Uptake of COVID-19 Booster Dose among Saudi Arabian Population.

Backgroundand objectives: Although several vaccines have been produced and administered around the world, new SARS-CoV-2 worsened the COVID-19 infection risk and impacted the initial vaccine dosage effectiveness. Based on studies indicating that the third and fourth COVID-19 vaccine doses significantly reduced COVID-19 transmission, Saudi Arabia has been administering COVID-19 booster vaccine doses to its citizens. The purpose of this study was to evaluate the uptake of the COVID-19 vaccine booster in relation to the socio-demographic characteristics and other associated factors among the Saudi population. Materials and Methods: This study was an online analytical cross-sectional study using a self-administered questionnaire. Pearson Chi-square test and multiple logistic regression analyses were used to determine factors associated with the uptake of COVID-19 booster dose vaccines. Results: A total of 2332 responded to our study. Overall, 527 (22.6%) participants had received a booster dose. An age of 55 and above (aOR: 5.415; 95% CI: 2.719-10.783), Eastern region (aOR: 2.513; 95% CI: 1.566-4.033), history of influenza vaccination at annual intervals (aOR: 2.387; 95% CI: 1.730-3.293), the first dose of Moderna vaccine (aOR: 1.324; 95% CI: 1.160-1.510), and cancer (aOR: 2.161; 95% CI: 1.218-3.879) were independent factors most associated with a higher uptake of the COVID-19 vaccine booster dose. In contrast, the second dose of Moderna vaccine (aOR: 0.794; 95% CI: 0.683-0.922), AstraZeneca vaccine (aOR: 0.691; 95% CI: 0.509-0.939), strong symptoms from side effects after the second dose of the COVID-19 vaccine (aOR: 0.615; 95% CI: 0.404-0.935) were independent factors most associated with a lower uptake of the COVID-19 vaccine booster dose. Conclusions: Our findings indicate low COVID-19 vaccine booster uptake. This necessitates the need for strategies to address discouraging factors of the COVID-19 vaccine booster dose uptake and engage the Saudi population to raise awareness about the importance of the booster dose.

The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09.

BACKGROUND: The aim of this study was to estimate the prevalence of pneumonia and secondary bacterial infections during the pandemic of influenza A(H1N1)pdm09. METHODS: A systematic review was conducted to identify relevant literature in which clinical outcomes of pandemic influenza A(H1N1)pdm09 infection were described. Published studies (between 01/01/2009 and 05/07/2012) describing cases of fatal or hospitalised A(H1N1)pdm09 and including data on bacterial testing or co-infection. RESULTS: Seventy five studies met the inclusion criteria. Fatal cases with autopsy specimen testing were reported in 11 studies, in which any co-infection was identified in 23% of cases (Streptococcus pneumoniae 29%). Eleven studies reported bacterial co-infection among hospitalised cases of A(H1N1)2009pdm with confirmed pneumonia, with a mean of 19% positive for bacteria (Streptococcus pneumoniae 54%). Of 16 studies of intensive care unit (ICU) patients, bacterial co-infection identified in a mean of 19% of cases (Streptococcus pneumoniae 26%). The mean prevalence of bacterial co-infection was 12% in studies of hospitalised patients not requiring ICU (Streptococcus pneumoniae 33%) and 16% in studies of paediatric patients hospitalised in general or pediatric intensive care unit (PICU) wards (Streptococcus pneumoniae 16%). CONCLUSION: We found that few studies of the 2009 influenza pandemic reported on bacterial complications and testing. Of studies which did report on this, secondary bacterial infection was identified in almost one in four patients, with Streptococcus pneumoniae the most common bacteria identified. Bacterial complications were associated with serious outcomes such as death and admission to intensive care. Prevention and treatment of bacterial secondary infection should be an integral part of pandemic planning, and improved uptake of routine pneumococcal vaccination in adults with an indication may reduce the impact of a pandemic.

Evidence compendium and advice on social distancing and other related measures for response to an influenza pandemic.

The role of social distancing measures in mitigating pandemic influenza is not precisely understood. To this end, we have conducted a systematised review, particularly in light of the 2009 pandemic influenza, to better inform the role of social distancing measures against pandemic influenza. Articles were identified from relevant databases and the data were synthesised to provide evidence on the role of school or work place-based interventions, case-based distancing (self-isolation, quarantine), and restriction of mobility and mass gatherings. School closure, whether proactive or reactive, appears to be moderately effective and acceptable in reducing the transmission of influenza and in delaying the peak of an epidemic but is associated with very high secondary costs. Voluntary home isolation and quarantine are also effective and acceptable measures but there is an increased risk of intra-household transmission from index cases to contacts. Work place-related interventions like work closure and home working are also modestly effective and are acceptable, but likely to be economically disruptive. Internal mobility restriction is effective only if prohibitively high (50% of travel) restrictions are applied and mass gatherings occurring within 10 days before the epidemic peak are likely to increase the risk of transmission of influenza.

Efficacy of face masks and respirators in preventing upper respiratory tract bacterial colonization and co-infection in hospital healthcare workers.

OBJECTIVE: We compared the efficacy of medical masks (MM) and N95 respirators (N95) in preventing bacterial colonization/infection in healthcare workers (HCWs). METHODS: A cluster randomized clinical trial (RCT) of 1441 hospital HCWs randomized to medical masks or N95 respirators, and compared to 481 control HCWs, was performed in Beijing, China, during the winter season of 2008-2009. Participants were followed for development of clinical respiratory illness (CRI). Symptomatic subjects were tested for Streptococcus pneumoniae, Bordetella pertussis, Chlamydia pneumoniae, Mycoplasma pneumoniae or Haemophilus influenza type B by multiplex polymerase chain reaction (PCR). RESULTS: The rate of bacterial colonization was 2.8% in the N95 group (p=0.02), 5.3% among medical mask users (p<0.01) and 7.5% among the controls (p=0.16). N95 respirators were significantly protective (adjusted RR 0.34, 95% CI: 0.21-0.56) against bacterial colonization. Co-infections of two bacteria or a virus and bacteria occurred in up to 3.7% of HCWs, and were significantly lower in the N95 arm. CONCLUSIONS: N95 respirators were significantly protective against bacterial colonization, co-colonization and viral-bacterial co-infection. We showed that dual respiratory virus or bacterial-viral co-infections can be reduced by the use of N95 respirators. This study has occupational health and safety implications for health workers.

Pertussis in older adults: prospective study of risk factors and morbidity.

BACKGROUND: There is limited information on the incidence, morbidity and risk factors for pertussis in adults, particularly those aged over 65 years. METHODS: Population-based prospective cohort study of 263094 adults aged over 45 years (mean 62.8 years) recruited in the Australian state of New South Wales (the 45 and Up Study) between 2006 and 2008, and followed by record-linkage to laboratory-confirmed pertussis notifications, hospitalizations, and death records. The incidence of pertussis notifications and hospitalizations and relative risk (RR) of pertussis according to various participant characteristics was estimated using proportional hazards models. RESULTS: Over a total follow-up of 217524 person-years, 205 adults had a pertussis notification and 12 were hospitalized; the incidence rate was 94 (95% confidence interval [CI], 82-108) and 5.5 (95% CI, 3.1-9.7) per 100000 person-years, respectively. The incidence of a pertussis notification did not differ by age but hospitalization rates progressively increased (2.2, 8.5, and 13.5 per 100000 person-years in age groups 45-64, 65-74, and 75+ years, respectively; P(trend) = .01). After adjusting for age, sex, and other factors, adults with a high body mass index (BMI; RR=1.52; 95% CI, 1.06-2.19 for BMI 30+kg/m(2) vs BMI <25 kg/m(2)) and with preexisting asthma (RR=1.64; 95% CI, 1.06-2.55 compared to those without asthma) were more likely to be notified. CONCLUSIONS: Adults older than 65 years are more likely to be hospitalized for pertussis than those aged 45-64 years. Obesity and preexisting asthma were associated with a higher likelihood of pertussis notification. These findings suggest that pertussis vaccination would be particularly important for adults with these characteristics.

Differences in the attitude and knowledge of hospital health care workers regarding older patient vaccinations.

UNLABELLED: Streptococcus pneumoniae infections are lethal for certain high-risk groups including adults aged 65 years and over. Despite long-standing recommendations for their routine use among elderly persons and other high-risk groups, these vaccines continue to be underused, especially in the very frail elderly. The implementation of organized vaccination programs are important facilitators of vaccine delivery. However, pneumococcal vaccination has not been well embraced by hospital health care workers. For a vaccination program to be able to succeed multiple components should be incorporated such as standing orders, special clinics and provider feedback. This survey aims to compare attitudes and knowledge of hospital-based doctors and nurses. RESULTS: The nurses are less enthusiastic about vaccination and consider the diseases less serious. This has implications particularly for hospital-based strategies for improving vaccination uptake, where gaining the support of nursing staff will be crucial. DISCUSSION: Vaccine delivery efforts must make dramatic improvements if the pneumococcal vaccination goals for elderly persons and other high-risk adults are to be met. MATERIAL AND METHODS: Self administered survey of hospital nurses and doctors utilizing all wards in a large, tertiary referral adult hospital in Sydney, Australia.

Persistence of immunity to conjugate and polysaccharide pneumococcal vaccines in frail, hospitalised older adults in long-term follow up.

BACKGROUND: Data on long-term antibody responses to pneumococcal vaccines in the elderly, especially the frail elderly at greatest risk of severe disease, are limited. We followed up participants in a randomised trial of the immunogenicity of 23-valent polysaccharide vaccine (23vPPV) and 7 valent pneumococcal conjugate vaccines (PCV7) in hospitalised older adults. METHODS: We measured antibody to vaccine serotypes by standardised enzyme-linked immunosorbent assay (ELISA) and opsonophagocytic (OPA) assays. A follow up study was conducted six years after vaccination with 23vPPV alone or with PCV7 followed by 23vPPV six months later. RESULTS: Of 215 surviving trial participants, 136 (63%) completed follow up; 62 received 23vPPV and 74 received PCV7 + 23vPPV. There was no significant difference in death and readmission between arms. Antibody levels by ELISA and OPA did not differ significantly between the two study arms at 72 months post-vaccination. ELISA and OPA antibody remained higher than baseline except for OPA antibody to 4, 6A, 6B, 9v, 19F and 23F, including in subjects with undetectable immunity at baseline. DISCUSSION: While ELISA responses in both study arms remained high 6 years post-vaccination, considerable waning was observed by OPA in both study arms, which should be considered given the current single-dose recommendation in Australia. Further research is needed to inform pneumococcal vaccine recommendations in people over the age of 65.

Burden of clinical infections due to S. pneumoniae during Hajj: A systematic review.

The burden of pneumococcal disease at Hajj has not been precisely evaluated through a systematic review. To this end we have conducted a systematic review on the burden of clinical infections due to Streptococcus pneumoniae among Hajj pilgrims. Major electronic databases including OVID Medline, Web of Science, OVID Embase, Social Sciences Citation Index, Google Scholar and relevant websites (e.g., online Saudi Epidemiology Bulletin) were searched by using MeSH terms and text words containing but not limited to 'Hajj', pneumonia and S. pneumoniae. This was buttressed by hand searching of reference lists of identified studies. Of 21 full text papers reviewed, nine articles were included in this review. Seven studies reported the burden of pneumococcal pneumonia and the other two reported the burden of invasive pneumococcal diseases including meningitis and sepsis. The proportion of pneumonia that was pneumococcal ranged from 1% to 54% of bacteriologically confirmed pneumonias. The pneumococcus accounted for 2/3rd of bacteriologically diagnosed meningitis cases, and 1/3rd of confirmed cases of sepsis. Case fatality rate of pneumococcal pneumonia was recorded in only two studies: 33.3% and 50%. Only one study provided data on antimicrobial susceptibility of S. pneumoniae isolates, reporting 33.3% to be penicillin resistant. None of the included studies provided data on serotype distribution of S. pneumoniae. This systematic review highlights the significance of pneumococcal disease during Hajj, and demonstrates paucity of data on its burden particularly on disease-causing serotype.

A cluster-randomised controlled trial to test the efficacy of facemasks in preventing respiratory viral infection among Hajj pilgrims.

BACKGROUND: Cost-effective interventions are needed to control the transmission of viral respiratory tract infections (RTIs) in mass gatherings. Facemasks are a promising preventive measure, however, previous studies on the efficacy of facemasks have been inconclusive. This study proposes a large-scale facemask trial during the Hajj pilgrimage in Saudi Arabia and presents this protocol to illustrate its feasibility and to promote both collaboration with other research groups and additional relevant studies. METHODS/DESIGN: A cluster-randomised controlled trial is being conducted to test the efficacy of standard facemasks in preventing symptomatic and proven viral RTIs among pilgrims during the Hajj season in Mina, Mecca, Saudi Arabia. The trial will compare the 'supervised use of facemasks' versus 'standard measures' among pilgrims over several Hajj seasons. Cluster-randomisation will be done by accommodation tents with a 1:1 ratio. For the intervention tents, free facemasks will be provided to be worn consistently for 7days. Data on flu-like symptoms and mask use will be recorded in diaries. Nasal samples will be collected from symptomatic recruits and tested for nucleic acid of respiratory viruses. Data obtained from questionnaires, diaries and laboratory tests will be analysed to examine whether mask use significantly reduces the frequency of laboratory-confirmed respiratory viral infection and syndromic RTI as primary outcomes. CONCLUSIONS: This trial will provide valuable evidence on the efficacy of standard facemask use in preventing viral respiratory tract infections at mass gatherings. This study is registered at the Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN: ACTRN12613001018707 (http://www.anzctr.org.au).

Pneumococcal infections at Hajj: current knowledge gaps.

Hajj attendance increases the risk of respiratory infections including pneumonia. Streptococcus pneumoniae is a frequently identified pathogen, found in about 10% of respiratory tract samples of symptomatic Hajj pilgrims; and at least 20% of these isolates are penicillin resistant. However, the burden of pneumococcal disease at Hajj is not precisely defined at serotypic level, and it is postulated that due to intense mixing of pilgrims the distribution of pneumococcal serotypes at Hajj could be different from pilgrims' country of origin or of Saudi Arabia. In Saudi Arabia, the most prevalent pneumococcal serotypes are 23F, 6B, 19F, 18C, 4, 14, and 19A, and 90% of the serotypes are covered by 13-valent pneumococcal conjugate vaccine (PCV-13) as well as 23-valent pneumococcal polysaccharide vaccine (PPV-23). However, due to lack of Hajj-specific data, the Saudi Arabian Ministry of Health has not yet recommended pneumococcal vaccine for pilgrims, and the immunisation recommendation and uptake vary greatly across countries. As at least one third of Hajj pilgrims are 'at risk' of pneumococcal disease either by virtue of age or pre-existing medical conditions, consideration should be given to vaccinating high risk pilgrims against pneumococcal disease. Other preventive measures such as smoking cessation, pollution reduction and vaccinations against influenza and pertussis should also be considered. Precisely defining the epidemiology of pneumococcal disease to identify an optimum vaccination schedule for Hajj pilgrims is a current research priority.

Attitudes, knowledge and perceptions towards whooping cough and pertussis vaccine in hospitalized adults.

Whooping cough or pertussis is a major cause of morbidity and mortality for adults and children around the world. There has been a rise in pertussis-related deaths in the elderly; pertussis vaccination is not currently routinely recommended in adults, excepting new parents and other adults household members including grandparents and care-givers of young children. Currently, there is lack of clear vaccine recommendations after the age of 50 years. Given the increase in adult pertussis, adult vaccine recommendations are a policy consideration. The study surveyed a convenience sample of patients previously recruited in a case control study designed to examine the burden of influenza with and without AMI in adults aged ≥ 40 years. Our findings showed that only 9.6% had received the pertussis vaccination within the past five years and 79.4% of participants had no knowledge of the pertussis adult booster vaccine, and 30.7% of participants who had regular contact with children under the age of two years in the past 12 months. The results showed that even though there is general acceptance of prevention by vaccines, there is low awareness about pertussis vaccination. This lack of knowledge presents a barrier against pertussis vaccination thus it is imperative that any future adult immunisation policy recommendations around pertussis vaccine include awareness programs in the target population.

The Burden of Pertussis in Patients with and without Recurrent Ischaemic Vascular Events.

Pertussis seroepidemiology and associated factors in older adults aged ≥40 years with and without acute myocardial infarction (AMI) were studied to investigate whether unrecognised pertussis may precipitate AMI. Sera were obtained from a previous case-control study investigating the role of influenza in precipitating AMIs. Baseline sera were considered pertussis toxin (PT) IgG seropositive at levels ≥5 IU/mL. Levels ≥v62.5 IU/mL were considered indicative of infection in the previous year, and recent infection was indicative at levels ≥125 IU/mL. Of the serum samples tested, 55% (122/222) were seropositive for PT IgG, 5% (11/222) had evidence of infection in the past year and 1.4% (3/222) had evidence of recent infection. Evidence of infection in the past year was found in 3.2% of those aged 65-74 years. Overall, 47.8% of 40-64 year olds and 43.2% of those aged ≥65 years were seronegative for pertussis. Serological evidence of pertussis was not associated with AMI (46/92, 50.0% cases vs. 76/130, 58.5% controls, p=0.2). After adjusting for age, AMI and self-reported pertussis and GP verified influenza vaccination, females (OR = 2.2, 95% CI = 1.1-4.1, p=0.02) were more likely to be seronegative. Just under half of participants had no detectable pertussis immunity and are therefore susceptible to infection. Our study supports the need for an adult pertussis booster to supplement current recommendations.

Vaccination of Older Adults with Dementia Against Respiratory Infections.

People with dementia are at a greater risk of complications from respiratory infections therefore can benefit from vaccinations against influenza, pneumococcal disease and pertussis. This review aimed to evaluate the uptake and impact of vaccination in older adults with dementia against respiratory infections and identify knowledge gaps. Key databases were explored, search results were assessed, relevant studies identified, and data were synthesised and summarised. Most available data suggest that older adults with dementia are less likely to receive influenza or pneumococcal vaccine while a few studies indicate an increase in vaccination uptake but poor immunogenicity. Among dementia patients, community dwellers have a lower vaccination rate than home care residents. However, vaccinations against influenza and pneumococcal disease can benefit individuals with dementia by reducing both mortality and morbidity. Health professionals caring for patients with dementia could play a role in fostering vaccination of these individuals.

Carrier priming or suppression: understanding carrier priming enhancement of anti-polysaccharide antibody response to conjugate vaccines.

INTRODUCTION: With the availability of newer conjugate vaccines, immunization schedules have become increasingly complex due to the potential for unpredictable immunologic interference such as 'carrier priming' and 'carrier induced epitopic suppression'. Carrier priming refers to an augmented antibody response to a carbohydrate portion of a glycoconjugate vaccine in an individual previously primed with the carrier protein. This review aims to provide a critical evaluation of the available data on carrier priming (and suppression) and conceptualize ways by which this phenomenon can be utilized to strengthen vaccination schedules. METHODS: We conducted this literature review by searching well-known databases to date to identify relevant studies, then extracted and synthesized the data on carrier priming of widely used conjugate polysaccharide vaccines, such as, pneumococcal conjugate vaccine (PCV), meningococcal conjugate vaccine (MenCV) and Haemophilus influenzae type b conjugate vaccines (HibV). RESULTS: We found evidence of carrier priming with some conjugate vaccines, particularly HibV and PCV, in both animal and human models but controversy surrounds MenCV. This has implications for the immunogenicity of conjugate polysaccharide vaccines following the administration of tetanus-toxoid or diphtheria-toxoid containing vaccine (such as DTP). CONCLUSION: Available evidence supports a promising role for carrier priming in terms of maximizing the immunogenicity of conjugate vaccines and enhancing immunization schedule by making it more efficient and cost effective.

Pilot Randomised Controlled Trial to Test Effectiveness of Facemasks in Preventing Influenza-like Illness Transmission among Australian Hajj Pilgrims in 2011.

Studies to determine the effectiveness of facemasks in preventing influenza have been inconclusive, largely due to small sample size. The Hajj pilgrimage, where the incidence of influenza and other respiratory infections is high, provides an excellent opportunity to test the effectiveness of facemasks against syndromic and laboratory-confirmed infections. Hence, a pilot study was conducted among Australian pilgrims to assess the feasibility of such a large-scale trial in the coming years. At the 2011 Hajj, tents were randomised to 'supervised mask use' versus 'no supervised mask use'. Pilgrims with ILI symptoms for ≤3 days were recruited as 'cases' and those who slept within 2 meters of them as 'contacts'. Surgical facemasks were provided to cases and contacts in the 'mask' tents, but not in the 'control' tents. Pilgrims in both groups were given diaries to record their respiratory symptoms. Nasal or pharyngeal swabs were collected from the cases and contacts with ILI for point-of-care and nucleic acid tests. A total of 22 tents were randomised to 'mask' (n=12) or 'control' (n=10). There were 164 pilgrims recruited; 75 in 'mask' and 89 in 'control' group. Mask use compliance was 76% in the 'mask' group and 12% in the 'control' group. Based on developing syndromic ILI, less contacts became symptomatic in the 'mask' tents compared to the 'control' tents (31% versus 53%, p= 0.04). However, laboratory results did not show any difference between the two groups. This pilot study shows that a large trial to assess the effectiveness of facemasks use at Hajj is feasible.

Influenza vaccination among Australian Hajj pilgrims: uptake, attitudes, and barriers.

BACKGROUND: Hajj is the largest annual mass gathering where the risk of respiratory infection is high. Although the Saudi Arabian authority recommends influenza vaccination for Hajj pilgrims, the uptake is variable. Influenza vaccine uptake data among Australian Hajj pilgrims is not readily available. Therefore, we aimed to estimate the influenza vaccination uptake rate and identify both attitudes and barriers to vaccine uptake from two consecutives surveys at Hajj in 2011 and 2012. METHODS: Using an anonymous self-administered questionnaire, surveys were conducted in Mecca, Saudi Arabia, among Hajj pilgrims from Australia in 2011 and 2012. Pilgrims staying in "Australian" tents were recruited serially. RESULTS: In 2011, 431 Australian pilgrims completed the survey-median age was 42 (range 7-86) years, 55% were male; 65% reported receiving influenza vaccine. In 2012, 535 pilgrims of median age 43 (range 12-83) years completed the survey, 62% were male; 89% reported receiving the vaccine. Both in 2011 and 2012, common reasons for not receiving the vaccine were the pilgrims' reliance on their "natural immunity" (33 and 26%, respectively, p = 0.4) and believing that they would rarely catch influenza or come in contact with influenza patients (18 and 29%, respectively, p = 0.1). In 2012, when asked why they had received the vaccine, 65% pilgrims responded that it was because of the tour group leaders' recommendation. CONCLUSION: Influenza vaccine uptake among Australian Hajj pilgrims seems satisfactory and increasing but could be better because many pilgrims have misconceptions about vaccines. Tour operators may play a greater role in promoting vaccination.

A randomized clinical trial of the immunogenicity of 7-valent pneumococcal conjugate vaccine compared to 23-valent polysaccharide vaccine in frail, hospitalized elderly.

BACKGROUND: Elderly people do not mount strong immune responses to vaccines. We compared 23-valent capsular polysaccharide (23vPPV) alone versus 7-valent conjugate (PCV7) vaccine followed by 23vPPV 6 months later in hospitalized elderly. METHODS: Participants were randomized to receive 23vPPV or PCV7-23vPPV. Antibodies against serotypes 3, 4, 6A, 6B, 9V, 14, 18C, 19A, 19F, 23F were measured by enzyme-linked immunosorbent (ELISA) and opsonophagocytic (OPA) assays at baseline, 6 months and 12 months. RESULTS: Of 312 recruited, between 40% and 72% of subjects had undetectable OPA titres at baseline. After one dose, PCV7 recipients had significantly higher responses to serotypes 9V (both assays) and 23F (OPA only), and 23vPPV recipients had significantly higher responses to serotype 3 (ELISA), 19F and 19A (OPA only). In subjects with undetectable OPA titres at baseline, a proportionately greater rise in OPA titre (P<0.01) was seen for all serotypes after both vaccines. The GMT ratio of OPA was significantly higher at 12 months in the PCV7-23vPPV group for serotypes 6A, 9V, 18C and 23F. OPA titre levels for these serotypes increased moderately after 6 months, whereas immunity waned in the 23vPPV only arm. CONCLUSION: We did not show overwhelming benefit of one vaccine over the other. Low baseline immunity does not preclude a robust immune response, reiterating the importance of vaccinating the frail elderly. A schedule of PCV7-23vPPV prevents waning of antibody, suggesting that both vaccines could be useful in the elderly. Follow up studies are needed to determine persistence of immunity. TRIAL REGISTRATION: The Australian Clinical Trials Registry ACTRN12607000387426.