Beta blockers delay age of onset and clinical symptom deterioration in Huntington disease: Study

A new study published in the Journal of American Medical Association showed that in motor-manifest Huntington disease (mmHD), β-blocker usage was linked to a slower rate of symptom deterioration and a delayed motor onset in preHD. An increased quantity of cytosine-adenine guanine (CAG) repeats in the HTT gene, which codes for the creation of the Huntingtin protein, is the cause of Huntington disorder (HD), a hereditary neurodegenerative illness.

The reduced parasympathetic and increased sympathetic tone are signs of autonomic nervous system dysfunction in HD patients. Cognitive, psychological, and motor deterioration are hallmarks of Huntington disease. By reducing HD’s elevated sympathetic tone, β-Blockers could have a therapeutic effect. Thus, Jordan Schultz and colleagues carried out this investigation to assess how β-blockers affect the beginning of motor diagnosis and the development of HD symptoms.

Using the Enroll-HD platform database (launched in September 2011 to the present), this observational, longitudinal multicenter study included propensity score-matched cohorts of patients with premanifest HD (preHD) and early motor-manifest HD (mmHD) that were either β-blocker users or nonusers. The patients using β-blockers who had genetically proven preHD (n = 4683 eligible participants) or mmHD (n = 3024 eligible participants) and were matched to comparable non-β-blocker users were included in the study. The chance of eventually being given a motor diagnosis of HD is one of the primary outcomes and metrics for preHD in the case of mmHD, the pace at which the symbol digit modalities test, total motor score, and total functional capacity score progress. After the initial analyses were finished, post hoc analyses were carried out to evaluate more clarifying hypotheses.

The 174 preHD β-blocker users in this study were well matched to the 174 preHD non-β-blocker users, with a mean age of 46.4 years and a mean cytosine-adenine guanine repeat length of 41.1. The annualized risk of obtaining a motor diagnosis was statistically significantly lower for preHD β-blocker users than for nonusers. In comparison to 149 mmHD non-β-blocker users, 149 mmHD β-blocker users had a mean age of 58.9 years and a mean cytosine-adenine guanine repeat length of 42.0.

When compared to matched nonusers, the β-blocker users saw a slower mean annualized deterioration in the symbol digit modalities test, total motor score, and total functional capacity score. Overall, these findings showed that β-blocker medication in HD was linked to a later age of onset and a slower rate of clinical symptom deterioration by indicating that β-blockers may have therapeutic promise in HD.

Source:

Schultz, J. L., Ogilvie, A. C., Harshman, L. A., & Nopoulos, P. C. (2024). β-Blocker Use and Delayed Onset and Progression of Huntington Disease. In JAMA Neurology. American Medical Association (AMA). https://doi.org/10.1001/jamaneurol.2024.4108

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Benralizamab, new treatment effective for attacks of asthma and COPD: Study

An injection given during some asthma and COPD attacks is more effective than the current treatment of steroid tablets, reducing the need for further treatment by 30%.

The findings, published today in The Lancet Respiratory Medicine, could be “game-changing” for millions of people with asthma and COPD around the world, scientists say.

Asthma attacks and COPD flare-ups (also called exacerbations) can be deadly. Every day in the UK four people with asthma and 85 people with COPD will tragically die. Both conditions are also very common, in the UK someone has an asthma attack every 10 seconds. Asthma and COPD costs the NHS £5.9B a year.

The type of symptom flare-up the injection treats are called ‘eosinophilic exacerbations’ and involve symptoms such as wheezing, coughing and chest tightness due to inflammation resulting from high amounts of eosinophils (a type of white blood cell). Eosinophilic exacerbations make up to 30% of COPD flare-ups and almost 50% of asthma attacks. They can become more frequent as the disease progresses, leading to irreversible lung damage in some cases.

Treatment at the point of an exacerbation for this type of asthma has barely changed for over fifty years, with steroid drugs being the mainstay of medication. Steroids such as prednisolone can reduce inflammation in the lungs but have severe side-effects such as diabetes and osteoporosis. Furthermore, many patients ‘fail’ treatment and need repeated courses of steroids, re-hospitalisation or die within 90 days.

Results from the phase two clinical trial ABRA study, led by scientists from King’s College London and sponsored by the University of Oxford, show a drug already available can be re-purposed in emergency settings to reduce the need for further treatment and hospitalisations. The multi-centre trial was conducted at Oxford University Hospitals NHS Foundation Trust and Guy’s and St Thomas’ NHS Foundation Trust.

Benralizamab is a monoclonal antibody which targets specific white blood cells, called eosinophils, to reduce lung inflammation. It is currently used for the treatment of severe asthma. The ABRA trial has found a single dose can be more effective when injected at the point of exacerbation compared to steroid tablets.

The study investigators randomised people at high risk of an asthma or COPD attack into three groups, one receiving benralizumab injection and dummy tablets, one receiving standard of care (prednisolone 30mg daily for five days) and dummy injection and the third group receiving both benralizumab injection and standard of care. As a double-blind, double-dummy, active-comparator placebo-controlled trial, neither the people in the study, or the study investigators knew which study arm or treatment they were given.

After 28 days, respiratory symptoms of cough, wheeze, breathlessness and sputum were found to be better with benralizumab. After ninety days, there were four times fewer people in the benralizumab group that failed treatment compared to standard of care with prednisolone.

Treatment with the benralizumab injection took longer to fail, meaning fewer episodes to see a doctor or go to hospital. There was also an improvement in the quality of life for people with asthma and COPD.

Lead investigator of the trial Professor Mona Bafadhel from King’s College London said: “This could be a game-changer for people with asthma and COPD. Treatment for asthma and COPD exacerbations have not changed in fifty years despite causing 3.8 million deaths worldwide a year combined.

“Benralizumab is a safe and effective drug already used to manage severe asthma. We’ve used the drug in a different way – at the point of an exacerbation – to show that it’s more effective than steroid tablets which is the only treatment currently available. The big advance in the ABRA study is the finding that targeted therapy works in asthma and COPD attacks. Instead of giving everyone the same treatment, we found targeting the highest risk patients with very targeted treatment, with the right level of inflammation was much better than guessing what treatment they needed.”

The benralizumab injection was administered by healthcare professionals in the study but can be potentially administered safely at home, in the GP practice, or in the Emergency Department. Benralizumab was safe in the study and similar in safety to many past studies.

Professor Mona Bafadhel said, “We hope these pivotal studies will change how asthma and COPD exacerbations are treated for the future, ultimately improving the health for over a billion people living with asthma and COPD across the world.”

Dr Sanjay Ramakrishnan, Clinical Senior Lecturer at the University of Western Australia, who is the first author of the ABRA trial and started the work while at the University of Oxford, said: “Our study shows massive promise for asthma and COPD treatment. COPD is the third leading cause of death worldwide but treatment for the condition is stuck in the 20th century. We need to provide these patients with life-saving options before their time runs out.

“The ABRA trial was only possible with collaboration between the NHS and universities and shows how this close relationship can innovate healthcare and improve people’s lives.”

Geoffrey Pointing, 77 from Banbury, who took part in the study, said: “Honestly, when you’re having a flare up, it’s very difficult to tell anybody how you feel – you can hardly breathe. Anything that takes that away and gives you back a normal life is what you want. But on the injections, it’s fantastic. I didn’t get any side effects like I used to with the steroid tablets. I used to never sleep well the first night of taking steroids, but the first day on the study, I could sleep that first night, and I was able to carry on with my life without problems. I want to add that I’m just grateful I took part and that the everyone involved in the ABRA study are trying to give me a better life.”

Dr Samantha Walker, Director of Research and Innovation, at Asthma + Lung UK, said: “It’s great news for people with lung conditions that a potential alternative to giving steroid tablets has been found to treat asthma attacks and chronic obstructive pulmonary disease (COPD) exacerbations. But it’s appalling that this is the first new treatment for those suffering from asthma and COPD attacks in 50 years, indicating how desperately underfunded lung health research is.

“Every four minutes in the UK, someone dies from a lung condition. Thousands more live with the terror of struggling to breathe every day. With your help, we’re fighting for more life-changing, life-saving research to transform the future for everyone living with breathing problems. Together, we’ll make sure that families everywhere never face a lung condition without the best treatment and care.

“Our vision is a world where everyone has healthy lungs. We can only get there with your help.” 

Reference:

Monoclonal antibody better than standard treatment for some types of asthma attacks and COPD flare-ups, phase II clinical trial results suggest, The Lancet Respiratory Medicine (2024).

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Dexmedetomidine associated with lower levels of oxidative stress in CABG patients, finds study

Patients with coronary artery disease generally rely on coronary artery bypass grafting (CABG) surgery for treatment. In cardiac procedures, oxidative stress levels can rise due to factors such as the CPB pump, ischemia, reperfusion injury, hemolysis, and neutrophil activation. Oxidative stress is linked to various health conditions, surgical interventions, and medications administered before, during, and after surgery. Recent study investigated the effects of dexmedetomidine, an alpha-2 agonist anesthetic agent, on oxidative stress in patients undergoing coronary artery bypass grafting (CABG) surgery. Thiol-disulfide homeostasis (TDH) was used as a biomarker to assess oxidative stress, as it plays a crucial role in antioxidant defense and can detect ischemia status in tissues.

The study included 60 patients undergoing elective on-pump CABG surgery, divided into two groups: those receiving dexmedetomidine (Group D) and those not receiving dexmedetomidine (Group C). Blood samples were collected at three time points: 30 minutes before anesthesia induction (T1), 30 minutes after aortic cross-clamp removal (T2), and at the end of surgery (T3). Thiol-disulfide homeostasis was assessed using a novel automated method.

The results showed that in patients receiving dexmedetomidine, lower postoperative levels of disulfide, disulfide/native thiol, and disulfide/total thiol, along with higher native thiol/total thiol, were observed compared to the control group. Postoperative native thiol and total thiol levels were similar for both groups.

The study found that the difference in native thiol levels between T1 and T2 was significantly smaller in the dexmedetomidine group compared to the control group. Additionally, the differences in native thiol and disulfide levels between T1 and T3 were also significantly smaller in the dexmedetomidine group.

Conclusion

The authors conclude that the use of dexmedetomidine in CABG surgery was associated with lower levels of oxidative stress, as evidenced by the thiol-disulfide homeostasis measurements. They suggest that the positive effects of dexmedetomidine on oxidative stress could be beneficial in CABG surgery and that further studies in larger patient cohorts are warranted to explore the clinical utilization of dexmedetomidine.

Key Points

1. The study investigated the effects of dexmedetomidine, an alpha-2 agonist anesthetic agent, on oxidative stress in patients undergoing coronary artery bypass grafting (CABG) surgery.

2. Thiol-disulfide homeostasis (TDH) was used as a biomarker to assess oxidative stress, as it plays a crucial role in antioxidant defense and can detect ischemia status in tissues.

3. The study included 60 patients undergoing elective on-pump CABG surgery, divided into two groups: those receiving dexmedetomidine (Group D) and those not receiving dexmedetomidine (Group C).

4. In patients receiving dexmedetomidine, lower postoperative levels of disulfide, disulfide/native thiol, and disulfide/total thiol, along with higher native thiol/total thiol, were observed compared to the control group. Postoperative native thiol and total thiol levels were similar for both groups.

5. The difference in native thiol levels between the time before anesthesia induction (T1) and the time after aortic cross-clamp removal (T2) was significantly smaller in the dexmedetomidine group compared to the control group. Similarly, the differences in native thiol and disulfide levels between T1 and the end of surgery (T3) were also significantly smaller in the dexmedetomidine group.

6. The authors conclude that the use of dexmedetomidine in CABG surgery was associated with lower levels of oxidative stress, as evidenced by the thiol-disulfide homeostasis measurements, and suggest that the positive effects of dexmedetomidine on oxidative stress could be beneficial in CABG surgery, warranting further studies in larger patient cohorts.

Reference –

Ozguner, Y., Altınsoy, S., Kültüroğlu, G. et al. The effects of dexmedetomidine on thiol/disulphide homeostasis in coronary artery bypass surgery: a randomized controlled trial. BMC Anesthesiol 24, 402 (2024). https://doi.org/10.1186/s12871-024-02794-1

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Deucravacitinib Found to Be Safe and Effective for Psoriasis Over 3 Years: JAMA

Researchers have found that deucravacitinib for long-term treatment is well tolerated and has a sustained clinical response in the management of moderate to severe plaque psoriasis. Recently a new study was published in the JAMA Dermatology journal which was conducted by April W. Armstrong and his colleagues.

Data were derived from the randomized, double-blinded POETYK PSO-1 and PSO-2 trials and the nonrandomized LTE trial. The two lead-in trials had enrolled patients in a 1:2:1 ratio to placebo, deucravacitinib (6 mg/day), or apremilast (30 mg twice daily). Patients who had participated in these studies for 52 weeks were allowed to enter this LTE study and received open-label deucravacitinib. The LTE trial started enrolling patients from August 2019 up to June 2022, and safety and efficacy outcomes were monitored.

The study included 1,519 participants who received at least one dose of deucravacitinib. Among them, 513 patients received continuous treatment from day 1 and entered the LTE trial. This analysis considered outcomes across 1-year and 3-year cumulative periods, highlighting safety and efficacy trends over time.

Key Findings

Safety Profile:

  • Adverse events (AEs): EAIRs were lower at 3 years (144.8; 95% CI: 137.1-153.0) than at 1 year (229.2; 95% CI: 215.4-243.9).

  • Serious AEs: EAIRs were similar between 1 and 3 years (5.7 vs. 5.5).

  • Discontinuations due to AEs: Rates decreased from 4.4 per 100 person-years at 1 year to 2.4 at 3 years.

  • Deaths: EAIRs were all steady, reported as 0.2 at 1 year and 0.3 at 3 years.

Common Adverse Events:

  • Nasopharyngitis: EAIRs were lower at 3 years (11.4; 95% CI: 10.2-12.7) than at 1 year (26.1; 95% CI: 23.0-29.8).

  • COVID-19: EAIRs increased from 0.5 at 1 year to 8.0 at 3 years. It reflects the impact of the pandemic.

  • Upper respiratory tract infection: EAIRs declined from 13.4 at 1 year to 6.2 at 3 years.

Durable Clinical Response:

  • Clinical efficacy was maintained for up to three years with important improvements in Psoriasis Area and Severity Index (PASI 75/90) scores and static Physician Global Assessment (sPGA 0/1) scores.

This study concluded that deucravacitinib maintains a consistent safety profile and durable clinical response over three years of continuous treatment for moderate to severe plaque psoriasis. The findings offer robust evidence to support the long-term use of this oral therapy in clinical practice.

Reference:

Armstrong, A. W., Lebwohl, M., Warren, R. B., Sofen, H., Imafuku, S., Ohtsuki, M., Spelman, L., Passeron, T., Papp, K. A., Kisa, R. M., Vaile, J., Berger, V., Vritzali, E., Hoyt, K., Colombo, M. J., Scotto, J., Banerjee, S., Strober, B., Thaçi, D., & Blauvelt, A. (2024). Safety and efficacy of deucravacitinib in moderate to severe plaque psoriasis for up to 3 years: An open-label extension of randomized clinical trials. JAMA Dermatology (Chicago, Ill.). https://doi.org/10.1001/jamadermatol.2024.4688

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Small amounts of incidental vigorous physical exertion may halve major CV events risk in women: Study

Short bursts of incidental vigorous physical exertion, lasting less than a minute each, may almost halve the risk of a major cardiovascular event, such as heart attack or heart failure among women who don’t exercise regularly, finds research published online in the British Journal of Sports Medicine.

Just 1.5-4 daily minutes of high intensity routine activities, such as brisk stair climbing or carrying heavy shopping, may help to stave off cardiovascular disease among those either unwilling or unable to take part in structured exercise or sport, conclude the international team of researchers.

Longer bouts of high intensity physical activity in middle age are associated with significantly lower risks of cardiovascular disease, but it’s not clear if much shorter bursts of this level of activity that are often part of a daily routine-formally known as vigorous intermittent lifestyle physical activity, or VILPA for short-may also be effective at lowering risk, and if so, what the minimum threshold for measurable effects might be, they add.

This is particularly important for women who don’t or can’t exercise regularly, for whatever reason, because women tend to have a lower level of cardiorespiratory fitness than men at any given age, explain the researchers.

To explore this further, they drew on 81,052 middle-aged men and women (average age 61) from the UK Biobank who wore an activity tracker for a full week for 24 hours/day between 2013 and 2015.

Participants were divided into those who reported not doing any regular structured exercise or only going for a recreational walk once a week (22,368) and those who said they were regular exercisers or who went for a walk more than once a week (58,684).

Participants’ cardiovascular health was tracked until the end of November 2022, and details of hospital admissions or deaths from heart attack, stroke, and heart failure, collectively known as a major adverse cardiovascular event, or MACE for short, were collated.

Of the non-exercisers,13,018 women and 9350 men with complete data (22,368 in total) were included in the final analysis. And during a monitoring period of nearly 8 years, 331 women and 488 men had a heart attack or stroke, developed heart failure, and/or died of cardiovascular disease.

Specifically, these comprised 379 separate heart attacks (129 women and 250 men); 215 cases of heart failure (96 women and 119 men); and 225 strokes (106 women and 119 men).

After accounting for potentially influential risk factors, such as lifestyle, cardiovascular risk factors, co-existing conditions, and ethnicity, a clear dose–response association emerged for all MACE and separately for heart attack and heart failure in women who said they didn’t do any structured exercise but incorporated VILPA into their daily routine.

The associations were less clear and less significant, however, in men.

For example, women who clocked up a daily average of only 3.4 minutes of VILPA, but no formal exercise, were 45% less likely to have any type of MACE, 51% less likely to have a heart attack, and 67% less likely to develop heart failure than women who didn’t manage to include any VILPA .

Men who averaged 5.6 minutes of VILPA/day, but no formal exercise, were 16% less likely to have any type of MACE than men who didn’t record any VILPA. But there were no clear associations with the separate components of MACE.

Even smaller amounts of daily VILPA still showed measurable associations with lower cardiovascular risks for women: a minimum of 1.2-1.6 minutes a day was associated with a 30% lower risk of all MACE, and specifically, a 33% lower risk of heart attack, and a 40% lower risk of heart failure.

A minimum length of 2.3 minutes/day of VILPA for men, however, corresponded to only a 11% reduced risk of all MACE.

Among the regular exercisers, no such major sex differences were observed in the dose–response associations between vigorous physical activity and the overall risk of MACE, or heart attack and heart failure. There was evidence of a dose–response association with stroke, but only in men.

This is an observational study and therefore can’t establish cause and effect, and an average of 5.5 years elapsed between the activity tracker recordings and collection of data on potentially influential risk factors and leisure time physical activity measurement.

Nevertheless, the researchers conclude: “VILPA may be a promising physical activity target for major cardiovascular events prevention in women unable or not willing to engage in formal exercise.”

And although the VILPA findings were strongest for women who didn’t exercise, men who incorporate some VILPA into their daily routines should still engage in regular vigorous intensity structured exercise to lower their cardiovascular disease risk, they point out.

Reference:

Stamatakis E, Ahmadi M, Biswas RK, et alDevice-measured vigorous intermittent lifestyle physical activity (VILPA) and major adverse cardiovascular events: evidence of sex differencesBritish Journal of Sports Medicine Published Online First: 28 October 2024. doi: 10.1136/bjsports-2024-108484

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First Trimester Laparoscopic Cholecystectomy Under Combined Spinal and Epidural Anesthesia: A Case for New Standard Care

Romania: A recent case report and literature review have highlighted the use of combined spinal and epidural anesthesia (CSEA) as a potential gold standard for laparoscopic surgery during the first trimester of pregnancy. The case, published in the journal Life, involved a pregnant patient who underwent an emergency laparoscopic cholecystectomy to address worsening symptoms of obstructive jaundice. 

Gabriel-Petre Gorecki, Department of Anesthesia and Intensive Care, CF2 Clinical Hospital, Bucharest, Romania, and colleagues detail the successful laparoscopic cholecystectomy of an 11-week pregnant woman performed under combined spinal and epidural anesthesia.

The case concerns a 37-year-old pregnant woman in the 11th week of pregnancy who presented with obstructive jaundice symptoms, including right hypochondrium pain, nausea, and vomiting. After an initial conservative treatment, her condition worsened, leading to the diagnosis of acute cholecystitis with hepatocytolysis syndrome. Given the risks associated with surgery during early pregnancy, a decision was made to proceed with laparoscopic cholecystectomy under combined spinal and epidural anesthesia (CSEA) after unsuccessful medical management.

This unique approach was chosen to minimize the risks to both mother and fetus, as general anesthesia posed higher risks. The patient underwent the procedure without complications, with intraoperative monitoring ensuring safety. The combined anesthesia technique allowed effective pain management and stability throughout the surgery. The patient received appropriate antibiotics and fluids, completing the procedure in 45 minutes.

Postoperative monitoring showed no complications and fetal health remained stable, with normal heart rates observed in Doppler ultrasound. The patient was discharged 24 hours after surgery, with her pregnancy progressing normally. Follow-up after childbirth via cesarean section revealed no long-term effects from the laparoscopy. This case highlights the feasibility and safety of laparoscopic surgery under CSEA for pregnant women in the first trimester, especially when conservative measures fail.

“This case demonstrates that laparoscopic cholecystectomy, compared to open surgery, is a safe and effective option even in the first trimester. To minimize fetal risk, combined spinal and epidural anesthesia was used, with ropivacaine 0.2% delivered through an epidural catheter for postoperative pain relief, reducing systemic drug exposure and enhancing patient comfort. We believe this approach could become the gold standard for laparoscopic surgery in pregnant patients. Additionally, monitoring end-tidal CO2 (ETCO2) during such surgeries can be beneficial due to the changes in respiratory mechanics that may occur from increased intra-abdominal pressure and surgical positioning,” the researchers wrote.

“Combined spinal and epidural anesthesia could become a preferred option for laparoscopic surgeries in the first trimester of pregnancy due to its benefits in safety and analgesia,” they concluded.

Reference:

Gorecki, G., Bodor, A., Kövér, Z., Comănici, M., Sima, R., Panaitescu, A., Comănici, A., Constantin, A., Pleș, L., Diaconescu, A. S., & Lungu, V. (2024). Laparoscopic Cholecystectomy Under Combined Spinal and Epidural Anesthesia in the First Trimester of Pregnancy—Case Report and Literature Review. Life, 14(11), 1492. https://doi.org/10.3390/life14111492

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Young Adulthood Obesity Linked to Liver Disease Risk, But Weight Loss Reverses Effects, Study Finds

Netherlands: Stable or newly developed obesity during young adulthood significantly increases the risk of metabolic dysfunction-associated steatotic liver disease (MASLD). It also raises the likelihood of at-risk metabolic dysfunction-associated steatohepatitis (MASH) and elevated liver stiffness measurements (LSM) in individuals aged 40–80. This is the finding from a recent study published online in Liver International on November 22, 2024.

“In contrast, those who achieved weight loss and transitioned out of obesity did not exhibit an elevated risk, highlighting the potential for weight loss to mitigate these adverse metabolic outcomes,” the researchers reported.

Obesity can lead to lasting metabolic changes even after weight loss, potentially impacting liver health. For this purpose, Laurens A. van Kleef, Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands, and colleagues sought to explore the relationship between obesity in young adulthood and the risk of metabolic dysfunction-associated steatotic liver disease, at-risk steatohepatitis, and elevated liver stiffness measurements in a general population.

For this purpose, the researchers analyzed data from NHANES 2017–2020, focusing on community-dwelling participants aged over 40 with a BMI of 18.5 or higher and no history of heart failure. Weight at age 25 was collected through questionnaires and compared to current weight.

The study assessed the controlled attenuation parameter (CAP) and LSM. They examined the associations between changes in obesity status and the risks of MASLD, at-risk metabolic dysfunction-associated steatohepatitis, and elevated LSM, adjusting for demographics and metabolic health factors.

The following were the key findings of the study:

  • The study included 4,580 participants: 57% with stable non-obesity, 33% who gained obesity, 2% who lost obesity, and 8% with stable obesity.
  • Stable obesity was strongly associated with MASLD (OR: 5.47).
  • Gained obesity is also significantly associated with MASLD (OR: 4.68).
  • Lost obesity showed no increased risk of MASLD (OR: 1.26).
  • Stable and gained obesity were similarly associated with at-risk MASH and LSM ≥8 kPa.
  • No residual risk was observed for lost obesity concerning at-risk MASH (OR: 1.05) and LSM ≥8 kPa (OR: 0.85).
  • Sensitivity analyses, including changes in obesity over 10 years and weight change stratification by BMI categories, supported these findings.

The study showed that obesity in young adulthood was linked to higher odds of MASLD, at-risk MASH, and increased LSM in the general population. However, achieving weight loss normalized these odds, indicating that neither obesity at age 25 nor a history of obesity after successful weight loss poses a risk to liver health in individuals aged 40–80. Conversely, young adulthood obesity without successful weight loss was associated with higher odds of increased LSM compared to those who developed obesity later, suggesting prolonged exposure to overweight increases risk.

“These findings emphasize the critical need for preventing and addressing young adulthood obesity to support liver health,” the researchers concluded.

Reference:

Pustjens, J., Savas, M., Ayada, I., Li, P., Pan, Q., A. Janssen, H. L., & Brouwer, W. P. MASLD, At-Risk MASH and Increased Liver Stiffness Are Associated With Young Adulthood Obesity Without Residual Risk After Losing Obesity. Liver International. https://doi.org/10.1111/liv.16169

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Congenital heart defects could be triggered by problems with placenta, suggests study

Congenital heart defects are the most common form of human birth defect, but we still don’t fully understand what causes them. Previous research had suggested that some heart defects could be triggered by problems with the placenta, the organ that provides oxygen and nutrients to the developing embryo. Now, researchers at Nanjing University, China have confirmed this link by focusing on a protein whose levels are reduced in many patients with congenital heart defects, called SLC25A1. SLC25A1 plays a key role in transporting citric acid, an important metabolite whose derivatives can affect gene expression, to different regions of our cells. However, it was unclear how the protein’s loss might be linked to congenital heart defects. By disrupting this protein in different tissues in developing mice, the researchers have shown that loss of SLC25A1 does not affect the developing heart directly. Instead, it leads to problems with placental growth and this, in turn, causes heart defects in the mice. The researchers publish their study in the journal Development on 26 November 2024.

The researchers used gene editing tools to produce mouse embryos that completely lack the SLC25A1 protein. As expected, these embryos developed heart defects. However, they also had problems with their placentas, which were thinner than usual. “A rapidly increasing number of studies in mice have suggested that the placenta is involved in the regulation of embryonic heart development,” explained Professor Zhongzhou Yang from Nanjing University Medical School, whose research group carried out the study. “However, the molecular basis of this relationship was unclear.”

The research team wanted to explore this potential relationship between placental defects and heart defects. To identify where in the embryo the protein is needed, they decided to remove SLC25A1 from specific tissues, rather than just disrupting it across the whole embryo. First, they made mouse embryos that lacked the SLC25A1 protein only in their developing heart. Surprisingly, these mice did not develop heart defects, suggesting that SLC25A1 is not playing an important role in heart cells. In contrast, when the researchers generated mice that lacked the SLC25A1 protein only in their placental tissue, they found that the mice developed both placental defects and heart defects. This suggested that SLC25A1 plays a key role in development of the placenta and, if placental development goes wrong, heart defects can occur as a result. Indeed, measurements showed that loss of SLC25A1 alters the citric acid balance in placental cells, resulting in changes to the cells’ DNA that disrupt placental development.

The researchers next explored how these changes to the placenta might cause problems with heart development. They found that the placentas lacking SLC25A1 had low levels of PSG1, a protein that is produced by the placental cells and is known to help regulate development of endothelia (sheets of cells that line the insides of certain structures in the body, including blood vessels). “We showed that administration of human PSG1 to pregnant mice improves placental and heart defects in embryos lacking SLC25A1,” Professor Yang explains. “PSG1 might therefore become a potentially effective drug to help improve placental and heart development of the foetus in the uterus.” While further work is needed, these findings could lead to the development of a new treatment strategy to prevent congenital heart defects in foetuses that are exhibiting placental problems.

Reference:

Wenli Fan, Zixuan Li, Xueke He, Xiaodong Wang, Ming Sun, SLC25A1 regulates placental development to ensure embryonic heart morphogenesis, Development, https://doi.org/10.1242/dev.204290

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Adenomyosis has relatively high long-term recurrence rate after conservative surgery, finds study

Adenomyosis, a prevalent non-cancerous condition, is characterized by the erroneous presence of endometrial tissue within the myometrium. Symptoms include dysmenorrhea, abnormal uterine bleeding, and dyspareunia, adversely affecting patients’ quality of life. Diagnostic methods rely heavily on clinical judgment and imaging techniques like ultrasonography or magnetic resonance imaging due to the absence of definitive physical or laboratory indicators for adenomyosis. Recent retrospective study aimed to determine the recurrence rate after conservative surgery for adenomyosis and identify the risk factors for recurrence. Data from 133 eligible patients who underwent conservative surgery for adenomyosis between January 2013 and April 2023 were analyzed. The recurrence rate after conservative surgery was 39.1% (52/133) during a mean follow-up of 52 months. 2. Cox proportional hazards analysis identified several risk factors for recurrence: – Adenomyosis involving the posterior uterine wall (hazard ratio [HR] 6.505, p=0.018) – Two or more adenomyotic lesions (HR 6.310, p=0.030) – Laparotomy approach (HR 2.490, p=0.029) – Concomitant endometriosis (HR 2.313, p=0.036) – Higher number of abortions (HR 1.578, p=0.001) – Higher preoperative visual analog scale (VAS) pain score (HR 1.181, p=0.036) 3. In contrast, postoperative combined progestogen therapy (HR 0.126, p<0.001) or gonadotropin-releasing hormone agonist (GnRHa) therapy (HR 0.237, p=0.004) were found to protect against recurrence of adenomyosis.

Conclusion

The authors conclude that adenomyosis has a relatively high long-term recurrence rate after conservative surgery. Patients with adenomyosis involving the posterior uterine wall, multiple lesions, and concomitant endometriosis are at high risk of recurrence. Postoperative hormonal therapy with progestogens or GnRHa may reduce the risk of recurrence. Larger prospective studies are needed to confirm these findings.

Key Points

1. The recurrence rate after conservative surgery for adenomyosis was 39.1% during a mean follow-up of 52 months.

2. Several risk factors for recurrence were identified, including: – Adenomyosis involving the posterior uterine wall (hazard ratio [HR] 6.505) – Two or more adenomyotic lesions (HR 6.310) – Laparotomy approach (HR 2.490) – Concomitant endometriosis (HR 2.313) – Higher number of abortions (HR 1.578) – Higher preoperative visual analog scale (VAS) pain score (HR 1.181)

3. Postoperative combined progestogen therapy (HR 0.126) or gonadotropin-releasing hormone agonist (GnRHa) therapy (HR 0.237) were found to protect against recurrence of adenomyosis.

4. The authors conclude that adenomyosis has a relatively high long-term recurrence rate after conservative surgery.

5. Patients with adenomyosis involving the posterior uterine wall, multiple lesions, and concomitant endometriosis are at high risk of recurrence.

6. Larger prospective studies are needed to confirm these findings.

Reference –

Lu, K., Zhong, G., Lian, B. et al. Recurrence rates and associated risk factors after conservative surgery for adenomyosis: a retrospective study. BMC Women’s Health 24, 619 (2024). https://doi.org/10.1186/s12905-024-03457-6

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SC holds doctor guilty of medical negligence for surgery on wrong leg

New Delhi: Upholding the order of the National Consumer Disputes Redressal Commission (NCDRC) finding a surgeon liable for medical negligence while conducting surgery on the wrong foot of a patient, the Supreme Court recently dismissed the appeal filed by the doctor.

Challenging the NCDRC ruling, the concerned doctor, who worked as an Orthopaedic Surgeon at the Fortis Hospital in 2016, filed a plea before the Supreme Court.

After considering the doctor’s appeal, the top court bench comprising Justice PS Narasimha and Manoj Misra dismissed the same while noting, “Having considered the matter in detail, we are of the opinion that the National Consumers Disputes Redressal Commission, New Delhi has not committed any error in law or fact. In this view of the matter, the Civil Appeal is dismissed.”

The original consumer complaint was filed against the treating doctor and hospital based on the allegation that the surgery was performed on the left leg of the patient instead of his injured right leg. Later, the patient got himself admitted to another hospital for surgery.

The history of the case goes back to 2016 when the patient slipped from the stairs and sustained injuries. Thereafter he was taken to Fortis Hospital, Shalimar Bagh, where the treating doctor, after conducting X-rays, informed that the patient had suffered fracture on his right foot. The patient was also asked to get a CT Scan of his right foot and an X-ray of his left foot and spine and was asked to undertake physiotherapy.

As per the patient, despite the fact that the patient had undergone a hairline fracture on his spine, he was administered anaesthesia in his spinal cord before the surgery and in spite of operating on the right foot, the petitioner’s left foot was operated!

The Delhi Medical Council had taken suo motu cognizance of the issue and the Disciplinary Committee of the DMC, which after considering the justifications given by the doctors for conducting the surgery on the left foot noted that no written consent was taken from the patient for the change of plan of surgery being carried out on the left side. Further, the DMC Committee also noticed attempted tampering of records.

Accordingly, DMC had recommended removing the names of two treating doctors from the State Medical Register for 180 days. When the DMC order was challenged before the erstwhile Medical Council of India (MCI), it exonerated one doctor on the ground that he was not present in the operation theatre when the surgery was performed on the petitioner. However, MCI had sustained the punishment granted to the other doctor- Dr. Kakran, who filed this plea before the Supreme Court.

While considering the matter, the Apex Consumer Court back in June 2024 awarded the patient a total compensation of Rs 1.10 crores. Among this amount, the treating hospital was asked to pay Rs 90 lakhs and two treating doctors including the surgeon were directed to pay Rs 10 lakhs each.

Also Read: Negligence in Ankle Surgery: Doctor, hospital ordered to pay Rs 3 lakh compensation

Challenging the NCDRC order, the surgeon in his plea before the Supreme Court claimed that an injury was found in the left leg of the patient as well in the operation room and he was advised to take surgical treatment for the same. The doctor claimed that the patient gave oral consent for the surgery. 

Previously, the NCDRC bench had found that there was gross medical negligence after noting that all the pre-surgery tests (X-Ray, scan etc.) were taken for the right leg even though the consent was taken for the right leg.

“The Complainant appears to have virtually escaped from the Hospital and ran for his life on account of this mess having been created by the Opposite Parties in proceeding to perform a surgery of the left leg when the surgery was planned to rectify and treat the fracture of the right leg,” NCDRC had observed in its order, Live Law has reported. Further, the consumer court had found that the protocol regarding the consent was not followed before operating on the left leg.

Even though the NCDRC order was challenged by the surgeon, the Supreme Court bench affirmed the findings of the NCDRC by rejecting the surgeon’s appeal.

To view the order, click on the link below:

https://medicaldialogues.in/pdf_upload/supreme-court-order-medical-negligence-263671.pdf

Also Read: Surgery undertaken without necessary skill, records manipulated! Delhi Doctors, Hospital slapped Rs 48 lakh compensation for misconduct, negligence

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