Antagonism of STAT3 signalling by Ebola virus.

Many viruses target signal transducers and activators of transcription (STAT) 1 and 2 to antagonise antiviral interferon signalling, but targeting of signalling by other STATs/cytokines, including STAT3/interleukin 6 that regulate processes important to Ebola virus (EBOV) haemorrhagic fever, is poorly defined. We report that EBOV potently inhibits STAT3 responses to interleukin-6 family cytokines, and that this is mediated by the interferon-antagonist VP24. Mechanistic analysis indicates that VP24 effects a unique strategy combining distinct karyopherin-dependent and karyopherin-independent mechanisms to antagonise STAT3-STAT1 heterodimers and STAT3 homodimers, respectively. This appears to reflect distinct mechanisms of nuclear trafficking of the STAT3 complexes, revealed for the first time by our analysis of VP24 function. These findings are consistent with major roles for global inhibition of STAT3 signalling in EBOV infection, and provide new insights into the molecular mechanisms of STAT3 nuclear trafficking, significant to pathogen-host interactions, cell physiology and pathologies such as cancer.

Novel role of SARM1 mediated axonal degeneration in the pathogenesis of rabies.

Neurotropic viral infections continue to pose a serious threat to human and animal wellbeing. Host responses combatting the invading virus in these infections often cause irreversible damage to the nervous system, resulting in poor prognosis. Rabies is the most lethal neurotropic virus, which specifically infects neurons and spreads through the host nervous system by retrograde axonal transport. The key pathogenic mechanisms associated with rabies infection and axonal transmission in neurons remains unclear. Here we studied the pathogenesis of different field isolates of lyssavirus including rabies using ex-vivo model systems generated with mouse primary neurons derived from the peripheral and central nervous systems. In this study, we show that neurons activate selective and compartmentalized degeneration of their axons and dendrites in response to infection with different field strains of lyssavirus. We further show that this axonal degeneration is mediated by the loss of NAD and calpain-mediated digestion of key structural proteins such as MAP2 and neurofilament. We then analysed the role of SARM1 gene in rabies infection, which has been shown to mediate axonal self-destruction during injury. We show that SARM1 is required for the accelerated execution of rabies induced axonal degeneration and the deletion of SARM1 gene significantly delayed axonal degeneration in rabies infected neurons. Using a microfluidic-based ex-vivo neuronal model, we show that SARM1-mediated axonal degeneration impedes the spread of rabies virus among interconnected neurons. However, this neuronal defense mechanism also results in the pathological loss of axons and dendrites. This study therefore identifies a potential host-directed mechanism behind neurological dysfunction in rabies infection. This study also implicates a novel role of SARM1 mediated axonal degeneration in neurotropic viral infection.

Evaluation of an African swine fever (ASF) vaccine strategy incorporating priming with an alphavirus-expressed antigen followed by boosting with attenuated ASF virus.

In this study, an alphavirus vector platform was used to deliver replicon particles (RPs) expressing African swine fever virus (ASFV) antigens to swine. Alphavirus RPs expressing ASFV p30 (RP-30), p54 (RP-54) or pHA-72 (RP-sHA-p72) antigens were constructed and tested for expression in Vero cells and for immunogenicity in pigs. RP-30 showed the highest expression in Vero cells and was the most immunogenic in pigs, followed by RP-54 and RP-sHA-p72. Pigs primed with two doses of the RP-30 construct were then boosted with a naturally attenuated ASFV isolate, OURT88/3. Mapping of p30 identified an immunodominant region within the amino acid residues 111-130. However, the principal effect of the prime-boost was enhanced recognition of an epitope covered by the peptide sequence 61-110. The results suggest that a strategy incorporating priming with a vector-expressed antigen followed by boosting with an attenuated live virus may broaden the recognition of ASFV epitopes.

Zika virus-induced hyper excitation precedes death of mouse primary neuron.

BACKGROUND: Zika virus infection in new born is linked to congenital syndromes, especially microcephaly. Studies have shown that these neuropathies are the result of significant death of neuronal progenitor cells in the central nervous system of the embryo, targeted by the virus. Although cell death via apoptosis is well acknowledged, little is known about possible pathogenic cellular mechanisms triggering cell death in neurons. METHODS: We used in vitro embryonic mouse primary neuron cultures to study possible upstream cellular mechanisms of cell death. Neuronal networks were grown on microelectrode array and electrical activity was recorded at different times post Zika virus infection. In addition to this method, we used confocal microscopy and Q-PCR techniques to observe morphological and molecular changes after infection. RESULTS: Zika virus infection of mouse primary neurons triggers an early spiking excitation of neuron cultures, followed by dramatic loss of this activity. Using NMDA receptor antagonist, we show that this excitotoxicity mechanism, likely via glutamate, could also contribute to the observed nervous system defects in human embryos and could open new perspective regarding the causes of adult neuropathies. CONCLUSIONS: This model of excitotoxicity, in the context of neurotropic virus infection, highlights the significance of neuronal activity recording with microelectrode array and possibility of more than one lethal mechanism after Zika virus infection in the nervous system.

Mouse fibroblast L929 cells are less permissive to infection by Nelson Bay orthoreovirus compared to other mammalian cell lines.

In recent years, bats have been identified as a natural reservoir for a diverse range of viruses. Nelson Bay orthoreovirus (NBV) was first isolated from the heart blood of a fruit bat (Pteropus poliocephalus) in 1968. While the pathogenesis of NBV remains unknown, other related members of this group have caused acute respiratory disease in humans. Thus the potential for NBV to impact human health appears plausible. Here, to increase our knowledge of NBV, we examined the replication and infectivity of NBV using different mammalian cell lines derived from bat, human, mouse and monkey. All cell lines supported the replication of NBV; however, L929 cells showed a greater than 2 log reduction in virus titre compared with the other cell lines. Furthermore, NBV did not induce major cytopathic effects in the L929 cells, as was observed in other cell lines. Interestingly, the related Pteropine orthoreoviruses, Pulau virus (PulV) and Melaka virus (MelV) were able to replicate to high titres in L929 cells but infection resulted in reduced cytopathic effect. Our study demonstrates a unique virus-host interaction between NBV and L929 cells, where cells effectively control viral infection/replication and limit the formation of syncytia. By elucidating the molecular mechanisms that control this unique relationship, important insights will be made into the biology of this fusogenic virus.

Development and validation of an administrative data algorithm to estimate the disease burden and epidemiology of multiple sclerosis in Ontario, Canada.

BACKGROUND: Few studies have assessed the accuracy of administrative data for identifying multiple sclerosis (MS) patients. OBJECTIVES: To validate administrative data algorithms for MS, and describe the burden and epidemiology over time in Ontario, Canada. METHODS: We employed a validated search strategy to identify all MS patients within electronic medical records, to identify patients with and without MS (reference standard). We then developed and validated different combinations of administrative data for algorithms. The most accurate algorithm was used to estimate the burden and epidemiology of MS over time. RESULTS: The accuracy of the algorithm of one hospitalisation or five physician billings over 2 years provided both high sensitivity (84%) and positive predictive value (86%). Application of this algorithm to provincial data demonstrated an increasing cumulative burden of MS, from 13,326 patients (0.14%) in 2000 to 24,647 patients in 2010 (0.22%). Age-and-sex standardised prevalence increased from 133.9 to 207.3 MS patients per 100,000 persons in the population, from 2000 - 2010. During this same period, age-and-sex-standardised incidence varied from 17.9 to 19.4 patients per 100,000 persons. CONCLUSIONS: MS patients can be accurately identified from administrative data. Our findings illustrated a rising prevalence of MS over time. MS incidence rates also appear to be rising since 2009.

Canadian administrative health data can identify patients with myasthenia gravis.

INTRODUCTION: Incidence and prevalence estimates for myasthenia gravis (MG) have varied widely, and the ability of administrative health data (AHD) records to accurately identify cases of MG is yet to be ascertained. The goal of the current study was to validate an algorithm to identify patients with MG in Ontario, Canada using AHD - thereby enabling future disease surveillance. METHODS: A reference standard population was established using automated key word searching within EMRALD (Electronic Medical Record Administrative data Linked Database) and chart review of potential cases. AHD algorithms were generated and tested against the reference standard. The data was used to calculate MG prevalence rates. RESULTS: There were 123,997 eligible adult patients, and 49 patients had definite MG (forming the reference standard). An algorithm requiring: (1 hospital discharge abstract with MG listed as a reason for hospitalization or a comorbid condition), or (5 outpatient MG visits and 1 relevant diagnostic test, within 1 year), or (3 pyridostigmine prescriptions, within 1 year) identified MG with sensitivity = 81.6%, specificity = 100%, positive predictive value = 80.0% and negative predictive value = 100%. The population prevalence within our cohort was 0.04%. CONCLUSIONS: This novel validation method demonstrates the feasibility of using administrative health data to identify patients with myasthenia gravis among the Ontario population.

Validation of a Population-Based Algorithm to Detect Chronic Psychotic Illness.

OBJECTIVE: To validate algorithms to detect people with chronic psychotic illness in population-based health administrative databases. METHOD: We developed 8 algorithms to detect chronic psychotic illness using hospitalization and physician service claims data from administrative health databases in Ontario to identify cases of chronic psychotic illness between 2002 and 2007. Diagnostic data abstracted from the records of 281 randomly selected psychiatric patients from 2 hospitals in Toronto were linked to the administrative data cohort to test sensitivity, specificity, and positive predictive values (PPV) and negative predictive values. RESULTS: Using only hospitalization data to capture chronic psychotic illness yielded the highest specificity (range 69.9% to 84.7%) and the highest PPV (range 55.2% to 80.8%). Using physician service claims in addition to hospitalization data to capture cases increased sensitivity (range 90.1% to 98.8%) but decreased specificity (range 31.1% to 68.0%) and PPV (range 38.4% to 71.1%). CONCLUSION: Using health administrative data to study population-based outcomes for people with chronic psychotic illness is feasible and valid. Researchers can select case identification methods based on whether a more sensitive or more specific definition of chronic psychotic illness is desired.

A validation study of administrative data algorithms to identify patients with Parkinsonism with prevalence and incidence trends.

BACKGROUND: Epidemiological studies for identifying patients with Parkinson's disease (PD) or Parkinsonism (PKM) have been limited by their nonrandom sampling techniques and mainly veteran populations. This reduces their use for health services planning. The purpose of this study was to validate algorithms for the case ascertainment of PKM from administrative databases using primary care patients as the reference standard. METHODS: We conducted a retrospective chart abstraction using a random sample of 73,003 adults aged ≥ 20 years from a primary care Electronic Medical Record Administrative data Linked Database (EMRALD) in Ontario, Canada. Physician diagnosis in the EMR was used as the reference standard and population-based administrative databases were used to identify patients with PKM from the derivation of algorithms. We calculated algorithm performance using sensitivity, specificity, and predictive values and then determined the population-level prevalence and incidence trends with the most accurate algorithms. RESULTS: We selected, '2 physician billing codes in 1 year' as the optimal administrative data algorithm in adults and seniors (≥ 65 years) due to its sensitivity (70.6-72.3%), specificity (99.9-99.8%), positive predictive value (79.5-82.8%), negative predictive value (99.9-99.7%), and prevalence (0.28-1.20%), respectively. CONCLUSIONS: Algorithms using administrative databases can reliably identify patients with PKM with a high degree of accuracy.

Detailed morphological characterisation of Hendra virus infection of different cell types using super-resolution and conventional imaging.

BACKGROUND: Hendra virus (HeV) is a pleomorphic virus belonging to the Paramyxovirus family. Our long-term aim is to understand the process of assembly of HeV virions. As a first step, we sought to determine the most appropriate cell culture system with which to study this process, and then to use this model to define the morphology of the virus and identify the site of assembly by imaging key virus encoded proteins in infected cells. METHODS: A range of primary cells and immortalised cell lines were infected with HeV, fixed at various time points post-infection, labelled for HeV proteins and imaged by confocal, super-resolution and transmission electron microscopy. RESULTS: Significant differences were noted in viral protein distribution depending on the infected cell type. At 8 hpi HeV G protein was detected in the endoplasmic reticulum and M protein was seen predominantly in the nucleus in all cells tested. At 18 hpi, HeV-infected Vero cells showed M and G proteins throughout the cell and in transmission electron microscope (TEM) sections, in pleomorphic virus-like structures. In HeV infected MDBK, A549 and HeLa cells, HeV M protein was seen predominantly in the nucleus with G protein at the membrane. In HeV-infected primary bovine and porcine aortic endothelial cells and two bat-derived cell lines, HeV M protein was not seen at such high levels in the nucleus at any time point tested (8,12, 18, 24, 48 hpi) but was observed predominantly at the cell surface in a punctate pattern co-localised with G protein. These HeV M and G positive structures were confirmed as round HeV virions by TEM and super-resolution (SR) microscopy. SR imaging demonstrated for the first time sub-virion imaging of paramyxovirus proteins and the respective localisation of HeV G, M and N proteins within virions. CONCLUSION: These findings provide novel insights into the structure of HeV and show that for HeV imaging studies the choice of tissue culture cells may affect the experimental results. The results also indicate that HeV should be considered a predominantly round virus with a mean diameter of approximately 280 nm by TEM and 310 nm by SR imaging.

Assessing the validity of using administrative data to identify patients with epilepsy.

OBJECTIVE: Previous validation studies assessing the use of administrative data to identify patients with epilepsy have used targeted sampling or have used a reference standard of patients in the neurologist, hospital, or emergency room setting. Therefore, the validity of using administrative data to identify patients with epilepsy in the general population has not been previously assessed. The purpose of this study was to determine the validity of using administrative data to identify patients with epilepsy in the general population. METHODS: A retrospective chart abstraction study was performed using primary care physician records from 83 physicians distributed throughout Ontario and contributing data to the Electronic Medical Record Administrative data Linked Database (EMRALD) A random sample of 7,500 adult patients, from a possible 73,014 eligible, was manually chart abstracted to identify patients who had ever had epilepsy. These patients were used as a reference standard to test a variety of administrative data algorithms. RESULTS: An algorithm of three physician billing codes (separated by at least 30 days) in 2 years or one hospitalization had a sensitivity of 73.7% (95% confidence interval [CI] 64.8-82.5%), specificity of 99.8% (95% CI 99.6-99.9%), positive predictive value (PPV) of 79.5% (95% CI 71.1-88.0%), and negative predictive value (NPV) of 99.7% (95% CI 99.5-99.8%) for identifying patients who had ever had epilepsy. SIGNIFICANCE: The results of our study showed that administrative data can reasonably accurately identify patients who have ever had epilepsy, allowing for a "lifetime" population prevalence determination of epilepsy in Ontario and the rest of Canada with similar administrative databases. This will facilitate future studies on population level patterns and outcomes of care for patients living with epilepsy.

An administrative data validation study of the accuracy of algorithms for identifying rheumatoid arthritis: the influence of the reference standard on algorithm performance.

BACKGROUND: We have previously validated administrative data algorithms to identify patients with rheumatoid arthritis (RA) using rheumatology clinic records as the reference standard. Here we reassessed the accuracy of the algorithms using primary care records as the reference standard. METHODS: We performed a retrospective chart abstraction study using a random sample of 7500 adult patients under the care of 83 family physicians contributing to the Electronic Medical Record Administrative data Linked Database (EMRALD) in Ontario, Canada. Using physician-reported diagnoses as the reference standard, we computed and compared the sensitivity, specificity, and predictive values for over 100 administrative data algorithms for RA case ascertainment. RESULTS: We identified 69 patients with RA for a lifetime RA prevalence of 0.9%. All algorithms had excellent specificity (>97%). However, sensitivity varied (75-90%) among physician billing algorithms. Despite the low prevalence of RA, most algorithms had adequate positive predictive value (PPV; 51-83%). The algorithm of "[1 hospitalization RA diagnosis code] or [3 physician RA diagnosis codes with ≥1 by a specialist over 2 years]" had a sensitivity of 78% (95% CI 69-88), specificity of 100% (95% CI 100-100), PPV of 78% (95% CI 69-88) and NPV of 100% (95% CI 100-100). CONCLUSIONS: Administrative data algorithms for detecting RA patients achieved a high degree of accuracy amongst the general population. However, results varied slightly from our previous report, which can be attributed to differences in the reference standards with respect to disease prevalence, spectrum of disease, and type of comparator group.

Transcriptome analysis of pigeon milk production - role of cornification and triglyceride synthesis genes.

BACKGROUND: The pigeon crop is specially adapted to produce milk that is fed to newly hatched young. The process of pigeon milk production begins when the germinal cell layer of the crop rapidly proliferates in response to prolactin, which results in a mass of epithelial cells that are sloughed from the crop and regurgitated to the young. We proposed that the evolution of pigeon milk built upon the ability of avian keratinocytes to accumulate intracellular neutral lipids during the cornification of the epidermis. However, this cornification process in the pigeon crop has not been characterised. RESULTS: We identified the epidermal differentiation complex in the draft pigeon genome scaffold and found that, like the chicken, it contained beta-keratin genes. These beta-keratin genes can be classified, based on sequence similarity, into several clusters including feather, scale and claw keratins. The cornified cells of the pigeon crop express several cornification-associated genes including cornulin, S100-A9 and A16-like, transglutaminase 6-like and the pigeon 'lactating' crop-specific annexin cp35. Beta-keratins play an important role in 'lactating' crop, with several claw and scale keratins up-regulated. Additionally, transglutaminase 5 and differential splice variants of transglutaminase 4 are up-regulated along with S100-A10. CONCLUSIONS: This study of global gene expression in the crop has expanded our knowledge of pigeon milk production, in particular, the mechanism of cornification and lipid production. It is a highly specialised process that utilises the normal keratinocyte cellular processes to produce a targeted nutrient solution for the young at a very high turnover.

Developing a prevention synthesis and translation system to promote science-based approaches to teen pregnancy, HIV and STI prevention.

The Interactive Systems Framework for Dissemination and Implementation (ISF) is a multi-system framework that can guide research-to-practice efforts by building and supporting the work of three interacting systems: the Prevention Delivery, Support, and Synthesis and Translation Systems. The Synthesis and Translation system is vital to bridging science and practice, yet how to develop it and train support system partners to use it is under-researched. This article bridges this gap by offering a case example of the planning, development, and use of a synthesis and translation product called Promoting Science-based Approaches to Teen Pregnancy Prevention using Getting To Outcomes. The case presented documents the process used for developing the synthesis and translation product, reports on efforts to engage the Prevention Support system to use the product, and how we approached building interaction between the Synthesis and Translation System and the Support System partners. Practice-oriented evaluation data are also presented. Implications for practice, policy and research are discussed.

A neutralizing human monoclonal antibody protects against lethal disease in a new ferret model of acute nipah virus infection.

Nipah virus is a broadly tropic and highly pathogenic zoonotic paramyxovirus in the genus Henipavirus whose natural reservoirs are several species of Pteropus fruit bats. Nipah virus has repeatedly caused outbreaks over the past decade associated with a severe and often fatal disease in humans and animals. Here, a new ferret model of Nipah virus pathogenesis is described where both respiratory and neurological disease are present in infected animals. Severe disease occurs with viral doses as low as 500 TCID(50) within 6 to 10 days following infection. The underlying pathology seen in the ferret closely resembles that seen in Nipah virus infected humans, characterized as a widespread multisystemic vasculitis, with virus replicating in highly vascular tissues including lung, spleen and brain, with recoverable virus from a variety of tissues. Using this ferret model a cross-reactive neutralizing human monoclonal antibody, m102.4, targeting the henipavirus G glycoprotein was evaluated in vivo as a potential therapeutic agent. All ferrets that received m102.4 ten hours following a high dose oral-nasal Nipah virus challenge were protected from disease while all controls died. This study is the first successful post-exposure passive antibody therapy for Nipah virus using a human monoclonal antibody.

Training and technical assistance to enhance capacity building between prevention research centers and their partners.

INTRODUCTION: The Centers for Disease Control and Prevention has administered the Prevention Research Centers Program since 1986. We quantified the number and reach of training programs across all centers, determined whether the centers' outcomes varied by characteristics of the academic institution, and explored potential benefits of training and technical assistance for academic researchers and community partners. We characterized how these activities enhanced capacity building within Prevention Research Centers and the community. METHODS: The program office collected quantitative information on training across all 33 centers via its Internet-based system from April through December 2007. Qualitative data were collected from April through May 2007. We selected 9 centers each for 2 separate, semistructured, telephone interviews, 1 on training and 1 on technical assistance. RESULTS: Across 24 centers, 4,777 people were trained in 99 training programs in fiscal year 2007 (October 1, 2006-September 30, 2007). Nearly 30% of people trained were community members or agency representatives. Training and technical assistance activities provided opportunities to enhance community partners' capacity in areas such as conducting needs assessments and writing grants and to improve the centers' capacity for cultural competency. CONCLUSION: Both qualitative and quantitative data demonstrated that training and technical assistance activities can foster capacity building and provide a reciprocal venue to support researchers' and the community's research interests. Future evaluation could assess community and public health partners' perception of centers' training programs and technical assistance.

Pastoral care professionals in health and mental health care: recognizing classic and newer versions of ageism.

Pastoral care professionals are cognizant of many forms of prejudice and discrimination in society and health care environments. Ageism is perhaps the least likely to be challenged as prejudice or discrimination. Ageist perception is suspicious of the health and cognitive ability of older persons; without consideration of emotional, spiritual, or social abilities. While positive and negative ageist attributions are culturally abundant, new and subtle versions of ageism offer convincing guidance about personal responsibility for health status and insist on personal social engagement. Older persons who are not free of disease or disability may be viewed as culpable for their failure to age well. Additionally, elders may be expected to maintain social involvement; especially through volunteerism. Elders who are unable or unwilling to engage in volunteerism may be viewed as selfish or irresponsible. If individuals are held responsible for their health as they age, then services and reimbursement for service may be limited to evidence-based medical interventions that result in complete recovery rather than life-quality improvement and only for "worthy" individuals. This paper seeks to heighten the awareness of pastoral care professionals to common ageist themes found in health and mental care service delivery.

Perceptions of intimate partner violence, age, and self-enhancement bias.

Educational programs in human service professions such as social work, criminal justice, psychology, and public administration stress the importance of recognizing domestic/intimate partner violence as well as elder abuse. Students' abilities to recognize domestic violence in older couples have not been well-investigated. In this study, three vignettes were developed (Pat and Lee at age 75, Pat and Lee at age 30, Imagine yourself with Lee at age 75) in which intimate partner violence was perpetrated by the character Lee. Twenty-five items followed each vignette. When the variables of educational standing (graduate/undergraduate), ethnicity, and academic major were controlled, there were significant differences between the vignettes in 14 of 25 items (General Linear Model, F = 1.552, df = 50, p = .012). More than three out of four respondents for each vignette identified this as domestic violence and believed there was potential for serious harm. However, respondents were less likely to believe that a 75-year-old partner would know when to terminate a relationship in which there was intimate partner violence. Respondents who were asked to imagine themselves with Lee at 75 were likely to perceive Lee as more dangerous than respondents for the other vignettes. Implications are considered for educators.

Multidisciplinary management of pregnancy and labour in a patient with glycogen storage disease type 1a.

Glycogen storage disease type 1a (GSD 1a) is a metabolic disorder caused by deficiency of an enzyme required for glycogen breakdown, causing hypoglycaemia and lactic acidosis. Metabolic derangements cause disease manifestations affecting the kidneys, liver and platelet function. Physiological changes in pregnancy worsen fasting intolerance and increase reliance on exogenous glucose to avoid lactic acidosis. Fetal macrosomia and declining respiratory function result in high rates of caesarean sections. We report the multidisciplinary team (MDT) management of a 25-year-old woman with GSD 1a in an unplanned pregnancy. Existing percutaneous endoscopic gastrostomy tube feeding, alongside high-calorie drinks and intravenous dextrose during labour, managed the risks of hypoglycaemia and lactic acidosis. Metabolic parameters were regularly monitored and fortnightly growth scans were assessed for macrosomia. Allopurinol was continued throughout the pregnancy to reduce the risk of hyperuricaemia. MDT management optimised maternal and fetal care throughout pregnancy and labour, resulting in a successful vaginal delivery.

Mental health diagnoses in adults with phenylketonuria: a retrospective systematic audit in a large UK single centre.

BACKGROUND: Recently published European Society for Phenylketonuria (ESPKU) guidelines have recommended a lifelong diet with phenylalanine (Phe) control ≤ 600 µmol/L for phenylketonuria (PKU) patients. This study aimed to identify whether PKU adult patients are at a higher risk of mental health diagnoses if their 2-year average Phe level is higher than the ESPKU European guidelines. Published studies identified by a literature review showed that related studies have been published in American and European PKU study populations but not in the United Kingdom (UK) study populations. Previous studies also involved a smaller number of participants due to this being a rare disease. RESULTS: We undertook a retrospective audit at a single large PKU centre in the UK. 244 adult PKU patients at the centre were included, 220 of which had a recorded Phe level. Approximately 75% of the patients in this study did not meet the ESPKU European guidelines for Phe control. A systematic search of the electronic patient record was undertaken looking for mental health diagnoses. Compared to two-year average Phe levels ≤ 600 µmol/L, PKU adult patients with two-year average Phe levels > 600 µmol/L were more likely to have diagnoses of low mood, depression, anxiety, or mood swings, but only low mood reached statistical significance (p < 0.05). CONCLUSIONS: PKU patients with two-year average Phenylalanine levels greater than ESPKU guidelines may be at greater risk of mental health diagnoses and symptoms. Many of these adult PKU patients will be lost to follow-up, and therefore may be receiving treatment for mental health conditions in the community. Multicentre UK studies and international collaborations are required to overcome low participant numbers in the study of this rare disease.