactions

The Association Between Race and Frailty in Older Adults Presenting to a Nononcologic Urology Practice

ObjectiveTo explore whether there is an association between nonwhite race and frailty among older adults presenting to an academic nononcologic urology practice.Materials and methodsThis is a prospective study of individuals ages ≥65years presenting to a nononcologic urology practice between December 2015 and November 2016. All individuals had a Timed Up and Go Test (TUGT, where a slower TUGT time of ≥15 seconds is suggestive of frailty. TUGT times, race (white vs nonwhite), and other clinical data were extracted from the electronic medical record using direct queries. Multivariable logistic regression was used to identify the association between race and slower TUGT times while adjusting for age, gender, number of medications, body mass index, and number of urologic diagnoses.ResultsAmong the 1715 individuals in our cohort, 33.9% were of nonwhite race and 15.3% had TUGT ≥15 seconds. A higher percentage of nonwhite individuals had TUGT times ≥15 seconds compared to white individuals (23.6% vs 11.1%, P <.01). TUGT times ≥15 seconds were significantly associated with nonwhite race after adjusting for clinical factors (adjusted odds ratio 2.5, 95% confidence interval 1.8-3.3).ConclusionAmong older adults presenting to an academic nononcologic urology practice, nonwhite race was associated with increased odds of frailty. A greater understanding of the relationship between race and frailty is needed to better address the needs of this vulnerable population

Caregiver Burden Among Those Caring for Patients With Spina Bifida

Objective1) To identify baseline characteristics of caregivers of school-aged children with spina bifida; 2) To identify independent predictors of caregiver burden in this population.Materials and methodsA survey was distributed via Facebook advertising to caregivers of patients with congenital genitourinary anomalies from May to September 2018. Eligible participants (n = 408) entailed English-speaking adults who are involved in the patient's care and attend ≥50% of their medical appointments. Caregiver burden was assessed using the Caregiver Burden Inventory (CBI), where higher scores indicate higher burden. CBI ≥24 indicates need for respite and CBI ≥36 indicates high risk of burnout. Bivariate analyses (t-tests and chi-square tests) were conducted using STATA software.ResultsOur analysis includes 408 caregivers caring for patients with spina bifida. In our study population, 59.3% of caregivers were in need of respite due to caregiver burden and 26.7% of caregivers were so burdened that they are at risk of burning out (CBI score ≥36). Bivariate analysis showed that caregiver gender and number of tasks performed by the caregiver were significantly associated with risk of burnout (CBI ≥ 36). Multivariable analysis of overall caregiver burden showed increased risk of burnout (CBI ≥ 36) among older caregivers, female caregivers, and those performing more caregiving tasks.ConclusionCaregiver burden is common among caregivers of patients with spina bifida, and further research is needed to identify strategies and resources for mitigating caregiver burden