Dealing with digital paralysis: Surviving a cyberattack in a National Cancer center.

INTRODUCTION: Cyberattacks represent a growing threat for healthcare delivery globally. We assess the impact and implications of a cyberattack on a cancer center in Ireland. METHODS: On May 14th 2021 (day 0) Cork University Hospital (CUH) Cancer Center was involved in the first national healthcare ransomware attack in Ireland. Contingency plans were only present in laboratory services who had previously experienced information technology (IT) failures. No hospital cyberattack emergency plan was in place. Departmental logs of activity for 120 days after the attack were reviewed and compared with historical activity records. Daily sample deficits (routine daily number of samples analyzed - number of samples analyzed during cyberattack) were calculated. Categorical variables are reported as median and range. Qualitative data were collected via reflective essays and interviews with key stakeholders from affected departments in CUH. RESULTS: On day 0, all IT systems were shut down. Radiotherapy (RT) treatment and cancer surgeries stopped, outpatient activity fell by 50%. hematology, biochemistry and radiology capacity fell by 90% (daily sample deficit (DSD) 2700 samples), 75% (DSD 2250 samples), and 90% (100% mammography/PET scan) respectively. Histopathology reporting times doubled (7 to 15 days). Radiotherapy (RT) was interrupted for 113 patients in CUH. The median treatment gap duration was six days for category 1 patients and 10 for the remaining patients. Partner organizations paused all IT links with CUH. Outsourcing of radiology and radiotherapy commenced, alternative communication networks and national conference calls in RT and Clinical Trials were established. By day 28 Email communication was restored. By day 210 reporting and data storage backlogs were cleared and over 2000 computers were checked/replaced. CONCLUSION: Cyberattacks have rapid, profound and protracted impacts. While laboratory and diagnostic deficits were readily quantified, the impact of disrupted/delayed care on patient outcomes is less readily quantifiable. Cyberawareness and cyberattack plans need to be embedded in healthcare. POLICY SUMMARY: Cyberattacks pose significant challenges for healthcare systems, impacting patient care, clinical outcomes, and staff wellbeing. This study provides a comprehensive review of the impact of the Conti ransomware attack on cancer services in Cork University Hospital (CUH), the first cyberattack on a national health service. Our study highlights the widespread disruption caused by a cyberattack including shutdown of information technology (IT) services, marked reduction in outpatient activity, temporary cessation of essential services such as radiation therapy. We provide a framework for other institutions for mitigating the impact of a cyberattack, underscoring the need for a cyberpreparedness plan similar to those made for natural disasters and the profound legacy of a cyberattack on patient care.

Hepatitis C community prevalence is over-estimated: a prospective, birth cohort study.

BACKGROUND: Hepatitis C virus infection is often asymptomatic, and many patients may be unaware they are infected. Community-based, birth cohort screening has been advocated to identify these patients. It has been estimated that 0.7-1% of individuals born between 1965 and 1985 in Ireland are infected. The cost-effectiveness of screening is critically dependent on the population prevalence. AIMS: The aim is to determine the community prevalence of hepatitis C virus infection in the birth cohort 1965-1985. METHODS: Residual serum samples from blood tests ordered by community general practitioners were anonymised and analysed for the presence of hepatitis C antibody ± antigen. Twelve large general hospitals throughout the country participated. RESULTS: A total of 14,320 samples were tested, 9347 of which were from the birth cohort 1965-1985. Seventy-two samples were positive for hepatitis C antibody of which 12 were positive for hepatitis C antigen (17%). The overall prevalence of hepatitis C antigen in the birth cohort was 0.09%. A higher prevalence (0.39%) was identified in males in two urban areas of Dublin. CONCLUSIONS: Hepatitis C virus seroprevalence was much lower than previously estimated. The proportion of antibody positive patients with hepatitis C antigen was also lower than expected suggesting the effects of treatment and/or high spontaneous viral clearance. Universal birth cohort screening is unlikely to be cost-effective. Targeted birth cohort screening in high prevalence areas could be considered.

Current practice and recommendations for managing transgender patient data in clinical laboratories in the United Kingdom and Republic of Ireland.

BACKGROUND: Transgender people may avoid seeking medical care due to previous negative experiences and fear of discrimination. Clinical laboratories can contribute to a poor patient experience and clinical outcome when the design and functionality of laboratory information management systems (LIMS) do not consider the needs of transgender patients. This survey aimed to capture current practices in United Kingdom and Republic of Ireland clinical laboratories concerning how transgender patient data and test requests are managed throughout the total testing process. METHODS: An anonymous survey was distributed to clinical laboratory professionals in November 2021. Thirty-three questions covered how gender variables are recorded for transgender patients and used to inform gender-specific calculations, test access, and reference intervals (RIs). RESULTS: Of the 66 respondents, 70% were based in laboratories in England, with a majority of laboratories having ISO 15189 accreditation and processing 1000-10,000 blood samples daily. Eighty-five percent stated that their LIMS had a single field recording sex or gender information. Forty-three percent did not limit test access based on gender, but 68% did not append RIs for patients with unknown or indeterminate gender. CONCLUSIONS: This survey was the first to quantify how clinical laboratories manage sex and gender information and report results for transgender and non-binary patients, and details several key recommendations based on the survey responses.

Challenges of providing biochemistry results in a patient with Evans syndrome.

A case report of in vivo hemolysis in a female patient with Evans syndrome is described. The patient was admitted with anemia and jaundice and, during her 26-day hospital admission, had 83 samples taken for biochemistry analyses. The laboratory hemolytic index (HI) was frequently elevated due to persistent complement-mediated in vivo hemolysis despite multiple lines of therapy. Initially, the release of many biochemical parameters was blocked per the manufacturer´s recommendations and reported as "sample hemolyzed". The patient developed severe acute kidney injury, ultimately requiring dialysis. Automated and timely reporting of indicative creatinine and other biochemical results in the context of ongoing hemolysis, therefore, became essential to patient care. Following a review of literature from various sources, a laboratory algorithm was designed to ensure the timely release of numerical biochemical values, where possible, with appropriate interpretative comments appended. Biochemistry, hematology, and nephrology teams were in regular communication to ensure patient samples were rapidly identified, analyzed and validated according to the algorithm, informing timely, safe and appropriate patient care. Ultimately, the patient died due to multiple disease- and treatment-related complications. In conjunction with clinical users, laboratories should plan for situations, such as in vivo hemolysis, where significant unavoidable interferences in biochemistry methodologies may occur in an ongoing manner for certain patients. Reporting categorical or best-estimate biochemistry results in such cases can be safer for patients than failing to report any results. Interpretation of these results by clinical teams requires input from appropriately trained and qualified laboratory personnel.

Prenatal maternal cortisol, stress and anxiety, and childhood obesity at 5 years: a nested case-control study.

BACKGROUND: Paediatric obesity is a global public health issue. Prenatal maternal mental health is potentially implicated in the development of childhood obesity. This study examined associations between prenatal maternal cortisol, self-reported stress, anxiety and depression in the second trimester, and childhood overweight and obesity at 5 years of age. METHODS: A nested case-control study was conducted using data from the Irish prospective longitudinal birth cohort SCOPE BASELINE. Cases were children with overweight or obesity, operationalised as having a BMI z-score above +2 standard deviations. Controls were children with a BMI z-score between -0.5 and 0.5 standard deviations at 5 years of age. Two to one matching by sex was conducted. Thirty-eight cases and 83 sex-matched controls were included. Maternal serum cortisol concentration and self-reported stress, anxiety and depression were measured at 15 ± 1 and 20 ± 1 weeks gestation. Conditional logistic regression analyses were conducted to examine associations between prenatal maternal cortisol and self-reported stress, anxiety and depression, and childhood overweight and obesity. RESULTS: Despite some evidence for associations between anxiety and depression, and child BMI z-scores in univariate analyses, adjusted models indicated no associations between prenatal maternal stress (OR: 1.02, 95% CI: 0.94-1.12), anxiety (OR: 1.03, 95% CI: 0.97-1.09), depression (OR: 1.04, 95% CI: 0.91-1.19), or cortisol concentration (OR: 0.99, 95% CI: 0.99-1.00) and child BMI z-score. CONCLUSION: Our findings do not provide support for associations between foetal exposure during the second trimester of pregnancy and maternal cortisol, stress and anxiety, and childhood overweight or obesity at 5 years of age.

Instructions on appropriate fasting prior to phlebotomy; effects on patient awareness, preparation, and biochemical parameters.

OBJECTIVES: This study investigated the effect of appropriate pre-phlebotomy instructions on patients' awareness of the need to fast, their fasting status at phlebotomy, and the measurement of specific biochemical analytes and indices. METHODS: While booking their phlebotomy appointments, two-hundred outpatients, with a wide range of pre-existing medical conditions, were recruited and randomly assigned to either control or intervention groups. The control group received no instructions while the intervention group was verbally instructed to fast for precisely 12 h prior to their appointment. Serum samples were collected from participants to quantify common biochemical analytes and serum indices, some of which were known to be influenced by fasting status, such as triglyceride and the lipaemic index. At the same appointment, participants completed a survey assessing their perception of, and adherence to, fasting requirements. RESULTS: In the intervention group, 99% responded that they had fasted before phlebotomy vs. 16% of controls. Subjects stated they fasted for 12 h in 51% of the intervention group and 7% of the controls. Median concentrations for potassium and total bilirubin were statistically, but not clinically, significantly different. In the study, a single patient in the intervention group was found to have a lipaemic sample. CONCLUSIONS: Without instruction, it appears few patients will fast appropriately prior to blood collection. This study suggests that most patients recall and adhere to verbal instructions regarding fasting. Though many in the control group stated they did not fast, triglyceride concentration and lipaemia were not significantly different from the intervention group, and biochemical analyses appear unaffected by fasting status.

A survey of practice in the management of haemolysis, icterus and lipaemia in blood specimens in the United Kingdom and Republic of Ireland.

BACKGROUND: Haemolysis, icterus and lipaemia (HIL) are common interferants in laboratory medicine, potentially impacting patient care. This survey investigates HIL management in medical laboratories across the UK and Republic of Ireland (ROI). METHODS: A survey was sent to members of key professional organisations for laboratory medicine in the UK and ROI. Questions related to the detection, monitoring, quality control, and management of HIL. RESULTS: In total, responses from 124 laboratories were analysed, predominantly from England (52%) and ROI (36%). Most responses were from public hospitals with biochemistry services (90%), serving primary care (91%), inpatients (91%), and outpatients (89%). Most laboratories monitored H (98%), I (88%), and L (96%) using automated indices (93%), alone or in combination with visual inspection.Manufacturer-stated cut-offs were used by 83% and were applied to general chemistries in 79%, and immunoassays in 50%. Where HIL cut-offs are breached, 64% withheld results, while 96% reported interference to users. HIL were defined using numeric scales (70%) and ordinal scales (26%). HIL targets exist in 35% of laboratories, and 54% have attempted to reduce HIL. Internal Quality Control for HIL was lacking in 62% of laboratories, and just 18% of respondents have participated in External Quality Assurance. Laboratories agree manufacturers should: standardise HIL reporting (94%), ensure comparability between platforms (94%), and provide information on HIL cross-reactivity (99%). Respondents (99%) showed interest in evidence-based, standardised HIL cut-offs. CONCLUSIONS: Most respondents monitor HIL, although the wide variation in practice may differentially affect clinical care. Laboratories seem receptive to education and advice on HIL management.

The CRESS checklist for reporting stability studies: on behalf of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for the Preanalytical Phase (WG-PRE).

To ensure that clinical laboratories produce results that are both accurate and of clinical utility it is essential that only samples of adequate quality are analysed. Although various studies and databases assessing the stability of analytes in different settings do exist, guidance on how to perform and report stability studies is lacking. This results in studies that often do not report essential information, thus compromising transferability of the data. The aim of this manuscript is to describe the Checklist for Reporting Stability Studies (CRESS) against which future studies should be reported to ensure standardisation of reporting and easy assessment of transferability of studies to other healthcare settings. The EFLM WG-PRE (European Federation of Clinical Chemistry and Laboratory Medicine Working Group for the Preanalytical Phase) produced the CRESS checklist following a detailed literature review and extensive discussions resulting in consensus agreement. The checklist consists of 20 items covering all the aspects that should be considered when producing a report on a stability study including details of what should be included for each item and a rationale as to why. Adherence to the CRESS checklist will ensure that studies are reported in a transparent and replicable way. This will allow other laboratories to assess whether published data meet the stability criteria required in their own particular healthcare scenario. The EFLM WG-PRE encourage researchers and authors to use the CRESS checklist as a guide to planning stability studies and to produce standardised reporting of future stability studies.

Case report of a phantom pheochromocytoma.

Plasma free metanephrines or urinary fractionated metanephrines are the biochemical tests of choice for the diagnosis of pheochromocytoma as they have greater sensitivity and specificity than catecholamines for pheochromocytoma detection. This case highlights the preanalytical factors which can influence metanephrine measurement and cause a false positive result. It describes a patient with a high pre-test probability of pheochromocytoma due to hypertension and a past medical history of adrenalectomy for a purported pheochromocytoma in her home country. When biochemical screening revealed grossly elevated urine normetanephrine in the presence of a previously identified right adrenal lesion, there was high clinical suspicion of a pheochromocytoma. However, functional imaging did not support this view which prompted additional testing with plasma metanephrines. Results for plasma and urine metanephrines were discordant and preanalytical drug interference was suspected. Patient medications were reviewed and sulfasalazine, an anti-inflammatory drug was identified as the most likely analytical interferent. Urinary fractionated metanephrines were re-analysed using liquid chromatography tandem mass spectrometry (LC-MS/MS) and all metanephrines were within their reference intervals. This case illustrates how method-specific analytical drug interference prompted unnecessary expensive imaging, heightened patient anxiety and resulted in lengthy investigations for what turned out to be a phantom pheochromocytoma.

COVID-19 in adults: test menu for hospital blood science laboratories.

INTRODUCTION: Coronavirus disease 2019 (COVID-19), is a respiratory illness caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Clinical Blood Sciences Laboratory (CBSL) plays a key role in supporting the monitoring and management of patients with COVID-19 disease. OBJECTIVE: To provide a comprehensive CBSL testing protocol to support the medical management of SARS-CoV-2 infection. METHODS: Description of the biochemical, haematological and immunological tests that have a role in the assessment and monitoring of patients with COVID-19 infection. RESULTS: We provide a test menu for clinical laboratories to ensure the effective monitoring, management and prognostication of COVID-19 patients in hospital. CONCLUSION: Given the rapidity with which patients with COVID-19 disease can deteriorate, we recommend regular testing with vigilance paid to the rate and trajectory of change in each of these parameters.

Case report of spuriously low sodium and calcium in a 36-year-old male in primary care.

An unseparated serum specimen for a 36-year-old male was received from primary care. The specimen arrived in the laboratory at Cork University Hospital one day after collection, as documented on the paper request card, and was promptly centrifuged. Analysis was delayed for three days due to operational constraints and serum indices were run at the same time as the biochemical analyses. Results showed a moderately haemolysed specimen with remarkably low concentrations of both sodium (119 mmol/L) and total calcium (1.15 mmol/L), with all other parameters within their appropriate reference intervals (RIs). The complete report was released electronically and both sodium and calcium results were phoned to, and acknowledged by, the requesting general practitioner (GP). Discussion between the medical scientists and clinical biochemist on duty raised the possibility that the specimen was significantly older than initially thought. Further discussion of results with the GP clarified that the documented time of collection corresponded with specimen receipt by the courier, rather than the time of phlebotomy. Thus, the specimen was 7 days old when received in the laboratory and 10 days old when analysed. This case illustrates the dangers of multiple convergent preanalytical errors. Laboratories should be mindful of the stability of analytes in unseparated blood and unusual patterns of results which might suggest a specimen is "old", and that this may coexist with erroneous request information. Any potential adverse effects on patient care were prevented in this case by laboratory vigilance.

Managing hemolyzed samples in clinical laboratories.

Hemolysis is conventionally defined as membrane disruption of red blood cells and other blood cells that is accompanied by subsequent release of intracellular components into the serum or plasma. It accounts for over 60% of blood sample rejections in the laboratory and is the most common preanalytical error in laboratory medicine. Hemolysis can occur both in vivo and in vitro. Intravascular hemolysis (in vivo) is always associated with an underlying pathological condition or disease, and thus careful steps should always be taken by the laboratory to exclude in vivo hemolysis with confidence. In vitro hemolysis, on the other hand, is highly preventable. It may occur at all stages of the preanalytical phase (i.e. sample collection, transport, handling and storage), and may lead to clinically relevant, yet spurious, changes in patient results by interfering with laboratory measurements. Hemolysis interference is exerted through several mechanisms: (1) spectrophotometric interference, (2) release of intracellular components, (3) sample dilution and (4) chemical interference. The degree of interference observed depends on the level of hemolysis and also on the assay methodology. Recent evidence shows that preanalytical practices related to detection and management of hemolyzed samples are highly heterogeneous and need to be standardized. The Working Group for Preanalytical Phase (WG-PRE) of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) has published many recommendations for facilitating standardization and improvement of this important preanalytical issue. Some key EFLM WG-PRE publications related to hemolysis involve: (i) a call for more transparency and some practical recommendations for improving the harmonization of the automatic assessment of serum indices and their clinical usefulness, specifically the hemolysis index (H-index), (ii) recommendations on how to manage local quality assurance of serum or plasma hemolysis/icterus/lipemia-indices (HIL-indices) and (iii) recommendations on how to detect and manage hemolyzed samples in clinical chemistry testing. In this review we provide a comprehensive overview of hemolysis, including its causes and effects on clinical laboratory assays. Furthermore, we list and discuss the most recent recommendations aimed at managing hemolyzed samples in everyday practice. Given the high prevalence of hemolyzed blood samples, the associated costs, the great heterogeneity in how hemolysis is handled across healthcare settings, countries and continents, and increasing patient cross-border mobility, standardization and quality improvement processes aimed at combatting this important preanalytical problem are clearly warranted.

Method for measurement of serum copper, zinc and selenium using total reflection X-ray fluorescence spectroscopy on the PICOFOX analyser: Validation and comparison with atomic absorption spectroscopy and inductively coupled plasma mass spectrometry.

BACKGROUND: Total reflection X-ray fluorescence is a comparably new method for the measurement of trace elements in biological samples. METHODS: Results obtained by total reflection X-ray fluorescence were compared to atomic absorption spectroscopy for Cu and Zn and inductively coupled plasma mass spectrometry for Cu, Zn and Se in patient serum. The total reflection X-ray fluorescence assay was characterized for accuracy; recovery; intra- and inter-assay imprecision (using patients' samples, external quality assurance and quality control materials); limit of blank; limit of detection; linearity; interference and stability of prepared samples. RESULTS: Minimal sample preparation is required for total reflection X-ray fluorescence and simultaneous multi-elemental analysis is possible in clinical samples. There was a small positive bias for Cu and Zn measurements using total reflection X-ray fluorescence compared to atomic absorption spectroscopy and inductively coupled plasma mass spectrometry and a significant negative bias for Se measurements by total reflection X-ray fluorescence relative to inductively coupled plasma mass spectrometry. Recovery, imprecision and linearity were acceptable. The limit of detection was shown to be 1.2 µmol/L for serum Cu, 1.8 µmol/L for serum Zn and 0.2 µmol/L for serum Se. CONCLUSIONS: Measurement of Cu and Zn in serum samples using total reflection X-ray fluorescence would be a viable alternative to atomic absorption spectroscopy or inductively coupled plasma mass spectrometry. The volatility of some Se compounds results in lower Se results being reported using total reflection X-ray fluorescence and further work would be necessary to identify whether total reflection X-ray fluorescence has an acceptable clinical sensitivity and specificity for the assessment of Se deficiency. Measurement of copper, zinc and selenium on whole blood samples is possible using total reflection X-ray fluorescence which may provide a more accurate assessment of trace element deficiency for patients with an acute phase response.

Preanalytical errors in medical laboratories: a review of the available methodologies of data collection and analysis.

Preanalytical errors have previously been shown to contribute a significant proportion of errors in laboratory processes and contribute to a number of patient safety risks. Accreditation against ISO 15189:2012 requires that laboratory Quality Management Systems consider the impact of preanalytical processes in areas such as the identification and control of non-conformances, continual improvement, internal audit and quality indicators. Previous studies have shown that there is a wide variation in the definition, repertoire and collection methods for preanalytical quality indicators. The International Federation of Clinical Chemistry Working Group on Laboratory Errors and Patient Safety has defined a number of quality indicators for the preanalytical stage, and the adoption of harmonized definitions will support interlaboratory comparisons and continual improvement. There are a variety of data collection methods, including audit, manual recording processes, incident reporting mechanisms and laboratory information systems. Quality management processes such as benchmarking, statistical process control, Pareto analysis and failure mode and effect analysis can be used to review data and should be incorporated into clinical governance mechanisms. In this paper, The Association for Clinical Biochemistry and Laboratory Medicine PreAnalytical Specialist Interest Group review the various data collection methods available. Our recommendation is the use of the laboratory information management systems as a recording mechanism for preanalytical errors as this provides the easiest and most standardized mechanism of data capture.

A Metabolic Study of Huntington's Disease.

BACKGROUND: Huntington's disease patients have a number of peripheral manifestations suggestive of metabolic and endocrine abnormalities. We, therefore, investigated a number of metabolic factors in a 24-hour study of Huntington's disease gene carriers (premanifest and moderate stage II/III) and controls. METHODS: Control (n = 15), premanifest (n = 14) and stage II/III (n = 13) participants were studied with blood sampling over a 24-hour period. A battery of clinical tests including neurological rating and function scales were performed. Visceral and subcutaneous adipose distribution was measured using magnetic resonance imaging. We quantified fasting baseline concentrations of glucose, insulin, cholesterol, triglycerides, lipoprotein (a), fatty acids, amino acids, lactate and osteokines. Leptin and ghrelin were quantified in fasting samples and after a standardised meal. We assessed glucose, insulin, growth hormone and cortisol concentrations during a prolonged oral glucose tolerance test. RESULTS: We found no highly significant differences in carbohydrate, protein or lipid metabolism markers between healthy controls, premanifest and stage II/III Huntington's disease subjects. For some markers (osteoprotegerin, tyrosine, lysine, phenylalanine and arginine) there is a suggestion (p values between 0.02 and 0.05) that levels are higher in patients with premanifest HD, but not moderate HD. However, given the large number of statistical tests performed interpretation of these findings must be cautious. CONCLUSIONS: Contrary to previous studies that showed altered levels of metabolic markers in patients with Huntington's disease, our study did not demonstrate convincing evidence of abnormalities in any of the markers examined. Our analyses were restricted to Huntington's disease patients not taking neuroleptics, anti-depressants or other medication affecting metabolic pathways. Even with the modest sample sizes studied, the lack of highly significant results, despite many being tested, suggests that the majority of these markers do not differ markedly by disease status.

Monitoring and reporting of preanalytical errors in laboratory medicine: the UK situation.

BACKGROUND: Most errors in the clinical laboratory occur in the preanalytical phase. This study aimed to comprehensively describe the prevalence and nature of preanalytical quality monitoring practices in UK clinical laboratories. METHODS: A survey was sent on behalf of the Association for Clinical Biochemistry and Laboratory Medicine Preanalytical Working Group (ACB-WG-PA) to all heads of department of clinical laboratories in the UK. The survey captured data on the analytical platform and Laboratory Information Management System in use; which preanalytical errors were recorded and how they were classified and gauged interest in an external quality assurance scheme for preanalytical errors. RESULTS: Of the 157 laboratories asked to participate, responses were received from 104 (66.2%). Laboratory error rates were recorded per number of specimens, rather than per number of requests in 51% of respondents. Aside from serum indices for haemolysis, icterus and lipaemia, which were measured in 80% of laboratories, the most common errors recorded were booking-in errors (70.1%) and sample mislabelling (56.9%) in laboratories who record preanalytical errors. Of the laboratories surveyed, 95.9% expressed an interest in guidance on recording preanalytical error and 91.8% expressed interest in an external quality assurance scheme. CONCLUSIONS: This survey observes a wide variation in the definition, repertoire and collection methods for preanalytical errors in the UK. Data indicate there is a lot of interest in improving preanalytical data collection. The ACB-WG-PA aims to produce guidance and support for laboratories to standardize preanalytical data collection and to help establish and validate an external quality assurance scheme for interlaboratory comparison.

A 24-Hour Study of the Hypothalamo-Pituitary Axes in Huntington's Disease.

BACKGROUND: Huntington's disease is an inherited neurodegenerative disorder characterised by motor, cognitive and psychiatric disturbances. Patients exhibit other symptoms including sleep and mood disturbances, muscle atrophy and weight loss which may be linked to hypothalamic pathology and dysfunction of hypothalamo-pituitary axes. METHODS: We studied neuroendocrine profiles of corticotropic, somatotropic and gonadotropic hypothalamo-pituitary axes hormones over a 24-hour period in controlled environment in 15 healthy controls, 14 premanifest and 13 stage II/III Huntington's disease subjects. We also quantified fasting levels of vasopressin, oestradiol, testosterone, dehydroepiandrosterone sulphate, thyroid stimulating hormone, free triiodothyronine, free total thyroxine, prolactin, adrenaline and noradrenaline. Somatotropic axis hormones, growth hormone releasing hormone, insulin-like growth factor-1 and insulin-like factor binding protein-3 were quantified at 06:00 (fasting), 15:00 and 23:00. A battery of clinical tests, including neurological rating and function scales were performed. RESULTS: 24-hour concentrations of adrenocorticotropic hormone, cortisol, luteinizing hormone and follicle-stimulating hormone did not differ significantly between the Huntington's disease group and controls. Daytime growth hormone secretion was similar in control and Huntington's disease subjects. Stage II/III Huntington's disease subjects had lower concentration of post-sleep growth hormone pulse and higher insulin-like growth factor-1:growth hormone ratio which did not reach significance. In Huntington's disease subjects, baseline levels of hypothalamo-pituitary axis hormones measured did not significantly differ from those of healthy controls. CONCLUSIONS: The relatively small subject group means that the study may not detect subtle perturbations in hormone concentrations. A targeted study of the somatotropic axis in larger cohorts may be warranted. However, the lack of significant results despite many variables being tested does imply that the majority of them do not differ substantially between HD and controls.

Hepascore and hyaluronic acid as markers of fibrosis in liver disease of mixed aetiology.

OBJECTIVE: To evaluate hyaluronic acid (HA) and Hepascore as diagnostic replacements for liver biopsy in a population with mixed liver disease. MATERIALS AND METHODS: The utility of HA concentration and Hepascore for staging fibrosis, detecting any fibrosis and detecting advanced fibrosis, was assessed in 73 consecutive patients, with varied liver pathologies requiring biopsy. Subgroup analyses compared utility of disease-specific and universal cut-offs for HA and Hepascore. RESULTS: Forty-one patients (56.2%) had liver fibrosis on biopsy. HA and Hepascore varied significantly with METAVIR stage, although ranges overlapped, precluding their use in staging fibrosis. When detecting any fibrosis (METAVIR F1-F4), HA and Hepascore had areas under the receiver operator characteristic curve of 0.63 and 0.66, respectively, and approximately two-thirds of patients were correctly categorized using optimal cut-offs. For detection of advanced fibrosis (METAVIR F3/4), HA and Hepascore had areas under the receiver operator characteristic curve of 0.81 and 0.80, respectively, and three-quarters of patients were correctly categorized using optimal cut-offs. In subgroup analysis, locally derived, disease-specific cut-offs in hepatitis C virus patients yielded greatest diagnostic efficiency, whereas the tests performed worst in cryptogenic aetiologies. CONCLUSION: HA and Hepascore cannot accurately stage hepatic fibrosis in this population. Locally derived, disease-specific cut-offs for HA gave the higher diagnostic efficiency observed. Although HA and Hepascore may be useful where the disease aetiology is known, particularly in established hepatitis C virus, the high cost of false positives and false negatives are such that neither a reliable enough to replace biopsy without substantial further characterization.

Gene-targeted analysis of copy number variants identifies 3 novel associations with coronary heart disease traits.

BACKGROUND: Copy number variants (CNVs) are a major form of genomic variation, which may be implicated in complex disease phenotypes. However, investigation of the role of CNVs in coronary heart disease (CHD) traits has been limited. METHODS AND RESULTS: We examined the use of the cnvHap algorithm for CNV detection, using data for 2500 men from the Second Northwick Park Heart Study (NPHS-II). An Illumina custom chip, including 722 single-nucleotide polymorphisms covering 76 coronary heart disease-trait genes, was used. Common CNVs were significantly associated (at P<0.05, after correction) with coronary heart disease phenotypes in 5 genes. Novel associations of CNVs in toll-like receptor-4 with apolipoprotein AI were replicated (P<0.05) in the Whitehall II cohort (4887 subjects), whereas newly described associations of CNVs in sterol regulatory element-binding protein with apolipoprotein AI and associations of interleukin-6 signal transducer with apolipoprotein B were replicated in the data from 3546 subjects from the North Finnish Birth Cohort 1966 (P<0.05). CONCLUSIONS: This study supports the use of CNV detection algorithms such as cnvHap as potential tools for the identification of novel CNVs, some of which show significant association and replication with coronary heart disease risk phenotypes. However, the functional basis for these associations requires further substantiation.