Anterior Cruciate Ligament Reconstruction Improves Functional Scores and QoL in Patients over 50 Years of Age: study

Batuhan Cokyas et al conducted a study to evaluate quality of life changes and functional outcomes of anterior cruciate ligament reconstruction in patients older than 50 years of age with anterior cruciate ligament injury.

The article has been published in “Arthroscopy, Sports Medicine, and Rehabilitation” journal.

Patients who were older than 50 years of age and had undergone anterior cruciate ligament reconstruction with single-bundle hamstring tendon auto graft surgery were identified. Preoperative Tegner activity scores, Lysholm knee scores, International Knee Documentation Committee (IKDC) 2000 scores, and Short-Form 36 scores were compared with results that were documented 1 year after surgery.

Key findings of the study were:

• A total of 35 patients were included (20 male/15 female; mean age 52 years [range 50-59 years]).

• Patients’ preoperative mean Tegner score was 1.48.

• Mean Tegner score at 1-year follow-up was 3.82.

• Preoperative mean Lysholm score was 45.8. Postoperative mean Lysholm score was 88.

• Preoperative mean IKDC 2000 score was 33. Postoperative mean IKDC 2000 score was 82.

• All of these changes were statistically significant (P < .05).

• All of the parameter changes at Short Form-36 except for role limitations due to emotional problems were statistically significant.

The authors concluded that – “Improved functional knee scores, quality of life, and psychological status were achieved at anterior cruciate ligament reconstruction in patients older than 50 years of age.”

The authors commented – “The short postoperative follow-up period, small sample size, and lack of comparison with control groups are among the shortcomings of our study. The fact that we could not show to what extent the concomitant cartilage lesions and meniscal pathologies affected the results is another limitation. Finally, we did not note the level at which the patients returned to sports and in which sports they were engaged.”

Level of Evidence: Level IV, therapeutic case series.

Further reading:

Anterior Cruciate Ligament Reconstruction Improves Functional Scores and Quality of Life in Patients Older Than 50 Years of Age Batuhan Çokyas et al Arthroscopy, Sports Medicine, and Rehabilitation, Vol 5, No 6 (December), 2023: 100806 https://doi.org/10.1016/j.asmr.2023.100806

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COVID-19 vaccination linked to steepest decline in pediatric asthma prevalence, finds JAMA study

States with high rates of COVID-19 vaccination saw more pediatric asthma patients get a break from their symptoms, according to new research published in JAMA Network Open by leaders from Nemours Children’s Health and Endeavor Health.

“Asthma is one of the most common chronic illnesses among children in the United States, with about 4.7 million children experiencing symptoms each year,” said lead author Matthew M. Davis, MD, MAPP, Executive Vice-President, Enterprise Physician-in-Chief and Chief Scientific Officer of Nemours Children’s Health. “Whether asthma is mild or severe, it affects children’s quality of life. So anything we can do to help kids avoid flare-ups is beneficial.”

In the early months of the COVID-19 pandemic in 2020, social distancing and school closures are thought to have resulted in fewer flares of asthma for many pediatric patients. Dr. Davis and coauthor Lakshmi Halasyamani, MD, Chief Clinical Officer of Endeavor Health in Evanston, Illinois, wondered whether that benefit extended into 2021, as the first vaccines against COVID-19 were being widely administered to adults and then children.

In the study, Drs. Davis and Halasyamani compared the change in parent-reported childhood asthma symptoms between 2018-2019 and 2020-2021. They combined that data with state COVID-19 vaccination rates for people ages 5 and up in 2020-2021, as reported by the U.S. Centers for Disease Control and Prevention (CDC).

The researchers found that with each increase of 10 percentage points in COVID-19 vaccination coverage, parent-reported child asthma symptoms decreased by .36 percentage points.

States in the highest quarter of COVID-19 vaccination rates overall had a decrease in asthma symptoms of 1.7 percentage points—an almost 3 times more favorable impact than states in the lowest quarter of COVID-19 vaccination rates overall, which saw an average decrease in asthma symptoms of only 0.6 percentage points in 2020-2021, compared with 2018-2019.

The coauthors explained that several factors could have contributed to the reduction in asthma symptoms. Community-level immunity, also called “herd immunity,” in states with higher vaccination rates may have helped reduce children’s risk of contracting COVID-19 and developing asthma complications. Another possibility is that children living in states with higher COVID-19 vaccination rates may have been more likely to get the shots soon after immunizations were approved for their age groups.

According to the coauthors, these findings also raise the possibility that COVID-19 vaccinations may effectively fight other illnesses that stem from coronaviruses, including the common cold.

“Ongoing vaccination against COVID-19 may offer direct benefits for children with a history of asthma, but this must be confirmed with further research,” said Dr. Halasyamani. “It also raises the question of whether broader population-level COVID-19 vaccination among children and adults can help protect children with asthma, too.”

The coauthors pointed out that one limitation of the study is that it did not measure vaccination rates specifically in children with asthma. In addition, while parent-reported data is considered a meaningful measure of patient experience, additional data such as hospital stays or emergency department visits could be used to verify these findings.

Reference:

Davis MM, Halasyamani LK. COVID-19 Vaccination and Parent-Reported Symptomatic Child Asthma Prevalence. JAMA Netw Open. 2024;7(7):e2419979. doi:10.1001/jamanetworkopen.2024.19979.

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Selective caries removal to soft dentine feasible treatment for deep caries lesions in permanent teeth: Study

Selective caries removal to soft dentine feasible treatment option for the management of deep caries lesions suggests a study published in the Journal of Dentistry.This randomized controlled clinical trial aimed to evaluate the clinical performance of composite resin restorations placed after selective caries removal to soft dentin (SCRSD) or stepwise excavation (SW) over an 18-month period. Inclusion criteria were patients with permanent molars and/or premolars presenting deep caries lesions (≥50 % of the dentin thickness). Teeth were submitted to SCRSD (n = 76) or SW (n = 76). Evaluations were performed based on FDI (World Dental Federation) criterion. Survival analysis was performed to estimate the survival of restorations and its association with clinical variables and socio-demographic characteristics (adjusted Weibull regression model). The study was registered on Registro Brasileiro de Ensaios Clínicos (ReBEC 65ntbc). Results: The follow-up period ranged from 6 to 18 months (mean ± SD 16.3 ± 3.4 months). Patients’ ages ranged from 9 to 55 years (mean ± SD 29 ± 10.5 years). A total of 135 teeth (SCRSD = 72; SW = 63) from 101 patients were evaluated. There were 4 failures in the SCRSD group (2 loss of restoration in need of replacement and 2 marginal fractures in need of repair) and 2 in the SW group (fracture in need of repair). The association between explanatory variables and restoration failure showed similar success rates for SW (99.4 %) and SCRSD (97.9 %) (p = 0.16). Patients presenting gingivitis (≥20 % of sites with gingival bleeding) had 8.50 times more risk for failure than those with <20 % of bleeding sites (p = 0.03). This study showed that placing a composite resin restoration over soft dentin (after SCRSD) did not affect its clinical performance after 18 months. SCRSD is a feasible treatment option for the management of deep caries lesions in permanent teeth as it preserves tooth vitality and tooth structure without compromising restoration longevity.

Reference:

Andrea Fontoura Recchi, Rafael Schultz de Azambuja, Luana Severo Alves, Marisa Maltz, Juliana Jobim Jardim. Restorations performance after selective caries removal to soft dentine: 18-month follow-up of a controlled clinical trial. Journal of Dentistry, Volume 147, 2024, 105099, ISSN 0300-5712, https://doi.org/10.1016/j.jdent.2024.105099

(https://www.sciencedirect.com/science/article/pii/S0300571224002689)

Keywords:

Selective, caries removal, soft, dentine, feasible, treatment, option, management, deep caries lesions, study, Journal of Dentistry, Dental caries; Survival analysis; Composite resin; Selective caries removal; Clinical trial, Andrea Fontoura Recchi, Rafael Schultz de Azambuja, Luana Severo Alves, Marisa Maltz, Juliana Jobim Jardi

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Corticosteroids Improve Survival rate after Cardiac Surgery among Patients Under 65 Years, suggests research

A recent meta-analysis published in the Journal of Cardiothoracic and Vascular Anesthesia illuminated the potential life-saving benefits of corticosteroids in cardiac surgery patients younger than 65. This comprehensive study reviewed data from 17 randomized trials and encompassed a total of 6,598 patients which indicated that corticosteroids could reduce mortality rates among this demographic.

Cardiac surgeries which involve cardiopulmonary bypass (CPB) are often complicated by the development of a systemic inflammatory response syndrome (SIRS). This inflammatory response can contribute to postoperative morbidity and mortality. While corticosteroids can reduce inflammation, their overall impact, has been unclear and possibly age-dependent after considering potential harm versus benefit. 

The systemic review by Rosario Losiggio and team focused on the cardiac surgeries performed with CPB. This included patients younger than 65 years old involving both pediatric and non-elderly adult populations. The primary intervention measured was the perioperative use of corticosteroids when compared to placebo or standard care.

This study utilized data from PubMed, EMBASE and the Cochrane Library after covering literature from their inception until January 20, 2024. The primary outcome evaluated mortality that was at the longest follow-up available. The secondary outcomes included acute kidney injury, atrial fibrillation, myocardial injury, cerebrovascular events and infections.

The results of the meta-analysis found that the use of corticosteroids significantly reduced the mortality. Also, the corticosteroid group had a mortality rate of 2.3% (78 out of 3,321 patients) when compared to 3.5% (116 out of 3,277 patients) in the control group. This translated to a risk ratio of 0.69 that indicating a 31% reduction in the risk of death for the patients who were receiving corticosteroids. The analysis revealed no heterogeneity among the studies analyzed (I2=0%) by highlighting the consistency of these findings across different trials. 

In addition to reducing mortality, the corticosteroid group also showed a lower highest postoperative vasoactive inotropic score (VIS). This score measured the amount of support that was needed to maintain heart function and this was notably lower in patients treated with corticosteroids.

The study found no significant differences in secondary outcomes between the corticosteroid and control groups, including acute kidney injury, atrial fibrillation, myocardial injury, cerebrovascular events and infections. This suggests that while corticosteroids significantly improve survival rates, they do not substantially impact other common postoperative complications. Overall, these findings suggest that the perioperative use of corticosteroids could be beneficial in reducing mortality without increasing the risk of other serious postoperative complications in these patients. 

Reference:

Losiggio, R., Lomivorotov, V., Ursoleo, J. D., Kotani, Y., Monaco, F., Milojevic, M., Yavorovskiy, A., Lee, T. C., Landoni, G., Prof., Oriani, A., Prima, A. L. D., Mucchetti, M., Ortalda, A., Calabrò, M. G., & Zangrillo, A. (2024). The effect of corticosteroids on survival in pediatric and non-elderly adult patients undergoing cardiac surgery: a meta-analysis of randomized studies. In Journal of Cardiothoracic and Vascular Anesthesia. Elsevier BV. https://doi.org/10.1053/j.jvca.2024.07.001

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Pre-DMT Vitamin D Levels Influence MS Disease Activity and Onset, study finds

Italy: The risk of disease activity in multiple sclerosis (MS) can be affected by vitamin D levels before disease-modifying treatment (DMT) starts, a recent study has revealed.

“Having a genetic predisposition to higher vitamin D levels is linked to a reduced risk of disease activity and is associated with a delayed onset of multiple sclerosis,” Antonino Giordano, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy, and colleagues wrote in Journal of Neurology, Neurosurgery, and Psychiatry.

Multiple sclerosis is characterized by the immune system attacking the protective sheath (myelin) covering nerve fibers, disrupting communication between the brain and the rest of the body. Disease activity in MS can manifest in various forms, including relapses, progression of disability, and overall worsening of symptoms.

The role of Vitamin D (VitD) in multiple sclerosis (MS) risk is well-established, yet its specific influence on disease activity remains a topic of debate. Considering this, Dr. Giordano and colleagues aimed to evaluate whether VitD is associated with the No-Evidence of Disease Activity-3 (NEDA-3) status two years from the DMT start. They also assessed whether this association is causal or the result of confounding factors, and explored if a genetic predisposition to higher VitD levels impacts the risk of disease activity.

For this purpose, the researchers tested the association between seasonally adjusted VitD and disease activity in 230 untreated relapsing-remitting MS patients who also underwent serum 25-OH-vitamin-D measurement.

Using a polygenic risk score derived from a genome-wide association study involving approximately 400,000 individuals, the researchers investigated how genetic predisposition to higher Vitamin D levels impacts NEDA-3 status in a cohort of 1,408 independent patients with MS. We employed two-sample Mendelian randomization (MR) to evaluate causality.

The study led to the following findings:

  • Lower baseline VitD was associated with a decreased probability of NEDA-3 at two years.
  • VitD levels <20 ng/mL conferred an over twofold risk of disease activity (OR 2.36).
  • Genetic predisposition to higher VitD levels was associated with delayed age at MS onset and a higher probability of NEDA-3 status.
  • MR confirmed causality between VitD and the risk of disease activity.

Vitamin D levels before starting treatment were tied to subsequent multiple sclerosis disease activity. Genetic predisposition to higher vitamin D levels confers a lower disease activity risk and is tied to delayed MS onset,” the researchers wrote.

“Our research underscores the need for future prospective studies on Vitamin D supplementation and lifestyle interventions aimed at mitigating disease activity in MS,” they concluded.

Reference:

Giordano A, Clarelli F, Pignolet B, et al. Vitamin D affects the risk of disease activity in multiple sclerosis. Journal of Neurology, Neurosurgery & Psychiatry Published Online First: 14 July 2024. doi: 10.1136/jnnp-2024-334062

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Researchers develop improved model that evaluates risk and benefit of fish consumption during pregnancy

A new model developed by researchers could help inform guidelines and improve evidence-based advice on the risks and benefits of fish consumption, especially during pregnancy.

In a paper published in The American Journal of Epidemiology, researchers from Brigham and Women’s Hospital, a founding member of Mass General Brigham; Harvard T.H. Chan School of Public Health; University of Rochester Medical Center; and Cornell University present a new framework that takes into account estimated average mercury content in consumed fish, helping weigh the detrimental effects of mercury against the potential benefits of nutrients found in fish. Applying this approach to a fish-eating population in Massachusetts, the team found that, in general, consuming increasing amounts of low mercury-containing fish during pregnancy was beneficial, while consuming more high mercury-containing fish was harmful for neurodevelopment.

“For patients who are seeking guidance about fish consumption, public advisories can be confusing and lead to decreased fish intake,” said senior author Susan Korrick, MD, of the Brigham’s Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine. Korrick is also a member of the Harvard Chan-NIEHS Center for Environmental Health.

“Our study finds that eating more fish was generally beneficial for neurodevelopment when pregnant individuals consumed fish containing low levels of mercury but detrimental when individuals consumed fish with the highest average mercury levels. It’s important for people to think about what kind of fish they are consuming rather than simply cutting down on fish intake entirely,” said lead author Sally Thurston, PhD, of the University of Rochester Medical Center.

Methylmercury (MeHg) exposure can lead to neurodevelopmental toxicity. However, many nutrients in fish are beneficial for neurodevelopment, including polyunsaturated fatty acids, selenium, iodine and vitamin D. Many studies examining the relationship between mercury exposure and health outcomes measure mercury based on its accumulation in hair. However, relying on hair samples alone makes it impossible to disentangle the potentially harmful effects of mercury from the beneficial effects of fish intake. For example, eating lots of fish that contain low levels of mercury or very little fish that contains high amounts of mercury could result in the same level of mercury in a hair sample but have different potential health risks.

Results from analyses that use common statistical approaches to this issue can be challenging to interpret. To address these limitations, the researchers proposed a new model in which they considered the estimated average mercury content of the consumed fish. The team looked at data from participants in the New Bedford Cohort (NBC), a study that has followed 788 children of mothers living near the New Bedford Harbor Superfund site in Massachusetts. In addition to studying hair samples, the team used survey data from a food frequency questionnaire that mothers completed approximately 10 days after giving birth. Participants filled out details about the different types of fish they consumed during pregnancy.

The researchers looked at the relationship between fish consumption—broken out into low-, medium- and high-average fish mercury—and neurodevelopment among the children in the cohort. The team measured neurodevelopment based on tests of IQ, language, memory, and attention. For children whose mothers consumed more fish in the lowest mercury category, fish intake was positively (beneficially) associated with neurodevelopmental outcomes; conversely, for children whose mothers consumed fish with the highest mercury levels, the association between fish intake and neurodevelopmental outcomes was negative (detrimental).

References: Sally W Thurston, David Ruppert, Susan A Korrick American Journal of Epidemiology, kwae149, https://doi.org/10.1093/aje/kwae149

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Blood pressure high for years? Beware of stroke risk, reveals JAMA study

High blood pressure is known to increase a person’s chances of having a stroke.

But a study led by Michigan Medicine narrows in on the cumulative effects of years of high systolic blood pressure-the top number on the blood pressure reading and how hard the heart pumps blood to the arteries-finding that a higher average reading during adulthood is linked with a greater risk for the two most common types of stroke.

The study, published in JAMA Network Open, analyzed the average systolic blood pressure years ahead of the first stroke for more than 40,000 people who were 18 years or older with no history of stroke.

Researchers covered three types of stroke: ischemic, a clot that cuts blood supply to the brain and the cause of over 85% of all strokes; intracerebral hemorrhage, a bleed within the brain; and subarachnoid hemorrhage, bleeding between the brain and the tissues that cover it.

They found that having a mean systolic blood pressure that is 10-mm Hg higher than average was associated with a 20% higher risk of overall stroke and ischemic stroke, as well as a 31% greater risk of intracerebral hemorrhage.

“Our results suggest that early diagnosis and sustained control of high blood pressure over the lifespan are critical to preventing stroke, ischemic stroke and intracerebral hemorrhage, especially in Black and Hispanic patients who are more likely to have uncontrolled hypertension than white patients,” said senior author Deborah A. Levine, M.D., M.P.H., professor of internal medicine and neurology at University of Michigan Medical School.

Black patients had a 20% higher risk of ischemic stroke and a 67% higher risk of intracerebral hemorrhage than white patients.

Hispanic patients had a 281% higher risk of subarachnoid hemorrhage, but not any other stroke type, compared to white patients.

While Black and Hispanic patients had a higher risk of stroke, researchers found little evidence to suggest that race and ethnicity affected the association between cumulative systolic blood pressure and the type of stroke that affected any patient.

“Examining racial inequities advances our understanding of the social, economic and political structures that affect health behaviors and risk for stroke among racial and ethnic minority groups,” said Kimson E. Johnson, Ph.D., M.A., M.S.W., first author and postdoctoral research fellow at University of Michigan.

While systolic blood pressure is a modifiable target for preventing stroke and other cardiovascular diseases, a national study conducted in 2020 found that blood pressure control in the United States worsened from 2013 to 2018, especially for Black and Hispanic adults.

Self-monitoring of blood pressure improves blood pressure diagnosis and control and is accurate and cost effective, but it remains an underused tool, Levine says.

“Two major barriers to self-monitoring of blood pressure are lack of patient education and insurance not covering the home blood pressure monitors, which cost $50 or more,” she said.

“Health care systems and providers must educate and urge their patients to do home blood pressure monitoring, and insurers must pay for home blood pressure monitors to optimize people’s blood pressure and reduce their chances of having a stroke.”

Reference:

Johnson KE, Li H, Zhang M, et al. Cumulative Systolic Blood Pressure and Incident Stroke Type Variation by Race and Ethnicity. JAMA Netw Open. 2024;7(5):e248502. doi:10.1001/jamanetworkopen.2024.8502.

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Early Norepinephrine Administration may Reduce Pulmonary Edema risk in Septic Shock Patients: Study

In a recent study, early use of norepinephrine was associated with a reduced incidence of pulmonary edema in patients with septic shock not treated by restrictive fluid strategies and improved their survival rate. This research was published in the journal CHEST by authors including Chiwon Ahn et al. of South Korea.

Norepinephrine remains, to this day, a vasopressor of paramount importance in the management of septic shock, though the best timing of initiation is still debatable. Some higher and recent studies showed conflicting effects with respect to early or late NE administration about the outcome. This meta-analysis was intended to clarify these controversies compared to mortality and other outcomes between early versus late NE administration in patients with septic shock.

An extended search was done in studies on PubMed, EMBASE, the Cochrane Library, and KMBASE. They randomized adults with sepsis, divided into an early NE group and a late NE group according to specific time points or by differences in the protocols for NE use. Primary outcome measurements included overall mortality, secondary outcome measurements were ICU length of stay, ventilator-free days, renal replacement therapy-free days, vasopressor-free days, adverse events, and total fluid volume.

The study findings were as follows:

  • A total of 12 studies (4 randomized controlled trials [RCTs] and 8 observational studies) comprising 7,281 patients were analyzed.

  • No significant difference was found between the early NE group and the late NE group in RCTs (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.41–1.19) or observational studies (OR, 0.83; 95% CI, 0.54–1.29).

  • In the two RCTs that did not employ a restrictive fluid strategy and prioritized vasopressors over intravenous fluids, the early NE group showed significantly lower mortality than the late NE group (OR 0.49; 95% CI, 0.25–0.96).

  • The early NE group had more ventilator-free days in observational studies (mean difference [MD], 4.06; 95% CI, 2.82–5.30).

  • Three of the RCTs contributing data for this outcome measured the incidence of pulmonary edema, which was lower with early NE: OR 0.43; 95% CI, 0.25–0.74.

  • There were no differences in ICU length of stay, days free from renal replacement therapy, days free from vasopressor use, adverse events, or fluid volume between the two groups.

There was no significant difference in overall mortality for septic shock based on the timing of NE administration. On the other hand, early NE significantly reduced the incidence of pulmonary edema and dramatically reduced the mortality rate in those studies that used the intervention without fluid restriction, compared to late NE administration in the same studies.These results suggest that timing itself may not be as important to overall mortality regarding NE administration; there are other important clinical benefits to be derived.

Reference:

Ahn, C., Yu, G., Shin, T. G., Cho, Y., Park, S., & Suh, G. Y. (2024). Comparison of early and late norepinephrine administration in patients with septic shock: a systematic review and meta-analysis. Chest. https://doi.org/10.1016/j.chest.2024.05.042

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Enhancing Surgical Outcomes: Study Explores the Impact of Intraoperative Ultrasound in Complex Procedures

UK: In a groundbreaking advancement in surgical techniques, a randomized controlled trial has introduced the concept of Surgical Evacuation with Intraoperative Ultrasound (SEE U), showcasing promising results in enhancing surgical outcomes and patient safety.

A multicentre pilot study published in the European Journal of Obstetrics & Gynecology and Reproductive Biology showed that a large RCT comparing surgical management of miscarriage with and without intraoperative ultrasound is feasible.

“Intraoperative ultrasound could reduce the number of unsuccessful procedures or complications following surgical management of miscarriage (SMM),” the researchers wrote.

Paul P. Smith from Birmingham Women’s Hospital in Birmingham, UK, and colleagues aimed to test whether intraoperative ultrasound can reduce the incidence of early and late complications following surgical removal of products of conception.

For this purpose, the researchers conducted a prospective, multicentre, randomized, open clinical trial to assess feasibility. It was conducted in two University Teaching hospitals in the West Midlands, England.

The population comprised women aged 16 years or over referred for surgical management of miscarriage. Participants were randomly assigned to undergo surgical management for miscarriage with either continuous intraoperative ultrasound guidance or without it.

Process outcomes assessed during the study encompassed the percentage of eligible women screened and randomized, attrition rates, evaluation of outcome measurement tools, and acceptability among participants. The primary clinical endpoint focused on a composite outcome combining unsuccessful procedures or complications.

The study led to the following findings:

· Fifty-nine women requiring surgical management of miscarriage were randomized.

· The conversion rate for entry into the trial was 75%.

·19% of the patients who had surgery without ultrasound and 25% who had surgery with ultrasound (RR = 0.74) attained the composite clinical outcome.

· When patients who could not attend their hysteroscopy appointment, due to the COVID-19 pandemic were excluded, 19 % of patients who had surgery without ultrasound and 20% of patients who had surgery with ultrasound attained the composite clinical outcome (RR = 0.93).

In summary, the SEE U randomized controlled trial underscores the transformative potential of intraoperative ultrasound in enhancing surgical precision and patient safety during uterine evacuation procedures, marking a significant advancement in gynecological surgical techniques.

Reference:

Smith PP, Cheed V, Middleton L, Devall AJ, Izzat F, Clark TJ. Surgical evacuation with intraoperative ultrasound (SEE U): A randomised controlled trial. Eur J Obstet Gynecol Reprod Biol. 2024 Jul;298:6-11. doi: 10.1016/j.ejogrb.2024.04.004. Epub 2024 Apr 8. PMID: 38705012.

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Elagolix with add-back therapy promising for endometriosis-associated pain: Ongoing phase 3 trial reveals

USA: In a significant advancement in the treatment of endometriosis, preliminary findings from an ongoing randomized Phase 3 trial have unveiled promising outcomes with elagolix combined with add-back therapy.

The study, published in the American Journal of Obstetrics and Gynecology, showed that compared with placebo, elagolix with add-back therapy led to significant, clinically meaningful improvement in nonmenstrual pelvic pain, dysmenorrhea, and fatigue at six months that continued until month 12 for both nonmenstrual pelvic pain and dysmenorrhea.

In addition, elagolix combined with add-back therapy demonstrated good tolerability overall. Over 12 months, patients receiving this combination showed a slightly higher reduction in bone mineral density (BMD) compared to those on placebo. However, the decrease in BMD with elagolix plus add-back therapy was less than 1%, significantly lower than the bone loss seen in patients receiving elagolix alone.

Elagolix, an FDA-approved oral treatment for managing endometriosis-associated pain, is known to induce hypoestrogenic effects when used alone. Incorporating hormonal add-back therapy has shown promise in counteracting these effects. Considering this, Charles E. Miller, the Advanced Gynecologic Surgery Institute, Park Ridge, IL, and colleagues aimed to evaluate tolerability, efficacy, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol /0.5 mg norethindrone acetate (add-back) therapy once daily than placebo in premenopausal women with moderate-to-severe endometriosis-associated pain.

The ongoing, 48-month, phase 3 study comprised a 12-month, double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for six months followed by elagolix with add-back therapy, or placebo.

The study’s co-primary objectives were to determine the proportion of patients showing clinical improvement, termed “responders,” in dysmenorrhea and nonmenstrual pelvic pain by month 6. The study presents the 12-month findings on the effectiveness of elagolix combined with add-back therapy compared to placebo in reducing symptoms of nonmenstrual pelvic pain, dysmenorrhea, dyspareunia, and fatigue. Tolerability assessments included monitoring adverse events and evaluating changes in bone mineral density from baseline.

The study led to the following findings:

  • A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193).
  • Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% versus 23.7%) and nonmenstrual pelvic pain (51.3% versus 36.8%) at six months.
  • Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints, including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6).
  • The incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo.
  • The rate of severe adverse events did not meaningfully differ between treatment groups.
  • Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%).
  • Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of −2.43% (lumbar spine), −1.54% (total hip), and −1.78% (femoral neck) at month 6.
  • When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of −1.58% to −1.83% at month 12.
  • Patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in BMD (<1% change) at months 6 and 12.

The initial findings offer hope for improved treatment options and enhanced quality of life for women with chronic pain and complications of endometriosis.

Reference:

Miller, C. E., Kim, J. H., Kroll, R., Simon, J. A., Soliman, A. M., Thomas, J. W., Xu, Y., Ng, J., & Snabes, M. C. (2024). Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: 12 months of an ongoing randomized phase 3 trial. American Journal of Obstetrics and Gynecology. https://doi.org/10.1016/j.ajog.2024.06.040

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