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27th July 2023
The chimeric first-in-class immunoglobulin E (IgE) antibody MOv18 appears to have a manageable safety profile for cancer therapy, with additional evidence of anti-tumour activity in a patient with ovarian cancer.
Published in the journal Nature Communications, the researchers conducted a Phase I dose escalation trial, with the primary objective of exploring the safety and tolerability of the MOv18 IgE antibody.
The MOv18 antibody targets the human folate receptor-alpha (FRα) that is over-expressed in tumours such as ovarian, breast and lung cancers, but remains at low levels in normal tissue.
Eligible patients were over 16 years of age and had advanced or metastatic solid tumours that were not suitable for alternative standard treatment. In addition, all were required to have a solid tumour expressing FRα, although the majority had advanced ovarian cancer which had become platinum-resistant.
A total of 26 patients were enrolled and, overall, MOv18 IgE was generally well tolerated with the majority of adverse events being low grade. The most common events were localised cutaneous toxicities including urticaria, pruritus and rash, which appeared to be dose-related. Furthermore, the urticaria always resolved within hours of dosing, either spontaneously or with the administration of systemic steroids and antihistamines.
Although the primary focus of the study was the safety of MOv18 rather than efficacy, tumour shrinkage and an associated fall in the CA125 tumour marker level, was seen in one patient. Notably, the study authors observed that the anti-tumour activity ‘occurred at doses very much lower than typically observed for IgG antibodies‘, reflecting fundamental differences in Fc-receptor affinity and effector cell biology.
Professor James Spicer, professor of experimental cancer medicine at King’s College London, consultant in medical oncology at Guy’s and St Thomas’ NHS Foundation Trust and the study’s lead investigator, said: ‘IgE is a completely new form of antibody therapy which has shown great promise in this phase I trial. Our findings show that the drug was well tolerated in patients and shrunk a cancerous tumour in a patient with ovarian cancer.
‘The results pave the way to development of an entirely new class of anti-cancer drug for people with chemotherapy-resistant cancers. The immunology expertise in King’s College London laboratories allowed us to undertake this trial of a completely new form of antibody therapy.‘
A network meta-analysis of 221 randomised controlled trials with over 65,000 patients, has confirmed that oral isotretinoin is the most effective acne treatment.
Acne is extremely common, affecting virtually everyone between the ages of 15 and 17 years to some extent, but is moderate to severe in up to 20% of cases. Acne can be managed with broad range of topical and oral agents including antibiotics and even aldosterone receptor antagonists such as spironolactone.
Now, in the largest network meta-analysis into pharmacological interventions in acne vulgaris to date, published in the Annals of Family Medicine, researchers from Taiwan and the US concluded that oral isotretinoin is the most effective treatment.
The team sought to provide broad and detailed comparative efficacy data for a range of pharmacological interventions in acne to reduce both inflammatory and noninflammatory lesions. The primary outcome of interest was the mean percentage reduction in total, inflammatory, and noninflammatory lesions, and the mean absolute reduction in lesion counts were secondary outcomes.
The analysis included a total of 210 articles describing 221 trials, which enrolled a total of 65,601 patients. Across all of the trials, the mean age of patients was 20 years and the median duration of treatment was 12 weeks. In addition, the median baseline lesion counts were 71.5 for the total lesions, 27 for inflammatory lesions and 44 for noninflammatory lesions.
The comprehensive analysis compared 37 treatment nodes, which included six oral antibiotics, five topical antibiotics, oral isotretinoin, five topical retinoids, six combined oral contraceptives, topical clascoterone, 10 combination therapies, benzoyl peroxide (BPO), azelaic acid and placebo.
The most effective treatment, compared to placebo, was oral isotretinoin (mean difference, MD = 48.41, p = 1.0). The second most effective option was triple therapy containing a topical antibiotic, a topical retinoid and BPO (MD = 38.15, p = 0.95). This was followed closely by triple therapy with an oral antibiotic, a topical retinoid and BPO (MD = 34.83, p = 0.90).
The researchers also found a similar ranking of treatment efficacy in the analysis of absolute reduction in total lesion count.
When examining mono-therapies, both oral and topical antibiotics had comparable efficacy to topical retinoids for inflammatory lesions. In contrast, oral or topical antibiotic therapy was far less effective for noninflammatory lesions and the researchers advised against monotherapy due to the risk of developing bacterial resistance.
Another comparison revealed how the combination of a topical retinoid and BPO was as effective as a combination of an oral antibiotic with a topical retinoid at reducing inflammatory lesion counts.
Cabotegravir – the first and only long-acting injectable pre-exposure prophylaxis (PrEP) option proven superior to daily oral emtricitabine/tenofovir disoproxil fumarate in reducing HIV acquisition – has received a positive opinion from the EMA’s Committee for Medicinal Products for Human Use (CHMP).
Suitable for use in high-risk adults and adolescents weighing at least 35 kg to reduce the risk of sexually acquired HIV-1 in combination with safer sex practices, cabotegravir is an integrase strand transfer inhibitor, which prevents the HIV virus from integrating into the genetic material of human immune cells.
Developed by ViiV Healthcare, the CHMP positive opinion relates to the oral 30 mg tablet, which may be administered for approximately one month before initiating the first injection to assess the tolerability of the medicine, as well as the 600 mg prolonged-release injectable suspension.
The injection is administered six times per year by a healthcare professional and is initiated with a single 600 mg (3 ml) injection given one month apart for two consecutive months. After the second initiation injection, the recommended continuation injection dose is a single 600 mg (3 ml) injection every two months.
This represents an important step in the prevention of HIV, especially given the failure of a HIV vaccine earlier in 2023. Cabotegravir, which is sold under the brand name Apretude, has already been approved for use in the US, Australia, Zimbabwe, South Africa, Malawi, Botswana, and Brazil.
Kimberly Smith, head of research and development at ViiV Healthcare, said: ‘The expansion of prevention options is critical if we are to end the HIV epidemic. Long-acting options have the potential to play an important role in reducing challenges such as inconsistent adherence to taking daily pills, and stigma associated with oral PrEP use that can be faced by people who could benefit from PrEP.‘
She added: ‘With the CHMP positive opinion, we are hopeful that people in Europe will soon be able to benefit from greater choice.‘
The human immunodeficiency virus (HIV) remains one of the most important communicable diseases in Europe, with approximately 100,000 new diagnoses across the continent each year. Infection is associated with serious disease, persistently high treatment and care costs. Despite progress being made in the delivery of HIV treatment and prevention services, plus a continuous decline in the incidence of new cases, HIV still leads to a significant number of deaths and shortened life expectancy.
The positive opinion for cabotegravir in Europe was based on the results of two randomised, double-blind, placebo-controlled trials. The first, HPTN 083, compared the long-acting injectable cabotegravir, given intramuscularly every eight weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine for the prevention of HIV infection in at-risk cisgender men.
The primary end point was incident HIV infection, which was reduced by 76% in participants given cabotegravir (Hazard ratio, HR = 0.34, 95% CI 0.18 – 0.62).
The second trial, HPTN 084, compared the efficacy of injectable cabotegravir with daily oral tenofovir diphosphate plus emtricitabine for HIV prevention in uninfected women. This time, there was an even greater reduction in the risk of HIV infection in the cabotegravir group (HR = 0·12, 95% CI 0.05 – 0.31, p < 0.0001).
Women who are both diagnosed and treated for breast cancer appear to undergo accelerated biological ageing compared to those who remain free of the cancer, according to a recent study.
Biological aging is accelerated following a breast cancer diagnosis and treatment according to the findings of a new study led by a team from the National Institute of Environmental Health Sciences (NIEHS). Their research,
Published in the Journal of the National Cancer Institute, the researchers from the National Institute of Environmental Health Sciences examined paired blood samples through DNA methylation profiling collected from women enrolled in the prospective Sister Study cohort at the initial and follow-up visits, which were an average of 7.7 years apart.
Researchers also included patients who remained free of breast cancer for comparative purposes and used linear regression models to assess differences in several biological aging metrics at the second sample collection or follow-up by breast cancer status.
A total of 417 women, of whom 190 were diagnosed and treated for breast cancer between blood sampling, were included in the study.
Among women who developed breast cancer, diagnoses occurred an average of 3.5 years after the initial blood draw and four years before the second sample. After adjusting regression models for covariates and biological aging metrics measured at baseline, it was found that women diagnosed and treated for breast cancer had higher biological aging metrics at the follow-up.
In analyses assessing the associations with different breast cancer therapies, radiation had strong positive associations with biological aging. In contrast, surgery had little association with the biological aging metrics.
Commenting on the study, co-author Dale Sandler said ‘Radiation is a valuable treatment option for breast cancer, and we don’t yet know why it was most strongly associated with biological age.’ He added that ‘This finding supports efforts to minimise radiation exposures when possible and to find ways to mitigate adverse health effects among the approximately four million breast cancer survivors living in the United States.’
Empagliflozin has become the first SGLT2 inhibitor to be approved by the European Medicines Agency (EMA) for the treatment of adult patients with chronic kidney disease (CKD), Boehringer Ingelheim and Eli Lilly and Company have announced.
This EMA approval represents a major advance in the standard of care for the estimated 47 million patients living with the disease in Europe. CKD, characterised by a reduction in the glomerular filtration rate, is often progressive, and the presence of albuminuria is a key risk factor for the subsequent development of kidney failure. Hence, any treatment that slows disease progression offers a clinical benefit to patients.
In June 2023, the Committee for Medicinal Products for Human Use adopted a positive opinion to recommend a change to the terms of the marketing authorisation for the medicinal product Jardiance (empagliflozin). This was based on the findings of the EMPA-KIDNEY trial, which were published in the New England Journal of Medicine earlier in the year.
With existing indications in type 2 diabetes and heart failure, empagliflozin could help manage the risks of cardio-renal-metabolic conditions.
Leonard Glass, senior vice president, diabetes and obesity global medical affairs at Lilly, said: ’CKD is closely linked to other cardio-renal-metabolic conditions such as type 2 diabetes and heart failure – thus an integrated approach is vital for optimised treatment of these interconnected conditions. We look forward to continuing conversations with other regulatory bodies worldwide so that empagliflozin can be made available for as many people living with these conditions as quickly as possible.’
Commenting on the approval, Daniel Gallego, president of European Kidney Patients’ Federation, added: ’We celebrate this significant milestone in the field of chronic kidney disease. CKD is a silent killer and prevention and early detection are crucial in the general population.
’This new treatment option has the potential to further improve the management of cardiorenal metabolic syndrome and renal disease, offering renewed hope and improved quality of life for countless individuals living with CKD worldwide.’
The EMPA-KIDNEY trial enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area. Alternatively, enrolled participants could have an eGFR of at least 45 but less than 90 with a urinary albumin-to-creatinine ratio of at least 200.
EMPA-KIDNEY showed that during a median of 2.0 years of follow-up, the use of empagliflozin was associated with a 28% lower risk of progression of kidney disease or death from cardiovascular causes, compared to the placebo (Hazard ratio, HR = 0.72, 95% CI 0.64 – 0.82, p < 0.001).
These findings were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. In addition, the rate of hospitalisation from any cause was lower in the empagliflozin group (HR = 0.86, 95% CI 0.78 – 0.95, p = 0.003).
A higher intake of nuts in older adults at risk of cognitive decline could help to slow the decrease in cognitive performance, although the evidence to date is far from clear. Clinical writer Rod Tucker takes a closer look.
The term ‘dementia’ embraces a number of diseases that affect memory, thinking and the ability to perform daily activities. In short, dementia represents the loss of cognitive health, which is key feature of healthy aging.
Unfortunately, the level of dementia appears to be on the rise, becoming a growing and global problem. According to the World Health Organization, there are currently an estimated 55 million people living with dementia worldwide, and this figure is expected to rise in the coming years. Moreover, dementia the seventh leading cause of death and one of the major causes of disability and dependency among older people globally.
There are no known cures for dementia, but efforts have been directed at a range of potential modifiable risk factors, outlined in a 2020 Lancet review. One such factor is diet – particularly the Mediterranean diet, which consists of a high intake of vegetables, legumes, fruits, nuts, cereals and olive oil. But is there evidence to support a higher intake of the individual components in the Mediterranean diet as a means of reducing the risk of cognitive decline?
One constituent that has gained interest in recent years as a strategy to modify cognitive decline, is a higher intake of nuts, but the strength of the evidence supporting this proposition requires more analysis.
Tree nuts and peanuts (henceforth, nuts) are nutrient-dense foods with a myriad of biologically active ingredients such as unsaturated fatty acids and high-quality vegetable protein, combined with an array of vitamins and beneficial minerals, dietary fibre, phenolic compounds and phytosterols. Peanuts, though botanically classified as legumes rather than nuts, do contain a similar nutrient profile as tree nuts and to all intents and purposes can be considered a nut.
To date, there is compelling evidence for the cardiovascular protective effect of a higher nut intake, largely through an improvement in the lipid profile. For example, it is recognised that a daily intake of small amounts of walnuts lowers LDL cholesterol.
Despite the cardiovascular benefits, much less is known about whether the intake of nuts impacts on brain health, and in particular, if this reduces the risk of cognitive decline. Nevertheless, nuts are likely to have an important effect on the brain as recognised by a recent systematic review on depression.
The review, which included 10 studies with over 60,000 participants, concluded that a higher nut consumption could be associated with a lower risk of depression, fewer depressive symptoms and better mood state in the general population.
In relation to cognitive health, another recent review suggested that while the available evidence was limited and inconclusive, there was likely to be a possible role for nuts for the maintenance of cognitive health and the prevention of cognitive decline, particularly in older adults and those at higher risk.
With supportive data from observational studies, the real test of efficacy can only really be determined from randomised, interventional, controlled trials. So, how does this evidence stack up?
Unfortunately, findings have been somewhat mixed. For instance, the PREDIMED-NAVARRA randomised trial explored the impact of a Mediterranean diet on cognitive function. Some 522 participants at high vascular risk were assessed and compared a Mediterranean diet supplemented with either extra-virgin olive oil or mixed nuts versus a low-fat control diet. Interestingly, the study found that both Mediterranean diets appeared to improve cognition compared with a low-fat diet.
In contrast, the MedLey Study, which used a Mediterranean diet in older adults compared to a control diet, failed to detect any effect of a Mediterranean diet on cognitive function among healthy older adults. Similarly, a trial in which healthy older adults were randomised to receive an additional intake of almonds found no improvement in cognitive function. A second interventional trial, this time using walnuts, while showing no effect on cognition in healthy elders, did observe that that walnuts might delay cognitive decline in subgroups at higher risk.
The most recent study to examine the effect of consuming nuts on cognitive function, published in June 2023, looked at the two-year impact on cognitive performance in 6,630 adults with a mean age of 65 years who were deemed at risk of cognitive decline.
Nut consumption was categorised as less than one serving per week, one to three servings, between three and seven servings or more than seven serving per week, with a serving defined as 30g. Although the study was prospective in nature, and therefore subject to several recognised limitations, the researchers did see a benefit from increased nut consumption.
Using those who consumed less than one serving of nuts per week as a comparator, the results showed that eating between three and seven servings per week or more than seven portions both demonstrated more favourable changes in general cognitive performance. Although not the main focus of the study, the researchers also found a potential synergistic interaction between nut consumption and depression. In other words, participants with depressive symptoms at baseline tended to benefit more from the consumption of nuts than those without depression.
There seems to be plenty of observational evidence that nut consumption may help to delay the onset of cognitive decline, as randomised interventional studies have not provided consistent findings. In addition, no studies have specifically addressed the effect of eating nuts on hard clinical outcomes such as the development of dementia or Alzheimer’s disease.
While the latest prospective study does suggest a possible cognitive benefit, there is an urgent need for more randomised, interventional trials before recommending increased consumption of nuts to either delay cognitive decline or prevent the onset or progression of cognitive impairment and dementia.
But given a possible link between the cardiovascular and dementia biochemical pathways, it remains plausible that inclusion of more nuts into an individual’s diet might not only improve their cardiovascular health but could help to ameliorate cognitive decline.
26th July 2023
While interventional neuroradiology endovascular procedures are normally controlled using joystick movements, a new study suggests that a device mimicking robotic controller, which directly copies the operator’s movements, allows for a better performance and outcomes.
Published in the International Journal of Computer Assisted Radiology and Surgery, researchers developed an interventional radiology simulator with a profile of vessels, catheters and guidewire beam modelling.
The participants were six experienced interventional neuroradiologists, two novice neuroradiologists and one interventional radiologist. These individuals then performed a navigation task on the simulator with three different human-computer interfaces.
A number of metrics were used to evaluate and characterise each interface, including the time taken for navigation, number of incorrect catheterisations, number of catheter and guidewire prolapses and forces applied to vessel walls. Finally, participants responded to a questionnaire to evaluate the perception of the robotic controllers.
The researchers found that the time taken for navigation, the number of incorrect catheterisations and the number of catheter and guidewire prolapses were better for the device mimicking robotic controller compared to a joystick controlled approach. In feedback, the interventional radiologists reported a preference for the device mimicking controller for interventional neuroradiology procedures.
Lead author on the study, and PhD candidate in cancer imaging, Benjamin Jackson said: ‘There is a lack of interventional neuroradiologists across the UK and globally. In the UK alone, around 6,000 patients per year are unable to access the most beneficial stroke care. This paper is the first steps towards developing tele-operated robotic solutions to help give patients access to the care they need.‘
Study author Thomas Booth, reader in neuroimaging, School of Biomedical Engineering and Imaging Sciences at King’s College London, added: ‘Whilst this is an intuitive result, robots in interventional radiology are typically controlled using button presses and joystick movements, so the findings may change the direction of robotic development in this emerging field.‘
25th July 2023
A novel membrane efflux pump inhibitor has been developed by a team of researchers at King’s College London, providing hope in the fight against antimicrobial resistance.
Bacteria can become resistant to antibiotics by drawing on their efflux pumps – proteins which allow them to regulate their internal environment by removing toxic substances. These reduce the concentration of antibiotics that reach the inside of the cell, increasing the likelihood of treatment failure.
King’s College London chemists have discovered how an efflux pump inhibitor can prevent this mechanism and therefore stop bacteria from becoming resistant to currently used antibiotics. This new method could prove cheaper and more efficient at dealing with antimicrobial resistance.
In 2017, researchers identified NSC 60339 as a periplasmic adaptor protein (AcrA) inhibitor with diverse functions, however the mechanism of AcrA inhibition was unclear.
In the current study, researchers used a combination of native and hydrogen/deuterium exchange mass spectrometry, molecular dynamics simulations and biophysical and cellular efflux assays to determine a mechanism of action for the AcrA inhibitor NSC 60339.
Their findings suggest that NSC 60339 becomes wedged between the lipoyl and αβ barrel domains, significantly restricting the structural dynamics of AcrA. They suspect that once locked in this position, AcrA cannot perform the necessary conformational transitions required during the functional rotation of the AcrAB-TolC pump used by bacteria to eject an antibiotic.
Ultimately, the work provides molecular insights into multi-drug adaptor protein function, which could be valuable for developing antimicrobial therapeutics.
Benjamin Russell Lewis from the Department of Chemistry at King’s College London said: ‘We discovered an inhibitor that acts as a ‘molecular wedge’ to neutralise the effective movement of the protein controlling the efflux pump response. Previous studies have identified that this particular inhibitor helped antibiotics kill bacteria but no one knew why or how, until now.
‘Traditional methods have focused on inhibitors targeting proteins in the inner cell membrane of bacteria. We demonstrate that inhibitors targeting the area between the inner and outer cell membranes could work better.‘
Dr Eamonn Reading, research fellow, Department of Chemistry at King’s College London, added: ‘Bacterial multidrug resistance continues to spread at alarming rates, threatening human health globally. If there ever is going to be a quick solution to dealing with something like a pandemic, employing efflux pump inhibitors will help us re-tool the existing treatments we already have.
‘We’ve helped lay the foundations with which future researchers and drug manufacturers can make more impactful alternative therapeutics to treat these devastating diseases without the need to make brand new antibiotics.‘
By providing the groundwork for how these cells and proteins interact at a molecular level, it is hoped that pharmacologists will be able to produce this new class of inhibitors and antibiotic treatments at speed and in time for the next generation of superbugs.
Researchers have identified that a particular gene highly over-expressed in macrophages during atrial fibrillation (AFib) could serve as a future therapeutic target.
AFib leads to disrupted contraction of the atria, increasing the risk of both a stroke and heart failure. Now, a research study led by investigators at Massachusetts General Hospital (MGH) and published in the journal Science, shows that macrophage immune cells appear to have an important role in the development of AFib.
Their study was able to decipher how immune and stromal cells contribute to the arrhythmia. The team compared atrial tissue from patients with and without AFib and developed a mouse model of AFib which integrated hypertension, obesity and mitral valve regurgitation (HOMER) in which these cellular and transcriptomic changes were recapitulated.
Using single-cell transcriptomes from human atria, researchers found inflammatory monocyte and SPP1+ macrophage expansion in atrial fibrillation. In addition, gene expression analyses showed that, in both human and mouse hearts, the SPP1 gene is highly over-expressed in macrophages during AFib. The gene produces a protein called SPP1 protein which promotes tissue scarring and is elevated in the blood of patients with AFib. In contrast, in the HOMER mice model, there were a reduced numbers of atrial macrophages when SPP1 was absent.
Through the use of cell-cell interaction analysis, it was revealed how SPP1 provided a pleiotropic signal that promoted atrial fibrillation through cross-talk with local immune and stromal cells. Moreover, the deletion of SPP1 in HOMER mice reduced AFib, which suggests that SPP1+ macrophages could serve as a target for immunotherapy in patients with atrial fibrillation.
Commenting on the research, senior author Matthias Nahrendorf from Massachusetts General Hospital, said: ‘We found that recruited macrophages support inflammation and fibrosis, or scarring, of the atria, which hinder electrical conduction between heart cells and lead to AFib. Inhibiting macrophage recruitment reduced AFib.
‘We think that this research lays the groundwork for immunomodulatory therapy of AFib, and we are currently working on several strategies to make this happen.‘
24th July 2023
A single subcutaneous injection of zilebesiran, which inhibits hepatic angiotensinogen synthesis, maintained a reduced 24-hour ambulatory blood pressure for 24 weeks, an international research team has found.
If approved, the drug paves the way for a more convenient means of managing hypertension, which is normally treated with oral antihypertensive agents.
In the study, published in the New England Journal of Medicine, the research team, which included experts from the University of Edinburgh’s Centre for Cardiovascular Science, examined the value of zilebesiran – an investigational RNA interference therapeutic agent which inhibits hepatic angiotensinogen synthesis – as a treatment for hypertension.
The study consisted of five different parts (A to E) but the current analysis focused on only three: Parts A, B and E.
In Part A, patients with hypertension were randomised 2:1 to either a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400 or 800 mg) or placebo and followed for 24 weeks. Part B focused on the effect of an 800 mg dose of zilebesiran on blood pressure under conditions of either a low- or high-salt diet. Finally, the team provided the results from Part E, which was an open-label study of a single fixed dose of zilebesiran in combination with daily irbesartan.
Of the 107 patients enrolled, there were no reports of hypotension, hyperkalaemia or worsening of renal function that required medical intervention.
In Part A, patients who received zilebesiran had decreases in serum angiotensinogen levels that correlated with the administered dose after eight weeks (r = –0.56). Single doses of the drug exceeding 200 mg were associated with decreases in both systolic (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) after only eight weeks and which were sustained after 24 weeks.
The findings from part B were consistent with attenuation of the effect on blood pressure by a high-salt diet. Similarly, patients in part E experienced a reduction in blood pressure with zilebesiran co-administration with irbesartan.
Professor David Webb, Christison chair of therapeutics and clinical pharmacology at the University of Edinburgh, who led the Edinburgh study site, said: ‘This is a potentially major development in hypertension. There has not been a new class of drug licensed for the treatment of high blood pressure in the last 17 years. This novel approach leads to a substantial reduction in blood pressure, both by day and night, that lasts for around six months after a single injection. This is attractive because it helps avoid the difficulty with adherence to treatment seen with current medicines. The next stage of clinical trials will focus on developing robust safety data, and broader evidence of efficacy, before zilebesiran can be licensed for use.‘
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