Psychobiological stress response to a lung cancer diagnosis: a prospective study of patients in Iceland and Sweden.

BACKGROUND: A diagnostic work-up leading to a lung cancer diagnosis is a severely stressful experience that may impact tumor progression. Yet, prospective data are scarce on psychological and biological components of stress at the time of lung cancer diagnosis. The aim of this study was to assess pre-to-post diagnosis change in psychological distress and urinary excretion of catecholamines in patients with suspected lung cancer. METHODS: Participants were 167 patients within the LUCASS study, recruited at referral for suspected lung cancer to University Hospitals in Iceland and Sweden. Patients completed questionnaires on perceived distress (Hospital Anxiety and Depression Scale, HADS) before and after diagnosis of lung cancer or a non-malignant origin. A subpopulation of 85 patients also provided overnight urine for catecholamine analysis before and at a median of 24 days after diagnosis but before treatment. RESULTS: A lung cancer diagnosis was confirmed in 123 (73.7%) patients, with a mean age of 70.1 years. Patients diagnosed with lung cancer experienced a post-diagnosis increase in psychological distress (p = 0.010), while patients with non-malignant lung pathology showed a reduction in distress (p = 0.070). Both urinary epinephrine (p = 0.001) and norepinephrine (p = 0.032) levels were higher before the diagnosis among patients eventually diagnosed with lung cancer compared to those with non-malignant lung pathology. We observed indications of associations between pre-to-post diagnosis changes in perceived distress and changes in urinary catecholamine levels. CONCLUSION: Receiving a lung cancer diagnosis is associated with an increase in psychological distress, while elevated catecholamine levels are evident already before lung cancer diagnosis.

Age, Sex, Body Mass Index, Diet and Menopause Related Metabolites in a Large Homogeneous Alpine Cohort.

Metabolomics in human serum samples provide a snapshot of the current metabolic state of an individuum. Metabolite concentrations are influenced by both genetic and environmental factors. Concentrations of certain metabolites can further depend on age, sex, menopause, and diet of study participants. A better understanding of these relationships is pivotal for the planning of metabolomics studies involving human subjects and interpretation of their results. We generated one of the largest single-site targeted metabolomics data sets consisting of 175 quantified metabolites in 6872 study participants. We identified metabolites significantly associated with age, sex, body mass index, diet, and menopausal status. While most of our results agree with previous large-scale studies, we also found novel associations including serotonin as a sex and BMI-related metabolite and sarcosine and C2 carnitine showing significantly higher concentrations in post-menopausal women. Finally, we observed strong associations between higher consumption of food items and certain metabolites, mostly phosphatidylcholines and lysophosphatidylcholines. Most, and the strongest, relationships were found for habitual meat intake while no significant relationships were found for most fruits, vegetables, and grain products. Summarizing, our results reconfirm findings from previous population-based studies on an independent cohort. Together, these findings will ultimately enable the consolidation of sets of metabolites which are related to age, sex, BMI, and menopause as well as to participants' diet.

Effects of a Brief Transdiagnostic Cognitive Behavioural Group Therapy on Disorder Specific Symptoms.

BACKGROUND: In recent years, cognitive behavioural group therapies (CBGT) have been increasingly deployed as a strategy to increase the efficiency and cost-effectiveness in treatment of common mental health problems. The vast majority of these therapies are disorder specific, but in the last few years there has been growing interest in transdiagnostic CBGT. AIMS: The aim of this study was twofold: to evaluate the treatment effects of transdiagnostic CBGT on disorder specific symptoms and what (if any) differences would be observed in the treatment effects with regard to general as opposed to disorder specific symptoms measured pre- and post-treatment. METHOD: The participants were 233 adult patients diagnosed with depression and/or anxiety disorders. They underwent a 6-week transdiagnostic CBGT. To compare treatment effects on general and disorder specific symptoms, raw scores on all measures were converted to standardized scores. RESULTS: Pre-post differences were significant and there was no evidence that treatment was differentially effective for general and disorder specific symptoms. Effect sizes ranged from medium to large. CONCLUSION: The 6-week transdiagnostic CBGT is feasible for a wide range of mood and anxiety disorders. The results indicate that low-intensity transdiagnostic group therapies may have similar effects on both general and disorder specific symptoms.

Influence of collection tubes during quantitative targeted metabolomics studies in human blood samples.

BACKGROUND: Plasma and serum are the most widely used matrices in clinical studies. However, some variability in absolute concentrations of metabolites are likely to be observed in these collection tubes matrices. METHODS: We analyzed 189 metabolites using the same protocol for quantitative targeted metabolomics (LC-MS/MS AbsoluteIDQ p180 Kit Biocrates) in three types of samples, serum, plasma EDTA and citrate, of 80 subjects from the Cooperative Health Research In South Tyrol cohort (40 healthy elderly and 40 healthy young). RESULTS: The concentration levels were higher in serum than citrate and EDTA, in particular for amino acids and biogenic amines. The average Pearson's correlation coefficients were however always higher than 0.7 for these two classes of metabolites. We could also demonstrate that blank EDTA vacutainer tubes contain a significant amount of sarcosine. Finally, we compared the metabolome of young people against elderly subjects and found that the highest number of metabolites significantly changing with age was detected in serum. CONCLUSION: Serum samples provide higher sensitivity for biomarker discovery studies. Due to the presence of spurious amount of sarcosine in vacutainer EDTA tubes, plasma EDTA is not suitable for studies requiring accurate quantification of sarcosine.

Pre-analytic evaluation of volumetric absorptive microsampling and integration in a mass spectrometry-based metabolomics workflow.

Volumetric absorptive microsampling (VAMS) is a novel approach that allows single-drop (10 µL) blood collection. Integration of VAMS with mass spectrometry (MS)-based untargeted metabolomics is an attractive solution for both human and animal studies. However, to boost the use of VAMS in metabolomics, key pre-analytical questions need to be addressed. Therefore, in this work, we integrated VAMS in a MS-based untargeted metabolomics workflow and investigated pre-analytical strategies such as sample extraction procedures and metabolome stability at different storage conditions. We first evaluated the best extraction procedure for the polar metabolome and found that the highest number and amount of metabolites were recovered upon extraction with acetonitrile/water (70:30). In contrast, basic conditions (pH 9) resulted in divergent metabolite profiles mainly resulting from the extraction of intracellular metabolites originating from red blood cells. In addition, the prolonged storage of blood samples at room temperature caused significant changes in metabolome composition, but once the VAMS devices were stored at - 80 °C, the metabolome remained stable for up to 6 months. The time used for drying the sample did also affect the metabolome. In fact, some metabolites were rapidly degraded or accumulated in the sample during the first 48 h at room temperature, indicating that a longer drying step will significantly change the concentration in the sample. Graphical abstract Volumetric absorptive microsampling (VAMS) is a novel technology that allows single-drop blood collection and, in combination with mass spectrometry (MS)-based untargeted metabolomics, represents an attractive solution for both human and animal studies. In this work, we integrated VAMS in a MS-based untargeted metabolomics workflow and investigated pre-analytical strategies such as sample extraction procedures and metabolome stability at different storage conditions. The latter revealed that prolonged storage of blood samples at room temperature caused significant changes in metabolome composition, but if VAMS devices were stored at - 80 °C, the metabolome remained stable for up to 6 months.

Quantitative UPLC-MS/MS assay of urinary 2,8-dihydroxyadenine for diagnosis and management of adenine phosphoribosyltransferase deficiency.

Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary disorder that leads to excessive urinary excretion of 2,8-dihydroxyadenine (DHA), causing nephrolithiasis and chronic kidney disease. Treatment with allopurinol or febuxostat reduces DHA production and attenuates the renal manifestations. Assessment of DHA crystalluria by urine microscopy is used for therapeutic monitoring, but lacks sensitivity. We report a high-throughput assay based on ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) for quantification of urinary DHA. The UPLC-MS/MS assay was optimized by a chemometric approach for absolute quantification of DHA, utilizing isotopically labeled DHA as an internal standard. Experimental screening was conducted with D-optimal design and optimization of the DHA response was performed with central composite face design and related to the peak area of DHA using partial least square regression. Acceptable precision and accuracy of the DHA concentration were obtained over a calibration range of 100 to 5000ng/mL on three different days. The intra- and inter-day accuracy and precision coefficients of variation were well within ±15% for quality control samples analyzed in replicates of six at three concentration levels. Absolute quantification of DHA in urine samples from patients with APRT deficiency was achieved wihtin 6.5min. Measurement of DHA in 24h urine samples from three patients with APRT deficiency, diluted 1:15 (v/v) with 10mM ammonium hydroxide (NH4OH), yielded a concentration of 3021, 5860 and 10563ng/mL and 24h excretion of 816, 1327 and 1649mg, respectively. A rapid and robust UPLC-MS/MS assay for absolute quantification of DHA in urine was successfully developed. We believe this method will greatly facilitate diagnosis and management of patients with APRT deficiency.

Transdiagnostic cognitive behavioural treatment and the impact of co-morbidity: An open trial in a cohort of primary care patients.

BACKGROUND: The development of initiatives to improve access to psychological therapies has been driven by the realization that untreated anxiety and depression are both very common and costly to individuals as well as society. Effective and efficient treatments, mostly in the form of cognitive behavioural therapies (CBT), can be used in ways which enhance their acceptability and accessibility. To date, numbers of group therapies have been developed to improve cost efficiency, but in spite of growing interest in transdiagnostic approaches, group therapies have so far mostly been diagnosis specific. AIMS: This study is aimed at evaluating a brief transdiagnostic cognitive behavioural group therapy (TCBGT) designed to treat both anxiety and depression among patients in primary care. METHOD: The participants were 287 adult patients in primary care with diagnoses of depression and/or anxiety disorders. They underwent a 5-week TCBGT. A mixed design ANOVA was used to evaluate differential effects of treatment according to diagnostic groups (anxiety versus depression) and number of diagnoses (co-morbidity). RESULTS: Pre-post differences were significant and the treatment was equally effective for both anxiety disorders and depression. Number of diagnoses did not affect the outcome. CONCLUSIONS: The study indicates feasibility of the brief transdiagnostic group therapy for a wide range of mood and anxiety disorders in primary care. The results indicate that low intensity, brief transdiagnostic group therapies may be a feasible way to improve access to psychological therapies for a large number of patients.

Evaluation of the psychometric properties of the Icelandic version of the Clinical Outcomes in Routine Evaluation-Outcome Measure, its transdiagnostic utility and cross-cultural validation.

BACKGROUND: The development of transdiagnostic standardized measures of psychological distress have contributed to the development of practice-based evidence networks. The translation and validation of such measures cross culturally is important if such research is to be generalized across health care systems in different countries. METHOD: Translation of the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) from English into Icelandic was undertaken according to recommended protocols. The resulting instrument was evaluated for reliability and validity in three groups: patients undergoing psychological treatment in general practice (n = 289), psychiatric outpatients (n = 98) and student controls (n = 207). The Mini-International Neuropsychiatric Interview was administered to the clinical participants. They also completed the CORE-OM and the Beck depression and anxiety inventories before and after treatment. The transdiagnostic relationship between CORE-OM scores and scores on those diagnostic measures was assessed. RESULTS: Good levels of validity, reliability and internal consistency were found for the CORE-OM and its domains and sensitivity to change over treatment shown. As anticipated, the risk domain had different characteristics than other domains. CORE-OM scores correlated strongly with both Beck Depression Inventory-Second edition and Beck Anxiety Inventory, particularly the problem domain. CONCLUSION: The Icelandic translation of the CORE-OM is psychometrically sound and can be applied in Icelandic mental health studies as it has been in English speaking settings. Nevertheless, the validity of the Icelandic version of the CORE-OM needs to be further investigated in larger and more diverse samples. KEY PRACTITIONER MESSAGE: The psychometric properties of the Icelandic version of the CORE-OM are comparable with the original English version. The results indicate transdiagnostic utility of the CORE-OM. The CORE-OM is a valuable instrument in outcome research on psychological treatment, specifically transdiagnostic treatment.

Phonological development in relation to native language and literacy: variations on a theme in six alphabetic orthographies.

Phonological development was assessed in six alphabetic orthographies (English, French, Greek, Icelandic, Portuguese and Spanish) at the beginning and end of the first year of reading instruction. The aim was to explore contrasting theoretical views regarding: the question of the availability of phonology at the outset of learning to read (Study 1); the influence of orthographic depth on the pace of phonological development during the transition to literacy (Study 2); and the impact of literacy instruction (Study 3). Results from 242 children did not reveal a consistent sequence of development as performance varied according to task demands and language. Phonics instruction appeared more influential than orthographic depth in the emergence of an early meta-phonological capacity to manipulate phonemes, and preliminary indications were that cross-linguistic variation was associated with speech rhythm more than factors such as syllable complexity. The implications of the outcome for current models of phonological development are discussed.

Cyclodextrin solubilization of carbonic anhydrase inhibitor drugs: formulation of dorzolamide eye drop microparticle suspension.

Topically applied carbonic anhydrase inhibitors (CAIs) are commonly used to treat glaucoma. However, their short duration of action requiring multiple daily dosing can hamper patient compliance. The aim of this study was to develop novel aqueous CAI eye drop formulation containing self-assembled drug/cyclodextrin (D/CD) microparticles that enhance and prolong drug delivery to the eye. Phase-solubility of each drug tested (i.e. methazolamide, brinzolamide and dorzolamide HCl) was determined in either pure water or an aqueous eye drop medium. The pH was adjusted to maximize the fraction of unionized drug. Dorzolamide had the highest affinity for γ-cyclodextrin (γCD) and, thus, was selected for further investigation. Hydroxypropyl methylcellulose (HPMC) was the most effective polymer tested for stabilization of the dorzolamide/γCD complexes and gave the highest mucoadhesion at 0.5% w/v concentration. Thus, the dorzolamide eye drop vehicle containing γCD (18% w/v) and HPMC (0.5% w/v) was developed. The physicochemical properties of this formulation complied with the specifications of the eye drop suspension monograph of the European Pharmacopoeia. The in vivo testing of the formulation showed that the drug was delivered to the aqueous humor in rabbits for at least 24h with the maximum drug concentration at 4h. Furthermore, this formulation delivered the drug to the posterior segment of the eye after topical administration. These results indicate that this CAI eye drop formulation has the potential of being developed into a once-a-day product.

Orthography as a handicap? A direct comparison of spelling acquisition in Danish and Icelandic.

Spelling of cross-linguistically very similar nonwords was compared in 115 Danish and 77 Icelandic children (primarily 3rd and 4th graders). Danish children made more errors than Icelandic children on word medial consonant doublets and on word initial consonant clusters, even when the groups compared were matched on simpler spelling tasks. These results suggest that the acquisition of phonemic encoding skills is slower in "deep" orthography such as Danish than in more "transparent" orthography such as Icelandic. The effect of orthography was expected for consonant doublets because of the relatively more complex sound-letter correspondences in Danish. For consonant clusters, however, sound-letter correspondences are perfectly regular in both languages. The study thus points to the conclusion that even the mastery of regular sound-letter correspondences may be delayed in deep orthography.