Tailoring Pain Management: Study Sheds Light on Enhancing Living Liver Donor Outcomes Through Innovative Analgesia

HEADING: Tailoring Pain Management: Study Sheds Light on Enhancing Living Liver Donor Outcomes Through Innovative Analgesia

India: A recent review published online in Apollo Medicine has shed light on the evolving strategies for pain management in living liver donors undergoing hepatectomy. 

The review emphasizes the need for tailored analgesic approaches that consider individual patient characteristics and requirements. It highlights the potential advantages of adopting innovative methods to improve pain management, decrease opioid use, and ultimately enhance outcomes and satisfaction for living liver donors undergoing hepatectomy.

Speaking on the study’s relevance in the current medical landscape, the lead author, Dr. Ashish Malik, the Department of Anaesthesia and Critical Care at Indraprastha Apollo Hospital in New Delhi, India, shared his insights with Medical Dialogues:

“Donor analgesia has been of paramount importance for the development of the living donor liver transplant program, serving as the cornerstone for motivating donation. Multiple methods for providing pain relief have been adopted. This article contributes to discussing the merits and demerits of various techniques and explores how a multimodal approach can be formulated to ensure donor safety. 

Dr. Malik also highlighted the unique aspects of the study, stating, “This review article provides in-depth knowledge about all available methods for donor analgesia, based on which a blended approach can be formulated.” His insights emphasize the comprehensive nature of the research, which aims to enhance pain management strategies for living liver donors.

The study authors note that donor hepatectomy is a complex surgical procedure that often leads to considerable postoperative pain, affecting both short-term recovery and long-term outcomes. Effective pain management is essential for the well-being of living liver donors and for optimizing their overall experience. The review by Dr. Malik and the team seeks to offer a thorough overview of current practices and emerging strategies in analgesic management for donor hepatectomy.

For this purpose, the team conducted searches on PubMed and Google Scholar to identify relevant materials. Their evaluation included review articles, clinical trials, retrospective studies, observational studies, and case-control studies. The review explores recent advancements in pain management, including enhanced recovery after surgery protocols, personalized analgesic regimens, and innovative pharmaceutical agents. Additionally, it examines the role of psychological factors and patient-centered care in shaping postoperative pain experiences.

The review revealed the following findings:

  • The traditional approach to pain management employs a multimodal strategy that combines opioids, non-steroidal anti-inflammatory drugs, and regional anesthesia techniques.
  • Concerns about opioid-related side effects and potential complications have led to a re-evaluation of analgesic protocols.
  • Alternative methods, such as thoracic epidural analgesia, transversus abdominis plane blocks, and continuous wound infusion systems, are gaining attention for their ability to reduce opioid use and improve recovery outcomes.

Dr. Malik highlighted the implications and key findings of the review, stating that the article aims to enhance recovery after surgery by establishing a standardized approach to pain management. He emphasized the significance of regional anesthesia techniques and the use of novel pharmaceutical agents such as magnesium, dexmedetomidine, gabapentin, and ketamine, all of which can help reduce opioid consumption during these procedures. As surgical methods evolve from open donor hepatectomies to laparoscopic and robotic techniques, these strategies are becoming increasingly relevant.

However, Dr. Malik noted that there is still limited research data in the field of donor analgesia. Randomized controlled trials involving large patient populations are necessary to determine the most effective techniques for managing donor pain. He stressed the importance of focusing future research on acute and chronic pain scores in living donors, as these factors directly influence the quality of life for donors.

Reference:

Malik, A., & Pal, A. (2024). Analgesia for Donor Hepatectomy: Recent Perspectives. Apollo Medicine.https://doi.org/10.1177/09760016241248310

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Ultra processed food intake effective in reducing type 2 diabetes mellitus risk: Lancet

A recent study by Samuel Dicken and team suggests concentrating on cutting back on the consumption of particular ultra-processed foods (UPF) in order to minimize the risk of type 2 diabetes. The findings of this study were published in The Lancet Regional Health – Europe journal.

People who have type 2 diabetes mellitus also have a higher risk of all-cause mortality and other cardiometabolic disorders, which lowers their quality of life. The question of whether diets heavy in ultra-processed foods (UPF) present health concerns in addition to those related to diet quality is up for dispute. UPF consumption is rising globally and accounts for a considerable amount of dietary intake. Increased UPF consumption have been linked to detrimental health effects, including as obesity and weight gain, as well as cardiovascular disease. Thus, the relationship between the degree of food processing and the occurrence of type 2 diabetes mellitus was investigated in this study.

The European Prospective Investigation into Cancer and Nutrition (EPIC) prospective cohort analysis was used for this study. Using dietary questionnaires, dietary consumption was measured at baseline and categorized into four categories namely, processed food (PF), unprocessed/minimally processed food (MPF), processed culinary ingredients (PCI), and UPF. Cases of type 2 diabetes mellitus were confirmed using a variety of techniques. In order to assess the correlations between MPF + PCI, PF, and UPF consumption and incidence type 2 diabetes mellitus, Cox regression and statistical substitution analysis were employed. UPF sub-group analysis was done to look into any heterogeneity in the relationship between UPF and incidence type 2 diabetes mellitus.

  • The key outcomes of this study found 14,236 instances of type 2 diabetes mellitus over a 10.9-year follow-up of 311,892 people.
  • Each 10% increase in total daily food consumption from UPF (%g/day) was related with 17% greater incidence of type 2 diabetic mellitus.
  • Each 10% increase in MPF + PCI or PF consumption was linked with a decreased incidence of type 2 diabetes mellitus.
  • Replacing UPF with MPF + PCI or PF was related with a decreased incidence of type 2 diabetes mellitus.
  • Also, there was variation between UPF subgroups, with breads, biscuits, and sweets and desserts, morning cereals, and plant-based alternatives being related to a decreased incidence of type 2 diabetes mellitus.

Overall, higher UPF consumption was linked with an increase in incidence type 2 diabetes mellitus, while higher intakes of less processed foods were associated with a decrease in the incidence of type 2 diabetes mellitus.

Source:

Dicken, S. J., Dahm, C. C., Ibsen, D. B., Olsen, A., Tjønneland, A., Louati-Hajji, M., Cadeau, C., Marques, C., Schulze, M. B., Jannasch, F., Baldassari, I., Manfredi, L., Santucci de Magistris, M., Sánchez, M.-J., Castro-Espin, C., Palacios, D. R., Amiano, P., Guevara, M., van der Schouw, Y. T., … Batterham, R. L. (2024). Food consumption by degree of food processing and risk of type 2 diabetes mellitus: a prospective cohort analysis of the European Prospective Investigation into Cancer and Nutrition (EPIC). In The Lancet Regional Health – Europe (p. 101043). Elsevier BV. https://doi.org/10.1016/j.lanepe.2024.101043

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Monlunabant found effective for weight loss obesity and metabolic syndrome in phase 2a trial

Novo Nordisk today announced that in a phase 2a trial, monlunabant, a novel oral cannabinoid receptor 1 inverse agonist, was associated with weight loss in people with obesity and metabolic syndrome. Monlunabant, formerly INV-202, was part of the acquisition of Inversago Pharmaceuticals Inc. announced in August 2023.

The trial investigated the efficacy and safety of a once-daily 10 mg, 20 mg and 50 mg dose of monlunabant compared to placebo on body weight after 16 weeks in 243 people with obesity and metabolic syndrome1. People were equally randomised among the four treatment arms.

From a baseline body weight of 110.1 kg, all doses of monlunabant achieved a statistically significant weight loss compared to placebo. After 16 weeks of treatment, people treated with a once-daily 10 mg dose of monlunabant achieved a weight loss of 7.1 kg compared to a reduction of 0.7 kg with placebo2. Limited additional weight loss was seen at higher doses of monlunabant.

In the trial, the most common adverse events were gastrointestinal, with the vast majority being mild to moderate and dose dependent. Reporting of mild to moderate neuropsychiatric side effects, primarily anxiety, irritability, and sleep disturbances, was more frequent and dose dependent with monlunabant compared to placebo. No serious adverse events were reported in relation to neuropsychiatric side effects.

“The phase 2a results indicate the weight-lowering potential of monlunabant and that further work is needed to determine the optimal dosing to balance safety and efficacy,” said Martin Holst Lange, executive vice president and head of Development at Novo Nordisk. “Obesity is a complex disease with a significant unmet need, and as an oral small molecule having a new mechanism of action, monlunabant is one of the novel projects in our pipeline with the potential of treating obesity.”

Based on the results, Novo Nordisk expects to initiate a larger phase 2b trial in obesity to further investigate dosing and the safety profile of monlunabant over a longer duration in a global population. The phase 2b trial is expected to be initiated in 2025.About monlunabant and CB1 Monlunabant is an inverse agonist of the CB1 receptor which plays an important role in metabolism and appetite regulation in the central nervous system as well as in peripheral tissues such as adipose tissues, the gastrointestinal tract, kidneys, liver, pancreas, muscles and lungs. CB1 plays an important role in appetite regulation and cardiometabolic pathways.

About monlunabant and CB1

Monlunabant is an inverse agonist of the CB1 receptor which plays an important role in metabolism and appetite regulation in the central nervous system as well as in peripheral tissues such as adipose tissues, the gastrointestinal tract, kidneys, liver, pancreas, muscles and lungs. CB1 plays an important role in appetite regulation and cardiometabolic pathways.

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Gadolinium Enhancement Improves Sudden Cardiac Death in kids with Hypertrophic Cardiomyopathy: Study

Researchers have found that late gadolinium enhancement (LGE) by cardiovascular magnetic resonance imaging (CMR) is an important predictor of sudden cardiac death in children and adolescents suffering from hypertrophic cardiomyopathy (HCM). This finding suggests the inadequacy of currently used methods to predict sudden cardiac death among this younger population, where the risk stratification of patients is a challenging issue. A study was recently published in the journal JAMA Cardiology by Raymond H. and colleagues.

Hypertrophic cardiomyopathy, a genetic heart disorder characterised by hypertrophied walls of the heart, typically predisposes patients to serious arrhythmias and sudden cardiac death (SCD). This study enrolled 700 patients with HCM less than 21 years old who were undergoing CMR imaging from April 2015 to September 2022. Overall, the cohort was predominantly males (74.0%) with a median age of 14.8 years (IQR, 11.9-17.4). Follow-up was performed in all participants for about 2 years to monitor events for SCD or resuscitated cardiac arrests and appropriate defibrillator discharges.

The study established several important findings:

• LGE was detected in 230 patients (32.9%), with a mean burden of 5.9% (SD, 7.3%) of the left ventricular myocardium.

• SCD or equivalent events occurred in 35 patients (5.0%) during the follow-up period.

• Patients whose myocardium was covered by LGE in 10% or greater were at high risk for SCD; the unadjusted hazard ratio was 2.19 (95% CI, 1.59-3.02; P < .001).

• The original HCM Risk-Kids score was at 0.66 (95% CI, 0.58 to 0.75); with the inclusion of LGE, the score was at 0.73 (95% CI, 0.66 to 0.81).

• Similar increases were noted in the Precision Medicine in Cardiomyopathy score, which, when combined with the LGE burden, rose from 0.68 (95% CI, 0.49 to 0.77) to 0.73 (95% CI, 0.64 to 0.82).

The researchers concluded that this study identifies a prognostic value of LGE in pediatric and adolescent patients with hypertrophic cardiomyopathy, especially if quantitative LGE analysis is used as the strongest predictor for death due to arrhythmias.

Reference:

Chan, R. H., van der Wal, L., Liberato, G., Rowin, E., Soslow, J., Maskatia, S., Chan, S., Shah, A., Fogel, M., Hernandez, L., Anwar, S., Voges, I., Carlsson, M., Buddhe, S., Laser, K. T., Greil, G., Valsangiacomo-Buechel, E., Olivotto, I., Wong, D., … Grosse-Wortmann, L. (2024). Myocardial scarring and sudden cardiac death in young patients with hypertrophic cardiomyopathy: A multicenter cohort study. JAMA Cardiology. https://doi.org/10.1001/jamacardio.2024.2824

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Adhesive 2-octyl safe and effective wound closure technique for patients undergoing TKA: study

Good wound healing is critical to infection prophylaxis and satisfactory rehabilitation in Total Knee Arthroplasty (TKA). Currently, two techniques, i.e., barbed continuous subcuticular suture without skin adhesive or combined use skin adhesive (n-butyl-2) are being used for superficial wound closure of TKA. While a new skin adhesive (2-octyl) with self-adhesive mesh has been employed as an alternative to conventional surgical skin closure in TKA, its superiority, especially in reducing wound complications and improving wound cosmetic outcomes has not been investigated.

Liu et al conducted a study to compare 2-octyl, n-butyl-2, and no skin adhesive in terms of safety and efficacy in TKA superficial wound closure. It has been published in ‘Arthroplasty’ journal.

The authors conducted a multicenter, prospective, randomized controlled study in 105 patients undergoing primary TKA. Each patient’s knee was randomized to receive 2-octyl, n-butyl-2, or no skin adhesive skin closure with all using barbed continuous sutures in deep tissue. Wounds were followed 1, 3, 5 days, 2, 6 weeks, and 3 months after surgery. Wound discharge, complications, cosmetic outcomes, patient satisfaction, and wound-related costs were compared among these three methods.

Key findings of the study were:

• Wound discharge was less in 2-octyl group and n-butyl-2 group than in non-adhesive group at 1 day, with the discharge only being less in 2-octyl group than in the non-adhesive group at day 3 and day 5 days (P<0.05).

• There was no statistical difference in the incidence of other wound complications among the groups (P>0.05).

• The 2-octyl group achieved better cosmetic efects than the other two groups in 6 weeks and 3 months (P<0.05).

• Compared to the non-adhesive group, 2-octyl group scored higher in overall patient satisfaction score in 2 weeks and incurred lower costs (P<0.05).

The authors concluded that – “Skin closure in TKA using 2-octyl adhesive material showed superiority to no skin adhesive or n-butyl-2. It reduced wound discharge and improved cosmetic outcomes, without increasing wound complications. In addition, the use of 2-octyl could achieve excellent patient satisfaction and lowered costs compared to no skin adhesive. Our study demonstrated that the use of 2-octyl was a safe and effective as a wound closure technique in patients undergoing TKA.”

2-octyl: 2 -Octyl cyanoacrylate skin adhesive with flexible self-adhesive polyether mesh (DERMABOND PRINEO Ethicon, Inc)

n-butyl-2: N-butyl-2-cyanoacrylate skin adhesive (HISTOACRYL® B.Braun, Melsungen, German)

Further reading:

Comparison of the safety and efficacy of three superficial skin closure methods for multi-layer wound closure in total knee arthroplasty: a multicenter, prospective, randomized controlled trial. Liu et al Arthroplasty (2024) 6:51 https://doi.org/10.1186/s42836-024-00271-1

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Genetic link between bipolar disorder and epilepsy unveiled in groundbreaking study

A team of researchers from the Chinese Academy of Sciences has uncovered compelling evidence of a genetic link between bipolar disorder type I (BD-I) and epilepsy, potentially revolutionizing our understanding of these complex neuropsychiatric conditions. The study, published in Genomic Psychiatry on September 30, 2024, reveals shared genetic variants and a causal relationship between the two disorders, opening new avenues for research and treatment.

Led by Dr. Ming Li from the Kunming Institute of Zoology, the study utilized genome-wide association study (GWAS) data from European populations, encompassing over 26,000 epilepsy cases and 25,000 BD-I cases, along with their respective controls. The researchers employed advanced statistical methods to uncover the genetic underpinnings shared by these seemingly distinct neurological conditions.

Key findings of the study include:

1. A significant positive genetic correlation (rg = 0.154) between BD-I and epilepsy

2. Identification of approximately 1,300 genetic variants influencing both conditions

3. Discovery of six independent genomic loci significantly linked to BD-I and epilepsy

4. A notable causal effect of epilepsy on BD-I (P = 0.0079)

Dr. Li explains, “Our findings provide a novel rethinking of the connection between epilepsy and bipolar disorder, which aligns with the clinical observation that mood stabilizers are effective in treating both illnesses.”

One of the most intriguing discoveries is the role of the SP4 gene, which showed strong associations with both BD-I and epilepsy. The SP4 protein, modulated by neuronal activity, has been linked to mood disorder management through its stabilization by lithium, a common mood stabilizer. This connection raises an important question: Could the SP4 gene be a key target for developing more effective treatments for both bipolar disorder and epilepsy?

The study’s implications extend beyond these two conditions. By demonstrating shared genetic underpinnings, it suggests that other neuropsychiatric disorders might have more in common than previously thought. This leads to an intriguing question: How might this genetic overlap inform our understanding of other brain disorders, such as schizophrenia or autism spectrum disorders?

Furthermore, the research highlights the potential for personalized medicine approaches. As Dr. Li notes, “Understanding the genetic basis of these disorders could lead to more targeted treatments based on an individual’s genetic profile.” This raises another critical question: How can we translate these genetic insights into practical, personalized treatment strategies for patients with BD-I or epilepsy?

The study also sheds light on the complex relationship between mood regulation and seizure activity in the brain. Given the shared genetic factors, researchers are now pondering: What specific neurobiological mechanisms link mood instability in bipolar disorder with the electrical disturbances seen in epilepsy?

While the findings are groundbreaking, the researchers acknowledge limitations, including the focus on European populations and the reliance on public GWAS data without sex-specific information. This opens up avenues for future research: How do these genetic associations manifest across different ethnic groups, and are there sex-specific genetic factors at play in the development of BD-I and epilepsy?

As the scientific community digests these findings, the potential for collaborative research across neurology and psychiatry becomes evident. Could this study catalyze a new era of interdisciplinary research aimed at understanding and treating complex brain disorders?

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Kidney dysfunction may predict sudden cardiac death in patients with heart failure: Study

Patients with congestive heart failure (CHF) having a compromised blood supply, are at greater risk of sudden cardiac death (SCD). With an estimated incidence as high as 22% among these patients, current clinical guidelines recommend using implantable cardioverter defibrillators (ICDs) to help mitigate the risk of SCD.

Although the application of ICDs in patients with CHF is backed by substantial evidence, these studies did not include people with chronic kidney disease (CKD), who are an important clinical population. In other words, it is unclear whether the use of ICDs is justified in patients with CKD, especially with mild and moderate presentations, given the inherent risk involved in installing these devices.

To address this knowledge gap, researchers led by Associate Professor Yoshihiro Sobue from Fujita Health University, Japan, investigated to what extent kidney function can be a good predictor for the risk of SCD. This study was published in ESC Heart Failure on June 10 2024, and was co-authored by Hideo Izawa, also from Fujita Health University, and Eiichi Watanabe from Fujita Health University Bantane Hospital.

Elaborating on the rationale behind this examination, Dr. Sobue says, “The objective of our study was to prospectively investigate the risk factors for SCD in a cohort of over 1,500 patients hospitalized with CHF classified based on the left ventricular ejection fraction (LVEF) and the New York Heart Association (NYHA) functional class, as well as the potential role of kidney function as a determinant of SCD.” Adding further on the importance of using renal dysfunction for SCD, he says, “The determination of renal dysfunction as an independent risk factor of SCD is important because patients with moderate-to-severe renal dysfunction were excluded in the studies on which current ICD implantation guidelines are based.”

The study ultimately included 1,676 patients who had visited Fujita Health University Hospital for decompensated heart failure. During the follow-up period, 198 of these patients suffered from SCD. Among these events, 23% occurred within 3 months of discharge.

On conducting statistical analyses of the gathered data, the research team identified two key independent predictors for the risk of SCD following discharge. The first was LVEF, which is already considered in the current guidelines. The second was the estimated glomerular filtration rate (eGFR), which is a measure of how well the kidneys can filter blood.

By adding eGFR as a predictor alongside LVEF, regression models could predict SCD more accurately. However, as the researchers noted, the predictive power of kidney function in this way diminished over time, being more effective in the first few months after discharge. Coincidentally, roughly a quarter of all cases of SCD occurred within three months of discharge.

In summary, the findings of this study underline the importance of considering additional factors, such as kidney condition, when weighing the benefits of using ICD in a patient. “Refining the criteria for ICD implantation holds the potential for significantly improving the prevention of SCD and reducing the incidence of complications arising from unnecessary ICD implantations. Hopefully, applying an enhanced stratification methodology involving eGFR may yield better clinical outcomes,” remarks Dr. Sobue.

In the long term, these findings may steer the way for the revision of guidelines for the use of ICDs and improve the outcomes for patients with CHF, both with and without CKD.

Reference:

Yoshihiro Sobue, Eiichi Watanabe, Yusuke Funato, Masanobu Yanase, Hideo Izawa, Renal dysfunction is a time-varying risk predictor of sudden cardiac death in heart failure, ESC Heart Failure, https://doi.org/10.1002/ehf2.14892.

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Study Highlights Role of Surgical Factors in Post-Laryngectomy Hypocalcemia Management

Iran: A recent spanning eight years has shed light on the key factors contributing to post-surgical hypocalcemia (< 8.5 mg/dl) in laryngectomy patients.

“Although average calcium levels showed no significant change, adjusting for albumin levels revealed a decrease in postoperative calcium. Total thyroidectomy, neck dissection, pre-operative hypocalcemia, and prior radiotherapy emerged as robust predictors of post-laryngectomy hypocalcemia,” the researchers reported in the Indian Journal of Otolaryngology and Head & Neck Surgery.

Laryngeal cancer represents a prevalent form of advanced head and neck malignancy. Treatment typically involves surgery, radiation therapy, chemotherapy, or a combination thereof, for managing locally advanced cases. Despite its invasive nature, total laryngectomy is commonly recommended for T3-4 laryngeal cancers. Following neck compartment surgeries like laryngectomy, patients are susceptible to post-surgical hypocalcemia due to the potential development of hyperparathyroidism.

Against the above background, Mahdi Khajavi, Shahid Beheshti University of Medical Sciences, Tehran, Iran, and colleagues aimed to investigate the risk factors and prevalence of hypocalcemia in individuals following laryngectomy.

For this purpose, the researchers conducted a retrospective study investigating 50 consecutive laryngectomy patients over eight years. Data on medical history, demographic characteristics, surgical details, neck dissection laterality, pre- and post-operative calcium levels, and history of radiotherapy were collected.

Hypocalcemia was defined as calcium levels below 8.5 mg/dl or corrected calcium levels below 8.5 mg/dl. Statistical analyses included Wilcoxon signed-rank tests, paired t-tests, and binary logistic regression using R studio.

The study led to the following findings:

· The mean age of participants was 59 years, predominating males (94%) and habitual smokers (94%).

· Squamous cell carcinoma was the most prevalent (98%) pathological diagnosis, and various surgical techniques were employed.

· While initial comparisons showed no significant changes in calcium levels pre- and post-operatively, adjusting for albumin levels revealed a significant association.

· Logistic regression identified neck dissection, low pre-operative calcium, radiotherapy, and total thyroidectomy as significant predictors of postoperative hypocalcemia.

The findings showed that surgical factors such as total thyroidectomy and neck dissection, alongside albumin levels, significantly impact postoperative hypocalcemia, the researchers wrote.

“These findings emphasize the importance of vigilant monitoring and proactive measures to address calcium imbalance following laryngectomy,” they concluded.

Reference:

Zaker, A., Peyvandi, A., Fazli, M. et al. Investigating the Incidence and Risk Factors of Hypocalcemia After Laryngectomy. Indian J Otolaryngol Head Neck Surg (2024). https://doi.org/10.1007/s12070-024-04790-w

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Study Reveals Different CV Risks for Insomnia Medications: Z-Drugs Safe, Benzodiazepines Raise Concerns

China: As insomnia continues to affect millions globally, the choice of treatment options remains crucial for patient health. Recent studies highlight a significant distinction in cardiovascular (CV) risk between two common classes of sleep medications: Z-drugs and benzodiazepines. This differentiation underscores the importance of informed prescribing practices for those with sleep disorders.

A recent study published in the European Journal of Preventive Cardiology has revealed that Z-drugs for insomnia typically do not show a connection to cardiovascular issues, whereas benzodiazepines are associated with cardiovascular risks.

Z-drugs, including medications such as zolpidem, zaleplon, and eszopiclone, are frequently prescribed for short-term management of insomnia. They are generally preferred for their minimal impact on sleep architecture and relatively safer profile. Recent research suggests that these drugs do not carry a substantial risk of cardiovascular harm. In contrast, benzodiazepines, such as diazepam, lorazepam, and alprazolam, have been associated with a higher incidence of cardiovascular issues.

Yao Xie, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China, and colleagues aimed to examine the association between hypnotic agents and cardiovascular outcomes in general individuals with insomnia.

For this purpose, the researchers utilized a propensity score-matched cohort of UK Biobank (UKB) participants with insomnia. They applied the Cox proportional hazards model to estimate the relationship between regular use of hypnotic agents and various cardiovascular outcomes, including coronary heart disease (CHD), heart failure (HF), stroke, and cardiovascular mortality.

To ensure robustness, they conducted sensitivity analyses using inverse probability of treatment weighting, competing risk models and shared frailty models. Additionally, drug-target Mendelian randomization (MR) analyses were employed to further investigate the association between the therapeutic targets of hypnotics and cardiovascular diseases.

The study led to the following findings:

  • During a median follow-up of 14.3 years, the matched cohort documented a total of 929 CHD cases, 360 HF cases, 262 stroke cases, and 180 cardiovascular deaths.
  • There was no significant association between Z-meds and CHD, stroke, and cardiovascular mortality.
  • Benzodiazepine use was significantly associated with the increased risk of CHD, HF, and cardiovascular mortality.
  • The inverse probability of treatment weighting, competing risk models, and shared frailty models did not alter the above associations.
  • Drug-target MR analyses corroborated Z-meds’ safety in the general population regarding cardiovascular health.

“Our findings revealed varied associations between different types of hypnotics and the occurrence of cardiovascular events in individuals with insomnia,” the researchers wrote.

In the study, benzodiazepines were notably linked to a heightened risk of coronary heart disease, heart failure, and cardiovascular mortality. In contrast, observational and Mendelian randomization analyses found no evidence suggesting that Z-drugs pose a cardiovascular safety risk.

Reference:

Xie, Y., Zhu, S., Wu, S., Liu, C., Shen, J., Jin, C., Ma, H., & Xiang, M. Hypnotic Use and the Risk of Cardiovascular Diseases in Insomnia Patients. European Journal of Preventive Cardiology. https://doi.org/10.1093/eurjpc/zwae263

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How doxycycline for STI prevention affects the gut microbiome, unravels research

Taking a dose of the oral antibiotic doxycycline after a high-risk sexual encounter has dramatically reduced the incidence of sexually transmitted infections (STIs) in places where the strategy is being tried.

Despite its effectiveness, the new strategy, known as doxy-PEP, may come with risks, especially with chronic use. Experts worry about the impact on the community of gut bacteria, also known as the microbiome, and the potential that the antibiotic will give rise to resistant strains of bacteria. 

Now, using metagenomic sequencing to see the impact of doxycycline on the gut microbiome of those who took it frequently for six months, UC San Francisco researchers have found both reassurance and possible cause for concern. 

Doxy-PEP did not have much impact on the overall composition of bacterial communities in gastrointestinal tracts. But scientists noted signs of resistance building against tetracycline, the class of antibiotic that doxycycline belongs to, which could make it less effective. 

The study appears Oct. 3 in the journal Nature Medicine.

“While doxy-PEP did not appear to have global impacts on the gut microbiome, it did have impacts on the antimicrobial resistance of gut bacteria, both in terms of the proportion of tetracycline class resistance genes and the amount that were turned on, or expressed,” said Chaz Langelier, MD, PhD, an associate professor of medicine in UCSF’s Division of Infectious Diseases and senior author of the paper. “So, it’s not totally innocuous.”  

San Francisco’s high-profile STI prevention role 

Doxy-PEP is short for doxycycline post-exposure prophylaxis, and it involves taking two 100-milligram pills within 72 hours of condomless sex.

Prompted by early promising clinical trial results, San Francisco became the first city in the country in October of 2022 to recommend doxy-PEP to gay and bisexual men and transgender women with a history of having unprotected encounters with multiple partners.

In March of 2024, the San Francisco Department of Public Health released results showing that after about a year, the approach halved the incidence of chlamydia and early syphilis. In June, the U.S. Centers for Disease Control and Prevention (CDC) issued guidelines recommending doxy-PEP for these groups. It was the first new STI prevention tool to be adopted in decades.

But the widespread use of antibiotics raises concerns about resistance and the potential harmful impact on gut health, specifically the balance of bacteria and other microbes. Disruption can lead to diarrhea, nausea, fever and abdominal pain; and until now, there had been very limited research into these side effects. 

Working with the Chan Zuckerberg Biohub and scientists in Washington and Georgia, UCSF researchers studied participants from the recent doxy-PEP clinical trial in San Francisco and Seattle, led by Annie Luetkemeyer, MD, a professor of medicine in the Division of Infectious Diseases at UCSF. 

The study included 100 individuals who used doxy-PEP and 50 individuals who received standard-of-care and did not use doxy-PEP. Researchers analyzed rectal swabs collected at enrollment and after six months to study the presence of DNA and RNA from gut bacteria and their antibiotic resistance genes.

“While we found no major changes to the community of gut bacteria in doxy-PEP users, we saw that doxy-PEP users over time had increasing amounts of tetracycline resistance genes present in their gut,” said Victoria T. Chu, MD, MPH, an assistant professor of pediatrics in the Division of Global Health and Infectious Diseases at UCSF and a first author of the study. “It also appeared to be dose dependent, meaning the more doxy-PEP they used, the larger the increase was.” 

More research is needed to determine which gut bacteria are turning on these tetracycline-resistant genes to know whether this will lead to more doxycycline-resistant infections among both individuals taking doxy-PEP and in the greater community.

“Right now, it looks like the pros outweigh the cons,” Langelier said. “Especially given the dramatic rise in STIs, in particular syphilis, over the past decade.” 

Reference:

 Victoria T. Chu, Abigail Glascock, Deborah Donnell, Cole Grabow, Clare E. Brown, Ryan Ward, Christina Love, Katrina L. Kalantar, Stephanie E. Cohen, Chase Cannon, Michael H. Woodworth, Colleen F. Kelley, Connie Celum, Anne F. Luetkemeyer, Charles R. Langelier. Impact of doxycycline post-exposure prophylaxis for sexually transmitted infections on the gut microbiome and antimicrobial resistome. Nature Medicine, 2024; DOI: 10.1038/s41591-024-03274-2

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