Differences in Reimbursements, Procedural Volumes, and Patient Characteristics Based on Surgeon Gender in Total Hip Arthroplasty.

BACKGROUND: Prior studies have suggested there may be differences in reimbursement and practice patterns by gender. The purpose of this study was to comprehensively evaluate differences in reimbursement, procedural volume, and patient characteristics in total hip arthroplasty (THA) between men and women surgeons from 2013 to 2021. METHODS: The Medicare Physician and Other Practitioners database from 2013 to 2021 was queried. Inflation-adjusted reimbursement, procedural volume, surgeon information, and patient demographics were extracted for surgeons performing over 10 primary THAs each year. Wilcoxon, t-tests, and multivariate linear regressions were utilized to compare men and women surgeons. RESULTS: Only 1.4% of THAs billed to Medicare between 2013 and 2021 were billed by women surgeons. Men surgeons earned significantly greater reimbursement nationally in 2021 compared to women surgeons per THA ($1018.56 versus $954.17, P = 0.03), but no difference was found when assessing each region separately. Reimbursement declined at similar rates for both men and women surgeons (-18.3 versus -19.8%, P = 0.38). An increase in the proportion of women surgeons performing THA between 2013 and 2021 was seen in all regions except the South. In 2021, the proportion of all THAs performed by women surgeons was highest in the West (3.5%) and lowest in the South (1.0%). Women surgeons had comparable patient populations in terms of age, race, comorbidity status, and Medicaid eligibility to their men counterparts, but performed significantly fewer services per beneficiary (5.6 versus 8.1, P < 0.001) and fewer unique services (51.1 versus 69.6, P < 0.001). CONCLUSIONS: Average reimbursement per THA has declined at a similar rate for men and women physicians between 2013 and 2021. Women's representation in THA surgery nationwide has nearly doubled between 2013 and 2021, with the greatest increase in the West. However, there are notable differences in billing practices between genders.

Lower Income and Nonheterosexual Orientation Are Associated With Poor Access to Care in Patients With Knee Osteoarthritis.

Background: Social determinants of health are implicated in the experience of knee osteoarthritis, a key component of which is access to care and healthcare utilization. The objective of this study was to describe difficulties in access to care and healthcare utilization in the United States knee osteoarthritis population. Methods: The publicly available All of Us Database was utilized to conduct a retrospective cohort study. Patients with a diagnosis of knee osteoarthritis were included and matched to a control group who did not have knee osteoarthritis. The association of knee osteoarthritis and patient-specific demographic features with self-reported domains of access to care was analyzed. Results: Among 15,718 patients with knee osteoarthritis, 27.6% reported delayed care (n = 4343), 25.6% reported inability to afford care (n = 4015), 12.8% reported skipped medications (n = 2011), and 1.6% reported not seeing a healthcare provider in over 1 year (n = 247). Patients with knee osteoarthritis were more likely to be unable to afford care (odds ratio 1.21, P < .001) or skip medications (odds ratio 1.12, P = .004) in comparison to matched patients without knee osteoarthritis. Among the knee osteoarthritis cohort, low income and nonheterosexual orientation were both associated with increased rates of delayed care and an inability to afford care. Conclusions: Patients with knee osteoarthritis report significant challenges with delayed care, affordability of care, and medication adherence. Among patients with knee osteoarthritis, patients who are younger age, female sex, low-income, low-education, nonheterosexual orientation, or have poor physical and mental health are at increased risk of having decreased access to treatment.

Regional Differences in Reimbursement, Volume, and Patient Characteristics Exist for Rotator Cuff Repairs: A Temporal Analysis from 2013 to 2021.

BACKGROUND: Prior studies have demonstrated declining reimbursement and changing procedural utilization across multiple orthopedic subspecialties, yet a comprehensive examination of this has not been performed for rotator cuff repair, particularly at a geographic level. The purpose of this study was to evaluate changes in reimbursement, utilization, and patient populations for open and arthroscopic rotator cuff repairs (RCR) from 2013 to 2021 at a national and regional level. METHODS: The Medicare Physician and Other Practitioners database from years 2013 to 2021 were queried to extract all episodes of open chronic RCR, open acute RCR, and arthroscopic RCR. Utilization was measured as procedural volume per 10,000 Medicare beneficiaries. Inflation-adjusted reimbursement, utilization, surgeon information, and patient characteristics were extracted for each procedure for each year. Data was stratified geographically based on US Census regions and rural-urban commuting codes. Kruskal-Wallis tests and linear regressions were performed to compare geographical areas. RESULTS: Between 2013 and 2021, arthroscopic RCR utilization increased by 9.4% (11.0/10,000 to 12.0/10,000), while open chronic RCR utilization decreased by 58.8% (2.0/10,000 to 0.8/10,000). During that time, average inflation-adjusted reimbursement declined by 10.0% and 11.3% for arthroscopic and open chronic RCR, respectively. The increase in utilization and decrease in reimbursement was greatest in the Midwest. In 2021, arthroscopic RCR utilization was 12.0/10,000, while average reimbursement for was $846.87, nationally. Utilization was highest in the South (14.5/10,000) and lowest in the Northeast (8.1/10,000) (p<0.001). Alternatively, reimbursement was highest in the Northeast ($904.60) and lowest in the South ($830.80) (p<0.001). The proportion of patients who were male, Medicaid eligible, or non-White was highest in the West (p<0.001). Patients in the West also had the fewest comorbidities. Increased patient comorbidities, when controlling patient demographics, was associated with lower reimbursement nationally and within the Northeast (p<0.001). CONCLUSION: Geographical discrepancies in rotator cuff repair utilization and reimbursement exist. The South consistently demonstrates the highest utilization of RCR, while also having the lowest reimbursement. Alternatively, the Northeast has the lowest utilization but the highest reimbursement. Increased patient population comorbidities were associated with reduced RCR reimbursement for surgeons in the Northeast, but not in other regions.

Regional Variation from 2013 to 2021 in Primary Total Shoulder Arthroplasty Utilization, Reimbursement, and Patient Populations.

BACKGROUND: Total shoulder arthroplasty (TSA), encompassing both anatomical and reverse total shoulder arthroplasty, has increased in popularity worldwide. The purpose of this study was to assess how TSA utilization, reimbursement, surgeon practices, and patient populations have evolved within the Medicare population from 2013 to 2021 at a national and regional level. METHODS: The Medicare Physician and Other Practitioners dataset was queried for all episodes of primary TSA (CPT-23472), both anatomic and reverse, between years 2013 and 2021. TSA utilization was assessed as volume per 10,000 Medicare beneficiaries. Average inflation-adjusted reimbursement, physician practice styles, and patient demographics of each TSA surgeon were extracted each year. Data was stratified geographically based on US census classifications and rural-urban commuting codes. Kruskal-Wallis and multivariate regressions were utilized to determine differences between regions. RESULTS: Between 2013 and 2021, TSA utilization increased by 121.8% nationally. The increase was greatest in the Northeast (+147.2%) and least in the Midwest (+115.5%). Average TSA reimbursement declined by 8.8% nationally, with the least decline in the Northeast (6.4%) and the greatest decline in the Midwest (-11.9%). In 2021, the Midwest had the highest TSA utilization (18.1/10,000), while having the lowest average reimbursement ($1,108.59; p<0.001). The Northeast had the lowest utilization (11.5/10,000) and highest reimbursement ($1,223.44; p<0.001) in 2021. Nationally, the number of Medicare beneficiaries per surgeon performing shoulder arthroplasty declined by 5.9%, while the average number of TSAs per surgeon (+8.5%) and average number of billable services per beneficiary (+16.6%) both increased. Surgeons in the South performed the most services per beneficiary in 2021 (9.0; p<0.001). The average comorbidity burden of patients decreased by 4.8% between 2013 and 2021, with the West having the healthiest patients in 2021. Higher patient comorbidities were associated with lower physician reimbursement nationally (p<0.001). CONCLUSION: This study demonstrates that TSA utilization in the Medicare population has more than doubled between 2013 and 2021, while average inflation-adjusted reimbursement has declined by nearly 10%. The Midwest has the highest per-capita TSA utilization, while simultaneously having the lowest average reimbursement per TSA. Over time, TSA surgeons are seeing fewer and healthier beneficiaries but performing more services per beneficiary. Additionally, increased patient complexity may be associated with lower reimbursement. Together, these findings are concerning for long-term equitable access to care within shoulder surgery.

Geographical Differences in Surgeon Reimbursement, Volume, and Patient Characteristics in Primary Total Hip Arthroplasty.

BACKGROUND: The purpose of this study was to evaluate changes in regional and national variations in reimbursement to arthroplasty surgeons, procedural volumes, and patient populations for total hip arthroplasty (THA) from 2013 to 2021. METHODS: The Medicare Physician and Other Practitioners database was queried for all billing episodes of primary THA for each year between 2013 and 2021. Inflation-adjusted surgeon reimbursement, procedural volume, physician address, and patient characteristics were extracted for each year. Data were stratified geographically based on the United States Census regions and rural-urban commuting codes. Kruskal-Wallis and multivariable regressions were utilized. RESULTS: Between 2013 and 2021, the overall THA volume and THAs per surgeon increased at the highest rate in the West (+48.2%, +20.2%). A decline in surgeon reimbursement was seen in all regions, most notably in the Midwest (-20.3%). Between 2013 and 2021, the average number of Medicare beneficiaries per surgeon declined by 12.6%, while the average number of services performed per beneficiary increased by 18.2%. In 2021, average surgeon reimbursement was the highest in the Northeast ($1,081.15) and the lowest in the Midwest ($988.03) (P < .001). Metropolitan and rural areas had greater reimbursement than micropolitan and small towns (P < .001). Patient age, race, sex, Medicaid eligibility, and comorbidity profiles differ between regions. Increased patient comorbidities, when controlling for patient characteristics, were associated with lower reimbursement in the Northeast and West (P < .01). CONCLUSIONS: Total hip arthroplasty (THA) volume and reimbursement differ between US regions, with the Midwest exhibiting the lowest increase in volume and greatest decline in reimbursement throughout the study period. Alternatively, the West had the greatest increase in THAs per surgeon. Patient comorbidity profiles differ between regions, and increased patient comorbidity is associated with decreased reimbursement in the Northeast and the West. This information is important for surgeons and policymakers as payment models regarding reimbursement for arthroplasty continue to evolve.

Low-Income, Poor Physical Health, Poor Mental Health, and Other Social Risk Factors Are Associated With Decreased Access to Care in Patients With Carpal Tunnel Syndrome.

BACKGROUND: Carpal Tunnel Syndrome (CTS) is associated with a significant personal and societal burden. Evaluating access to care can identify barriers, limitations, and disparities in the delivery of healthcare services in this population. The purpose of this study was to evaluate access to overall healthcare and healthcare utilization among patients with CTS. METHODS: This is a retrospective cohort study conducted with the All of Us database. Patients diagnosed with CTS that completed the access to care survey were included and matched to a control group. The primary outcomes were access to care across 4 domains: (1) delayed care, (2) could not afford care, (3) skipped medications, and (4) over 1 year since seeing provider. Secondary analysis was then performed to identify patient-specific factors associated with reduced access to care. RESULTS: In total, 7649 patients with CTS were included and control matched to 7649 patients without CTS. In the CTS group, 33.7% (n = 2577) had delayed care, 30.4% (n = 2323) could not afford care, 15.4% (n = 1180) skipped medications, and 1.6% (n = 123) had not seen a provider in more than 1 year. Within the CTS cohort, low-income, worse physical health, and worse mental health were associated with poor access to care. CONCLUSION: Patients experience notable challenges with delayed care, affordability of care, and medication adherence regardless of having a diagnosis of CTS. Targeted interventions on modifiable risk factors such as low income, poor mental health, and poor physical health are important opportunities to improve access to care in this population.

Mental Health in Elite Athletes: A Systematic Review of Suicidal Behaviour as Compared to the General Population.

BACKGROUND AND OBJECTIVE: Previous systematic reviews on mental health in athletes have found athletes to be at a potentially increased risk for mental health diagnoses compared to the public. Multiple cross-sectional studies have examined suicide behaviour within different athlete populations, but there is a need for a comprehensive review to synthesize and identify risk factors and epidemiology regarding suicide behaviour in the elite athlete population, especially as it compares to the general population. METHODS: A systematic literature search was performed in MEDLINE, EMBASE, Scopus, and Web of Science from 1990 to January 2023. Inclusion criteria included original peer-reviewed research articles examining suicidal ideation, suicide attempt, or suicide completion within elite athlete populations. Exclusion criteria included athletes participating in high-school or Paralympic level sports, studies that did not report results regarding elite athletes and non-athletes separately, and non-peer reviewed work. All studies were screened for inclusion by two independent reviewers. The primary outcome variables extracted from included studies included rates, risk factors, and protective factors for suicide behaviour. The study quality and risk of bias was evaluated for each study using the Joanna-Briggs Institute (JBI) critical appraisal tools. RESULTS: Of the 875 unique studies identified, 22 studies, all of which were cross-sectional in nature, met the inclusion criteria. Seven studies evaluated previous athletes, 13 studies evaluated current athletes, and two studies included a combination of previous and current athletes. Seven studies involved varsity college athletes, nine involved professional athletes of various sports, and six focused on international or Olympic level athletes. The rate of suicidal ideation in professional athletes ranged from 6.9 to 18% across four studies, while the rate in collegiate athletes ranged from 3.7 to 6.5% across three studies. Ten studies compared athletes to the general population, the majority of which found athletes to be at reduced risk of suicidal ideation, suicide attempt, and suicide completion. Only one study found athletes to have increased rates of suicide compared to matched non-athletes. Risk factors for suicide behaviour identified across multiple studies included male sex, non-white race, older age, and depression. Player position, athletic level, sport played, and injuries showed trends of having limited effect on suicide behaviour risk. CONCLUSION: This review suggests that elite athletes generally demonstrate reduced risk of suicidal ideation, suicide attempt, and suicide completion compared to the general population. Coaches should remain aware of specific factors, such as male sex, non-white race, and higher athletic level, in order to better identify at-risk athletes. Limitations of this review include the heterogeneity in the methodology and athlete populations across the included studies. Therefore, future targeted research is essential to compare suicide behaviour between sports and identify sport-specific suicide risk factors. TRIAL REGISTRATION: PROSPERO Registration: CRD42023395990.

Meniscectomy Reimbursement and Utilization Are Declining at Different Rates Across the United States.

PURPOSE: To evaluate how arthroscopic meniscectomy utilization, reimbursement, physician billing practices, and patient populations have changed within the Medicare population from 2013 to 2021 at a national level and regional level. METHODS: The Medicare Physician & Other Practitioners database was queried for all episodes of 2-compartment and single-compartment arthroscopic meniscectomy between 2013 and 2021. Utilization per 10,000 beneficiaries and average inflation-adjusted reimbursement were assessed. Physician practice styles, measured through changes in the services billed, and Medicare beneficiary demographic characteristics were extracted each year. The Kruskal-Wallis test was performed to compare regions. RESULTS: Between 2013 and 2021, two-compartment meniscectomy utilization per 10,000 Medicare beneficiaries declined by 54.9% and single-compartment meniscectomy utilization declined by 54.2%. Average reimbursement declined by 9.3% and 12.5% for 2-compartment meniscectomy and single-compartment meniscectomy, respectively. In 2021, the South had the highest utilization of both 2-compartment (3.8/10,000) and single-compartment (4.7/10,000) meniscectomies while having the lowest average reimbursement for 2-compartment meniscectomy ($383.02, P < .001). Nationally, the average number of beneficiaries per surgeon performing single-compartment meniscectomy declined by 3.8% whereas the average number of billable services performed per beneficiary increased by 46.6%. The comorbidity risk score of these patients decreased by 8.7%, with the West having the healthiest patients in 2021. CONCLUSIONS: Meniscectomy utilization and reimbursement have been declining nationally within the Medicare population. Surgeons in the South performed the most meniscectomies while having among the lowest reimbursement. The practice patterns of surgeons performing meniscectomies have been changing, with surgeons performing nearly 50% more total billable services per beneficiary while performing fewer unique billable services. Additionally, the patient population of surgeons who perform meniscectomy was healthier in 2021 than in 2013. CLINICAL RELEVANCE: This study highlights changes in meniscectomy utilization and reimbursement over time in the face of changing evidence of meniscectomy use in elderly patients and new Medicare legislature regarding reimbursement.

Athletes Continue to Show Functional Performance Deficits at Return to Sport After Anterior Cruciate Ligament Reconstruction: A Systematic Review.

PURPOSE: To systematically review the existing literature on the functional performance of athletes at the time of return-to-sport (RTS) clearance after anterior cruciate ligament reconstruction (ACLR). METHODS: A systematic literature search of the MEDLINE, EMBASE, Scopus, and Web of Science databases was performed. The inclusion criteria were original research reports with study populations of athletes who had undergone ACLR and had undergone objective functional testing immediately after clearance to RTS. Functional testing was stratified by hop tests, strength tests, kinetic assessment, and kinematic assessment, and data were extracted from each study using a standardized template. RESULTS: Of the 937 unique studies identified, 46 met the inclusion criteria. The average time between ACLR and functional testing was 7.9 months among the included studies. In 10 of 17 studies, patients were found to have an average quadriceps strength limb symmetry index of less than 90%. However, only 2 of 12 studies found the average hop test limb symmetry index to be less than 90%. Kinematics included reduced knee flexion angle and increased trunk flexion on landing in ACLR patients compared with matched controls. On evaluation of kinetics, ACLR patients showed reduced peak vertical ground reaction force, lower peak knee extension and knee flexion moments, and altered energy absorption contribution compared with matched controls. CONCLUSIONS: This systematic review suggests that athletes show functional deficits at the time of RTS at an average of 7.9 months after ACLR. Traditional functional tests, such as strength and hop tests, are not able to accurately identify patients who continue to show deficits. The most common biomechanical deficits that persist after RTS clearance include diminished peak knee extension moment, decreased knee flexion angle, increased trunk flexion angle, reduced vertical ground reaction force, and increased hamstring central activation ratio during various functional gait and landing tasks. LEVEL OF EVIDENCE: Level III, systematic review of Level I to III studies.

Functional Return-to-Sport Testing Demonstrates Inconsistency in Predicting Short-Term Outcomes Following Anterior Cruciate Ligament Reconstruction: A Systematic Review.

PURPOSE: To systematically review the relationship between functional testing at the time of return to sport (RTS) and short-term outcomes, such as second anterior cruciate ligament (ACL) tear and return to a preinjury level of sport, among athletes who underwent anterior cruciate ligament reconstruction (ACLR). METHODS: A systematic literature search was performed in MEDLINE, EMBASE, Scopus, and Web of Science to identify studies examining athletes who underwent functional RTS testing and were followed for at least 12 months following ACLR. Studies were screened by 2 reviewers. A standardized template was used to extract information regarding study characteristics, ACLR information, functional test results, and risk factors associated with retear or reduced RTS. RESULTS: Of the 937 studies identified, 22 met the inclusion criteria. The average time between ACLR and RTS testing was 8.5 months. Single leg hop for distance performance had no association with retear risk in any study and no association with RTS rates in most studies. Quadriceps strength had conflicting results in relation to retear risk, whereas it had no relationship with RTS rates. Rates of reinjury and RTS were similar between patients who passed and did not pass combined hop and strength batteries. Asymmetric knee extension and hip moments, along with increased knee valgus and knee flexion angles, demonstrated increased risk of retear. CONCLUSIONS: Individual hop and strength tests that are often used in RTS protocols following ACLR may have limited and inconsistent value in predicting ACL reinjury and reduced RTS when used in isolation. Combined hop and strength test batteries also demonstrate low sensitivity and negative predictive value, highlighting conflicting evidence to suggest RTS testing algorithm superiority. Biomechanical assessment is promising for stratifying ACL reinjury risk, but further research is necessary. LEVEL OF EVIDENCE: Level IV, systematic review of Level I-IV studies.

Risk Factors in Patients Who Had Prior Renal or Liver Transplant Undergoing Primary Total Knee Arthroplasty.

BACKGROUND: More solid organ transplant (SOT) patients are undergoing total knee arthroplasty (TKA). This study identifies risk factors for complications, implant survivorship, and mortality in TKA patients who had prior SOT. METHODS: We identified 176 TKAs in patients who had prior SOT. Of these, 77 had a prior renal (RT), 77 had a prior liver (LT) transplant, and 22 had multiple prior transplants (MT). Median survival was estimated using Kaplan-Meier. Univariate analyses were assessed with mixed-effects logistic regressions for complications and Cox-regressions for mortality. Median follow-up was 63 months (range, 24 to 109). RESULTS: At least one acute medical complication occurred in 25, 13, and 27% of cases with prior RT, LT, and MT, respectively (P = .12). None of the variables were significantly associated with acute medical complications. At least one surgical complication occurred in 14, 13 and 14% of cases with prior RT, LT, and MT, respectively (P = 1). Vitamin D supplementation (Odds Ratio [OR] = 0.38, P < .03) was associated with lower risk of surgical complications. Reoperation and revision rates were 5 and 3%, respectively. Older age at time of transplantation and greater level of serum creatinine at time of TKA were associated with lower risk (OR = 0.96, P = .01), and higher risk of reoperation (OR = 4.9, P = .01), respectively. Coronary artery disease was associated with higher mortality (Hazard Ratio = 2.35, P = .01). CONCLUSIONS: Vitamin D was associated with lower surgical complications, whereas a younger age at time of transplantation increased the risk of reoperation. Additionally, SOT patients with coronary artery disease demonstrated higher mortality after TKA.

Biomechanics and situational patterns associated with anterior cruciate ligament injuries in the National Basketball Association (NBA).

OBJECTIVES: Perform a comprehensive video analysis of all anterior cruciate ligament (ACL) injuries in National Basketball Association (NBA) athletes from 2006 to 2022 to determine the associated biomechanics, injury mechanism and game situation. METHODS: NBA players diagnosed with an ACL tear from 2006 to 2022 were identified and videos of each injury evaluated by two reviewers. Visual evaluation included assessment of joint kinematics at three time points: initial contact of the injured leg with the ground (IC), 33 milliseconds later (IC+33) and 66 milliseconds later (IC+66). Game situation was assessed qualitatively. RESULTS: Videos of 38 out of 47 (80.9%) ACL tears were obtained. 9 injuries were non-contact, while 29 involved indirect contact. Between IC and IC+33, average knee valgus increased from 5.1° to 12.0° and knee flexion increased from 12.6° to 32.6°. At all time points, the majority of injuries involved trunk tilt and rotation towards the injured leg, hip abduction and neutral foot rotation. The most common game situations for injury included the first step when attacking the basket following picking up the ball (n=13), landing following contact in the air (n=11) and jump stop (n=5). CONCLUSION: Three major mechanisms predominate ACL tears in NBA players: the first step following picking up the ball when attacking, landing and jump stops. None of the injuries reviewed demonstrated direct contact to the knee, emphasising the importance of body kinematics in this injury pattern. The increase in knee valgus and knee flexion between IC and IC+33 should be noted as a possible precipitant to injury.

Bibliometric Analysis of the Top 50 Most Influential Studies on Patellar Tendon Injury.

Background: There is a wide range of literature on patellar tendon injury, making it increasingly difficult to stay informed on the most influential studies in this field. It is essential to be familiar with the foundational articles of patellar tendon injury research to understand the current state of the literature and deliver high quality care. Purpose: To objectively identify the 50 most influential articles relating to patellar tendon injury and conduct a bibliometric analysis to identify key features of these articles. Study Design: Cross-sectional study. Methods: The Clarivate Analytics Web of Knowledge database was utilized to gather metrics on the 50 most cited articles on patellar tendon injury on June 27, 2022. The information extracted from each article included publication year, number of citations, author information, article type, level of evidence, country of origin, journal name, study focus, and industry influence. Results: The top 50 studies were cited a total of 8543 times and published between 1977 and 2015. The majority of articles were published after 2003, and the majority of citations were accrued after 2011. The most prevalent article types were cohort studies (n = 23), and the majority of studies were of evidence level 2 (n = 14) or 4 (n = 13). Australia and the United States (US) each published the most studies (n = 11). Only 4 (8%) studies focused on patellar tendon rupture, and 12 (24%) of the top 50 studies were associated with industry. Conclusion: The majority of the top 50 most influential articles in patellar tendon injury were published and accumulated citations in the past 10 to 20 years. Non-US countries, institutions, and journals published many of the top 50 studies, reflecting a global interest and commitment to research in this field. Patellar tendon rupture and surgical repair represents a minority of research in the top 50 studies and could be a point of growth in the future.

Wear and tear of the intestinal visceral musculature by intrinsic and extrinsic factors.

BACKGROUND: The gut visceral musculature plays essential roles in not only moving substances through the lumen but also maintaining the function and physiology of the gut. Although the development of the visceral musculature has been studied in multiple model organisms, how it degenerates is poorly understood. RESULTS: Here, we employ the Drosophila midgut as a model to demonstrate that the visceral musculature is disrupted by intrinsic and extrinsic factors, such as aging, feeding, chemical-induced tissue damage, and oncogenic transformation in the epithelium. Notably, we define four prominent visceral musculature disruption phenotypes, which we refer as "sprout," "discontinuity," "furcation," and "crossover" of the longitudinal muscle. Given that the occurrence of these phenotypes is increased during aging and under various stresses, we propose that these phenotypes can be used as quantitative readouts of deterioration of the visceral musculature. Intriguingly, administration of a tissue-damaging chemical dextran sulfate sodium (DSS) induced similar visceral musculature disruption phenotypes in zebrafish larvae, indicating that ingestion of a tissue-damaging chemical can disrupt the visceral musculature in a vertebrate as well. CONCLUSIONS: Our study provides insights into the deterioration of the gut visceral musculature and lays a groundwork for investigating the underlying mechanisms in Drosophila as well as other animals.

Improved virological outcomes in British Columbia concomitant with decreasing incidence of HIV type 1 drug resistance detection.

BACKGROUND: There have been limited studies evaluating temporal changes in the incidence of detection of drug resistance among human immunodeficiency virus type 1 (HIV-1) isolates and concomitant changes in plasma HIV load for treated individuals in a population-wide setting. METHODS: Longitudinal plasma viral load and genotypic resistance data were obtained from patients receiving antiretroviral therapy from the British Columbia Drug Treatment Program from July 1996 through December 2008. A total of 24,652 resistance tests were available from 5422 individuals. The incidence of successful plasma viral load suppression and of resistance to each of 3 antiretroviral categories (nucleoside/nucleotide reverse-transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors) was calculated for the population receiving therapy. RESULTS: There has been a drastic decrease in the incidence of new cases of HIV-1 drug resistance in individuals followed during 1996-2008. In 1997, the incidence rate of any newly detected resistance was 1.73 cases per 100 person-months of therapy, and by 2008, the incidence rate had decreased >12-fold, to 0.13 cases per 100 person-months of therapy. This decrease in the incidence of resistance has occurred at an exponential rate, with half-times on the order of 2-3 years. Concomitantly, the proportion of individuals with plasma viral load suppression has increased linearly over time (from 64.7% with HIV RNA levels <50 copies/mL in 2000 to 87.0% in 2008; R2=0.97; P<.001). CONCLUSIONS: Our results suggest an increasing effectiveness of highly active antiretroviral therapy at the populational level. The vast majority of treated patients in British Columbia now have either suppressed plasma viral load or drug-susceptible HIV-1, according to their most recent test results.

Silent mutations are selected in HIV-1 reverse transcriptase and affect enzymatic efficiency.

OBJECTIVE: Missense mutations in HIV-1 reverse transcriptase are frequently selected in response to therapy; we examined whether silent mutations were also selected for by HIV therapy. DESIGN: Retrospective, observational analysis. Biochemical assays. METHODS: A comparison of the reverse transcriptase gene, from antiretroviral- naive (N = 812) and experienced individuals (N = 2212), reveals two silent mutations (K65K and K66K) that are strongly associated with treatment experience. To assess reverse transcription efficiency, steady-state kinetic assays were carried out using recombinant purified HIV-1 reverse transcriptase and a series of synthetic RNA/DNA template/primer substrates. The RNA templates spanned codons 60-77 in the reverse transcriptase and included different combinations of mutations at codons 65, 66, 67, and 70. RESULTS: Silent AAG mutations (or mixtures) at reverse transcriptase codons 65 and/or 66 were observed in 812 samples from 351 patients and 2129 samples from 829 patients, respectively. In clade B samples, there was a very strong relationship between the silent mutations and the thymidine analogue mutations, in particular D67N. Steady-state kinetic experiments demonstrated that HIV-1 reverse transcriptase exhibited a strong tendency to pause and/or dissociate at codons 65 and 66 on RNA templates that contained the D67N and K70R mutations. However, when the K66 or K66 AAA to AAG mutations were added to the background of the 67 and 70 mutational changes, these pausing and/or dissociation events were largely alleviated. CONCLUSION: Silent mutations at codons 65 and/or 66 are strongly coselected with thymidine analogue mutations. These data provide the first evidence for an RNA-level mechanism of direct relevance to drug resistance.

Increased resilience to the development of drug resistance with modern boosted protease inhibitor-based highly active antiretroviral therapy.

BACKGROUND: We explore the temporal and regimen-specific changes of HIV-1 drug resistance in a large cohort of antiretroviral-naive individuals starting highly active antiretroviral therapy (HAART). METHODS: Individuals (n = 2350) initiating first HAART between August 1996 and November 2004 were followed until November 2005 (median follow-up, 4.8 years; n = 6066 tests). A logistic regression model was used to predict the probability of the emergence of resistance, adjusting for baseline predictors. RESULTS: The cohort included 991 individuals initiating nonboosted protease inhibitor (PI)-based regimens, 475 initiating ritonavir-boosted PI-based regimens, and 884 initiating nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based regimens. There was no difference in the development of resistance between nonboosted PI-based regimens (reference group) and NNRTI-based HAART regimens (odds ratio [OR], 1.09 [95% confidence interval {CI}, 0.84-1.42]), but there were greatly reduced odds for boosted PI-based regimens (OR, 0.42 [95% CI, 0.28-0.62]). Individuals initiating HAART more recently (2002-2004) were at a reduced risk of resistance, compared with those who started HAART between 1996 and 1998 (OR, 0.43 [95% CI, 0.30-0.61]). CONCLUSIONS: Individuals initiating first HAART with a boosted PI-based regimen had a 2.4-fold lower OR for developing HIV drug resistance than did those starting nonboosted PI-based or NNRTI-based HAART, at all adherence levels. The data demonstrate marked temporal improvement in the likelihood of the development of drug resistance for those initiating more recent HAART regimens.