Understanding and addressing vaccine hesitancy in the context of COVID-19: development of a digital intervention.

OBJECTIVES: Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) was identified in late 2019, spreading to over 200 countries and resulting in almost two million deaths worldwide. The emergence of safe and effective vaccines provides a route out of the pandemic, with vaccination uptake of 75-90% needed to achieve population protection. Vaccine hesitancy is problematic for vaccine rollout; global reports suggest only 73% of the population may agree to being vaccinated. As a result, there is an urgent need to develop equitable and accessible interventions to address vaccine hesitancy at the population level. STUDY DESIGN: & Method: We report the development of a scalable digital intervention seeking to address COVID-19 vaccine hesitancy and enhance uptake of COVID-19 vaccines in the United Kingdom. Guided by motivational interviewing (MI) principles, the intervention includes a series of therapeutic dialogues addressing 10 key concerns of vaccine-hesitant individuals. Development of the intervention occurred linearly across four stages. During stage 1, we identified common reasons for COVID-19 vaccine hesitancy through analysis of existing survey data, a rapid systematic literature review, and public engagement workshops. Stage 2 comprised qualitative interviews with medical, immunological, and public health experts. Rapid content and thematic analysis of the data provided evidence-based responses to common vaccine concerns. Stage 3 involved the development of therapeutic dialogues through workshops with psychological and digital behaviour change experts. Dialogues were developed to address concerns using MI principles, including embracing resistance and supporting self-efficacy. Finally, stage 4 involved digitisation of the dialogues and pilot testing with members of the public. DISCUSSION: The digital intervention provides an evidence-based approach to addressing vaccine hesitancy through MI principles. The dialogues are user-selected, allowing exploration of relevant issues associated with hesitancy in a non-judgmental context. The text-based content and digital format allow for rapid modification to changing information and scalability for wider dissemination.

A step-wise approach to developing indicators to compare the performance of maternity units using hospital administrative data.

Hospital administrative data are attractive for comparing performance of maternity units because of their often large sample sizes, lack of selection bias and the relatively low costs of accessing these data compared with conducting primary data collection. However, using administrative data to develop indicators can also present challenges including varying data quality, the limited detail on clinical risk factors and a lack of structural and user experience measures. This review illustrates how to develop performance indicators for maternity units using hospital administrative data, including methods to address the challenges that administrative data pose. TWEETABLE ABSTRACT: How to develop maternity indicators from administrative data.

Posttransplant Lymphoproliferative Disorders in Neuronal Xenotransplanted Macaques.

Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations that occur in the setting of depressed T-cell function due to immunosuppressive therapy used following solid organ transplantation, hematopoietic stem cell transplantation, and also xenotransplantation. In the present study, 28 immunosuppressed parkinsonian Macaca fascicularis were intracerebrally injected with wild-type or CTLA4-Ig transgenic porcine xenografts to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Nine of 28 (32%) immunosuppressed primates developed masses compatible with PTLD, located mainly in the gastrointestinal tract and/or nasal cavity. The masses were classified as monomorphic PTLD according to the World Health Organization classification. Immunohistochemistry and polymerase chain reaction (PCR) analyses revealed that the PTLDs were associated with macaca lymphocryptovirus as confirmed by double-labeling immunohistochemistry for CD20 and Epstein-Barr nuclear antigen 2 (EBNA-2), where the viral protein was located within the CD20+ neoplastic B cells. In sera from 3 distinct phases of the experimental life of the primates, testing by quantitative PCR revealed a progression of the viral load that paralleled the PTLD progression and no evidence of zoonotic transmission of porcine lymphotropic herpesvirus through xenoneuronal grafts. These data suggest that monitoring the variation of macaca lymphocryptovirus DNA in primates could be used as a possible early diagnostic tool for PTLD progression, allowing preemptive treatment such as immunosuppression therapy reduction.

A global reference for caesarean section rates (C-Model): a multicountry cross-sectional study.

OBJECTIVE: To generate a global reference for caesarean section (CS) rates at health facilities. DESIGN: Cross-sectional study. SETTING: Health facilities from 43 countries. POPULATION/SAMPLE: Thirty eight thousand three hundred and twenty-four women giving birth from 22 countries for model building and 10,045,875 women giving birth from 43 countries for model testing. METHODS: We hypothesised that mathematical models could determine the relationship between clinical-obstetric characteristics and CS. These models generated probabilities of CS that could be compared with the observed CS rates. We devised a three-step approach to generate the global benchmark of CS rates at health facilities: creation of a multi-country reference population, building mathematical models, and testing these models. MAIN OUTCOME MEASURES: Area under the ROC curves, diagnostic odds ratio, expected CS rate, observed CS rate. RESULTS: According to the different versions of the model, areas under the ROC curves suggested a good discriminatory capacity of C-Model, with summary estimates ranging from 0.832 to 0.844. The C-Model was able to generate expected CS rates adjusted for the case-mix of the obstetric population. We have also prepared an e-calculator to facilitate use of C-Model (www.who.int/reproductivehealth/publications/maternal_perinatal_health/c-model/en/). CONCLUSIONS: This article describes the development of a global reference for CS rates. Based on maternal characteristics, this tool was able to generate an individualised expected CS rate for health facilities or groups of health facilities. With C-Model, obstetric teams, health system managers, health facilities, health insurance companies, and governments can produce a customised reference CS rate for assessing use (and overuse) of CS. TWEETABLE ABSTRACT: The C-Model provides a customized benchmark for caesarean section rates in health facilities and systems.

A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

Immunohistochemical Characterization of Large Intestinal Adenocarcinoma in the Rhesus Macaque (Macaca mulatta).

In rhesus macaques, adenocarcinomas of either the ileocecal junction or colon are common spontaneous tumors in aging populations. The macaque tumors have similar gross and histologic characteristics compared with their human counterpart, but little is known regarding the immunohistochemical expression of proteins that are commonly implicated in the pathogenesis of these tumors in humans. We performed a retrospective review of 22 cases of large intestinal carcinoma in the rhesus macaque and evaluated the expression pattern of a panel of potentially prognostically significant proteins identified from human studies. Histologic characteristics of the tumors included abundant mucin deposition, transmural spread, and lymphatic invasion. All rhesus adenocarcinomas displayed altered expression of 1 or more of CD10, ß-catenin, sirtuin 1, cytokeratin 17, and p53 compared with age-matched controls. Zymographic analysis of active matrix metalloproteinases 2 and 9 in the serum from 5 animals failed to reveal statistically significant differences between adenocarcinoma cases and controls. Based on the data presented herein, large intestinal carcinomas in the macaque share many histomorphologic and immunohistochemical similarities to large intestinal tumors in humans. Further validation of this animal model is considered important for the development of novel therapeutics and a better understanding of the pathogenesis.

rhesus cytomegalovirus (macacine herpesvirus 3)-associated facial neuritis in simian immunodeficiency virus-infected rhesus macaques (Macaca mulatta).

Peripheral neuropathies are common sequelae to human immunodeficiency virus (HIV) infection in humans and are due to a variety of mechanisms, including direct antiretroviral toxicity, HIV-mediated damage, immune-mediated disorders, and opportunistic viral infections. Rhesus macaques (Macaca mulatta) infected with simian immunodeficiency virus (SIV) remain the most consistent animal model for unraveling the pathogenesis of lentiviral-associated disease and its associated opportunistic infections. Rhesus cytomegalovirus (RhCMV) is the most common opportunistic viral infection in rhesus macaques infected with SIV and causes multiorgan pathology; however, its role in peripheral nerve pathology has not been explored. We have identified 115 coinfected cases with SIV and RhCMV, of which 10 cases of RhCMV-associated facial neuritis were found (8.7% prevalence). Histologic lesions were consistent in all cases and ranged from partial to complete obliteration of the nerves of the tongue, lacrimal gland, and other facial tissues with a mixed inflammatory population of neutrophils and macrophages, of which the latter commonly contained intranuclear inclusion bodies. Luxol fast blue staining and myelin basic protein immunohistochemistry confirmed the progressive myelin loss in the peripheral nerves. Bielschowsky silver stain revealed progressive loss of axons directly related to the severity of inflammation. Double immunohistochemistry with spectral imaging analysis revealed RhCMV-infected macrophages directly associated with the neuritis, and there was no evidence to support RhCMV infection of Schwann cells. These results suggest that peripheral nerve damage is a bystander effect secondary to inflammation rather than a direct infection of Schwann cells and warrants further investigations into the pathogenesis of RhCMV-induced peripheral neuropathy.

Vaginal birth after caesarean section: a cohort study investigating factors associated with its uptake and success.

OBJECTIVES: To investigate the demographic and obstetric factors associated with the uptake and success rate of vaginal birth after caesarean section (VBAC). DESIGN: Cohort study using data from Hospital Episode Statistics. SETTING: English National Health Service. POPULATION: Women whose first birth resulted in a live singleton delivery by caesarean section between 1 April 2004 and 31 March 2011, and who had a second birth before 31 March 2012. METHODS: Logistic regression to estimate adjusted odds ratios (OR). MAIN OUTCOME MEASURES: Attempted and successful VBAC. RESULTS: Among the 143,970 women in the cohort, 75,086 (52.2%) attempted a VBAC for their second birth. Younger women, those of non-white ethnicity and those living in a more deprived area had higher rates of attempted VBAC. Overall, 47,602 women (63.4%) who attempted a VBAC had a successful vaginal birth. Younger women and women of white ethnicity had higher success rates. Black women had a particularly low success rate (OR, 0.54; 95% confidence interval [CI], 0.50-0.57). Women who had an emergency caesarean section in their first birth also had a lower VBAC success rate, particularly those with a history of failed induction of labour (OR, 0.59; 95% CI, 0.53-0.67). CONCLUSION: In this national cohort, just over one-half of women with a primary caesarean section who were eligible for a trial of labour attempted a VBAC for their second birth. Of these, almost two-thirds successfully achieved a vaginal delivery.

Polioencephalomalacia secondary to hypernatremia in squirrel monkeys (Saimiri sciureus).

Squirrel monkeys (Saimiri spp) are one of the most consistently used New World primates in biomedical research and are increasingly being used in neuroscience research, including models of drug abuse and addiction. Spontaneous neurologic disease in the squirrel monkey is uncommonly reported but includes various infectious diseases as well as cerebral amyloidosis. Hypernatremia is an extremely serious condition of hyperosmolarity that occurs as a result of water loss, adipsia, or excess sodium intake. Neurologic effects of hypernatremia reflect the cellular dehydration produced by the shift of water from the intracellular fluid space into the hypertonic extracellular fluid space. Severe hypernatremia may result in cerebrocortical laminar necrosis (polioencephalomalacia) in human patients as well as in a number of domestic species, including pigs, poultry, and ruminants. We report the clinical, histopathologic, and immunohistochemical findings of polioencephalomalacia in 13 squirrel monkeys. Polioencephalomalacia in these animals was associated with hypernatremia that was confirmed by serum levels of sodium greater than 180 mmol/L (reference range, 134.0-154.0 mmol/L [mEq/L]). All animals had concurrent diseases or experimental manipulation that predisposed to adipsia. Immunohistochemical investigation using antibodies to neuronal nuclei (NeuN), CNPase, Iba-1, and CD31 revealed necrosis of predominantly cerebral cortical layers 3, 4, and 5 characterized by neuronal degeneration and loss, oligodendrocytic loss, microglial proliferation, and vascular reactivity. The squirrel monkey is exquisitely sensitive to hyperosmolar metabolic disruption and it is associated with laminar cortical necrosis.

Anthropometric protocols for the construction of new international fetal and newborn growth standards: the INTERGROWTH-21st Project.

The primary aim of the INTERGROWTH-21(st) Project is to construct new, prescriptive standards describing optimal fetal and preterm postnatal growth. The anthropometric measurements include the head circumference, recumbent length and weight of the infants, and the stature and weight of the parents. In such a large, international, multicentre project, it is critical that all study sites follow standardised protocols to ensure maximal validity of the growth and nutrition indicators used. This paper describes, in detail, the selection of anthropometric personnel, equipment, and measurement and calibration protocols used to construct the new standards. Implementing these protocols at each study site ensures that the anthropometric data are of the highest quality to construct the international standards.

Implementation of the INTERGROWTH-21st Project in Oman.

The Middle Eastern site in the INTERGROWTH-21(st) Project was Muscat, the capital city of Oman, with approximately 10,500 births per year. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from two hospitals covering 96% of the region's births. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from four primary health facilities serving Khoula Hospital, using the eligibility criteria in the INTERGROWTH-21(st) protocol. Special activities to encourage participation in this population included local advocacy campaigns to encourage early antenatal booking and ultrasound dating in the population. The major challenges at the site were the recruitment of sufficient numbers of women at an early gestational age, and the timely measurement of all newborns within 12 hours of birth. Many individuals and institutions collaborated effectively over a period of several years on these studies, which required careful planning and close monitoring for their successful implementation.

Anthropometric standardisation and quality control protocols for the construction of new, international, fetal and newborn growth standards: the INTERGROWTH-21st Project.

The primary aim of the INTERGROWTH-21(st) Project is to construct new, prescriptive standards describing optimal fetal and preterm postnatal growth. The anthropometric measurements include the head circumference, recumbent length and weight of the infants, and the stature and weight of the parents. In such a large, international, multicentre project, it is critical that all study sites follow standardised protocols to ensure maximal validity of the growth and nutrition indicators used. This paper describes in detail the anthropometric training, standardisation and quality control procedures used to collect data for these new standards. The initial standardisation session was in Nairobi, Kenya, using newborns, which was followed by similar sessions in the eight participating study sites in Brazil, China, India, Italy, Kenya, Oman, UK and USA. The intraobserver and inter-observer technical error of measurement values for head circumference range from 0.3 to 0.4 cm, and for recumbent length from 0.3 to 0.5 cm. These standardisation protocols implemented at each study site worldwide ensure that the anthropometric data collected are of the highest quality to construct international growth standards.

Implementation of the INTERGROWTH-21st Project in China.

The East Asian site in the INTERGROWTH-21(st) Project was Shunyi County, Beijing, China, which is an affluent suburb of north Beijing delivering approximately 7000 women annually. The Newborn Cross-Sectional Study (NCSS) sample was drawn from two hospitals, covering >85% of births in the county. The Fetal Growth Longitudinal Study sample (FGLS) was recruited from the antenatal clinic of Shunyi Maternal & Child Health Hospital, the larger of the two institutions. Special activities to promote the study in this population included: (1) the distribution of health education materials about the importance of antenatal care and (2) the organisation of seminars by the study team to brief key stakeholders at the two hospitals about the goals of the research. One of the major challenges at this site in the early stages of the study was a reluctance to have an early ultrasound dating scan (<14(+0) weeks of gestation). This challenge was overcome after a thorough evaluation of the literature regarding the benefits of an early ultrasound scan for dating purposes, as a result of which there was a formal change in hospital policy.

Implementation of the INTERGROWTH-21st Project in the UK.

There are approximately 10,000 births per year in the county of Oxfordshire in the UK, which is one of the two European sites for the International Fetal and Newborn Growth Consortium for the 21(st) Century (INTERGROWTH-21(st) ) Project. The samples for both components of the project--the Fetal Growth Longitudinal Study (FGLS) and Newborn Cross-Sectional Study (NCSS)--were drawn from the John Radcliffe Hospital, a major university hospital with a large regional role that covers more than 75% of deliveries in the county. Special activities to encourage participation in this population included the formation of a research coalition to streamline recruitment in the Maternity Unit and the distribution of study information leaflets to women using the hospital's antenatal care service. This was a demanding project and several challenges were overcome to reach recruitment targets and to maintain high standards of data quality. Amongst the major challenges for FGLS at this study site was the level of ineligibility because of maternal age, smoking and body mass index (BMI) ≥ 30. The major challenge for the NCSS field teams was to ensure that all anthropometric data were collected before the early discharge of uncomplicated deliveries, often within 6 hours of birth. It is evident from our experience in implementing this project that, when large-scale clinical studies are meticulously planned and avoid major disruption to routine clinical care, they are well received by hospital staff and can contribute to the improvement of the overall standard of clinical care.

Implementation of the INTERGROWTH-21st Project in Brazil.

The Latin American site in the INTERGROWTH-21(st) Project was Pelotas, Brazil, with approximately 4000 births per year. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from four hospitals, covering 99% of births in the city. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from one of the largest private ultrasound clinics in the city and 30 smaller, private, antenatal clinics serving middle to high socio-economic status women. Among this site's major challenges was the recruitment of women for FGLS from numerous different clinics. Several public relations activities were conducted to improve collaborative efforts between the research team and obstetricians, paediatricians and community leaders in Pelotas.

Implementation of the INTERGROWTH-21st Project in India.

The South Asian site in the INTERGROWTH-21(st) Project was the city of Nagpur, in Maharashtra State, India, with approximately 4500 births per year among the target population with middle to high socio-economic status. These deliveries are mainly concentrated in 20 small private hospitals, most of which are in the city centre. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from ten of these hospitals, covering 76% of the target low-risk pregnant population. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from the largest of these institutions, Ketkar Hospital, as well as several ancillary antenatal care clinics. Special activities to encourage participation and raise awareness of the study at this site included translating patient information leaflets into local languages and securing local media interest. Among the unique challenges of the Indian site was the coordination of the large number of hospitals involved in NCSS, a task that required careful planning and organisation by the field teams.

Standardisation of neonatal clinical practice.

The International Fetal and Newborn Growth Consortium for the 21(st) Century (INTERGROWTH-21(st) ) is a large-scale, population-based, multicentre project involving health institutions from eight geographically diverse countries, which aims to assess fetal, newborn and preterm growth under optimal conditions. Given the multicentre nature of the project and the expected number of preterm births, it is vital that all centres follow the same standardised clinical care protocols to assess and manage preterm infants, so as to ensure maximum validity of the resulting standards as indicators of growth and nutrition with minimal confounding. Moreover, it is well known that evidence-based clinical practice guidelines can reduce the delivery of inappropriate care and support the introduction of new knowledge into clinical practice. The INTERGROWTH-21(st) Neonatal Group produced an operations manual, which reflects the consensus reached by members of the group regarding standardised definitions of neonatal morbidities and the minimum standards of care to be provided by all centres taking part in the project. The operational definitions and summary management protocols were developed by consensus through a Delphi process based on systematic reviews of relevant guidelines and management protocols by authoritative bodies. This paper describes the process of developing the Basic Neonatal Care Manual, as well as the morbidity definitions and standardised neonatal care protocols applied across all the INTERGROWTH-21(st) participating centres. Finally, thoughts about implementation strategies are presented.

The objectives, design and implementation of the INTERGROWTH-21st Project.

INTERGROWTH-21(st) is a multicentre, multiethnic, population-based project, being conducted in eight geographical areas (Brazil, China, India, Italy, Kenya, Oman, UK and USA), with technical support from four global specialised units, to study growth, health and nutrition from early pregnancy to infancy. It aims to produce prescriptive growth standards, which conceptually extend the World Health Organization (WHO) Multicentre Growth Reference Study (MGRS) to cover fetal and newborn life. The new international standards will describe: (1) fetal growth assessed by clinical and ultrasound measures; (2) postnatal growth of term and preterm infants up to 2 years of age; and (3) the relationship between birthweight, length and head circumference, gestational age and perinatal outcomes. As the project has selected healthy cohorts with no obvious risk factors for intrauterine growth restriction, these standards will describe how all fetuses and newborns should grow, as opposed to traditional charts that describe how some have grown at a given place and time. These growth patterns will be related to morbidity and mortality to identify levels of perinatal risk. Additional aims include phenotypic characterisation of the preterm and impaired fetal growth syndromes and development of a prediction model, based on multiple ultrasound measurements, to estimate gestational age for use in pregnant women without access to early/frequent antenatal care.

Managing data for the international, multicentre INTERGROWTH-21st Project.

The INTERGROWTH-21(st) Project data management was structured incorporating both a centralised and decentralised system for the eight study centres, which all used the same database and standardised data collection instruments, manuals and processes. Each centre was responsible for the entry and validation of their country-specific data, which were entered onto a centralised system maintained by the Data Coordinating Unit in Oxford. A comprehensive data management system was designed to handle the very large volumes of data. It contained internal validations to prevent incorrect and inconsistent values being captured, and allowed online data entry by local Data Management Units, as well as real-time management of recruitment and data collection by the Data Coordinating Unit in Oxford. To maintain data integrity, only the Data Coordinating Unit in Oxford had access to all the eight centres' data, which were continually monitored. All queries identified were raised with the relevant local data manager for verification and correction, if necessary. The system automatically logged an audit trail of all updates to the database with the date and name of the person who made the changes. These rigorous processes ensured that the data collected in the INTERGROWTH-21(st) Project were of exceptionally high quality.

Implementation of the INTERGROWTH-21st Project in the United States.

The North American site in the INTERGROWTH-21(st) Project was North Seattle, Washington State, USA. The majority of the data were collected from within Seattle City, which has approximately 12 300 births per year. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from two hospitals (Swedish Medical Center and the University of Washington) covering almost 80% of deliveries within the target population. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from several antenatal clinics serving the University of Washington Medical Center and Providence Everett Medical Center. Special activities to encourage participation and raise awareness of the studies included furnishing the recruitment sites with fliers designed by the Project Coordinating Unit, and presenting the studies to clinical staff to encourage providers to refer appropriate patients. One of the major challenges at this site was the low recruitment rate in the early phase of the FGLS because of the high rates of smoking, maternal age >35 years and body mass index >30 years. This was remedied by the inclusion of other ancillary clinics, as well as increased advertising among the general public.