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Alzheimer’s disease (AD) is a progressive irreversible neurodegenerative disorder that represents a major global public health concern. Traditionally, AD is diagnosed using cerebrospinal fluid biomarker analysis or brain imaging modalities. Recently, less burdensome, more widely available blood biomarker (BBM) assays for amyloid-beta (Aβ42/40) and phosphorylated-tau concentrations have been found to accurately identify the presence/absence of brain amyloid plaques and tau tangles and have helped to streamline AD diagnosis. However, few BBMs have been rigorously analytically validated. Herein, we report the analytical validation of a novel liquid chromatography–tandem mass spectrometry (LC-MS/MS) multiplex method for quantifying plasma phosphorylated-tau217 (p-tau217) and non-phosphorylated-tau217 (np-tau217) peptide concentrations. We combined the p-tau217/np-tau217 concentrations ratio (%p-tau217) and the previously validated LC-MS/MS multiplex assay for plasma Aβ42/40 into a new multianalyte assay with algorithmic analysis (MAAA; PrecivityAD2™ test) that identifies brain amyloid status based on brain amyloid positron emission tomography. We found (a) the %p-tau217 assay is precise, accurate, sensitive, and linear over a wide analytical measurement range, and free from carryover and interference; (b) the pre-analytical specimen collection, processing, storage, and shipping conditions that maintain plasma tau peptide stability; and (c) using the measured analytical imprecision for plasma Aβ42/40 and p-tau217/np-tau217 levels in a worst-case scenario model, the PrecivityAD2 test algorithm for amyloid pathology classification changed for only 3.5% of participants from brain amyloid positive to negative, or from negative to positive. The plasma sample preparation and LC-MS/MS methods underlying the PrecivityAD2 test are suitable for use in the clinical laboratory and valid for the test’s intended purpose: to aid in the diagnostic evaluation of individuals aged 55 and older with signs or symptoms of mild cognitive impairment or dementia.

The focus of this dissertation is the synthesis, development and application of the amine containing modified targets for the fractionation of complex mixtures of peptides and digested proteins prior to MALDI-MS analysis. Even though MALDI-MS is increasingly used in proteomic applications and analysis, this method suffers from loss of performance in the analysis of mixtures, due to the ion suppression effect. In this effect, basic peptides ionize more readily than acidic peptides and there by suppress the ionization and detection of less basic peptides resulting in the loss in the detection of valuable sequence information and posttranslational modifications. In the approach taken, a modified target containing amine functionality was utilized as a mixture fractionation substrate. The substrates were chosen for the adsorption of targeted analytes. Incorporating this amine function into 3D brushes offer the ability to absorb higher quantities of peptides, allowing for a more thorough analysis and more sequence coverage. In this work fractionation occurs as the result of electrostatic attraction or repulsion between the positively charged polymer surface and negatively charged analytes in solution. Fractionation studies utilizing this amine chemistry for separation were done first with binary peptide mixtures. Basic peptides are observed to repel from the cationic polymer surfaces, allowing the suppressed acidic peptides to separate from the mixture by binding to the amine substrates. The acidic peptides can be eluted and observed. Following successful demonstrations, more complex mixtures of peptides derived from enzymatic tryptic digestion of proteins were studied. Following fractionation, MALDI mass spectra of both the washed and eluted fractions are obtained and ions signals are analyzed and associated with predicted peptide sequences. Complete analysis of the ion signals using Prowl and PeptideMap leads to a percent protein sequence coverage. Comparison of this number with the percent sequence obtained from unfractionated (conventional) digested peptide mixture mass spectra reveals that fractionation does in fact significantly increase and also increases discovery of post translational modifications (PTM). Fractionation studies were studied by varying the pH of tryptically digest proteins. Sequence coverages were found to increase upon fractionation at all pHs studied. In order to increase the discovery of PTMs, the cationic polymer brush was doped with copper ions to selectively capture phosphopeptides. Negatively charged phosphopeptides were shown to be selectively captured by the copper ions complexes within the polymer brush substrate, and subsequently released upon addition of acid.

In 2007–08, a genotype J mumps outbreak occurred among Aboriginal people in northern Western Australia, despite high vaccine coverage. In March, 2015, a second protracted mumps outbreak occurred in northern Western Australia and spread widely across rural areas of the state. This time the outbreak was caused by a genotype G virus and again primarily affected Aboriginal people. We aimed to describe the epidemiology of this outbreak. In this population-based surveillance study, we analysed statutory notifications and public health case follow-up data from the Western Australia Notifiable Infectious Diseases Database and vaccination information from the Australian Childhood Immunisation Register. An outbreak case of mumps was notified if the affected person was living in or visiting a community in Western Australia where there was active mumps transmission, and if mumps infection was confirmed by laboratory diagnosis or by an epidemiological link. We analysed case demographics, vaccination status, and age-standardised attack rates in Aboriginal and non-Aboriginal people by region of notification. Laboratory diagnoses were made by real-time RT-PCR, serology, or both, and carried out by the sole public pathology provider in Western Australia. Between March 1, 2015, and December 31, 2016, 893 outbreak cases were notified. 798 (89%) of 893 outbreak cases were reported in Aboriginal people. 40 (4%) of 893 people were admitted to hospital, and 33 (7%) of 462 men reported orchitis. Mumps attack rates increased sharply with age, peaking in the 15–19 age group. 371 (89%) of 419 people aged 1–19 years were fully vaccinated and 29 (7%) were partly vaccinated. Of the 240 people who tested positive by real-time RT-PCR and had also been tested for mumps-specific IgG and IgM, 165 (69%) were positive for IgG but negative for IgM, indicating the importance of RT-PCR testing for diagnosis in vaccinated populations. None of the cases from the 2007–08 genotype J outbreak were re-notified. The number of mumps outbreaks reported in recent years among highly vaccinated populations, including Indigenous populations, has been growing. More widespread and pre-emptive use of the third dose of measles, mumps, and rubella vaccine might be required to control and prevent future outbreaks in high-risk populations. Research should explore the benefit of increasing the intervals between vaccine doses to strengthen the durability of vaccine protection. None.

BACKGROUND With the availability of disease‐modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS High‐throughput, mass spectrometry‐based assays were used to measure %p‐tau217 and amyloid beta (Aβ)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS The area under the receiver operating characteristic curve (AUC‐ROC) for %p‐tau217 (0.94) was statistically significantly higher than that for p‐tau217 concentration (0.91). The AUC‐ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.

PurposeAfter cardiac surgery, fluid bolus therapy (FBT) with 20% human albumin may facilitate less fluid and vasopressor administration than FBT with crystalloids. We aimed to determine whether, after cardiac surgery, FBT with 20% albumin reduces the duration of vasopressor therapy compared with crystalloid FBT.MethodsWe conducted a multicentre, parallel-group, open-label, randomised clinical trial in six intensive care units (ICUs) involving cardiac surgery patients deemed to require FBT. We randomised 240 patients to receive up to 400 mL of 20% albumin/day as FBT, followed by 4% albumin for any subsequent FBT on that day, or to crystalloid FBT for at least the first 1000 mL, with use of crystalloid or 4% albumin FBT thereafter. The primary outcome was the cumulative duration of vasopressor therapy. Secondary outcomes included fluid balance.ResultsOf 480 randomised patients, 466 provided consent and contributed to the primary outcome (mean age 65 years; median EuroSCORE II 1.4). The cumulative median duration of vasopressor therapy was 7 (interquartile range [IQR] 0–19.6) hours with 20% albumin and 10.8 (IQR 0–22.8) hours with crystalloids (difference − 3.8 h, 95% confidence interval [CI] − 8 to 0.4; P = 0.08). Day one fluid balance was less with 20% albumin FBT (mean difference − 701 mL, 95% CI − 872 to − 530).ConclusionsIn patients after cardiac surgery, when compared to a crystalloid-based FBT, 20% albumin FBT was associated with a reduced positive fluid balance but did not significantly reduce the duration of vasopressor therapy.

Background Maternal multiple long-term conditions are associated with adverse outcomes for mother and child. We conducted a qualitative study to inform a core outcome set for studies of pregnant women with multiple long-term conditions. Methods Women with two or more pre-existing long-term physical or mental health conditions, who had been pregnant in the last five years or planning a pregnancy, their partners and health care professionals were eligible. Recruitment was through social media, patients and health care professionals’ organisations and personal contacts. Participants who contacted the study team were purposively sampled for maximum variation. Three virtual focus groups were conducted from December 2021 to March 2022 in the United Kingdom: (i) health care professionals (n = 8), (ii) women with multiple long-term conditions (n = 6), and (iii) women with multiple long-term conditions (n = 6) and partners (n = 2). There was representation from women with 20 different physical health conditions and four mental health conditions; health care professionals from obstetrics, obstetric/maternal medicine, midwifery, neonatology, perinatal psychiatry, and general practice. Participants were asked what outcomes should be reported in all studies of pregnant women with multiple long-term conditions. Inductive thematic analysis was conducted. Outcomes identified in the focus groups were mapped to those identified in a systematic literature search in the core outcome set development. Results The focus groups identified 63 outcomes, including maternal (n = 43), children’s (n = 16) and health care utilisation (n = 4) outcomes. Twenty-eight outcomes were new when mapped to the systematic literature search. Outcomes considered important were generally similar across stakeholder groups. Women emphasised outcomes related to care processes, such as information sharing when transitioning between health care teams and stages of pregnancy (continuity of care). Both women and partners wanted to be involved in care decisions and to feel informed of the risks to the pregnancy and baby. Health care professionals additionally prioritised non-clinical outcomes, including quality of life and financial implications for the women; and longer-term outcomes, such as children’s developmental outcomes. Conclusions The findings will inform the design of a core outcome set. Participants’ experiences provided useful insights of how maternity care for pregnant women with multiple long-term conditions can be improved.

Background Heterogeneity in reported outcomes can limit the synthesis of research evidence. A core outcome set informs what outcomes are important and should be measured as a minimum in all future studies. We report the development of a core outcome set applicable to observational and interventional studies of pregnant women with multimorbidity. Methods We developed the core outcome set in four stages: (i) a systematic literature search, (ii) three focus groups with UK stakeholders, (iii) two rounds of Delphi surveys with international stakeholders and (iv) two international virtual consensus meetings. Stakeholders included women with multimorbidity and experience of pregnancy in the last 5 years, or are planning a pregnancy, their partners, health or social care professionals and researchers. Study adverts were shared through stakeholder charities and organisations. Results Twenty-six studies were included in the systematic literature search (2017 to 2021) reporting 185 outcomes. Thematic analysis of the focus groups added a further 28 outcomes. Two hundred and nine stakeholders completed the first Delphi survey. One hundred and sixteen stakeholders completed the second Delphi survey where 45 outcomes reached Consensus In (≥70% of all participants rating an outcome as Critically Important ). Thirteen stakeholders reviewed 15 Borderline outcomes in the first consensus meeting and included seven additional outcomes. Seventeen stakeholders reviewed these 52 outcomes in a second consensus meeting, the threshold was ≥80% of all participants voting for inclusion. The final core outcome set included 11 outcomes. The five maternal outcomes were as follows: maternal death, severe maternal morbidity, change in existing long-term conditions (physical and mental), quality and experience of care and development of new mental health conditions. The six child outcomes were as follows: survival of baby, gestational age at birth, neurodevelopmental conditions/impairment, quality of life, birth weight and separation of baby from mother for health care needs. Conclusions Multimorbidity in pregnancy is a new and complex clinical research area. Following a rigorous process, this complexity was meaningfully reduced to a core outcome set that balances the views of a diverse stakeholder group.

Mental health is influenced by multiple complex and interacting genetic, psychological, social, and environmental factors. As such, developing state-of-the-art mental health knowledge requires collaboration across academic disciplines, including environmental science. To assess the current contribution of environmental science to this field, a scoping review of the literature on environmental influences on mental health (including conditions of cognitive development and decline) was conducted. The review protocol was developed in consultation with experts working across mental health and environmental science. The scoping review included 202 English-language papers, published between 2010 and 2020 (prior to the COVID-19 pandemic), on environmental themes that had not already been the subject of recent systematic reviews; 26 reviews on climate change, flooding, air pollution, and urban green space were additionally considered. Studies largely focused on populations in the USA, China, or Europe and involved limited environmental science input. Environmental science research methods are primarily focused on quantitative approaches utilising secondary datasets or field data. Mental health measurement was dominated by the use of self-report psychometric scales. Measures of environmental states or exposures were often lacking in specificity (e.g., limited to the presence or absence of an environmental state). Based on the scoping review findings and our synthesis of the recent reviews, a research agenda for environmental science’s future contribution to mental health scholarship is set out. This includes recommendations to expand the geographical scope and broaden the representation of different environmental science areas, improve measurement of environmental exposure, prioritise experimental and longitudinal research designs, and giving greater consideration to variation between and within communities and the mediating pathways by which environment influences mental health. There is also considerable opportunity to increase interdisciplinarity within the field via the integration of conceptual models, the inclusion of mixed methods and qualitative approaches, as well as further consideration of the socio-political context and the environmental states that can help support good mental health. The findings were used to propose a conceptual model to parse contributions and connections between environmental science and mental health to inform future studies.