The usability of daytime and night-time heart rate dynamics as digital biomarkers of depression severity.

BACKGROUND: Alterations in heart rate (HR) may provide new information about physiological signatures of depression severity. This 2-year study in individuals with a history of recurrent major depressive disorder (MDD) explored the intra-individual variations in HR parameters and their relationship with depression severity. METHODS: Data from 510 participants (Number of observations of the HR parameters = 6666) were collected from three centres in the Netherlands, Spain, and the UK, as a part of the remote assessment of disease and relapse-MDD study. We analysed the relationship between depression severity, assessed every 2 weeks with the Patient Health Questionnaire-8, with HR parameters in the week before the assessment, such as HR features during all day, resting periods during the day and at night, and activity periods during the day evaluated with a wrist-worn Fitbit device. Linear mixed models were used with random intercepts for participants and countries. Covariates included in the models were age, sex, BMI, smoking and alcohol consumption, antidepressant use and co-morbidities with other medical health conditions. RESULTS: Decreases in HR variation during resting periods during the day were related with an increased severity of depression both in univariate and multivariate analyses. Mean HR during resting at night was higher in participants with more severe depressive symptoms. CONCLUSIONS: Our findings demonstrate that alterations in resting HR during all day and night are associated with depression severity. These findings may provide an early warning of worsening depression symptoms which could allow clinicians to take responsive treatment measures promptly.

Patient preferences for key drivers and facilitators of adoption of mHealth technology to manage depression: A discrete choice experiment.

BACKGROUND: In time, we may be able to detect the early onset of symptoms of depression and even predict relapse using behavioural data gathered through mobile technologies. However, barriers to adoption exist and understanding the importance of these factors to users is vital to ensure maximum adoption. METHOD: In a discrete choice experiment, people with a history of depression (N = 171) were asked to select their preferred technology from a series of vignettes containing four characteristics: privacy, clinical support, established benefit and device accuracy (i.e., ability to detect symptoms), with different levels. Mixed logit models were used to establish what was most likely to affect adoption. Sub-group analyses explored effects of age, gender, education, technology acceptance and familiarity, and nationality. RESULTS: Higher level of privacy, greater clinical support, increased perceived benefit and better device accuracy were important. Accuracy was the most important, with only modest compromises willing to be made to increase other factors such as privacy. Established benefit was the least valued of the attributes with participants happy with technology that had possible but unknown benefits. Preferences were moderated by technology acceptance, age, nationality, and educational background. CONCLUSION: For people with a history of depression, adoption of technology may be driven by the desire for accurate detection of symptoms. However, people with lower technology acceptance and educational attainment, those who were younger, and specific nationalities may be willing to compromise on some accuracy for more privacy and clinical support. These preferences should help shape design of mHealth tools.

Predictors of engagement with remote sensing technologies for symptom measurement in Major Depressive Disorder.

BACKGROUND: Remote sensing for the measurement and management of long-term conditions such as Major Depressive Disorder (MDD) is becoming more prevalent. User-engagement is essential to yield any benefits. We tested three hypotheses examining associations between clinical characteristics, perceptions of remote sensing, and objective user engagement metrics. METHODS: The Remote Assessment of Disease and Relapse - Major Depressive Disorder (RADAR-MDD) study is a multicentre longitudinal observational cohort study in people with recurrent MDD. Participants wore a FitBit and completed app-based assessments every two weeks for a median of 18 months. Multivariable random effects regression models pooling data across timepoints were used to examine associations between variables. RESULTS: A total of 547 participants (87.8% of the total sample) were included in the current analysis. Higher levels of anxiety were associated with lower levels of perceived technology ease of use; increased functional disability was associated with small differences in perceptions of technology usefulness and usability. Participants who reported higher system ease of use, usefulness, and acceptability subsequently completed more app-based questionnaires and tended to wear their FitBit activity tracker for longer. All effect sizes were small and unlikely to be of practical significance. LIMITATIONS: Symptoms of depression, anxiety, functional disability, and perceptions of system usability are measured at the same time. These therefore represent cross-sectional associations rather than predictions of future perceptions. CONCLUSIONS: These findings suggest that perceived usability and actual use of remote measurement technologies in people with MDD are robust across differences in severity of depression, anxiety, and functional impairment.

Gender differences in adolescents with suicidal behaviour: Personality and psychopathology / Diferencias de género en adolescentes con conducta suicida: Personalidad y psicopatología

This study evaluates the relationship between gender, personality, psychopathology and suicidal behaviour among adolescents. For this purpose, across-sectional study with adolescent inpatients (N = 92) displaying suicidal behaviour was designed. Sociodemographic characteristics and datarelated to suicidal behaviour were collected. In addition, personality and clinical severity were assessed by administering the Millon Adolescent Clinical Inventory (MACI). Results revealed that the most prevalent personality dimensions for both genders were Introversive, Self-demeaning, Doleful,Oppositional, Borderline tendency and Inhibited. However, men scored higher in Inhibited (p = 0.02, Cohen’s d = 0.45) and women in Egotistic(p = 0.03, Cohen’s d = 0.40). Concerning clinical severity of syndromes, women scored higher in Delinquent Predisposition (p = 0.04, Cohen’sd = 0.45) and men in Anxious Feelings (p = 0.02, Cohen’s d = 0.51), Depressive Affect (p = 0.04, Cohen’s d = 0.41) and Suicidal Tendency (p= 0.03, Cohen’s d = 0.37), with men reporting more frequently Childhood Abuse (p < 0.001, Cohen’s d= 0.70). Results highlight the importanceof universal interventions to promote a change in attitudes towards seeking psychological help, specially in men, and the need to designeffective tailored treatments to acquire emotional management skills for both genders. (AU)

Este estudio evalúa la relación entre el género, lapersonalidad, la psicopatología y la conducta suicida entre los adolescentes. Para ello, se diseñó un estudio transversal con adolescentes hospitalizados (N = 92) que presentaban conductas suicidas. Se recogieron características sociodemográficas y datos relacionados con la conductasuicida. Además, se evaluó la personalidad y la gravedad clínica mediante la administración del Inventario Clínico de Adolescentes de Millon (MACI).Los resultados revelaron que las dimensiones de personalidad más prevalentes para ambos géneros fueron Introversivo, Auto-punitivo, Pesimista,Oposicionista, Tendencia límite e Inhibido. Sin embargo, los hombres puntuaron más alto en Inhibido (p = 0,02, d de Cohen = 0,45) y las mujeresen Egocéntrica (p = 0,03, d de Cohen = 0,40). En cuanto a la gravedad clínica de los síndromes, las mujeres puntuaron más alto en PredisposiciónDelictiva (p = 0,04, d de Cohen = 0,45) y los hombres en Sentimientos Ansiosos (p = 0,02, d de Cohen = 0. 51), Afecto Depresivo (p = 0,04, dde Cohen = 0,41) y Tendencia Suicida (p = 0,03, d de Cohen = 0,37), y los hombres informaron con mayor frecuencia de Abuso en la Infancia(p < 0,001, d de Cohen = 0,70). Los resultados ponen de manifiesto la importancia de las intervenciones universales para promover un cambiode actitud hacia la búsqueda de ayuda psicológica, especialmente en los hombres, y la necesidad de diseñar tratamientos eficaces a medidapara adquirir habilidades de gestión emocional para ambos géneros. (AU)

Sonographic analysis of the ankle in patients with psoriatic arthritis.

Foot involvement is very frequent in patients affected by psoriatic arthritis (PsA). However, evaluation of the painful foot can be problematic, because it is often difficult to distinguish between arthritis, tenosynovitis, and enthesopathy. Plain radiographs can show bone erosion or other features of joint involvement, but give little information about the soft tissues. We therefore studied foot involvement in 31 PsA patients using high resolution sonography, and compared the results with the findings on x-ray and clinical examination. Ultrasound revealed pathological findings in a large proportion of the patients, most of whom exhibited no clinical (pain or swelling) or radiological signs of foot involvement at the time of the study. Our data suggest that involvement of the tendons and entheses may be more frequent in PsA patients than has thus far been supposed, even in cases of not particularly aggressive disease, and that clinical evaluation tends to underestimate these manifestations.

Hepatitis C virus infection: prevalence in psoriasis and psoriatic arthritis.

OBJECTIVE: To study the prevalence of hepatitis C virus (HCV) infection in 2 groups of patients, one group with psoriasis and the other with psoriatic arthritis (PsA). METHODS: We detected anti-HCV antibodies by ELISA and by a recombinant immunoblot assay (RIBA) in the sera of 50 patients with psoriasis and 50 with PsA. As controls we used a group of 76 patients with rheumatoid arthritis (RA), and referred to data on the prevalence of HCV in the general Italian population. RESULTS: By ELISA, anti-HCV antibodies were detected in 6/50 (12%) patients with PsA, in 5/50 (10%) patients with psoriasis, and in 4/76 (5.2%) patients with RA. All the reactive PsA and RA sera also tested positive on RIBA, while only 3 of the 5 positive results for sera of patients with psoriasis were confirmed by RIBA. The prevalence of HCV infection in patients with psoriasis was not significantly higher than in controls. In contrast, the rate of HCV infection observed in the 50 patients with PsA was higher than that in the other groups, the difference being statistically significant between patients with PsA and the general population. CONCLUSION: Our data do not support the hypothesis that HCV infection may play a role in the pathogenesis of psoriasis. On the other hand they show a statistically significant difference between the prevalence of HCV infection in patients with PsA and the general population.

Immune response to an epitope of the NS4 protein of hepatitis C virus in HCV-related disorders.

NS4, a nonstructural protein of HCV, is a frequent target of antibodies in infected subjects. According to recent data, the antibodies frequently recognize the sequence 1921-40 of the NS4 protein. The aim of this work was to analyze antibody reactivity with the sequence 1921-40 in different HCV-related disorders. Although this sequence is located in a relatively invariant region of viral genome, two strain-specific sequences are described. Thus, three NS4 1921-1940 peptides were synthesized: the BK shared by most viral strains, the J6 (strain 2a), and the J8 (strain 2b). The peptides were used as antigens in the solid phase for measuring serum IgG antibodies in an ELISA assay. Antibodies reactive with the 1921-40 BK peptide were detected in 64% of sera from patients with autoimmune hepatitis (AIH), 51% from chronic hepatitis C (CHC), and 22% from mixed cryoglobulinemia (MC). The frequency of positive sera in MC was significatively lower than in AIH (P < 0.0001) or CHC (P < 0.0021). Similar results were obtained with the J6 and J8 peptides. All sera that did not react with the BK peptide were negative on J6 and J8 and conversely most sera reacting with the BK peptide also bound the J6 and the J8 peptides. No correlation was found between the genotype of the infecting virus and the presence of antibodies to any of the NS4 peptides. These results indicate that many HCV-infected subjects produce antibodies to the NS4 sequence 1921-40. The immune response to this sequence is not strain specific and varies with the different disorders associated with HCV infection.

Interstitial lung fibrosis and rheumatic disorders in patients with hepatitis C virus infection.

A possible aetiopathogenetic role of hepatitis C virus (HCV) has been reported in various immune-mediated disorders, such as mixed cryoglobulinaemia, which may be complicated by interstitial lung involvement; moreover, different viruses, including HCV, have been correlated with idiopathic pulmonary fibrosis. Here, a cohort of eight HCV-positive patients (M/F = 4/4, mean age 61 +/- 8 S.D. yr) with interstitial lung fibrosis and a variable number of rheumatic disorders are described. Interstitial lung involvement appeared medially 4.5 +/- 3.2 S.D. yr after the clinical onset of chronic hepatitis. During the clinical follow-up, some rheumatic symptoms were also recorded: articular involvement (four patients): mild sicca syndrome (one patient); severe polymyositis and cranial neuropathy (one patient); serum cryoglobulins and/or autoantibodies (eight patients). In all patients, a moderate (four patients) or severe (four patients) lung fibrosis was evaluated by means of high-resolution computed tomography. The presence of parenchymal radiotracer uptake on 67Ga scan (7/7 patients) and increased percentages of neutrophils (4/4 patients) and lymphocytes (2/4) at bronchoalveolar lavage suggested an active lung involvement. Different degrees of reduction of single breath diffusing capacity for carbon monoxide (DLco) (mean value 57.6 +/- 15%, range 37-80) were observed in all cases, while spirometric abnormalities, consistent with a global restrictive pattern, were less frequently found. In all cases, anti-HCV antibodies and HCV viraemia were demonstrated: viral genome was also detected in peripheral lymphocytes from 4/4 subjects and in one case in lung biopsy specimens. A desquamative interstitial pneumonia pattern was demonstrated in two cases by lung biopsy. The present work supports the hypothesis that HCV chronic infection could represent a trigger factor for interstitial lung fibrosis and various rheumatic disorders.

Psoriatic arthritis with spinal involvement in a patient receiving alpha-interferon for chronic hepatitis C.

A 26-year-old male patient being treated with alpha-interferon for chronic hepatitis C developed psoriasis, seronegative oligoarthritis and sacroiliitis after four months. The close temporal relationship between the alpha-interferon therapy and the onset of skin and articular lesions strongly suggests that the drug played a role in the induction of the disease despite the absence of HLA antigens related to psoriatic arthritis. We cannot exclude the possibility that immunological alterations associated with HCV infection could have constituted a predisposing factor in the onset of the disease.

Lymphotropic virus infection of peripheral blood mononuclear cells in B-cell non-Hodgkin's lymphoma.

Some lymphotropic viruses such as Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have been proposed as causative agents of B cell non-Hodgkin's lymphoma (NHL). More recently, the presence of hepatitis C virus (HCV), which is both a hepatotropic and lymphotropic virus, has been reported in one third of B cell NHL patients. The aim of this study was to investigate in a series of B cell NHL the prevalence of three lymphotropic viruses, i.e. EBV, HHV-6 and HCV, in peripheral blood mononuclear cells (PBMC). Eighteen unselected B cell NHL patients (10 men, 8 women; mean age 62 +/- 12 years, range 31-77 years; mean disease duration 1.8 +/- 1.4 years) and 40 age- and sex-matched healthy controls were included in the study. In all cases, an acquired-immunodeficiency-syndrome-related lymphoma was excluded. By means of the polymerase chain reaction technique, EBV DNA, HHV-6 DNA and HCV RNA were detected in PBMC. HCV genomic sequences were significantly more frequent in PBMC of NHL patients than in controls (33 vs. 2.5%; p < 0.01); on the other hand, in the same two groups EBV DNA (39 vs. 60%; p = not significant) and HHV-6 DNA (22 vs. 32%; p = not significant) were present in a comparable percentage of individuals in the same two groups. The infection of PBMC by HCV alone was present in the majority (5 of 6) of HCV-positive NHL. These data support the implication of HCV infection in a statistically significant number of B cell NHL, whereas a possible co-operation between HCV and other well-known lymphotropic viruses seems to be excluded.

Exacerbation of peripheral neuropathy during alpha-interferon therapy in a patient with mixed cryoglobulinemia and hepatitis B virus infection.

An association between hepatotropic viruses, chiefly hepatitis C virus (HCV), occasionally hepatitis B virus (HBV), and mixed cryoglobulinemia has been widely reported. Alpha-interferon (IFN-alpha) has usefully been employed in the treatment of mixed cryoglobulinemia, particularly for liver and renal involvement. IFN-alpha treatment may be associated with neurological complications, including peripheral neuropathy. We describe an HBV positive patient with mixed cryoglobulinemia with recurrent purpura, mild sensory peripheral neuropathy, and active hepatitis treated with IFN-alpha. Rapid improvement of the purpura, liver enzymes, and cryocrit, and disappearance of serum HBV DNA were observed after a 4 week treatment period. However, concomitant worsening of the neuropathy prompted us to discontinue IFN-alpha. Although in this case, a positive effect of IFN-alpha on the clinico-serological and virological variables was confirmed, due to the possible exacerbation of neurological manifestations, a careful patient evaluation is necessary before starting IFN-alpha in patients with mixed cryoglobulinemia.

Chronic hepatitis C and B-cell non-Hodgkin's lymphoma.

Hepatitis C virus (HCV), a hepatotropic and lymphotropic virus, is the major causative agent of nonA-nonB chronic hepatitis; moreover, it is frequently associated with benign and malignant lymphoproliferative disorders such as mixed cryoglobulinaemia and B-cell non-Hodgkin's lymphoma (NHL). We investigated the clinical and virological features of B-cell NHL complicating chronic hepatitis C in a series of 10 patients (M/F 1/9; mean age 63 +/- 6SD years). The malignancy appeared after median 8 +/- 4SD years from onset and was low-grade in six patients, intermediate in three, and high-grade in one. 'One-tube nested' PCR detected serum HCV RNA and viral ongoing replication in both fresh and cultured peripheral lymphocytes in all ten. Analysis of HCV genotypes showed a relatively higher prevalence of 2a/III type compared with unselected chronic hepatitis C (50% vs. 15%). In one patient, HCV RNA was also found in the neoplastic bone marrow and lymph-node specimens. B-cell NHL can complicate chronic hepatitis C and affect the overall prognosis of the disease. The increasing frequency of chronic hepatitis C worldwide suggests that the actual prevalence of this complication may be underestimated. Careful clinical work-up at diagnosis and during follow-up is particularly recommendable.

Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia.

OBJECTIVE: To investigate the possible role of HCV variants in the pathogenesis of mixed cryoglobulinemia. SETTING: Medical service (rheumatology and hepatology units) of urban, university-affiliated teaching hospitals. DESIGN: Analysis of viral genotypes in a cohort of patients with hepatitis C virus (HCV) infection and mixed cryoglobulinemia. PATIENTS: 90 unselected HCV-positive (anti-HCV antibody-positive and HCV RNA-positive) patients consecutively recruited at routine ambulatory visits: 29 with and 61 without (control group) mixed cryoglobulinemia. MEASUREMENTS: Clinical and histologic data; HCV RNA detection in serum and peripheral blood mononuclear cells by polymerase chain reaction (PCR); HCV genotype determination by two methods based on genotype-specific primer PCR and genotype-specific probe hybridization, respectively. RESULTS: Persistent aminotransferase increases were found in 55% of patients with mixed cryoglobulinemia. Peripheral blood mononuclear cells were infected in 80% of cases. In serum samples, HCV genotype 2a/III was detected with a higher prevalence in patients with mixed cryoglobulinemia than in controls (41% compared with 15%). The overall prevalence of genotype 2a/III in mixed cryoglobulinemia increased to 52% when findings in peripheral blood mononuclear cells were also considered. Among patients with mixed cryoglobulinemia, this genotype was more frequent in those without clinical and biochemical signs of liver disease (85%) or with serum autoantibodies (75%). CONCLUSIONS: Mixed cryoglobulinemia may be related, at least in part, to the HCV genotype infecting the host.

Etiopathogenetic role of hepatitis C virus in mixed cryoglobulinemia, chronic liver diseases and lymphomas.

Hepatitis C virus (HCV) infection has been found in the majority of patients with mixed cryoglobulinemia (MC) in studies conducted in different countries. In our series of 110 MC patients the frequency of HCV markers was significantly high (91%) compared with other rheumatic diseases (6.4%) and with healthy Italian controls (1.2%). Moreover, HCV RNA was detected in 81% of the peripheral lymphocytes from MC patients. Comparable percentages of HCV infection were detectable in other disorders, i.e. porphyria cutanea tarda (77%) and autoimmune hepatitis type 1 (77%). The HCV infection of peripheral lymphocytes suggests that this virus could be the triggering factor for the lymphoproliferation underlying MC. In a number of patients with MC the evolution from a benign lymphoproliferation to frank B-cell lymphoma was observed. In these subjects HCV RNA in the sera and in fresh and cultured peripheral lymphocytes was constantly detected. The same phenomenon has been observed in patients with long-lasting type C chronic hepatitis. Interestingly, HCV infection has also been recorded in 32% of idiopathic B-cell non-Hodgkin's lymphomas. Taken together, the above findings suggest that HCV can cause benign B-cell proliferation with the consequent production of various autoantibodies, including rheumatoid factor and mixed cryoglobulins. These serological abnormalities characterise different clinical disorders, including the appearance of lymphoma in a not negligible number of individuals.

Guidelines for the management of essential mixed cryoglobulinemia.

The principal therapeutic procedures and when they are clinically indicated in the management of essential mixed cryoglobulinemia (EMC) have been the subject of much debate. This paper reviews current knowledge and our experience in the treatment of this complex disease. It is generally agreed that patients with purpura, the primary symptom of EMC, should avoid long periods of sitting or standing in the same position. Non-steroidal antiinflammatory drugs can be used for the management of arthralgias and/ or arthritis. Low dose steroids (0.5-0.3 mg/kg/die) are usually sufficient to control the purpura, arthralgias, arthritis and weakness, while larger doses (0.5-1.5 mg/kg/die) are needed to treat the renal involvement, peripheral neuropathy and serositis. Since the discovery of the association between EMC and viral infections, the appropriateness of cytotoxic drugs has been re-evaluated and they are no longer used. With the low antigen content diet, a regimen designed to restore a saturated mononuclear phagocytic system, good results have been obtained in the treatment of purpura, arthralgias, weakness and peripheral neuropathy. Furthermore, this dietary regimen may play a steroid sparing role. Plasma exchange is widely used in the management of severe renal involvement, hyperviscosity syndrome, sensory motor neuropathy and liver involvement in EMC.

Inner ear involvement in mixed cryoglobulinaemia patients.

In order to evaluate the nature and prevalence of audiovestibular disturbances in mixed cryoglobulinaemia (MC), 32 consecutive MC patients were studied by a wide audiological and vestibular examination. Pure tone audiometry, impedance audiometry, brainstem response audiometry and vestibular function were performed. Patients with a previous history of ear damage due to other well-known agents were excluded from the study. In MC patients we found a rather frequent audiovestibular involvement (34.3%). Bilateral sensorineural hearing loss was found in seven MC patients (22%) and altered vestibular function test values in other seven subjects (22%). Moreover, anamnestic and clinical data revealed a high incidence of benign positional paroxysmal vertigo in our MC series. We can suppose that immune complex-mediated microvascular involvement of the labyrinthine vessels may be responsible for inner ear damage in MC. Thus, audiovestibular disturbances may be included among various organ involvement of the MC.

Hepatitis C virus infection in patients with non-Hodgkin's lymphoma.

Hepatitis C virus (HCV), which is both a hepatotropic and a lymphotropic virus, has been proposed as a possible causative agent of mixed cryoglobulinaemia. This 'benign' lymphoproliferative disorder can switch over to a malignant B-cell non-Hodgkin's lymphoma (NHL). Therefore HCV infection has been investigated in a series of 50 unselected Italian patients with B-cell NHL. Antibodies against HCV were found in 30% of NHL and HCV viraemia in 32% of cases. HCV-related markers were detected in 34% (17/50) of our NHL patients; this prevalence is particularly significant when compared with HCV seropositivity in Hodgkin's lymphoma (3%) and healthy controls (1.3%).