Reduction in inflammation does not improve coronary microvascular dysfunction in rheumatoid arthritis: LiiRA Study

USA: Rheumatoid arthritis (RA) is not just a disease of the joints; it affects multiple systems in the body, including the cardiovascular system. In a groundbreaking development, the LiiRA study has uncovered the intricate interplay between systemic inflammation, myocardial injury, and coronary microvascular dysfunction in individuals with rheumatoid arthritis. These findings offer crucial insights into the cardiovascular complications associated with RA and may pave the way for targeted interventions to improve patient outcomes.

Researchers found that in RA patients on anti‐inflammatory therapy, despite a reduction in inflammatory markers like high‐sensitivity CRP (hs-CRP) & interleukin‐1b, there was no significant improvement in myocardial flow reserve (MFR). Nearly half had coronary microvascular dysfunction at baseline, yet neither high‐sensitivity cardiac troponin T (hs‐cTnT) nor MFR levels changed significantly.

The study findings were published online in the Journal of the American Heart Association on April 30, 2024.

Coronary microvascular dysfunction, measured by myocardial flow reserve, is associated with increased cardiovascular risk in rheumatoid arthritis. Brittany Weber, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, and colleagues aimed to determine the association between reducing inflammation with MFR and other measures of cardiovascular risk.

For this purpose, the researchers enrolled patients with RA with active disease about to initiate a tumor necrosis factor inhibitor. All participants underwent a cardiac perfusion PET scan to quantify MFR at baseline before tumor necrosis factor (TNF) inhibitor initiation and after the initiation of TNF inhibitor at 24 weeks. MFR <2.5 in the absence of obstructive coronary artery disease was defined as coronary microvascular dysfunction. Blood samples were measured at baseline and 24 weeks for inflammatory markers (eg, hs-CRP, interleukin‐1b, and hs‐cTnT).

The primary outcome was mean MFR before and after TNF inhibitor initiation, with Δhs‐cTnT as the secondary outcome. Secondary and exploratory analyses included the correlation between ΔhsCRP and other inflammatory markers with MFR and hs‐cTnT. 66 subjects were studied; 82% were women, and the mean RA duration was 7.4 years.

The following were the study’s key findings:

  • The median atherosclerotic cardiovascular disease risk was 2.5%; 47% had coronary microvascular dysfunction, and 23% had detectable hs‐cTnT.
  • There was no change in mean MFR before (2.65) and after treatment (2.64) or hs‐cTnT.
  • A correlation was observed between a reduction in hs-CRP and interleukin‐1b with a decrease in hs‐cTnT.

The findings showed that nearly 50% of subjects had coronary microvascular dysfunction at baseline in the RA cohort with a low prevalence of cardiovascular risk factors. A reduction in inflammation was not associated with improved myocardial flow reserve. However, a modest reduction in interleukin‐1b and no other inflammatory pathways correlated with a decrease in subclinical myocardial injury.

Reference:

Weber B, Weisenfeld D, Massarotti E, Seyok T, Cremone G, Lam E, Golnik C, Brownmiller S, Liu F, Huang S, Todd DJ, Coblyn JS, Weinblatt ME, Cai T, Dahal K, Kohler M, Yinh J, Barrett L, Solomon DH, Plutzky J, Schelbert HR, Campisi R, Bolster MB, Di Carli M, Liao KP. Interplay Between Systemic Inflammation, Myocardial Injury, and Coronary Microvascular Dysfunction in Rheumatoid Arthritis: Results From the LiiRA Study. J Am Heart Assoc. 2024 Apr 30:e030387. doi: 10.1161/JAHA.123.030387. Epub ahead of print. PMID: 38686879.

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Monoclonal Antibody Shows Promise in Preventing Malaria in Children, reports study

Researchers have found that a single subcutaneous injection of an investigational monoclonal antibody called L9LS significantly reduces the risk of malaria in children. This phase II trial in Mali demonstrated that the antibody was both safe and effective in preventing Plasmodium falciparum infections among children aged 6 to 10 years. This study was published in The New England Journal Of Medicine by Kayentao and colleagues.

Malaria, a life-threatening disease caused by Plasmodium parasites, continues to pose a significant health burden worldwide, particularly in sub-Saharan Africa. In 2022, the World Health Organization (WHO) reported over 600,000 deaths due to malaria, the majority among young children. The development of long-acting drugs for malaria prevention could be a major step forward in controlling the disease.

The Mali Malaria mAB trial included 225 children aged 6 to 10 years and evaluated the safety and efficacy of L9LS in preventing malaria. Children were randomized to receive either a 150-mg dose, a 300-mg dose, or a placebo injection. Before the trial, participants were treated with antimalarial medication to clear any existing infections.

The key findings of the study were as follows:

  • Infection rates were significantly lower in both L9LS dose groups compared to the placebo group.

  • Specifically, 48% of children in the 150-mg dose group and 40% in the 300-mg dose group became infected, compared to 81% in the placebo group.

  • The antibody provided 67% efficacy with the 150-mg dose and 77% efficacy with the 300-mg dose against clinical malaria, compared to the placebo group.

  • No safety concerns were identified in either phase of the study.

  • Adverse events were rare, mild to moderate in severity, and resolved without intervention.

The study indicates that the L9LS monoclonal antibody offers substantial protection against malaria, providing a potentially transformative approach to malaria prevention in high-risk populations. The long-acting nature of the antibody, with its single-dose delivery, could enhance accessibility and adherence.

The trial’s findings support the use of L9LS as a promising new tool in the fight against malaria. The antibody demonstrated a high level of efficacy and safety in preventing Plasmodium falciparum infection in children. As the global malaria community seeks new strategies to combat the disease, monoclonal antibodies like L9LS may play a critical role in achieving malaria eradication.

Reference:

Kayentao, K., Ongoiba, A., Preston, A. C., Healy, S. A., Hu, Z., Skinner, J., Doumbo, S., Wang, J., Cisse, H., Doumtabe, D., Traore, A., Traore, H., Djiguiba, A., Li, S., Peterson, M. E., Telscher, S., Idris, A. H., Adams, W. C., McDermott, A. B., … Crompton, P. D. (2024). Subcutaneous administration of a monoclonal antibody to prevent malaria. The New England Journal of Medicine, 390(17), 1549–1559. https://doi.org/10.1056/nejmoa2312775

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Validation of capnodynamic approach for evaluating critically sick patients’ end-expiratory lung volume: Study

Recently published research paper discusses the significance of reduced end-expiratory lung volume (EELV) in mechanically ventilated patients and its association with increased risk for ventilation-induced lung injury. It also explores the challenges associated with clinical measurement of EELV in this patient population. The study aimed to validate a novel continuous capnodynamic method based on expired carbon dioxide (CO2) kinetics for measuring EELV in mechanically ventilated critically ill patients. The study included 46 patients, 25 of whom had a diagnosis of acute respiratory distress syndrome (ARDS), most of which were COVID-19-related. The findings demonstrated that both EELVCT and EELVCO2 were significantly reduced compared to theoretical values of functional residual capacity, indicating a decrease in lung volume among the studied patients.

The capnodynamic method provided good estimates of both total and functional EELV, with bias improving after correcting EELVCO2 for extra-alveolar CO2 content when compared with CT estimated volume. The study concluded that the capnodynamic method presented reasonable estimates of EELV in critically ill patients on mechanical ventilation, with potential implications in clinical monitoring by quantifying the size of the baby lung, monitoring dynamic lung strain, adjusting tidal volume, and assessing the response to PEEP or lung recruitment.

However, the method exhibited a small bias but large limits of agreement, reducing its precision in measuring EELV. The study also highlighted certain methodological aspects, limitations, and potential biases, acknowledging the need for further evaluations to confirm the findings in a larger population and different ICU patient populations. The authors suggested that with further validations, the capnodynamic method may become a promising bedside tool for continuous monitoring of EELV in critically ill mechanically ventilated patients.

The paper provides a detailed overview of the development, validation, and potential applications of the novel capnodynamic method, highlighting its implications for improving clinical assessments and management of mechanically ventilated patients with reduced EELV. The methodology of the study, including the use of CT scans as a reference method and the analysis of benefits and limitations of the capnodynamic method, contributes to the understanding of the challenges and opportunities in monitoring and managing EELV in critically ill patients.

Key Points

– The study focuses on the significance of reduced end-expiratory lung volume (EELV) in mechanically ventilated patients and its association with increased risk for ventilation-induced lung injury, particularly in patients with acute respiratory distress syndrome (ARDS).

– The research validates a novel continuous capnodynamic method based on expired carbon dioxide (CO2) kinetics for measuring EELV in mechanically ventilated critically ill patients. The findings demonstrate that the capnodynamic method provides good estimates of both total and functional EELV, with potential implications in clinical monitoring, adjusting tidal volume, and assessing the response to PEEP or lung recruitment.

– While the capnodynamic method presents reasonable estimates of EELV, it exhibits a small bias and large limits of agreement, reducing its precision in measuring EELV. Further evaluations are required to confirm the findings in a larger population and different ICU patient populations, but the method shows promise as a bedside tool for continuous monitoring of EELV in critically ill mechanically ventilated patients.

Reference –

Sanchez Giralt, J.A., Tusman, G., Wallin, M. et al. Clinical validation of a capnodynamic method for measuring end-expiratory lung volume in critically ill patients. Crit Care 28, 142 (2024). https://doi.org/10.1186/s13054-024-04928-w

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Ghrelin shows promise for neuroprotection in post-cardiac arrest coma: reveals Groundbreaking trial

Netherlands: In a groundbreaking development in critical care medicine, a recent randomized clinical trial has shed light on the potential neuroprotective effects of Ghrelin in patients experiencing post-cardiac arrest coma. The findings, published in the prestigious journal JAMA Neurology, offer new hope for improving outcomes in this vulnerable patient population.

Acyl-ghrelin demonstrated potential efficacy and safety in enhancing neurological outcomes. There is a need for Phase 3 trials for conclusive evidence.

“In phase 2, a placebo-controlled, multicenter, randomized clinical trial (RCT) that comprised 160 patients in a coma within 12 hours of cardiac arrest, treatment with IV (intravenous) acyl-ghrelin for one week was safe,” the researchers reported.

“Neurological outcome by the categories of cerebral performance was nonsignificantly better, and neuron-specific enolase levels were significantly lower in the intervention group.”

Post-cardiac arrest coma, a devastating consequence of cardiac arrest, is characterized by profound neurological dysfunction and impaired consciousness, often resulting from global cerebral ischemia-reperfusion injury. Despite advancements in resuscitation techniques, neurological recovery remains a significant challenge, prompting researchers to explore novel therapeutic strategies aimed at mitigating brain injury and enhancing neuronal survival.

Despite research on more than 20 neuroprotective strategies involving patients in comas after cardiac arrest, none have shown unequivocal evidence of efficacy; however, acyl-ghrelin treatment has demonstrated improved functional and histological brain recovery in experimental models of cardiac arrest and was safe in a wide variety of human study populations.

Against the above background, Sjoukje Nutma, University of Twente, Enschede, the Netherlands, and colleagues aimed to determine the safety and efficacy of IV acyl-ghrelin to improve neurological outcomes in patients in a coma after cardiac arrest.

For this purpose, the researchers conducted the GRECO trial between 2019 and 2022. The researchers assessed adult patients 18 years or older who were in a comatose state after cardiac arrest for eligibility; patients were from 3 intensive care units (ICUs) in the Netherlands. Expected death within 48 hours or unfeasibility of treatment initiation within 12 hours were exclusion criteria.

Patients were randomized to receive IV acyl-ghrelin, 600 μg (intervention group), or placebo (control group) within 12 hours after cardiac arrest, continued for seven days, twice daily, in addition to standard care.

The study’s primary outcome was the Cerebral Performance Categories (CPC) scale score at six months. Safety outcomes included any severe adverse events. Secondary outcomes were neuron-specific enolase (NSE) levels and mortality on days 1 and 3.

Seven hundred eighty-three adult patients in a coma after cardiac arrest were assessed for eligibility, and 160 patients (median age, 68 years; 75% were males) were enrolled. Eighty-one patients were assigned to the intervention group, and 79 were assigned to the control group.

The study revealed the following findings:

  • The common odds ratio (OR) for any CPC improvement in the intervention group was 1.78. This was consistent over all CPC categories.
  • Mean NSE levels on day one after cardiac arrest were significantly lower in the intervention group (34 μg/L versus 56 μg/L) and on day 3 (28 μg/L versus 52 μg/L).
  • Serious adverse events were comparable in incidence and type between the groups.
  • Mortality was 37% in the intervention group vs 51% in the control group (absolute risk reduction, 14%).

“In phase 2, placebo-controlled, RCT, IV treatment with acyl-ghrelin for 1 week was safe and potentially effective to improve neurological and brain recovery in patients in a coma after cardiac arrest,” the researchers wrote. “There is a need for phase 3 trials for conclusive evidence of efficacy.”

Reference:

Nutma S, Beishuizen A, van den Bergh WM, et al. Ghrelin for Neuroprotection in Post–Cardiac Arrest Coma: A Randomized Clinical Trial. JAMA Neurol. Published online May 06, 2024. doi:10.1001/jamaneurol.2024.1088

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Personalized screening early in pregnancy may improve preeclampsia detection, reports study

A new screening algorithm for preeclampsia combining maternal history, ultrasound data and several tests for blood markers may better predict the majority of preeclampsia cases in the first trimester of pregnancy, when it may still be preventable, according to new research published today in Hypertension, an American Heart Association journal.

Preeclampsia is the most dangerous form of high blood pressure during pregnancy (blood pressure measures ≥140/90 mm Hg), and it is a leading cause of maternal death worldwide. Preeclampsia is potentially life-threatening when untreated. It affects 1 in 25 pregnancies in the U.S. and is more common in first-time pregnancies. Symptoms include headaches, vision changes and swelling of the mother’s hands, feet, face or eyes; or a change in the well-being of the baby. Recent research has found that preeclampsia can be linked to an increased risk of developing cardiovascular complications for women later in life.

“Preeclampsia is one of the most severe illnesses of pregnancy and may lead to preterm birth and/or maternal death,” said senior study author Emmanuel Bujold, M.D., M.Sc., professor in the department of obstetrics and gynecology at the Université Laval in Québec City, Canada.

The biological mechanisms that lead preeclampsia usually start in the first trimester of pregnancy (weeks 1 through 12), however, the initial symptoms of preeclampsia most often do not appear before week 20, Bujold noted.

The current risk factor-based guidelines from the American College of Obstetricians and Gynecologists (ACOG) recommend pregnant women take aspirin if they have a major risk factor such as chronic high blood pressure, Type 2 diabetes, chronic kidney disease, lupus or preeclampsia in a prior pregnancy. Aspirin is also recommended by ACOG for pregnant women with two moderate risk factors such as being a Black woman, having a sister or mother with history of preeclampsia, having a first pregnancy, obesity or an IVF pregnancy.

“Following those guidelines, almost all Black women should take aspirin during pregnancy, as should about one-third of all women of other races and ethnicities,” Bujold said.

Previous studies from the Fetal Medicine Foundation have found that preterm preeclampsia, defined as developing preeclampsia before 37 weeks of gestation, can be predicted in the first trimester using a combination of ultrasound and blood biomarker tests. In this study, researchers recruited over 7,000 women with first-time pregnancies across Canada who were between 11 and 14 weeks pregnant to evaluate the Fetal Medicine Foundation’s screening model. The model consisted of maternal history, ultrasound data and several tests for blood markers.

The study found:

  • Using the Fetal Medicine Foundation’s screening model for participants between 11 and 13 weeks of pregnancy, the preeclampsia detection rate was 63.1% for preterm preeclampsia (before 37 weeks of gestation) and 77.3% for early preeclampsia (before 34 weeks of gestation). The false positive rate was 15.8%.
  • Using the risk factor-based guidelines from the American College of Obstetricians and Gynecologists, the detection rate for preterm preeclampsia would be 61.5% and 59.1% for early preeclampsia, with a false-positive rate of 34.3%. This would be more than twice the false-positive rate of the Fetal Medicine Foundation’s screening model.

The only way to resolve preeclampsia once it has developed is to deliver the baby. by the study  previous meta-analysis found that taking one low-dose aspirin daily may reduce the risk of developing preeclampsia by up to 53%.

“Using this new screening model, treatment decisions were based on each individual’s personal risk,” Bujold said. “With their personal risk calculated, it’s much easier for a woman to make the right decision, for example, if she chooses to take daily low-dose aspirin, she is much more likely to follow through because it’s based on personalized screening test.”

Study background and details:

  • The study was conducted between 2014 and 2020 at five health centers across Canada. Of note: Canada has a national health care service, and coverage is universal for all Canadian citizens and permanent residents.
  • 7,554 women who were pregnant for the first time were recruited between 11 and 14 weeks of pregnancy. 7,325 delivered after 20 weeks and remained eligible for the final analysis; 229 had pregnancies with fetal anomalies and were excluded from the analyses for the study.
  • At time of enrollment in the study, participants underwent screening for preeclampsia. The data collected included age, weight, ethnicity, smoking status and chronic health conditions (chronic hypertension, Type 1 diabetes or Type 2 diabetes and antiphospholipid syndrome, an autoimmune disease that may be associated with pregnancy complications).
  • The study participants had an average age of 29 years. 92% of participants self-identified as white; 4% as Black; 2.6% as South Asian; 0.9% as East Asian; 0.3% as First Nations; and 0.2% as mixed race or undetermined.
  • The study excluded women who were taking antihypertensive medication for chronic hypertension, low-dose aspirin or low-molecular-weight-heparin (a blood thinner) on a daily basis were excluded from the study.
  • Participants were followed until delivery. The primary outcome was preterm preeclampsia. The secondary outcome was early preeclampsia.
  • Of the 7,325 women included in the analysis, 65 (0.9%) developed preterm preeclampsia, and 22 (0.3%) developed early preeclampsia.

Among the study’s limitations, several women with risk factors for preeclampsia, such as high blood pressure and Type 2 diabetes before pregnancy, were not included in the study if they were already taking aspirin for preeclampsia prevention. This would make it difficult to determine whether this population would rely solely on the Fetal Medicine Foundation’s screening model to decide whether or not to take daily, low-dose aspirin, Bujold noted. Additionally, only one lab was used to analyze blood samples, and blood samples collected at other centers across Canada were frozen and shipped for analysis, meaning that biomarkers were measured several weeks after the blood was drawn, which may have affected the results.

“It’s reasonable to believe that the inclusion of the entire population and immediate analysis of blood samples may both have improved the screening process. If we implemented a screening program in big cities across North America, the screening would be expected to be even better and more accurate,” Bujold said. “The good news is that we now have a more precise screening approach using existing tests that can predict preeclampsia early in pregnancy. The next step is to make this screening available to all pregnant women so that more women could receive a diagnosis early in pregnancy and begin preventative aspirin treatment, potentially preventing complications of severe preeclampsia.”

According to Sadiya S. Khan, M.D., M.Sc., FAHA, chair of the writing group for the Association’s 2023 scientific statement on Optimizing Prepregnancy Cardiovascular Health to Improve Outcomes in Pregnant and Postpartum Individuals and Offspring, predicting risk for term and preterm preeclampsia remains an important goal and priority to improve maternal health and mitigate disparities. Khan is the Magerstadt Professor of Cardiovascular Epidemiology and an associate professor of medicine and preventive medicine at the Northwestern University Feinberg School of Medicine in Chicago and a preventive cardiologist at Northwestern Medicine.

“Since the risks for preeclampsia may be largely influenced by health before pregnancy, the ability of a screening model to be applied in early pregnancy is very helpful and can initiate conversations between the clinician and patient about strategies to optimize heart health,” Khan said. “However, challenges remain with implementation of models such as this one that integrate biomarkers that are not routinely assessed and may not be widely available, especially among people in vulnerable populations who are most likely to have the highest risk for preterm preeclampsia.”

Reference:

Paul Guerby, Francois Audibert, Jo-Ann Johnson, Nanette Okun, Yves Giguère, Jean-Claude Forest, Nils Chaillet, Benoit Mâsse, David Wright, Louise Ghesquiere and Emmanuel Bujold, Prospective Validation of First-Trimester Screening for Preterm Preeclampsia in Nulliparous Women (PREDICTION Study), Hypertension, https://doi.org/10.1161/HYPERTENSIONAHA.123.22584.

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Botulinum Toxin A emerges as promising treatment for female pattern hair loss: Study

China: In a breakthrough discovery in dermatology, a recent study has illuminated the potential of botulinum toxin A as a novel therapeutic option for female pattern hair loss (FPHL). The findings, published in Skin Research and Technology, offer new hope for individuals grappling with this distressing condition and signify a paradigm shift in hair loss management.

The study suggested the effectiveness of Botulinum Toxin Type A (BTA) for female pattern hair loss is limited to three months. However, it can be considered for tentative use after effective communication with patients. Further observation and study are needed for BTA’s long-term safety and efficacy in treating FPHL.

Female pattern hair loss, characterized by progressive hair thinning primarily over the crown and frontal scalp regions, affects a significant proportion of women worldwide, exerting profound psychological and emotional impact. Despite its prevalence, treatment options have traditionally been limited, with topical minoxidil and oral medications like spironolactone comprising the mainstay of therapy.

However, the emergence of botulinum toxin A, commonly known for its cosmetic applications in wrinkle reduction, heralds a promising alternative for FPHL sufferers. Xiuzu Song, The Department of Dermatology, Hangzhou Third People’s Hospital, Hangzhou City, China, and colleagues aimed to assess the safety and efficacy of subcutaneous injections of Botulinum Toxin Type A in FPHL treatment.

The study included outpatients with FPHL who exhibited an allergic reaction to minoxidil solution. FPHL diagnosis was established through trichoscopy and clinical examination. Inclusion criteria involved patients with no prior treatment within the last year and without comorbidities.

BTA, specifically 100 units, was mixed with 2 mL of 0.9% normal saline. Twenty injection target sites, spaced 2–3 cm apart, were symmetrically marked on the scalp’s hairless area. At each target site, a dosage of five units was injected intradermally. Scalp’s representative photographs and dermoscopic images were captured before and after three months of treatment.

The study included ten women with FPHL, aged between 26 and 40 years. The average age was 30.3 ± 4.64 years, and all patients had a positive family history of Androgenetic Alopecia. The average disease duration was 3.70 ± 1.42 years.

The study led to the following findings:

  • According to patients’ self-assessment, after one month of treatment, 10 FPHL patients reported experiencing moderate to marked improvement in symptoms related to scalp oil secretion.
  • Three months later, dermatological assessments showed that three had mild improvement, six had no change, and one had a worsening condition.
  • No adverse effects were observed.

The study showed that the effectiveness of Botulinum Toxin Type A for treating Female Pattern Hair Loss treatment is limited to 3 months. However, it can be considered for tentative use after effective communication with patients.

The study limitations were the small sample size of this experiment, FPHL patients of different severity have not been grouped and stratified compared, and for a short follow-up period.

“The long-term safety and efficacy of BTA in treating FPHL require further observation and study,” the researchers concluded.

Reference:

Hu, L., Dai, Y., Zhang, H., Wu, Y., Wang, T., & Song, X. (2024). Efficacy and safety of botulinum toxin A in the treatment of female pattern hair loss. Skin Research and Technology, 30(4), e13696. https://doi.org/10.1111/srt.13696

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Study reveals long-term asthma control with tezepelumab beyond treatment cessation

UK: In a significant stride forward in asthma treatment research, the extended follow-up from the 2-year DESTINATION study sheds light on the dynamics of biomarkers and clinical outcomes following the cessation of tezepelumab, a novel biologic therapy. The findings offer valuable insights into the long-term effects of tezepelumab discontinuation on asthma control and inflammatory biomarkers.

“Our analysis demonstrates the benefits of continued tezepelumab treatment in managing patients with severe, uncontrolled asthma, compared with stopping treatment after two years,” the researchers stated in Annals of Allergy, Asthma & Immunology. Tezepelumab for severe asthma maintained its efficacy after two years of treatment cessation.

The analysis revealed that biomarker suppression, and improved clinical outcomes achieved during two years of treatment with tezepelumab did not rebound but gradually waned after cessation of tezepelumab treatment in patients with severe, uncontrolled asthma. During the 40-week follow-up period after treatment cessation, none of the outcomes assessed returned to baseline levels. 

The DESTINATION study, a landmark trial in asthma management, evaluated the efficacy and safety of tezepelumab, a monoclonal antibody targeting thymic stromal lymphopoietin (TSLP), in patients with severe, uncontrolled asthma. It found that long-term tezepelumab treatment resulted in reduced asthma exacerbations, reduced biomarker levels, and improved lung function and symptom control in patients with severe, uncontrolled asthma.

Building upon the initial findings, in the extended follow-up, Christopher E. Brightling, University of Leicester, Leicester, UK, and colleagues explored the time course of changes in biomarkers and clinical manifestations following treatment cessation after two years of tezepelumab treatment.

DESTINATION was a two-year, phase 3, multicenter, randomized, placebo-controlled, double-blind study of tezepelumab treatment in severe asthma patients (12–80 years old). Patients received their last treatment doses at week 100 and could enroll in an extended follow-up (EFU) period from week 104 to 140.

Change over time in clinical outcomes and key biomarkers were assessed in tezepelumab versus placebo recipients for 40 weeks after stopping treatment. Of 569 patients enrolled in the EFU period, the analysis included 426 patients (289 received tezepelumab and 137 placebo).

The researchers reported the following findings:

  • Over the 40 weeks after the last tezepelumab dose, there was a gradual increase from weeks 4–10 in blood eosinophil counts (BEC), fractional exhaled nitric oxide (FeNO) levels and Asthma Control Questionnaire-6 scores, with gradual reduction in pre-bronchodilator forced expiratory volume in 1 second such that BECs, FeNO levels and clinical outcomes returned to placebo levels; however, none of these outcomes returned to baseline levels.
  • Total immunoglobulin E levels increased from week 28 and remained well below placebo and baseline levels during the 40 weeks after the last tezepelumab dose.

“The overall results of this analysis demonstrate the benefits of continuation of tezepelumab treatment in the management of asthma in patients with severe, uncontrolled asthma, compared with stopping treatment after 2 years,” the study stated.

In conclusion, the extended follow-up from the DESTINATION study provides valuable insights into the long-term effects of tezepelumab cessation on biomarkers and clinical outcomes in patients with severe asthma. These findings hold promise for the development of targeted therapies and personalized treatment approaches, ultimately improving the lives of individuals living with this chronic respiratory condition.

Reference:

Brightling CE, Caminati M, Llanos JP, Caveney S, Kotalik A, Griffiths JM, Lundahl A, Israel E, Pavord ID, Wechsler ME, Porsbjerg C, Corren J, Gołąbek M, Martin N, Ponnarambil S. Biomarkers and clinical outcomes after tezepelumab cessation: extended follow-up from the 2-year DESTINATION study. Ann Allergy Asthma Immunol. 2024 Apr 30:S1081-1206(24)00280-1. doi: 10.1016/j.anai.2024.04.031. Epub ahead of print. PMID: 38697286.

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Renal Pelvis Urine Density Linked to Severe Infections in Post-Lithotripsy Patients: Study

China: In a groundbreaking multi-center prospective study, researchers have unearthed a crucial association between renal pelvis urine density and the peril of severe infectious complications in patients with symptom-free hydronephrosis following shock wave lithotripsy (SWL). The findings, which have significant implications for post-lithotripsy patient care, were published in the latest edition of the renowned medical journal Urolithiasis.

The study revealed a positive linear association between Hounsfield units (HU) in renal pelvis urine and the risk of severe infectious complications in patients with ureteral stones and symptom-free hydronephrosis after SWL, irrespective of gender, age, BMI, stone location, stone size, and hydronephrosis grade. The findings might be helpful in the SWL treatment decision-making process.

“There was a linear association between higher HU values and increased infection risk, & a cut-off value of 12.0 HU was determined, providing 85.94% specificity and 78.59% sensitivity,” the researchers reported.

Shock wave lithotripsy, a commonly employed non-invasive procedure for kidney stone removal, has revolutionized urological practice over the past few decades. However, despite its effectiveness, certain patients develop symptom-free hydronephrosis post-SWL, posing a clinical conundrum regarding optimal management strategies and risk assessment for potential complications. So, finding easy-to-obtain and reliable predictors of severe infectious complications after shock wave lithotripsy is a major clinical need, particularly in symptom-free hydronephrosis.

Zhenhua Li, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China, and colleagues aimed to prospectively investigate the predictive value of Hounsfield units in renal pelvis urine for the risk of severe infectious complications in patients with ureteral stones and symptom-free hydronephrosis after SWL.

For this purpose, the researchers conducted a multi-center prospective study from June 2020 to December 2023. The HU of renal pelvis urine was measured by non-enhanced computed tomography. The severe infectious complications included septic shock, sepsis, and systemic inflammatory response syndrome. Finally, the researchers enrolled 1,436 patients with ureteral stones.

The researchers reported the following findings:

  • 8.9% of patients experienced severe infectious complications after SWL treatment.
  • After adjusting confounding variables, compared with the patients in the lowest renal pelvis urine density quartile, the OR for the highest quartile was 32.36.
  • There was a positive linear association between the HU value of renal pelvis urine and the risk of severe infectious complications after SWL.
  • This association was also seen stratified by age, gender, BMI, stone size, stone location and hydronephrosis grade.
  • The nonlinear association employed by restricted cubic splines is not statistically significant.
  • The AUROC and 95%CI of renal pelvis urine density were 0.895.
  • The cut-off value was 12.0 HU with 78.59% sensitivity and 85.94% specificity.

“The findings underscored the potential of renal pelvis urine density, measured in HU, as a reliable predictor for infectious complications post-SWL in patients with ureteral stones and symptom-free hydronephrosis,” the researchers wrote.

Reference:

Liu, D., Liu, J., Li, Z. et al. The association between renal pelvis urine density and the risk of severe infectious complications in patient with symptom-free hydronephrosis after shock wave lithotripsy: a multi-center prospective study. Urolithiasis 52, 72 (2024). https://doi.org/10.1007/s00240-024-01572-5

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Cytisinicline can help people quit vaping, shows JAMA study

Eleven million U.S. adults use e-cigarettes to vape nicotine, and about half of them say that they want to stop, but many have trouble doing so because nicotine is an addictive drug.

A plant-based medication called cytisinicline may be an effective therapy to help them stop vaping, according to the results of a new clinical trial co-led by an investigator from Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system. The trial’s findings are published in JAMA Internal Medicine.

In the double-blind randomized clinical trial, 160 adults who vaped nicotine but did not currently smoke cigarettes were assigned to take either oral cytisinicline or placebo tablets for 12 weeks. All participants had weekly behavioral support to stop vaping.

At the end of treatment, participants receiving cytisinicline were more than twice as likely as those receiving placebo to have successfully abstained from vaping for weeks 9 to 12 (31.8% vs 15.1%, p=.04). The drug was well tolerated, with comparable rates of side effects between the groups. The study was conducted at Massachusetts General Hospital and 4 other sites.

“No medication has been approved by the FDA for vaping cessation in the United States,” said lead author Nancy A. Rigotti, MD, director of Massachusetts General Hospital’s Tobacco Research and Treatment Center and a professor of medicine at Harvard Medical School. “Our study indicates that cytisinicline might be an option to fill this gap and help adult vapers to stop using e-cigarettes.”

The team tested cytisinicline for vaping because the drug binds to nicotine receptors on brain cells. In their previous clinical trial, the research team found that cytisinicline helped people to quit smoking traditional cigarettes. They hypothesized that it might also help people to stop vaping nicotine. “The results of our study need to be confirmed in a larger trial with longer follow-up,” said Rigotti, “but they are promising.”

Reference:

Rigotti NA, Benowitz NL, Prochaska JJ, et al. Cytisinicline for Vaping Cessation in Adults Using Nicotine E-Cigarettes: The ORCA-V1 Randomized Clinical Trial. JAMA Intern Med. Published online May 06, 2024. doi:10.1001/jamainternmed.2024.1313.

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Mindfulness training enhances opioid addiction treatment: JAMA

Supplementing standard opioid addiction treatment with Mindfulness Oriented Recovery Enhancement (MORE)-an intervention that incorporates mindfulness training, savoring skills, and cognitive reappraisal-cuts program dropout rates by 59 percent and relapses by 42 percent, according to Rutgers-led research.

These trial results come from Rutgers Health amid unprecedented opioid abuse. An estimated 10 million Americans misuse opioids or have opioid use disorder, while annual overdose deaths have exceeded 80,000.

Treatment with methadone or buprenorphine-alone or in combination with cognitive behavioral therapy-is imperfect. Half of all people drop out of treatment within a year, and half of all people who continue treatment keep using opioids.

“Better treatment protocols could save thousands of lives per year, and the data we have from our pilot study and this phase II trial suggest mindfulness training may create a genuinely better treatment protocol,” said Nina Cooperman, an associate professor of psychiatry at Rutgers Robert Wood Johnson Medical School and first author of the study published in JAMA Psychiatry.

Mindfulness training teaches people to focus on the present moment, without judgment, and on sensory inputs such as the feeling of breathing in and out. Previous studies demonstrating that such training can prevent addiction to opioid pain medication led Cooperman’s team to ask whether similar techniques could help people who already have an opioid use disorder.

A small pilot study found that mindfulness training combined with methadone treatment produced good outcomes. The pilot’s success paved the way for this larger study, which, in turn, has justified two large-scale studies that could change standards of care.

The current trial provided eight two-hour sessions to 77 of 154 patients in methadone treatment for opioid use disorder.

“Opioid use disorder changes your brain so that opioid use becomes the only thing that feels rewarding. MORE helps people retrain themselves to find healthy experiences rewarding again by focusing mindfully on the taste of a meal, the beauty of a landscape or the smell of a flower,” said Cooperman, who added the program literally includes observing and smelling roses during sessions.

Mindfulness training also gives people another tool for handling cravings.

“Cognitive behavioral therapy, which is common in treatment programs, teaches people to reframe their thoughts and distract themselves from cravings,” Cooperman said. “Mindfulness training teaches them to stay present with the craving and notice that they pass. Both strategies can work, so both are valuable.”

The success of mindfulness training in Cooperman’s study may stem from its ability to help patients manage pain. Most patients began the study with significant chronic pain-and, thus, a strong incentive to use pain-killing opioids-but patients who received MORE reported a 10 percent reduction in pain over the 16 weeks of the study.

Looking forward, Cooperman and her team are working on larger studies, which are designed to provide further evidence for the efficacy of MORE and to optimize protocols for use in the real world.

“We still have lots of open questions. How can we train clinicians to implement MORE in treatment programs? What is the best structure for implementing MORE-in-person or virtual? Our current research is working to answer some of these questions,” Cooperman said. “The findings from this study suggest MORE really can improve outcomes for a lot of people in substance abuse treatment.”

Reference:

Cooperman NA, Lu S, Hanley AW, et al. Telehealth Mindfulness-Oriented Recovery Enhancement vs Usual Care in Individuals With Opioid Use Disorder and Pain: A Randomized Clinical Trial. JAMA Psychiatry. 2024;81(4):338–346. doi:10.1001/jamapsychiatry.2023.5138.

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