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Take a look at a selection of our recent media coverage:

Pre-existing heart disease improves survival after out-of-hospital cardiac arrest

29th December 2021

Despite pre-existing heart disease, a study suggests that this appears to improve the odds of surviving an out-of-hospital cardiac arrest

Having pre-existing heart disease (PEHD) seems to improve the chance of survival to hospital after experiencing an out-of-hospital cardiac arrest. This was the somewhat counter-intuitive conclusion of a retrospective analysis by a team from the Department of Cardiology, Amsterdam UMC, The Netherlands.

Out-of-hospital (OOH) cardiac arrests are a common problem and in one European study of 37,054 such arrests, the hospital survival rate was only 26.4%. Patient characteristics are undoubtedly a potentially important contributor to overall survival and in particular, the presence of existing heart disease, although the impact of this factor on survival has been poorly studied. In one such study, having ischaemic heart disease led to a 50% improved odds of survival. However and in contrast, a second study showed that PEHD was an independent predictor of a poorer survival after an OOH cardiac arrest.

Given these contradictory findings, the Dutch researchers set out to explore the relationship between OOH cardiac arrest and prior cardiovascular disease. They retrospectively examined data from the AmsteRdam REsuscitation STudies (ARREST) registry, which contains information on all OOH cardiac arrests in the Northern part of Holland. Patient’s medical histories were obtained from their GP’s medical records for evidence of a wide range of cardiac diseases and patients were dichotomised as either having or not having PEHD. For the purposes of the study, the primary outcomes were survival to hospital admission and survival to hospital discharge and this data was obtained from hospital records. Secondary outcomes were a shockable initial rhythm (SIR) and acute myocardial infarction (AMI) as an immediate cause of OOH cardiac arrest. Using regression analysis, the team examined the association between PEHD and survival to hospital and survival to discharge and adjusted models for several co-morbidities.

Findings

A total of 3760 OOH cardiac arrest patients with a mean age of 68 years (70.9% male) were included in the analysis. Overall, 48.1% of the cohort had PEHD and on average were slightly older (mean age 71.4 vs 64.7, p < 0.001) and with a higher incidence of cardiovascular risk factors e.g., hypertension (59.3% vs 42.2, p < 0.01), obesity and hypercholesterolaemia.

Among those with PEHD, 41.9% survived to hospital admission compared to 38% of those without prior cardiovascular disease (p = 0.014). The presence of existing heart disease was associated with an increased survival odds after adjustment for all covariates (adjusted odds ratio, aOR = 1.25, 95% CI 1.05 – 1.47). However, prior cardiac disease was not associated with survival to discharge in fully adjusted models (aOR = 1.16, 95% CI 0.95 – 1.42).

Among 1680 patients with SIR, prior heart disease was also not associated with survival to hospital (aOR = 1.12, 95% CI 0.90 – 1.39) but prior heart disease was associated with a lower proportion of AMI (aOR = 0.33, 95% CI 0.25 – 0.42).

In their discussion, the authors recognised that their findings were somewhat counter-intuitive and were unable to explain the result. Nevertheless, they concluded that survival gains after an OOH cardiac arrest applied to a wide range of patients with prior heart disease.

Citation

van Dongen LH et al. Higher chances of survival to hospital admission after out-of-hospital cardiac arrest in patients with previously diagnosed heart disease Open Heart 2021

Omicron infection causes fewer hospitalisations and severe disease compared with Delta variant

24th December 2021

Omicron infection appears to be associated with a lower risk of hospitalisation and less severe disease than the Delta COVID-19 variant, according to a recent study

According to a preprint study by researchers from the Centre for Respiratory Diseases and Meningitis, Johannesburg, South Africa, Omicron infections appear to be associated with reduced risk of hospitalisation and after admission, less severe disease than the Delta variant.

While the Omicron COVID-19 variant was only identified in November 2021, there has been a flurry of research activity directed at trying to understand its transmissibility, the level of disease severity and effect on healthcare services. While initial laboratory studies have indicated that the variant can escape neutralisation by antibodies generated in fully vaccinated and boosted sera samples, these studies cannot foretell the clinical impact of the variant.

The South African researchers undertook a data linkage study of COVID-19 infections, case data and genomic information to establish whether an Omicron infection was associated with higher rates of hospitalisation and more severe disease among those who were hospitalised in comparison to the Delta COVID-19 variant. Although whole genome sequencing was not used, they utilised the presence of a S Gene Target Failure (SGTF), which serves as a proxy for Omicron and samples were examined between 1st October 2021 and 6th December 2021. Positive infections were therefore classified as either an SGTF or non-SGTF. The severity of an Omicron infection was assessed by comparison of SGTF and non-SGTF infections and to infections known to be caused by the Delta variant and regression models created and adjusted for several factors known to be associated with hospitalisation (e.g., age, sex, co-morbidities).

Findings

During the period of study there were 161,328 COVID-19 cases recorded and the proportion of SGTFs increased from 3% (early October 2021) to 98% (early December).

A total of 11,495 hospital admissions occurred with 2.5% due to an SGTF compared to 12.8% with a non-SGTF (p < 0.001). Multivariate analysis revealed that individuals with a SGTF had a lower odds of hospitalisation (adjusted odds ratio, aOR = 0.2, 95% CI 0.1 – 0.3, p < 0.001). In addition, once hospitalised, the odds of having severe disease were also reduced in those with SGTF although there was uncertainty over this estimate given the wide confidence intervals (aOR = 0.70, 95% CI 0.30 – 1.40).

Finally, the researchers found that compared to infection with the Delta variant, those with an SGTF had a significantly lower risk of severe disease (aOR = 0.30, 95% CI 0.20 – 0.50, p < 0.001).

The authors suggested that these data suggested that an Omicron infection was probably less severe than other variants such as Delta but recognised that this reduced severity might be accounted for by the higher levels of population immunity due to either natural infection and/or vaccination.

These results are broadly similar to those of a second recently published preprint from Scotland which found a nearly 70% reduced risk of hospitalisation (expected ratio = 0.32, 95% CI 0.19 – 0.52) for those with an Omicron infection. The study also found that giving a third or booster dose was associated with a 57% reduced risk of symptomatic infection.

Although both studies are preliminary, they do suggest the possibility that infection with the new variant is potentially less severe than other forms.

Citation

Wolter N et al. Early assessment of the clinical severity of the SARS-CoV-2 Omicron variant in South Africa. MedRxiv 2021

Alcoholic spirit intake associated with increased risk of ventricular arrhythmias

23rd December 2021

Only increased alcoholic spirit intake has been found to be associated with a higher risk of ventricular arrhythmias among regular drinkers

Increased alcoholic spirit intake is associated with an increased risk of ventricular arrhythmia but this elevated risk is absent for other forms of alcoholic beverages. This was a key finding from a retrospective analysis by a team from the Centre for Heart Rhythm Disorders, University of Adelaide and Royal Adelaide Hospital, Australia.

Higher intakes of alcohol are generally considered to damage the cardiovascular system although light to moderate alcohol intake appears to be protective. The term ‘holiday heart syndrome‘ has been coined to describe any alcohol-induced atrial arrhythmias and/or conduction disturbance associated with heavy consumption in a person without other clinical evidence of heart disease. Whilst the relationship between atrial arrhythmias and alcohol has become well recognised, there is a paucity of data linking alcohol intake with ventricular arrhythmias (VA). In fact, the available evidence is inconsistent, with some data showing a non-significant association whereas other studies suggesting that heavy alcohol consumption is an important contributing factor. Moreover, the influence of the type of alcoholic drink on VA or even sudden cardiac death (SCD) is also uncertain.

For the present study, researchers used information held in the UK Biobank which provides data on approximately half a million community-dwelling individuals aged 40 to 69 years across the UK. For their analysis, the researchers focused on incident cases of VA but excluded those with a previous history of the condition and former drinkers. The amount of alcohol intake was reported in terms of a standard drink, defined as 8g of alcohol and the average number of standard drinks consumed per week. For alcohol intake, the team also considered the type of each beverage consumed and created regression models which adjusted for several covariates such as age, sex, race, education.

Findings

Data for a total of 408,712 individuals with an average age of 58.3 years (52.1% female) were included in the analysis and who were followed up for a median duration of 11.5 years. The median alcohol intake for the whole cohort was 8 drinks per week although 5.5% of the group reported having never consumed alcohol.

There were a total of 1733 incident VA events and 2044 SCDs which occurred during the follow-up period. Overall, there was no statistically significant association between total alcohol intake and the risk of VA. However, when considered by type of alcoholic beverage, only alcoholic spirit intake was linearly linked with an increased risk of VA among those consuming greater than 14 drinks per week (hazard ratio, HR = 1.15, 95% CI 0.98 – 1.34) and this became statistically significant with more than 28 drinks per week (HR = 1.33, 95% CI 1.03 – 1.73).

For SCD there was a U-shaped distribution of risk with the lowest risk at around 7 drinks per week.

The authors concluded that they were unable to find an association between total intake of beer, cider and wine and VA and that only increased alcoholic spirit intake was linked to a higher risk. In fact, wine intake was associated with a lower risk of SCD although the authors suggested that these findings require clarification from experimental studies.

Citation

Tu SJ et al. Alcohol consumption and risk of ventricular arrhythmias and sudden cardiac death: An observational study of 408,712 individuals Heart rhythm 2021

Oxford vaccine protection against severe COVID-19 wanes three months after second dose

22nd December 2021

The Oxford vaccine protection against severe COVID-19 wanes three months after the second dose highlighting the importance of a booster dose

Protection against severe COVID-19 from the Oxford vaccine (ChAdOx1) appears to wane as early as three months after the second dose according to a study by researchers from the MRC/CSO Social and Public Health Sciences Unit, University of Glasgow, UK.

Clinical trial data have shown that the currently available COVID-19 vaccines including ChAdOx1 provide a high level of protection against infection, however, evidence began to emerge of an increased incidence of infection among those who had been fully vaccinated. It was suggested that this might be due to either a waning of vaccine effectiveness or an increase in the dominance of new variants capable of immune escape. However, other data gathered over a 6 month period using the BNT162b2 vaccine found that its efficacy gradually reduced over this period of time.

For the present study, the UK team turned to data from Scotland and Brazil to examine the association between the time since the second vaccination with the Oxford vaccine (ChAdOx1) and the risk of severe COVID-19 outcomes. They chose Scotland and Brazil for comparative purposes because the Delta COVID-19 variant was the dominant strain in Scotland, whereas this was uncommon in Brazil. Consequently, if vaccine effectiveness reduced in both countries this would be unlikely to be because of the delta variant.

Using a retrospective design, the researchers linked data from the EAVE II study which provides COVID-19 data from 5.4 million people in Scotland and databases in Brazil to determine rates of infection, hospitalisation and deaths. They identified individuals from both countries aged 18 years and over who had received two doses of ChAdOx1 and set the primary outcome as the rate of severe COVID-19 outcomes, i.e., hospital admission or death, approximately two to three weeks after the second dose.

Findings

A total of 1972454 adults in Scotland and 42558839 in Brazil received two doses of ChAdOx1. However, an estimate of the vaccine effectiveness was based on a smaller cohort of 2534527 individuals with a mean age of 52 (49.9% male) in Scotland and 56013638 individuals in Brazil with a mean age of 48 years (47% male).

In Scotland the relative risk (RR) of severe COVID-19 was 2.01 (95% CI 1.54 – 2.62) 10 – 11 weeks after the second dose and increased further to 3.01 (after 14 – 15 weeks) and to 5.43 (after 18 – 19 weeks) compared with 2 – 3 weeks after the second dose. In Brazil there was a similar pattern at each time point, for example, the RR was 4.71 after 18 to 19 weeks.

The effectiveness of ChAdOx1 in Scotland decreased from 83.7% (95% CI 79.7 – 87) at weeks 2 – 3 to 63.7% (weeks 18 to 19). Similarly in Brazil vaccine efficacy reduced from 86.4% (2 – 3 weeks after second dose) to 42.2% (weeks 18 to 19).

Commenting on these findings, the authors noted how the similar drop in vaccine effectiveness was unlikely to be due to differences in circulating strains of the virus. They concluded on how these findings clearly illustrate how vaccine effectiveness reduces over time, highlighting the need for a booster vaccination dose.

Citation

Katikireddi SV et al. Two-dose ChAdOx1 nCoV-19 vaccine protection against COVID-19 hospital admissions and deaths over time: a retrospective, population-based cohort study in Scotland and Brazil. Lancet 2021

Third booster sera samples have reduced neutralisation against Omicron COVID-19 variant

Third booster sera samples have been found to produce a four- six-fold decrease in neutralisation when tested against the Omicron variant

In a laboratory-based study, third booster sera samples from patients have been shown to produce a four to six-fold reduction in neutralisation against the Omicron COVID-19 variant. This was the finding of a preprint study by researchers from the Aaron Diamond AIDS Research Center, New York, US.

The Omicron COVID-19 variant (B.1.1.529) was first identified in southern Africa and appears to have a high level of transmissibility and will likely cause outbreaks across the globe. A concern with this particular variant is that it contains more than 30 mutations,15 of which are present in the receptor-binding domain region which is the target for neutralising antibodies produced in response to vaccination. It is therefore possible that the Omicron might lead to an increased level of infection despite vaccination although current opinion is that this could be mitigated by a third booster sera sample.

In the absence of clinical data, the US team sought to better understand the extent to which the Omicron variant is able to evade antibody neutralisation, by testing the activity of serum collected from a number of different patient samples. Initially the team created an Omicron pseudovirus and tested this against 10 sera samples collected from the Spring of 2020, which were likely to have been infected with the wild-type (original) COVID-19 virus. While there was a robust response to the wild-type, there was a greater than 32-fold reduction against Omicron and only two samples produced antibody titres above the limit of detection.

Vaccinated samples

The team then turned their attention to both fully vaccinated and third booster sera (TBS) samples. For the two mRNA-based vaccines, BNT162b2 and mRNA-1273, there was a >21-fold decrease in ID50 and > 8.6-fold decrease in boosted sera samples. For the other vaccines, Ad26.COV2.S and ChAdOx1, all samples produced antibody titres below the limit of detection apart from two samples for which the individual had a history of a prior infection.

Using 15 third booster sera samples obtained from BNT162b2 (13) and mRNA-1273, the researchers discovered that although each of these third booster sera produced antibody titres above the limit, there was a mean 6.5-fold drop compared to the wild-type.

Using authenticated Omicron isolates and samples from BNT162b2 and mRNA-1273, there was a greater than 6-fold drop in titres for fully vaccinated and a greater than 4.1-fold drop for boosted samples.

Finally, testing sera with monoclonal antibodies, the researchers found that all four combinations of monoclonal antibodies in clinical use lost substantial activity against Omicron.

Although this was a laboratory-based study and might not be replicated in clinical practice, the authors believed that COVID-19 is potentially only a mutation or two away from being resistant to current antibodies and that it was important to devise strategies that anticipate the evolutional direction of the virus and that future work should focus on the development of agents targeting conserved parts of the virus.

Citation

Liu L et al. Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2 BioRxiv 2021

Apatinib therapy improves progression-free survival in iodine-refractory thyroid cancer

Apatinib therapy in patients with radioactive iodine-refractory thyroid cancer is safe and able to improve progression-free survival

The use of apatinib therapy in patients with radio-active iodine-refractory thyroid cancer has been found to be safe and effective, improving progression-free survival. This was the main result from the Efficacy of Apatinib in Radioactive Iodine-refractory Differentiated Thyroid Cancer [REALITY] trial, undertaken by a team from the Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking, China.

The incidence of thyroid cancer has been increasing globally over the past three decades and affects around 5 to 6% of men and women. Differentiated thyroid cancer (DTC) , which includes papillary and follicular histologies, is the most common type, accounting for over 90% of all thyroid cancers. Although radioactive iodine therapy is effective for a large proportion of patients with DTC, unfortunately around 5 to 15% of patients become refractory to therapy, prompting the need for alternatives.

Apatinib is a small-molecule angiogenesis inhibitor which suppresses vascular endothelial growth factor (VEGF) signalling. The value of apatinib therapy in radioactive iodine-refractory DTC has been examined in two small studies. In the first including 10 patients, the drug was described as a promising therapy, whereas in the second, dosing schedule study, undertaken with 20 patients, the drug produced a similar efficacy with both doses.

Based on these preliminary studies, the Chinese team, decided to undertake a randomised, double-blind, placebo trial of apatinib in patients with progressive, locally advanced or metastatic radioactive iodine-refractory DTC. The REALITY trial was conducted in adults (18 years and over) and the inclusion criteria were those whose target lesion had lost iodine uptake function, where the lesion had progressed within 12 months after radioactive iodine treatment. In addition, iodine refractory patients receiving chemotherapy or radiotherapy, at least one month prior to the first use of study treatment were also included. Participants were randomised 1:1 to apatinib, given at a dose of 500 mg once daily until disease progression or intolerable side-effects developed or matching placebo. Tumour assessment was performed with CT or MRI imaging and the primary endpoint was investigator assessed progression-free survival (PFS), which was defined as the time from randomisation to disease progression or death from any cause. Secondary endpoints included overall survival (OR) and the objective response rate (ORR).

Findings

A total of 92 patients with a mean age of 57.7 years (60.9% female) were randomised to apatinib therapy or placebo.

With a median follow-up time of 18.1 months, the median PFS was 22.2 months in the apatinib group and 4.5 months in the placebo group (hazard ratio, HR = 0.26, 95% CI 0.14 – 0.47). The 12-month PFS rate was 60.3% for apatinib compared to 12.4% in the placebo arm although this decreased to 37.2% and 4.1% (apatinib vs placebo). The ORR was 54.3% for apatinib compared to 2.2% (placebo) and the overall 12-month survival rate was 95.4% vs 79.7% (apatinib vs placebo).

In terms of safety, the most common adverse event (grade 3 or higher) was hypertension (34.8%), hand-foot syndrome (17.4%) and proteinuria (15.2%) and none of these effects were observed in the placebo group.

The authors concluded that apatinib therapy significantly improved PFS and suggested that it should be considered as a new treatment for patients with radioactive iodine-refractory DTC.

Citation

Lin Y et al. Apatinib vs Placebo in Patients With Locally Advanced or Metastatic, Radioactive Iodine–Refractory Differentiated Thyroid Cancer. The REALITY Randomized Clinical Trial JAMA Oncol 2021

Add-on dupilumab therapy reduces exacerbations in children with moderate-to-severe asthma

21st December 2021

Add-on dupilumab therapy for children with uncontrolled moderate-to-severe asthma led to a significant reduction in disease exacerbations

Add-on dupilumab treatment in children with uncontrolled moderate-to-severe asthma produced a significant reduction in the number of exacerbations over a 52-week period, according to results of a Phase III, randomised, double-blind, placebo-controlled trial by researchers from the Division of Allergy, Immunology, and Pulmonary Medicine, Monroe Carell Jr. Children’s Hospital Nashville, US.

The global prevalence of asthma in children varies across the world with an estimated 10.8% of 6–7-year-old children having the disease although rates are lower rates in Northern and Eastern Europe (4.5%) but much higher in North America (20.0%) and Oceania (29.2%). While there are differences in the definition of ‘severe’ asthma, it has been suggested that prevalence of severe childhood asthma may be up to 5% and there is more concerning evidence indicating that childhood asthma increases the risk of COPD in adults.

Asthma appears, in part, to be a Th2-driven inflammatory process, characterised by the release of the cytokines interleukin (IL)-4, IL-5 and IL-13 and higher levels of Th2 inflammation are associated with greater airway hyper-responsiveness and more severe disease though only around 50% of patients have this endotype. The monoclonal antibody, dupilumab, blocks the action of IL-4 and IL-13 and has been approved for the treatment of adults and adolescents with asthma.

In Europe, the EMA has approved add-on dupilumab (brand name Dupixent) to ‘treat severe asthma in patients aged 12 years or over whose asthma is not properly controlled by a combination of high-dose corticosteroids taken by inhalation plus another medicine used for the prevention of asthma. Dupixent is only for use in patients with a type of inflammation of the airways called ‘type 2 inflammation’. 

For the present study, the US team recruited children aged 6 to 11 years with physician diagnosed moderate-to-severe asthma. Children were defined as those with type 2 inflammatory asthma phenotype defined by an eosinophil count of > 150 cells/cubic/ml or at least 300 cells/cubic/ml at baseline.

These children were randomised 2:1 to receive subcutaneous dupilumab (or matching placebo) every two weeks for 52 weeks at a dose of 100 mg (if their weight was <30 kg) or 200 mg (if weighing >30 kg). The primary endpoint was the annualised rate of severe exacerbations during the treatment period, defined as a deterioration of asthma control requiring systemic glucocorticoids for at least 3 days, hospitalisation or an emergency department visit that resulted in systemic glucocorticoid use. A key secondary outcome was the change from baseline to week 12 in the percentage of predicted prebronchodilator FEV1 (ppFEV1).

Findings

A total of 408 children with type 2 inflammatory asthma and a mean age of 8.9 years (66.4% male) were randomised to add-on dupilumab therapy or placebo. Among these children, 43% used high-dose inhaled glucocorticoids and had an average of 2.2 severe asthma exacerbations in the past year. An additional 259 children with an eosinophil count > 300 were similarly matched to dupilumab and placebo.

In the type 2 inflammation group, the adjusted annualised rate of severe asthma exacerbations was 0.31 (95% CI 0.22 – 0.42) in the add-on dupilumab group and 0.75 (95% CI 0.54 – 1.03) in the placebo group, giving a relative risk reduction, RR of 59.3% (p < 0.001). Similarly, among those with eosinophil counts > 300, the adjusted annualised rate of severe exacerbations was 0.24 (dupilumab) and 0.67 (placebo).

Overall, the percentage of participants who had no exacerbations during the 52-week study period was 77.1% in the dupilumab group and 59.6% in the placebo group and 79% vs 58.3% in the eosinophil vs placebo groups.

The changes in ppFEV1 were also significantly better for those in the add-on dupilumab group for both asthma phenotypes.

The authors concluded that dupilumab led to a meaningful improvement through asthma exacerbations and improvements in lung function in 6 to 11 year olds with moderate-to-severe asthma.

Citation

Bacharier LB et al. Dupilumab in Children with Uncontrolled Moderate-to-Severe Asthma. N Engl J Med 2021

Molnupiravir treatment halves rate of hospitalisation in unvaccinated COVID-19 patients

20th December 2021

Molnupiravir treatment initiated within 5 days of symptom onset in unvaccinated individuals with COVID-19 halved the risk of hospitalisation

The use of oral molnupiravir treatment within 5 days of COVID-19 symptom onset, led to a 50% reduction in the risk of hospitalisation for any cause of death among unvaccinated patients. This was the main finding of a study by the MOVe-OUT group which was supported by the manufacturer of the drug, Merck Sharp and Dohme.

Molnupiravir is a small-molecule ribonucleoside pro-drug of N-hydroxycytidine (NHC) and which has been shown to inhibit the influenza virus and is phosphorylated in vivo and incorporated into viral RNA, rendering the virus non-infectious. Early trial data suggested that the drug was efficacious and safe in patients infected with COVID-19 which formed the basis for the current MOVe-OUT trial.

For the Phase II-III trial, non-hospitalised patients with mild or moderate, laboratory confirmed COVID-19, symptom onset of no more than 5 days and at least one risk factor for more severe disease, were enrolled in the study. Risk factors included age (> 60 years), active cancer, chronic kidney disease, COPD, obesity, diabetes or serious heart conditions such as heart failure and coronary artery disease. Patients were excluded where there was an anticipated need for hospitalisation (due to COVID-19) within the next 48 hours.

Those enrolled were randomised 1:1 to molnupiravir treatment (800 mg) twice daily for five days or identical placebo. The primary efficacy endpoint was the incidence of hospitalisation for any cause, which the researchers defined as > 24 hours of acute hospital care or death through to day 29. The researchers also included a primary safety outcome as the incidence of adverse events.

Findings

A total of 1433 participants with a median age of 42 (53.6% female) were assigned to molnupiravir treatment (716) or placebo. Overall, 99.4% of these individuals had at least one risk factor for severe COVID-19, most commonly obesity (73.7%), age > 60 (17.2%) and diabetes (15.9%) with disease severity classed as mild in more than half (55.2%) of all cases.

The percentage of patients meeting the primary endpoint was 7.3% (molnupiravir) and 14.1% (placebo), a treatment difference of 6.8% (95% CI -11.3 to – 2.4, p = 0.001). Patients receiving molnupiravir had a lower risk of hospitalisation or death through to day 29 (6.8% vs 9.7%). There was one death reported in the molnupiravir group and 9 in the placebo group, all of which were considered to be COVID-19-related.

In terms of safety, 30.4% vs 33% of participants in the molnupiravir treatment arm vs placebo, experienced > 1 adverse event including diarrhoea, nausea and dizziness.

Since the trial was undertaken among unvaccinated participants, the potential value of the drug in preventing breakthrough infections could not be evaluated. Nevertheless, authors concluded that molnupiravir treatment was effective for the treatment of COVID-19 and that it did not appear to have any major safety concerns.

Citation

Bernal AJ et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients N Engl J Med 2021

Antipsychotic drugs raising prolactin elevate risk of breast cancer in women

Antipsychotic drugs especially those elevating prolactin levels appears to be associated with an increased risk of breast cancer in women

A study of antipsychotic drugs used by women has revealed an increased risk of breast cancer, which is worse in those drugs which elevate prolactin levels. This was the conclusion by researchers from the Department of Psychiatry, Washington, US.

Over expression of the prolactin (PRL) receptor is seen in more than 95% of human breast cancers and in fact, hyperprolactinaemia inducing antipsychotics cause precancerous cells to progress to cancer via JAK/STAT5 to suppress the apoptosis anticancer barrier. However, although data shows an increasing body of evidence supporting the involvement of PRL in breast carcinogenesis, results of human prospective studies are limited, equivocal, and correlative.

For the present analysis, the US team undertook a large epidemiological study, seeking to examine breast cancer risk by categorising antipsychotic drugs based on their ability to raise prolactin levels. Using lithium and anticonvulsants as a comparator, the researchers turned to a commercial health insurance database and identified women between the ages of 18 and 64 with an outpatient prescription for an antipsychotic, anticonvulsant or lithium between 2007 and 2016. They separated antipsychotics into three categories (1, 2 and 3) based on the propensity to raise prolactin, with drugs in category 1 being the highest. Examples included in the different categories were typical neuroleptics such as haloperidol, risperidone (category 1), olanzepine (category 2) and clozapine, quetiapine (category 3). The team identified invasive breast cancer from coding in the medical records and used multivariable Cox hazard models to evaluate the risk of breast cancer and adjusted for several factors including benign breast diseases, smoking, diabetes etc.

Findings

A total of 312,702 women with a median age of 41 years were identified as new users of antipsychotic drugs and 228, 035 women with a median age of 39 years, who were new users of anticonvulsants. From the whole sample, 914 women (0.2%) with a median age of 53 years, developed invasive breast cancer.

Women with use of any antipsychotic medication has a higher overall risk of breast cancer compared to those taking anticonvulsants or lithium (hazard ratio, HR = 1.40, 95% CI 1.19 – 1.64) although after adjustment, the hazard ratio reduced to 1.35 (95% CI 1.14 – 1.61).

In fully adjusted models, for the highest prolactin elevating category (1), the adjusted hazard ratio, aHR was 1.62 (95% CI 1.30 – 2.03), 1.54 (95% CI 1.19 – 1.99) for category 2 and non-significant for category 3. When analysing by age, younger women remained at an increased risk after adjustment (aHR = 1.91, 95% CI 1.21 – 3.01) compared to women aged 51 to 64 years (aHR = 1.43, 95% CI 1.01 – 2.03).

Discussing these findings, the authors noted how women using category 1 and 2 antipsychotic drugs had a significantly elevated risk of breast cancer compared to the comparator drugs. They suggested that younger women prescribed category 1 or 2 drugs should be considered for more frequent mammography screening.

Citation

Rahman T et al. Risk of Breast Cancer With Prolactin Elevating Antipsychotic Drugs. An Observational Study of US Women (Ages 18–64 Years) J Clin Psychopharmacol 2021

RNA aptamer binds to COVID-19 spike protein preventing cellular entry

17th December 2021

An RNA aptamer has been developed which attaches to the spike protein and the receptor binding domain of COVID-19 preventing entry into cells

An RNA aptamer which specifically binds to the spike protein and the receptor binding domain (RBD) of COVID-19 has been found to block entry of the virus into cells and could serve as a promising treatment for the virus, according to researchers from the Interdisciplinary Nanoscience Center, Aarhus University, Denmark.

RNA aptamers (RNA AP) are RNA oligonucleotides (i.e., single strands of RNA) that bind to a specific target with high affinity and specificity in much the same way that an antibody binds to an antigen and RNA aptamers have been used previously both diagnostically and therapeutically in the management of viruses.

For the present study, the Danish researchers described the development of a serum-stable RNA AP, RDB-PB6, which binds with nanomolar affinity to the RBD of the COVID-19 spike protein and in doing so, neutralises infectivity of the virus. The aptamer contains 2-fluoropyrimidine modifications which increases its chemical stability and resistance to degradation by viral nucleases. The researchers developed the RNA AP to specifically target the spike protein which is used by COVID-19 to bind with the angiotensin converting enzyme 2 (ACE2) to gain entry into cells. Their analysis revealed how RBD-PB6 bound with high affinity to the virus RBD alone but also interacted with the spike protein. The binding with the spike protein was confirmed in a separate experiment and again demonstrated that once bound to the spike protein, this complex was unable to interact with the ACE2 receptor.

Using virus-like particles the researchers were able to show that RBD-PB6 did not bind with other viruses such as the Middle East Respiratory syndrome (MERS) or Severe Acute Respiratory Syndrome (SARS) suggesting that the agent was highly specific, for COVID-19 displaying no cross-reactivity despite the similarity in the RBD sequence of these two coronaviruses.

Finally, the Danish team examined whether RBD-PB6 could bind to COVID-19 variants and tested this with the alpha and beta variants. They demonstrated high affinity binding between RBD-PB6 and the two variants indicating that these mutated strains were still able to recognise RBD-BP6.

The authors described how RBD-PB6 was very easy to mass produce and in a fast and reproducible way using conventional synthetic methods, adding that it was a potentially less expensive treatment compared to monoclonal antibodies. They concluded that their RNA aptamer provided a promising lead for COVID-19 treatment and a cost-effective platform for the rapid diagnosis of the virus.

Citation

Valero J et al. A serum-stable RNA aptamer specific for SARS-CoV-2 neutralizes viral entry PNAS 2021