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.

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.

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.

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.

Isolation of very virulent pathotypes of Marek's disease virus from vaccinated chickens in Europe.

Two very virulent strains of Marek's disease virus were isolated from two separate farms in northern Italy that had experienced outbreaks of Marek's disease in vaccinated flocks. The isolates were similar to very virulent strains reported in the USA in terms of their enhanced pathogenicity, both for chickens vaccinated with the herpesvirus of turkeys, and for genetically resistant chickens. This first description of very virulent strains of Marek's disease virus from outside the USA suggests that at least some of the increasingly frequent disease outbreaks reported in Europe may be associated with such strains and that the adoption of bivalent or polyvalent vaccines containing, for example, attenuated Marek's disease virus plus herpesvirus of turkeys may be beneficial in the field.

Carbon disulfide in blood: a method for storing and analysing samples.

Concentrations of free and acid-labile carbon disulfide in human blood were determined by gas chromatography mass-spectrometry. Carbon disulfide was measured in the blood of 62 subjects not occupationally exposed to the solvent, and in 27 subjects treated with disulfiram (which is partially biotransformed into carbon disulfide). In blood, a small part of carbon disulfide is free (it can be analysed without any blood treatment); most carbon disulfide is bound ("acid labile" carbon disulfide), and requires acid hydrolysis to become free and detectable. During the first phase of our study, stored samples of blood (storage at 4 degrees C for 15-40 days) were used. Later, we analysed fresh blood samples. A significant decrease in carbon disulfide was found in stored samples in comparison to fresh samples. During storage, free and acid-labile carbon disulfide in blood decreased respectively to 26% and 27% of the initial concentration within a month. In fresh samples, free carbon disulfide concentrations in blood showed a median of 139 ng/l in normal subjects. Acid-labile carbon disulfide concentrations were much higher (median 2743 ng/l). Free and acid-labile carbon disulfide in blood were closely correlated (r = 0.9358). Blood samples stored at -80 degrees C maintained a constant concentration of carbon disulfide over almost three weeks.

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.

Reference values for blood benzene in the occupationally unexposed general population.

Blood benzene was determined by gas chromatography-mass spectrometry in 431 "normal" subjects, subdivided into 155 rural subjects and 276 urban subjects. Blood benzene (mean value 262 ng/l) was significantly lower in rural (200 ng/l) than in urban (296 ng/l) workers, as well as differing significantly between 293 non-smokers and 138 smokers (205 ng/l and 381 ng/l, respectively). Among non-smokers, values were significantly higher (307 ng/l) in 76 chemical workers. In the total study population, in 95% of cases blood benzene was less than 718 ng/l, the 95th percentile being 514 ng/l in non-smokers vs 901 ng/l in smokers and 576 ng/l in rural vs 822 ng/l in urban subjects. Within each population subgroup, the difference between non-smokers and smokers was statistically significant, except among office workers (non-smokers 234 ng/l, smokers 304 ng/l). Blood benzene (y) was directly proportional to the number of cigarettes smoked (x) (y = 201 + 12x; r = 0.44; n = 431), and inversely proportional to the interval between the last cigarette and the time at which the blood samples was taken (z) (log y = 6.167-0.0015z; r = -0.461; n = 135). The blood half-life of benzene was about 8h. The multiple correlation between blood benzene (Cb), number of cigarettes per day (x) and time since the last cigarette (z) is: Cb = 417 + 7.2x - 0.41z (n = 135; R = 0.20; P less than 0.00001).

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.

Cryoglobulinemic membranoproliferative glomerulonephritis associated with hepatitis C virus.

A striking association between hepatitis C virus (HCV) and mixed cryoglobulinemia (MC) has been reported by various authors, regardless of the presence of chronic hepatitis. The aim of this study is to evaluate the prevalence of HCV-related markers in cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) which is one of the most severe complications of MC. Antibodies against HCV have been detected by second-generation Chiron ELISA and RIBA in 26/26 (100%) cryoglobulinemic MPGN. In addition, serum HCV RNA, expression of the ongoing viral replication, was present in 7/7 patients by the polymerase chain reaction technique. The high percentage of anti-HCV seropositivity suggests that this virus may play an important role in the pathogenesis of this immunemediated glomerulonephritis.

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.

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.

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.

Hepatitis C virus chronic infection as a common cause of mixed cryoglobulinaemia and autoimmune liver disease.

OBJECTIVES: Mixed cryoglobulinaemia (MC) and autoimmune chronic hepatitis (AI-CH) are frequently associated with hepatitis C virus (HCV) chronic infection. Because HCV represents a possible common aetiological factor, the aim of the present study is to investigate the clinico-serological alterations of both MC and AI-CH and to verify a possible overlap between these disorders. SETTING: Patients from three tertiary referral centres. SUBJECTS: Two Italian series of 88 MC patients and 30 AI-CH type 1 were studied. RESULTS: MC and AI-CH share several clinico-serological features. The patients' mean age (MC vs. AI-CH: 60 +/- 9 vs. 57 +/- 13 years), disease duration (10.5 +/- 5 vs. 9.6 +/- 6 years), and female/male ratio (3.4 vs. 3.3) were very similar in the two series. Typical hallmarks of MC, i.e. purpura, arthralgias, and weakness, circulating mixed cryoglobulins with rheumatoid factor activity, and hypocomplementemia were also recorded in a significant number of AI-CH patients. Similarly, chronic active hepatitis was found in 68% of MC patients and its histological and serological alterations were comparable with those of AI-CH; moreover, amongst various autoantibodies, antinuclear antibodies and/or anti-smooth-muscle antibodies were detected in half of the cases of MC. Anti-HCV antibodies, detected by second-generation Chiron ELISA and RIBA, were present in a high percentage of both MC and AI-CH (94 vs. 80%), and frequently associated with HCV viraemia (86 vs. 77%). Finally, anti-GOR, the HCV-related autoantibodies, were found in half cases of MC and AI-CH. CONCLUSIONS: On the whole, these data suggest that HCV in combination with other infectious and environmental and genetic factors can trigger a complex immunological disorder with different clinical patterns.