Objective
Accumulation of misfolded superoxide dismutase‐1 (SOD1) is a pathological hallmark of SOD1‐related amyotrophic lateral sclerosis (ALS) and is observed in sporadic ALS where its role in ...pathogenesis is controversial. Understanding in vivo protein kinetics may clarify how SOD1 influences neurodegeneration and inform optimal dosing for therapies that lower SOD1 transcripts.
Methods
We employed stable isotope labeling paired with mass spectrometry to evaluate in vivo protein kinetics and concentration of soluble SOD1 in cerebrospinal fluid (CSF) of SOD1 mutation carriers, sporadic ALS participants and controls. A deaminated SOD1 peptide, SDGPVKV, that correlates with protein stability was also measured.
Results
In participants with heterozygous SOD1A5V mutations, known to cause rapidly progressive ALS, mutant SOD1 protein exhibited ~twofold faster turnover and ~ 16‐fold lower concentration compared to wild‐type SOD1 protein. SDGPVKV levels were increased in SOD1A5V carriers relative to controls. Thus, SOD1 mutations impact protein kinetics and stability. We applied this approach to sporadic ALS participants and found that SOD1 turnover, concentration, and SDGPVKV levels are not significantly different compared to controls.
Interpretation
These results highlight the ability of stable isotope labeling approaches and peptide deamidation to discern the influence of disease mutations on protein kinetics and stability and support implementation of this method to optimize clinical trial design of gene and molecular therapies for neurological disorders.
Trial Registration
Clinicaltrials.gov: NCT03449212.
To examine the quality and costs of care for patients evaluated for hematuria by urologic advanced practice providers (APPs) and urologists. The roles of APPs in urology are growing, but their ...clinical and financial outcomes compared to urologists are not well understood.
We conducted a retrospective cohort study of commercially insured patients using data from 2014 to 2020. We included adult beneficiaries with a diagnosis code for hematuria and an initial outpatient evaluation and management visit with a urologic APP or urologist.
We assessed receipt of cystoscopy procedure, imaging study, bladder biopsy procedure, and bladder cancer diagnosis within 6 months of the initial visit. Secondary outcomes included the time until each of these outcomes occurred and the out-of-pocket spending and total payments.
We identified 59,923 patients who were initially evaluated for hematuria. Visits with urologic nurse practitioners rather than urologists were associated with significantly lower odds of receiving cystoscopy procedures (odds ratio OR 0.93, 95% confidence interval 95% CI 0.54-0.72, P < .001), imaging studies (OR 0.79, 95% CI 0.69-0.91, P < .001), and bladder biopsy procedures (OR 0.61, 95% CI 0.41-0.92, P = .02). Visits with urologic physician assistants were associated with 11% greater out-of-pocket payments (incident risk ratio 1.11, CI 1.01-1.22, P = .02) and 14% greater total payments (incident risk ratio 1.14, CI 1.04-1.25, P = .004).
There are clinical and financial differences in hematuria care delivered by urologic APPs and urologists. The incorporation of APPs into urologic care warrants further study, and specialty-specific training for APPs should be considered.
To characterize differences between urologists and advanced practice providers (APPs) in the utilization of cystoscopy for hematuria.
We identified patients initially evaluated for hematuria by a ...urologist or urology APP between 2015 and 2020 in the MarketScan Research Databases. We determined whether they received a cystoscopy within 6 months of their urology visit and the number of days until cystoscopy. We used multivariable regression to analyze the association between these outcomes and whether the urology clinician was an advanced practice registered nurse (APRN), physician assistant (PA), or urologist.
We identified 34,470 patients with microscopic hematuria and 17,328 patients with gross hematuria. Patients evaluated by urologists more often received a same-day cystoscopy than those evaluated by APPs (13% vs 5.8%). The odds that patients evaluated for microscopic and gross hematuria received a cystoscopy were 46.2% and 26.2% lower, respectively, if they were evaluated by an APRN vs a urologist. Patients seeing an APRN for microscopic and gross hematuria also waited approximately 7 and 14 days longer for their cystoscopy, respectively. No differences were observed for patients evaluated by PAs vs urologists.
Patients evaluated for hematuria by an APRN were less likely to receive a cystoscopy and had a longer wait until the procedure compared to those evaluated by a urologist; however, no differences were observed between PAs and urologists. Better understanding APP integration into urology clinics is warranted.
To compare industry payments from drug and medical device companies to urologists and urologic advanced practice providers (APPs) in 2021.
We used the 2020 Medicare Data on Provider Practice and ...Specialty file to identify single-specialty urology practices, defined as those where the majority of physicians were urologists. We then used the Open Payments Program Year 2021 data to summarize the value and number of industry payments to urologists and APPs, including nurse practitioners and physician assistants, in these practices. We calculated the total value and number of payments and median total value and number of payments per provider for urologists and urologic APPs.
We identified 4418 urologists and 1099 APPs working in single-specialty urology practices in 2021 (Table 1). Of these, 3646 (87%) urologists received at least one industry payment, totaling $14,755,003 from 116,039 payments, and 954 urologic APPs (87%) received at least one industry payment, including 463 nurse practitioners (85%), totaling $401,283 from 13,035 payments, and 491 physician assistants (89%), totaling $543,429 from 14,626 payments. We observed significantly greater median total value and number of payments per provider for urologists ($620 and 24 payments) compared to urologic APPs ($473 and 21 payments; P < .001 and P = .017, respectively).
A similar percentage of urologists and urologic APPs received industry payments in 2021. While urologists received a higher total number and total value of payments in 2021, urologic APPs were a common target of industry marketing payments.
Summary Given the high and growing prevalence of obesity among adults in the United States, obesity treatment and prevention are important topics in biomedical and public health research. Although ...researchers recognize the significance of this problem, much remains unknown about safe and effective prevention and treatment of obesity in adults. In response to the worsening obesity epidemic and the many unknowns regarding the disease, a group of key scientific and program staff members of the National Institutes of Health (NIH) and other federal and non‐government agencies gathered virtually in September 2021 to discuss the current state of obesity research, research gaps, and opportunities for future research in adult obesity prevention and treatment. The current article synthesizes presentations given by attendees and shares their organizations' current initiatives and identified gaps and opportunities. By integrating the information discussed in the meeting and current initiatives, we identify potential targets and overlapping priorities for future research, including health equity and disparities in obesity, the heterogeneity of obesity, and the use of technological and innovative approaches in interventions.
Objective:
Genome‐wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility.
Methods:
A ...2‐stage design was used. First, individual level genotypic data from 5 recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta‐analyzed. Second, 768 single‐nucleotide polymorphisms (SNPs) were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls).
Results:
Genome‐wide significance was reached for SNPs in SNCA (rs356165; G: odds ratio OR = 1.37; p = 9.3 × 10−21), MAPT (rs242559; C: OR = 0.78; p = 1.5 × 10−10), GAK/DGKQ (rs11248051; T: OR = 1.35; p = 8.2 × 10−9/rs11248060; T: OR = 1.35; p = 2.0 × 10−9), and the human leukocyte antigen (HLA) region (rs3129882; A: OR = 0.83; p = 1.2 × 10−8), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K; OR = 1.71; p = 5 × 10−8 Combined Sample) (N370; OR = 3.08; p = 7 × 10−5 Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p = 5 × 10−5 Discovery Sample; p = 1.52 × 10−7 Replication sample; p = 2 × 10−10 Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes.
Interpretation:
We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA.ANN NEUROL 2012;
We sequenced the genome of Saccharomyces cerevisiae strain YJM789, which was derived from a yeast isolated from the lung of an AIDS patient with pneumonia. The strain is used for studies of fungal ...infections and quantitative genetics because of its extensive phenotypic differences to the laboratory reference strain, including growth at high temperature and deadly virulence in mouse models. Here we show that the almost equal to12-Mb genome of YJM789 contains almost equal to60,000 SNPs and almost equal to6,000 indels with respect to the reference S288c genome, leading to protein polymorphisms with a few known cases of phenotypic changes. Several ORFs are found to be unique to YJM789, some of which might have been acquired through horizontal transfer. Localized regions of high polymorphism density are scattered over the genome, in some cases spanning multiple ORFs and in others concentrated within single genes. The sequence of YJM789 contains clues to pathogenicity and spurs the development of more powerful approaches to dissecting the genetic basis of complex hereditary traits.
As the U.S. population ages, the incidence of urologic cancer diagnoses is expected to increase. The urologic workforce, however, is not growing at the same pace and may even be declining. Amid these ...demographic and workforce transitions, and in the context of growing specialization in medicine, we examined the urologic oncology surgical practices of early-career urologists (i.e., those submitting case logs for initial certification).
We examined case logs submitted by urologists applying for their American Board of Urology Certification Exam from 2014 to 2019. We included case logs spanning at least 120 days between the first and last record. We used Current Procedural Terminology codes to identify transurethral resection of bladder tumor, open radical cystectomy, open and minimally invasive radical nephrectomy, and open and minimally invasive radical prostatectomy. We calculated the proportion of urologists and the proportion of urologists specializing in oncology who reported completing at least one of these procedures during the reporting period.
We identified 1,492 unique urologists submitting case logs between 2014 and 2019. The average age was 35 years, 79.9% were male, and 15.8% specialized in urologic oncology. We noted reductions in the percentage of urologists who performed one or more radical cystectomy (36% to 22%), minimally invasive radical nephrectomy (73% to 59%), open radical nephrectomy (42% to 24%), and open prostatectomy (19% to 5%) cases from 2014 to 2019. Among urologists specialized in urologic oncology, the percentage who performed one or more open radical cystectomy declined from 73% to 65%. Those performing at least one open radical nephrectomy declined from 73% to 58%, while minimally invasive nephrectomy increased from 90% to 98%.
In this analysis of early career urologist case logs, we find that the proportion of urologists performing one or more radical cystectomy, radical nephrectomy, and open prostatectomy cases in this approximately six-month period declined. In contrast, oncology-specialized urologists had smaller changes in use of these procedures. These findings suggest ongoing specialization among early-career urologists. Urologic oncology training and career focus may be essential to developing an adequate supply of high-volume urologic oncology surgeons.
This cross-sectional study compares the prescribing practices among urologists and advanced practice clinicians who received vs did not receive payment from drug manufacturers.
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