Fewer Than One in 20 Current Academic Orthopaedic Surgeons Have Obtained National Institutes of Health Funding.

BACKGROUND: National Institutes of Health (NIH) funding is a key driver of orthopaedic research, but it has become increasingly difficult to obtain in recent years. An understanding of the types of grants that are commonly funded, how productive they are, and the factors associated with obtaining funding may help orthopaedic surgeons better understand how to earn grants. QUESTIONS/PURPOSES: In this study, we sought to determine (1) the proportion of current academic orthopaedic surgeons who have obtained NIH grant funding, (2) the productivity of these grants by calculating grant productivity metrics, and (3) the factors (such as gender, subspecialty, and additional degrees) that are associated with obtaining grant funding. METHODS: Current academic orthopaedic surgeons at the top 140 NIH-funded institutions were identified via faculty webpages; 3829 surgeons were identified. Demographic information including gender (men constituted 88% of the group [3364 of 3829]), academic rank (full professors constituted 22% [856 of 3829]), additional degrees (those with MD-PhD degrees constituted 3% [121 of 3829]), leadership positions, and orthopaedic subspecialty was collected. Funding histories from 1985 through 2021 were collected using the NIH Research Portfolio Online Reporting Tools Expenditures and Results. Grant type, funding, publications, and citations of each article were collected. A previously used grant impact metric (total citations per USD 0.1 million) was calculated to assess grant productivity. Multivariable binomial logistic regression was used to evaluate factors associated with obtaining funding. RESULTS: Four percent (150 of 3829) of academic orthopaedic surgeons obtained USD 338.3 million in funding across 301 grants, resulting in 2887 publications over the entire study period. The R01 was the most commonly awarded grant in terms of the total number awarded, at 36% (108 of 301), as well as by funding, publications, and citations, although other grant types including T32, F32, R03, R13, and R21 had higher mean grant impact metrics. There was no difference between men and women in the by-gender percentage of academic orthopaedic surgeons who obtained funding (4% [135 of 3229] versus 3% [15 of 450]; odds ratio 0.9 [95% confidence interval 0.5 to 1.7]; p = 0.80). A department having a single funded PhD researcher may be associated with surgeon-scientists obtaining grant funding, but with the numbers available, we could not demonstrate this was the case (OR 1.4 [95% CI 0.9 to 2.2]; p = 0.12). CONCLUSION: Fewer than one in 20 academic orthopaedic surgeons have received NIH funding. R01s are the most commonly awarded grant, although others demonstrate increased productivity metrics. Future studies should investigate the role of co-principal investigators on productivity and the role of different funding sources. CLINICAL RELEVANCE: Individuals should pursue both R01 and non-R01 grants, and departments should consider cultivating relationships with funded PhDs. The specific research infrastructure and departmental policies of the most productive institutions and grants should be surveyed and emulated.

A possible mechanism underlying mood disorders associated with LUTS: Chronic bladder outlet obstruction causes NLRP3-dependent inflammation in the hippocampus and depressive behavior in rats.

AIMS: Reports link urinary dysfunction and mood disorders, such as depression, but a causative mechanism has never been postulated. Contemporary discoveries demonstrate a local inflammatory response in peripheral organs can trigger inflammation in the brain, particularly the hippocampus, mediated through the NLRP3 inflammasome. Critically, central inflammation causes depressive behavior. Since bladder outlet obstruction (BOO) evokes a local inflammatory response in the bladder, we hypothesize it will induce NLRP3-dependent inflammation in the hippocampus and depressive behavior. METHODS: There were four groups of rats: control, sham, BOO, or BOO + glyburide (an NLRP3 inhibitor). BOO was created by urethral ligation over a 1 mm catheter. Sham was tied loosely. Glyburide was provided by slow-release pellet (subcutaneous 50 mg, 21 day, replaced as needed). Rats were analyzed 12 weeks post-op for: hippocampal inflammation, microglial density, neurogenesis, and depression symptoms (open field and sucrose preference). RESULTS: BOO elicited hippocampal inflammation, accompanied by an increase in activated microglia (22%) and a decrease in neurogenesis (35%), which was blocked by glyburide. In addition, BOO rats displayed anxiety (57% decrease in exploratory behavior in the open field assay) and anhedonia (21% decrease in sucrose preference), two symptoms of depression. Like inflammation, these symptoms were diminished by glyburide to levels not statistically significantly different from controls. CONCLUSIONS: BOO, a bladder-localized event, stimulates NLRP3-dependent inflammation in the rat hippocampus after 12 weeks and this inflammation causes depressive behavior. This is the first mechanistic explanation of the link between BOO and depression and provides evidence for a distinct bladder-brain axis.

Cyclophosphamide-induced cystitis results in NLRP3-mediated inflammation in the hippocampus and symptoms of depression in rats.

Recent breakthroughs demonstrate that peripheral diseases can trigger inflammation in the brain, causing psychosocial maladies, including depression. While few direct studies have been made, anecdotal reports associate urological disorders with mental dysfunction. Thus, we investigated if insults targeted at the bladder might elicit behavioral alterations. Moreover, the mechanism of neuroinflammation elicited by other peripheral diseases involves the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is present in microglia in the brain and cleaves and activates proinflammatory cytokines such as IL-1ß. Thus, we further explored the importance of NLRP3 in behavioral and neuroinflammatory changes. Here, we used the well-studied cyclophosphamide (CP)-treated rat model. Importantly, CP and its metabolites do not cross the blood-brain barrier or trigger inflammation in the gut, so that any neuroinflammation is likely secondary to bladder injury. We found that CP triggered an increase in inflammasome activity (caspase-1 activity) in the hippocampus but not in the pons. Evans blue extravasation demonstrated breakdown of the blood-brain barrier in the hippocampal region and activated microglia were present in the fascia dentata. Both changes were dependent on NLRP3 activation and prevented with 2-mercaptoethane sulfonate sodium (Mesna), which masks the effects of the CP metabolite acrolein in the urine. Finally, CP-treated rats displayed depressive symptoms that were prevented by NLRP3 inhibition or treatment with Mesna or an antidepressant. Thus, we conclude that CP-induced cystitis causes NLRP3-dependent hippocampal inflammation leading to depression symptoms in rats. This study proposes the first-ever causative explanation of the previously anecdotal link between benign bladder disorders and mood disorders.