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11th June 2021
Patients can be at risk from ultrasound-associated infections when low-level disinfection (LLD) is the standard of care. In order to quantify this risk, Scotland’s National Health Service undertook a retrospective analysis of microbiological and prescription data through linked national health databases. Patient records were examined in the 30-day period following semi-invasive ultrasound probe (SIUP) procedures.
The study analysed almost one million patient journeys that occurred during a six-year period from 2010.1
Of the 982,911 patients followed, 330,500 were gynaecological patients; and 60,698 of these gynaecological patients had undergone a transvaginal (TV) ultrasound procedure. These patients were found to be at a 41% greater risk of infection and a 26% greater risk of needing an antibiotic prescription in the 30 days following their transvaginal ultrasound procedure when compared to gynaecological patients who had not undergone a transvaginal ultrasound.
During the study period, 90.5% of facilities reported that they were performing low level disinfection for transvaginal ultrasound probes. These patients were at a greater risk of infection due to inadequate reprocessing and the study concluded that: “Hence failure to comply with existing guidance on [high-level disinfection] of SIUPs will continue to result in an unacceptable risk of harm to patients .”1
The diverse use of ultrasound probes is now prompting a renewed focus on correct probe reprocessing to ensure patient safety. To ensure best practice standards, decontamination experts and ultrasound users need to work together to reduce the risk of infection that is associated with using ultrasound probes.
Ultrasound procedures are performed in various inpatient and outpatient settings by a wide range of health professionals. This has increased the use of surface probes to guide procedures such as biopsies, cell retrieval, cannulation, catheterisation, injections, ablations, surgical aspirations, and drainages. Across these procedures, the probe has the potential to contact various patient sites – including intact skin, non-intact skin, mucous membranes and sterile tissue. This presents a complex challenge, as contact with these various body sites requires differing levels of disinfection or sterilisation between patient uses. Failure to adequately clean and disinfect medical devices like ultrasound probes between patients poses a serious risk to patient safety.
In 2012, a patient in Wales died from a hepatitis B infection – most likely caused by a failure to appropriately decontaminate a transoesophageal echocardiography probe between patients. As a result of this fatality, a Medical Device Alert was issued by the Medicines and Healthcare Products Regulatory Agency (UK) advising users to appropriately decontaminate all types of reusable ultrasound probes.2
The UK and European guidelines require ultrasound probes that come into contact with mucous membranes and non-intact or broken skin to be high-level disinfected. In particular, automated and validated processes for ultrasound reprocessing are preferred. This is supported by a study relating to manual disinfection methods, which found that only 1.4% of reprocessing systems were fully compliant when using manual methods, compared to 75.4% when using semi-automated disinfection methods.3
The Spaulding classification system4 must be applied before a procedure commences so that information about what tissues or body sites may be contacted is taken into account.
This classification system is a widely adopted disinfection framework for classifying medical devices, based on the degree of infection transmission risk, and requires the following approaches:
It is important to note the difference between cleaning and low-level disinfection. Cleaning is the removal of soil and visible material until the item is clean by visual inspection. Low level disinfection is the elimination of most bacteria, some fungi and some viruses.
A final and important point for consideration is the use of probe covers.
While many ultrasound users and sonographers believe that their transvaginal ultrasound patients are protected from infection risk by using barrier shields and/or condoms, research has shown that up to 13% of condoms fail and up to 5% of commercial covers fail. Probe covers may have microscopic tears or breakages which can allow microorganisms to pass through.5
Ultrasound users should work with their decontamination colleagues to understand the current UK and European guidelines for reprocessing ultrasound probes. There are patient risks associated with ultrasound usage when proper disinfection procedures are not followed, as well as from ancillary products such as contaminated ultrasound gel. While the increased use of ultrasound has brought many benefits for patients, effective education and disinfection protocols are required to minimise the risk of infection.
The trophon® system is designed to reduce the risks of infection transmission through automated high-level disinfection of transvaginal, transrectal and surface probes. With over 25,000 units operating worldwide, 80,000 people each day are protected from the risk of cross-contamination with trophon devices. As a fully enclosed system, trophon2 can be placed at the point of care to integrate with clinical workflows and maintain patient throughput. trophon technology# uses proprietary hydrogen peroxide disinfectant that is sonically activated to create a mist. Free radicals in the mist have oxidative properties enabling the disinfectant to kill bacteria, fungi and viruses. The mist particles are so small that they reach crevices, grooves and imperfections on the probe surface. Nanosonics works collaboratively with probe manufacturers to carry out extensive probe compatibility testing. More than 1000 surface and intracavity probes from all major and many specialist probe manufacturers are approved for use with trophon devices.
# The trophon family includes the trophon EPR and trophon2 devices which share the same core technology of sonically-activated hydrogen peroxide.
Acute myocarditis (aMC) has many different causes but the prevalence is unclear because the condition has similar clinical symptoms to an acute myocardial infarction (aMI). Although the diagnosis of myocarditis can be confirmed with cardiac magnetic resonance imaging, this technique is not always available. However, one approach to resolve the diagnosis involves the use of microRNAs (miRNAs), which are small, non-coding RNAs that play an important role in gene expression. Several miRNAs have been identified in the infarcted heart and this led a team from the Vascular Pathophysiology Area, Madrid, to try and identify a unique miRNA which could be used to distinguish between myocarditis and myocardial infarction. The team focused on circulating T cells, in particular T helper 17 (Th17) cells, which were confirmed as being a characteristic of myocardial injury in the acute phase of myocarditis. They performed a miRNA microarray analysis and quantitative polymerase chain reaction (qPCR) assays in Th17 cells after experimentally inducing myocarditis and myocardial infarction in mice to identify unique biomarkers.
The researchers identified the miRNA, mmu-miR-721, produced by Th17 cells in mice which was only produced in response to either autoimmune or viral myocarditis and which was absent from those with aMI. Using four patient cohorts with myocarditis, they subsequently identified a human homologue to mmu-miR-721, termed has-miR-Chr8:96. The researchers found that plasma levels of has-miR-Chr8:96 were considerably higher among myocarditis patients compared to both those with a myocardial infarction and in healthy controls. The area under the receiver-operating characteristics curve for has-miR-Chr8:96 was 0.927 (i.e., 92.7%) for distinguishing between aMC and aMI and this diagnostic value was retained even after adjusting for age, ejection fraction, and serum troponin levels.
Although the authors accepted that more work is needed to validate this biomarker in other cardiac disorders such as dilated cardiomyopathy, their preliminary findings suggest that raised plasma levels of has-miR-Chr8:96 are unique to those with myocarditis and have sufficient discriminatory power from myocardial infarction.
Blanco-Dominguez R et al. A Novel Circulating MicroRNA for the Detection of Acute Myocarditis. N Engl J Med 2021;384:2014-27
Psoriasis is a chronic, inflammatory conditions that affects 1% of children and adolescents in the US. Moreover, due to the visible nature of the condition, psoriasis can have a negative impact on children’s quality of life.
The interleukin-17A (IL-17A) inhibitor, secukinumab (brand name Cosentyx) can now be used for the treatment of moderate-to-severe psoriasis in children from the age of six who are candidates for systemic or phototherapy because of the severity of their psoriasis. The drug has more than 14 years of clinical experience and long-term, 5-year clinical data. The approved dosing is 75 or 150mg, depending on the child’s weight (i.e., 75mg for those < 50kg and 150mg > 50kg) and the drug is administered by subcutaneous injection every four weeks after an initial loading regime. A further advantage is that after suitable counselling, the dose can be given by an adult carer, hence avoiding the need to visit a healthcare professional.
The approval of Cosentyx was based on the results of two Phase III trials that were undertaken in children aged between 6 and 18 years. The first trial was a 52-week, randomised, double-blind, placebo controlled study with 162 children with severe plaque psoriasis. The study had a co-primary endpoint: the proportion achieving a psoriasis area severity index (PASI) 75 score (i.e., a 75% improvement in disease severity) and an investigator’s global assessment of either “clear” (no psoriasis) or “almost clear” at week 12.
Among children <50kg, after 12 weeks, 55% vs 10% (Cosentyx vs placebo) had achieved a PASI 75. Similarly in those weighing >50kg, the corresponding PASI 75 values were 86% vs 19% (Cosentyx vs placebo). For children weighing <50kg, the proportion achieving a score of clear or almost clear was 32% vs 5% (Cosentyx vs placebo). Similarly, among children weighing > 50kg, the corresponding values were 81% vs 5%.
The second trial was designed to assess safety although the press release contains no data from this study and at present, neither study has been published.
Discussing the new approval, Randy Beranek, President and CEO of the National Psoriasis Foundation, said “Having expanded treatment options for this patient population is a step in the right direction to help reduce the burden of plaque psoriasis“.
10th June 2021
Alzheimer’s disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills and ultimately, the ability to carry out simple tasks. The precise cause of the disease is still not fully clear but a defining feature in the brain of sufferers is an accumulation of amyloid beta plaques and neurofibrillary, or tau, tangles which result in loss of neurons and their connections. Aducanumab (Aduhelm) works by targeting the aggregated soluble and insoluble amyloid beta plaques.
The efficacy of Aduhelm has been evaluated in three separate studies with a total of 3078 patients and which have been described in the manufacturer’s prescribing information leaflet. The dosage is 10mg/kg and the drug is administered over one hour every 4 weeks and available at two different strengths, 170 mg and 300mg.
In clinical studies, the effect of Aduhelm on amyloid plaques was assessed in the trials using positron emission tomography (PET) and resulted in significant reductions in plaques after 26 and 78 weeks of treatment. Writing on the FDA site, Dr Patrizia Cavazzoni, Director, FDA Center for Drug Evaluation and Research noted that “the data included in the applicant’s submission were highly complex and left residual uncertainties regarding clinical benefit.” Nonetheless, she also added that “the Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy.”
Additionally, the FDA is requiring the manufacturer, Biogen, to conduct a post-approval clinical trial to verify the drug’s clinical benefit. If the drug does not work as intended, then the FDA can take steps to remove it from the market.
9th June 2021
The clinical symptoms of Crohn’s disease (CD) are similar in adults and children although there is evidence that cases of paediatric CD are on the rise, with one study estimating that the highest incidence, at 23 per 100,000 person-years occurred in Europe. Endoscopic evidence of mucosal healing is a valuable therapeutic goal that decreases the risk of disease relapse although little is known about the association between mucosal healing and therapeutic levels of biological treatments such as adalimumab. This prompted a team from the Department of Paediatrics, Samsung Medical Centre, Korea, to examine the relationship between therapeutic drug monitoring of adalimumab and mucosal healing and clinical remission in paediatric patients with CD. The team prospectively recruited paediatric patients with CD receiving adalimumab maintenance therapy and who underwent routine endoscopic evaluation of mucosal healing and therapeutic drug monitoring. Monitoring assessments were made at 4 months and then at years 1, 2 and 3.
In total, 31 children with a mean age of 14.8 years (74% male) were included in the analysis. After 1 year of treatment, 26 (83.9%) had achieved clinical remission and 17 (54.8%) had complete mucosal healing. The mean adalimumab trough levels were higher in patients who had achieved remission compared to those with active disease (7.6 mcg/ml vs 5.1 mcg/ml, remission vs active disease). Similarly, trough levels of adalimumab were significantly higher in those who achieved mucosal healing after 1 year (14.2 mcg/ml vs 7.8mcg/ml, mucosal healing vs non-healed, p = 0.03). Although only 23 children were evaluated after 3 years, adalimumab trough levels remained above 10 mcg/ml and a similar proportion of children maintained mucosal healing (64.3%) and clinical remission (92.9%). Using receiver operating curves, authors calculated that the optimal cut-off adalimumab trough levels to achieve mucosal healing was 8.18 mcg/ml.
In discussing their findings, the authors commented on the results demonstrated that mucosal healing rates increased when adalimumab was used over the longer term and that the drug maintained its efficacy. They concluded that there was merit in using therapeutic drug monitoring to guide proactive optimisation of drug levels to achieve the goal of mucosal healing.
Kim MJ et al. Therapeutic Drug Monitoring of Adalimumab During Long-term Follow-up in Paediatric Patients with Crohn Disease. JPGN 2021;72:870-6.
8th June 2021
Weight loss in patients with type 2 diabetes improves metabolic outcomes such as insulin resistance and glycaemic control. This is particularly important in Asian populations where data indicate an increased prevalence of obesity. While traditionally lifestyle interventions have been delivered in face-to-face sessions, potential barriers such as the need for formal appointments, travel and associated costs, together with potential time constraints, can limit the value of these sessions.
In recent years, the development of smartphone technology has enabled the delivery of lifestyle interventions for patients with long-term conditions and which circumvent some of the problems encountered with face-to-face meetings. However, the effectiveness of smartphone-based apps can depend, to some extent, on the cultural appropriateness of the material provided. In an attempt to examine the value of a culturally and contextualised smartphone app, designed to deliver lifestyle interventions, a team from the Department of Dietetics, National University Hospital, Singapore, undertook a randomised, controlled trial to compare a smartphone-based intervention with usual care. Included participants were adults with type 2 diabetes with a body mass index (BMI) of 23 or greater and at the start of the study, all participants received a single advisory session from a dietician concerning weight and physical activity. Intervention participants were then required to use the app for at least 6 months (to track weight and activity levels) and to communicate (via the app) regularly with a dietician. The primary outcome was the change in body weight after six months, whereas secondary outcomes were changes in metabolic profiles (e.g., HbA1c, fasting blood glucose, blood pressure).
In total, 204 participants were enrolled and randomised to the intervention (99) or control. The mean age of intervention participants was 51.6 years (33.3% female) with an average weight of 84 kg and BMI of 30.3. After six months, participants in the intervention group had a significantly greater mean weight loss (3.6 kg vs 1.2kg, intervention vs control, p < 0.01). In addition, there was a greater change in mean HbA1c levels (-0.7% vs 0.03%, intervention vs control) and in the proportion of participants seeing a reduction in their use of diabetic medications (23.3% vs 5.4%, intervention vs control). There were also favourable changes in fasting glucose levels and diastolic blood pressure. Finally, nearly two-thirds (62%) of intervention participants used the smartphone app at least 75% of the days during the 6-month period.
Commenting on their findings, the authors noted how the intervention group’s weight loss was comparable to the results achieved from face-to-face sessions and, more importantly, this loss was sustained over a six-month period. The authors concluded that the smartphone app led to significant weight loss and metabolic parameters and that future work should focus on the lifestyle factors more likely to achieve successful outcomes.
Lim SL et al. Effect of a Smartphone App on Weight Change and Metabolic Outcomes in Asian Adults with Type 2 Diabetes. A Randomised Clinical Trial. JAMA Netw Open 2021
According to the manufacturer, in March 2021, the vaccine was studied in a Phase III trial in 2260 adolescents, aged 12 to 15. In the trial, there were 18 confirmed positive COVID-19 cases in the placebo group but none in those given the vaccine. Furthermore, among those vaccinated, the neutralising antibody titre response was high (geometric mean titre, GMT = 1239.5) in a subset of participants one month after the second dose and higher than the response generated in 16 to 25 year olds (GMT = 705.1) in an earlier study.
According to June Raine, MHRA chief executive, “We have carefully reviewed clinical trial data in children aged 12 to 15 years and have concluded that the Pfizer/BioNTech COVID-19 vaccine is safe and effective in this age group and that the benefits of this vaccine outweigh any risk.”
Importantly, there were no new safety signals generated in the adolescent study and while the UK regulator has approved the vaccine, it is the responsibility of the Joint Committee on Vaccination and Immunisation (JCVI) to advise on whether this age group will be vaccinated as part of the deployment programme.
Urothelial carcinoma (UC) or transitional cell carcinoma, is the most common form of bladder cancer and is the tenth most common cancer in the world. The urothelial cells that line the bladder and urinary tract are constantly exposed to environmental agents that are filtered through the kidneys and not surprisingly, 90% of bladder cancers arise in these cells. Detection of UC is based on subjective microscopic features that are not always able to distinguish between benign and low-grade UC. Now a team from Yale Cancer Centre, US have developed a urine screening test based on immunocytochemistry and detects keratin 17, a molecule that has been found to be over-expressed in a range of cancers such as those affecting the breast, ovaries and pancreas. The researchers wanted to examine whether identification of keratin 17 could be used to screen for UC and detect recurrent UC in urine samples.
The study involved two patient cohorts: one with haematuria and one with recurrent UC. In screening samples with haematuria, the test was found to have a sensitivity of 100% and specificity of 83%. In patients with recurrent UC, the corresponding specificity and sensitivities were 92% and 100%.
The test itself, URO17 is developed by KDx diagnostics and commenting on the results of the study, co-author, Dr Nam Kim, said “there is now a growing body of evidence that the non-invasive K17 urine test will make a significant positive impact on detection and management of UC”. The study authors concluded that the study provides evidence to support the development of prospective trials to further define the clinical and diagnostic impact of K17.
Babu S et al. Keratin 17 Is a Novel Cytologic Biomarker for Urothelial Carcinoma Diagnosis. Am J Clin Pathol 2021
7th June 2021
While COVID-19 remains a predominately respiratory infection, early in the pandemic there were reports indicating how the virus appeared to give rise to neurological features. While originally this consisted of isolated case reports, over time case series and case-controlled studies began to emerge and at the present time, the establishment of prospective studies have enabled the reporting of neurological and neuropsychiatric complications and some of these preliminary findings have been published. In an attempt to provide a basis for understanding the neurological and neuropsychiatric complications associated with COVID-19, a team from the Division of Psychiatry, University College, London, undertook a systematic review and meta-analysis of the information already published to estimate the range and prevalence of these complications.
The review identified a total of 215 eligible studies, of which the most common type were cohort studies (37), 15 were case-controlled studies, 80 cross-sectional and 83 from 30 different countries. In total, 147 studies provided quantitative data and which were included in the meta-analysis. Symptoms with the highest prevalence were anosmia (43.1%), weakness (40%), fatigue (37.8%), dysgeusia, i.e., taste disturbance (37.2%).
In terms of specific neurological and neuropsychiatric complications, the most common was depression (23%), anxiety (15.9%), headache (20.7%), sleep disorder (23.5%), altered mental status (8.2%) and visual defect (3%). Nevertheless, major neurological problems such as ischaemic (1.9%) or haemorrhagic stroke (0.4%) and seizure (0.06%) were fortunately infrequently reported. Analysis of studies by type (i.e., prospective or retrospective), illness severity and country of origin, all affected the reported prevalence of symptoms and the authors only rated 10.7% of the studies as being of high quality which limits the generalisability of the findings.
In a discussion of the implications from these findings, the authors noted that practitioners need to aware that conditions such as anosmia, weakness, dysgeusia and fatigue were very common and while more serious neurological sequelae such as strokes and seizures appeared less common, given the large number of people infected, these conditions were likely to lead to a substantial burden of disease. They concluded that while there appears to be a substantial psychiatric morbidity in these studies, the absence of a control group limits the extent to which causality can be attributed.
Rodgers JP et al. Neurology and neuropsychiatry of COVID-19: a systematic review and meta-analysis of the early literature reveals frequent CNS manifestations and key emerging narratives. J Neurol Neurosurg Psychiatry 2021
As mutations enable the emergence of COVID-19 variants, it is crucial to determine if the available vaccines are able to induce a satisfactory level of neutralising antibodies (NAbs) against any new variants. In a laboratory study, a team from the Francis Crick Institute and the National Institute for Health Research, set out to assess the level of NAbs produced in response to five COVID-19 variants, including the original viral strain as well as three others that have been deemed variants of concerns; B.1.167.2 (Delta or Indian variant), B.1.351 (South African variant) and the B.1.1.7 (UK variant). They also compared the level of NAbs produced in participants who had received either one or two doses of the BNT162b vaccine.
Among 159 participants who had received both doses of the vaccine, all samples produced a satisfactory NAbs response against each of the strains although six and nine individuals lacked detectable antibodies against the B.1.617.2 and B.1.351 respectively. However, despite the induction of NABs, levels were 5.8-fold less against the Delta variant compared with the original strain and 2.6-fold less against the B.1.1.7 although of a similar order of magnitude for the B.1.351. Interestingly, there was a significant correlation between NAbs and age, with titres significantly reduced among older individuals. A further finding of concern was that among a smaller cohort (14), who had been vaccinated between 8 and 16 weeks earlier, there was a significant reduction in NAbs titre against all of the variants.
Perhaps of most interest were the data from participants who had received only a single vaccine dose. After a median of 30 days post-vaccination, 79% of individuals had sufficient NAbs against the original strain, but this reduced to 50% for B.1.1.1, 32% for B.1.617.2 and to 25% for B.1.351.
In a discussion of these findings, the authors suggested that although NAbs levels are considerably reduced against the B.1.617.2 and B.1.351 after a single vaccination, this emphasised the importance of reducing the delay period (which has been set at 12 weeks) between doses.
Lead author of the study Emma Wall, said “This virus is likely to be around for some time to come, so we need to remain agile and vigilant. Our study is designed to be responsive to shifts in the pandemic so that we can quickly provide evidence on changing risk and protection”.
Wall EC et al. Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination. Lancet 2021