The statistical analysis plan for the unification of treatments and interventions for tinnitus patients randomized clinical trial (UNITI-RCT).

BACKGROUND: Tinnitus is a leading cause of disease burden globally. Several therapeutic strategies are recommended in guidelines for the reduction of tinnitus distress; however, little is known about the potentially increased effectiveness of a combination of treatments and personalized treatments for each tinnitus patient. METHODS: Within the Unification of Treatments and Interventions for Tinnitus Patients project, a multicenter, randomized clinical trial is conducted with the aim to compare the effectiveness of single treatments and combined treatments on tinnitus distress (UNITI-RCT). Five different tinnitus centers across Europe aim to treat chronic tinnitus patients with either cognitive behavioral therapy, sound therapy, structured counseling, or hearing aids alone, or with a combination of two of these treatments, resulting in four treatment arms with single treatment and six treatment arms with combinational treatment. This statistical analysis plan describes the statistical methods to be deployed in the UNITI-RCT. DISCUSSION: The UNITI-RCT trial will provide important evidence about whether a combination of treatments is superior to a single treatment alone in the management of chronic tinnitus patients. This pre-specified statistical analysis plan details the methodology for the analysis of the UNITI trial results. TRIAL REGISTRATION: ClinicalTrials.gov NCT04663828 . The trial is ongoing. Date of registration: December 11, 2020. All patients that finished their treatment before 19 December 2022 are included in the main RCT analysis.

Unification of Treatments and Interventions for Tinnitus Patients (UNITI): a study protocol for a multi-center randomized clinical trial.

BACKGROUND: Tinnitus represents a relatively common condition in the global population accompanied by various comorbidities and severe burden in many cases. Nevertheless, there is currently no general treatment or cure, presumable due to the heterogeneity of tinnitus with its wide variety of etiologies and tinnitus phenotypes. Hence, most treatment studies merely demonstrated improvement in a subgroup of tinnitus patients. The majority of studies are characterized by small sample sizes, unstandardized treatments and assessments, or applications of interventions targeting only a single organ level. Combinatory treatment approaches, potentially targeting multiple systems as well as treatment personalization, might provide remedy and enhance treatment responses. The aim of the present study is to systematically examine established tinnitus therapies both alone and in combination in a large sample of tinnitus patients. Further, it wants to provide the basis for personalized treatment approaches by evaluating a specific decision support system developed as part of an EU-funded collaborative project (Unification of treatments and interventions for tinnitus patients; UNITI project). METHODS/STUDY DESIGN: This is a multi-center parallel-arm randomized clinical trial conducted at five different clinical sites over the EU. The effect of four different tinnitus therapy approaches (sound therapy, structured counseling, hearing aids, cognitive behavioral therapy) applied over a time period of 12 weeks as a single or rather a combinatory treatment in a total number of 500 chronic tinnitus patients will be investigated. Assessments and interventions are harmonized over the involved clinical sites. The primary outcome measure focuses on the domain tinnitus distress assessed via the Tinnitus Handicap Inventory. DISCUSSION: Results and conclusions from the current study might not only provide an essential contribution to combinatory and personalized treatment approaches in tinnitus but could also provide more profound insights in the heterogeneity of tinnitus, representing an important step towards a cure for tinnitus. TRIAL REGISTRATION: ClinicalTrials.gov NCT04663828 . Registered on 11 December 2020.

Increased prevalence of human papillomavirus in hairs plucked from patients with psoriasis treated with psoralen-UV-A.

BACKGROUND: Patients with psoriasis treated with psoralen-UV-A (PUVA) are at increased risk of skin cancer; however, the exact causes of this increased incidence are not well understood. It has been suggested that PUVA may increase expression of the tumorigenic agent human papillomavirus (HPV) in skin by directly stimulating virus replication, immune suppression, or both, thereby leading to skin cancer formation. OBJECTIVE: To determine whether HPV DNA prevalence in the skin is increased after long-term PUVA treatment. DESIGN: Screening for the presence of HPV sequences in DNA isolated from plucked body hairs of patients with psoriasis with a history of PUVA exposure and a history of skin cancer (group A), PUVA exposure and no history of skin cancer (group B), and no PUVA exposure and no history of skin cancer (group C). SETTING: University hospital. PATIENTS AND METHODS: Hair samples were obtained from 81 patients with psoriasis (56 men and 25 women; mean age, 52 years), including 16 in group A (mean number of PUVA exposures, 702), 35 in group B (mean number of PUVA exposures, 282), and 30 in group C. DNA was isolated from the hair samples and analyzed by polymerase chain reaction with the use of 2 nested primer systems specific for epidermodysplasia verruciformis-associated or related and genital or mucosal virus types, respectively. RESULTS: The rate of HPV DNA positivity was significantly higher in groups A (73% [11/15]) and B (69% [24/35]) than in group C (36% [10/28]) (A + B vs C, P =.009; chi(2) test; age adjusted). Conclusion The prevalence of HPV in the skin (hair follicles) is increased in patients with psoriasis who have a history of PUVA exposure.

Evidence for the association of human papillomavirus infection and cutaneous squamous cell carcinoma in immunocompetent individuals.

OBJECTIVE: The aim of our study was to evaluate human papillomavirus (HPV) infection as a risk factor for cutaneous squamous cell carcinoma (SCC) in immunocompetent individuals. DESIGN: Hospital-based case-control study. SETTING: Referral center for dermatologic diseases for central and southern Italy. PARTICIPANTS: Consecutive patients with histologically confirmed cutaneous SCC (n = 46) and control subjects (n = 84) chosen by frequency matching (age and sex) among patients admitted with unrelated diseases. MAIN OUTCOME MEASURE: Infection with epidermodysplasia verruciformis-related HPV types, blindly assessed by serologic testing (viruslike particle enzyme-linked immunosorbent assay). Information was obtained on known potentially confounding risk factors (family history, history and signs of sun exposure, and pigmentary traits) and on history of HPV-related lesions and diseases, assessed by interview and examination by a dermatologist. RESULTS: Positive serologic findings for HPV type 8 were associated with SCC (odds ratio, 3.2; 95% confidence interval, 1.3-7.9) independently of other risk factors, whereas positive serologic findings for HPV type 15 were negatively associated with SCC (odds ratio, 0.4; 95% confidence interval, 0.2-0.9). Other variables significantly associated with the tumor were family history of skin cancer, professional or recreational sun exposure, light eye color, high number of solar keratoses and seborrheic keratoses on the body surface, and residency in radon-emitting buildings. CONCLUSIONS: Positive serologic findings for HPV type 8 are associated with SCC occurrence in immunocompetent individuals. Viral infection could act as a cofactor in the tumor development, along with genetic predisposition, solar radiation, and other environmental exposures. If confirmed, these findings could open new perspectives for treatment and prevention of SCC.

Natural cell-mediated cytotoxicity of peripheral blood lymphocytes against target cells transfected with epidermodysplasia verruciformis-specific human papillomavirus type 8 L1 DNA sequences.

The aim of the present study was to characterise natural cell-mediated cytotoxicity against COS-7 cells transfected with potentially oncogenic HPV-8 L1 DNA sequences cloned in sense and antisense orientation and to evaluate their lysis by peripheral blood lymphocytes (PBL) from patients with epidermodysplasia verruciformis (EV), a rare disease associated with life-long infection by specific HPV types. COS-7 cells were transfected with HPV-8 Hinc II restriction fragment (nucleotide positions 5434-7654) cloned in sense (COS-L1S) and antisense (COS-L1A) orientation into pCB6 expression vector. Cytotoxic activity of isolated PBL against COS cell lines as well as K562 erythroleukaemic cells was evaluated by 51Cr-release assay. We found that lymphocytes responsible for natural lysis of COS and K562 cells are CD3-negative CD56-positive natural killer (NK) cells. Analysis of NK cell cytotoxic activity against different COS cell lines has revealed that lymphocytes from healthy subjects killed COS-L1S cells significantly more efficiently than wild COS-7 and COS-L1A cells. Significantly more efficient lysis of COS-L1S cells was also observed in EV patients. Thus, expression of HPV L1 renders target cells more susceptible to NK-mediated cytotoxicity that may enable more effective elimination of transformed cells.

Cortisol in hair and the metabolic syndrome.

CONTEXT: Although exposure to supraphysiological levels of glucocorticoids is known to contribute to the development of the metabolic syndrome (MetS), the importance of physiological variation in basal cortisol secretion is less clear. This issue can be addressed by using hair cortisol analysis, which for the first time allows the assessment of long-term integrated hormone levels. OBJECTIVE AND DESIGN: We used the analysis of cortisol in hair (hairF) to examine associations of long-term cortisol levels with prevalence of MetS and individual cardiometabolic parameters in a large occupational cohort. In additional exploratory analyses, we also studied cardiometabolic associations with hair cortisone levels. PARTICIPANTS: Participants included 1258 employees of a large aerospace company (aged 16-64 years; 84.8% males) who partook in a voluntary health assessment. MAIN OUTCOME MEASURES: The first 3 cm of scalp-near hair were analyzed for glucocorticoid concentrations using liquid chromatography tandem mass spectrometry. Relevant cardiometabolic risk factors were assessed and MetS was diagnosed (according to 2009 international task force criteria). RESULTS: A higher prevalence of MetS was seen in individuals falling into the third (odds ratio 1.71, 95% confidence interval 1.08-2.69) or fourth hairF quartile (odds ratio 2.42, 95% confidence interval 1.55-3.75) compared with the first quartile, in fully adjusted analyses. HairF also showed positive associations with weight-related anthropometric measures (body mass index, waist to hip ratio, waist circumference) and glycated hemoglobin. The exploratory analysis of hair cortisone also indicated relevant associations with cardiometabolic parameters. CONCLUSION: Normal physiological differences in long-term cortisol secretion, as assessed in hair, show relevant relationships with MetS and individual cardiometabolic parameters.