The safety assessment of tampons: illustration of a comprehensive approach for four different products.

Introduction: We illustrate a comprehensive tampon safety assessment approach that assures products can be used safely. Material biocompatibility, vaginal mucosa assessment, vaginal microbiome evaluation, and in vitro assessment of potential risk of staphylococcal toxic shock syndrome expressed through growth of Staphylococcus aureus (S. aureus) and production of TSST-1 are the four essential portions of the approach. Post-marketing surveillance informs of possible health effects that warrant follow up. The approach meets or exceeds US and international regulatory guidance and is described through the example of four tampon products. Methods/Results: Each product is comprised mostly of large molecular weight components (cotton, rayon, polymers) that cannot pass the vaginal mucosa, are widely used across the industry, and replete with a vast body of safety data and a long history of safe use in the category. Quantitative risk assessment of all small molecular weight components assured a sufficient margin of safety supporting their use. Vaginal mucosa assessment confirmed that pressure points, rough edges and/or sharp contact points were absent. A randomized cross-over clinical trial (ClinicalTrials.gov Identifier: NCT03478371) revealed favorable comfort ratings, and few complaints of irritation, burning, stinging, or discomfort upon insertion, wear, and removal. Adverse events were few, mild in severity, self-limited and resolved without treatment. Vaginal microbiota assessment in vitro presented no adverse effect on microbial growth. Culture-independent microbiome analyses from vaginal swab samples obtained during the clinical trial showed no differences attributable to tampon usage, but instead due to statistically significant subject-to-subject variability. Growth of S. aureus and TSST-1 toxin production in the presence of any of the four products in vitro were statistically significantly reduced when compared to medium control alone. Discussion: The data from the four elements of the comprehensive safety assessment approach illustrated herein confirm that tampons evaluated using this system can be used safely for menstrual protection. A post-marketing surveillance system that monitors and responds to in-market experiences indicated in-use tolerability of the product among consumers, thus confirming the conclusions of the pre-marketing safety assessment.

Safety assessment scheme for menstrual cups and application for the evaluation of a menstrual cup comprised of medical grade silicone.

BACKGROUND: Ensuring menstrual cup safety is paramount, yet a menstrual cup safety assessment scheme is lacking. This paper presents a quadripartite scheme, showing how it can be applied. METHODS: The Tampax Menstrual Cup was evaluated in the safety assessment scheme: (1) Biocompatibility and chemical safety of cup constituents. Extractables were obtained under different use condition; exposure-based risk assessments (EBRA) were conducted for extractables exceeding thresholds of toxicological concern. (2) Physical impact to vaginal mucosa. After physical evaluations, the Tampax Cup and another cup were assessed in a randomised double-blinded, two-product, two-period cross-over clinical trial (65 women, mean age 34.2 years). (3) Impact to vaginal microbiota (in vitro mixed microflora assay and evaluation of vaginal swabs). (4) In vitro growth of Staphylococcus aureus and toxic shock syndrome toxin-1 (TSST-1) production. FINDINGS: Biocompatibility assessments and EBRA of cup constituents showed no safety concerns. In the randomised clinical trial, all potentially product-related adverse effects were mild, vaginal exams were unremarkable, no clinically relevant pH changes occurred, post-void residual urine volume with and without cup were similar, and self-reported measures of comfort along with reports of burning, itching and stinging between cups were comparable. Cup use had no effect on microbial growth in vitro or in the 62 subjects who completed the trial or on in vitro TSST-1 production. INTERPRETATION: The quadripartite safety assessment scheme allows evaluation of menstrual cup safety. The Tampax Cup is safe and well-tolerated upon intended use. As with all feminine hygiene products, post-market safety surveillance confirmed this conclusion. FUNDING: By Procter & Gamble.

Decoding rumination: A machine learning approach to a transdiagnostic sample of outpatients with anxiety, mood and psychotic disorders.

OBJECTIVE: To employ machine learning algorithms to examine patterns of rumination from RDoC perspective and to determine which variables predict high levels of maladaptive rumination across a transdiagnostic sample. METHOD: Sample of 200 consecutive, consenting outpatient referrals with clinical diagnoses of schizophrenia, schizoaffective, bipolar, depression, anxiety disorders, obsessive compulsive and post-traumatic stress. Machine learning algorithms used a range of variables including sociodemographics, serum levels of immune markers (IL-6, IL-1ß, IL-10, TNF-α and CCL11) and BDNF, psychiatric symptoms and disorders, history of suicide and hospitalizations, functionality, medication use and comorbidities. RESULTS: The best model (with recursive feature elimination) included the following variables: socioeconomic status, illness severity, worry, generalized anxiety and depressive symptoms, and current diagnosis of panic disorder. Linear support vector machine learning differentiated individuals with high levels of rumination from those ones with low (AUC = 0.83, sensitivity = 75, specificity = 71). CONCLUSIONS: Rumination is known to be associated with poor prognosis in mental health. This study suggests that rumination is a maladaptive coping style associated not only with worry, distress and illness severity, but also with socioeconomic status. Also, rumination demonstrated a specific association with panic disorder.

Prospective cohort study of early biosignatures of response to lithium in bipolar-I-disorders: overview of the H2020-funded R-LiNK initiative.

BACKGROUND: Lithium is recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need. STRUCTURE: The H2020-funded Response to Lithium Network (R-LiNK; http://www.r-link.eu.com/ ) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including omics, neuroimaging, and actigraphy, etc. Individuals will be followed up for 24 months and an independent panel will assess and classify each participants' response to lithium according to predefined criteria that consider evidence of relapse, recurrence, remission, changes in illness activity or treatment failure (e.g. stopping lithium; new prescriptions of other mood stabilizers) and exposure to lithium. Novel elements of this study include the recruitment of a large, multinational, clinically representative sample specifically for the purpose of studying candidate biomarkers and biosignatures; the application of lithium-7 magnetic resonance imaging to explore the distribution of lithium in the brain; development of a digital phenotype (using actigraphy and ecological momentary assessment) to monitor daily variability in symptoms; and economic modelling of the cost-effectiveness of introducing biomarker tests for the customisation of lithium treatment into clinical practice. Also, study participants with sub-optimal medication adherence will be offered brief interventions (which can be delivered via a clinician or smartphone app) to enhance treatment engagement and to minimize confounding of lithium non-response with non-adherence. CONCLUSIONS: The paper outlines the rationale, design and methodology of the first study being undertaken by the newly established R-LiNK collaboration and describes how the project may help to refine the clinical response phenotype and could translate into the personalization of lithium treatment.

Rates of voluntary and compulsory psychiatric in-patient treatment in England: an ecological study investigating associations with deprivation and demographics.

BACKGROUND: Individual variables and area-level variables have been identified as explaining much of the variance in rates of compulsory in-patient treatment. AIMS: To describe rates of voluntary and compulsory psychiatric in-patient treatment in rural and urban settings in England, and to explore the associations with age, ethnicity and deprivation. METHOD: Secondary analysis of 2010/11 data from the Mental Health Minimum Dataset. RESULTS: Areas with higher levels of deprivation had increased rates of in-patient treatment. Areas with high proportions of adults aged 20-39 years had the highest rates of compulsory in-patient treatment as well as the lowest rates of voluntary in-patient treatment. Urban settings had higher rates of compulsory in-patient treatment and ethnic density was associated with compulsory treatment in these areas. After adjusting for age, deprivation and urban/rural setting, the association between ethnicity and compulsory treatment was not statistically significant. CONCLUSIONS: Age structure of the adult population and ethnic density along with higher levels of deprivation can account for the markedly higher rates of compulsory in-patient treatment in urban areas.

Youth Early-intervention Study (YES) - group interventions targeting social participation and physical well-being as an adjunct to treatment as usual: study protocol for a randomized controlled trial.

BACKGROUND: It is increasingly acknowledged that clinical interventions for young persons with mental disorders need to optimize social, vocational and physical functioning, and take into account developmental needs, rather than focusing only on the traditional target of psychiatric symptom change. However, few interventions for youth presenting to mental health services offer a coherent rationale for multi-faceted approaches that efficiently address all these targets. This trial uses two facilitated group therapy modules (social and physical activity) as a vehicle for promoting clinical, cognitive, social and vocational change. The modules are an adjunct to usual treatments offered to youth attending mental health services in Sydney, Australia. METHODS/DESIGN: The design is a 2-arm, parallel group cross-over, randomized clinical trial (RCT) that examines the efficacy of this adjunctive youth early intervention program (called "YES") for improving social, vocational, mental and physical health functioning in a trans-diagnostic sample of 120 young persons aged 14-25 years who are currently receiving a range of "usual treatments" for clinically diagnosed anxiety, affective and/or psychotic disorders. Individuals who provide written informed consent are offered 2 group therapy modules (each comprising 4 hours per week for 8 weeks) with a 3-week "pause" between modules. Randomization determines whether individuals commence with module A or module B. The sample will be assessed pre-randomization, and at week 1 and week 8 (after completion of the first module), and at week 11 (commencement of second module) and week 19 (completion of second module). Final follow-up is 1-year post trial entry. DISCUSSION: If the findings of this exploratory trial demonstrate benefits in the target domains, then it will be important to extend the research by undertaking: (a) a comparison of the YES program to a control intervention in a randomized controlled trial, (b) an explanatory study of putative mediators of change, and (c) a multi-center trial with a number of trained therapists offering the group modules combined with a longer follow-up period. TRIAL REGISTRATION: Australian New Zealand Controlled Trial Registration: ACTRN1262400175673 , Date: 16 July 2015.

Assessment of adherence problems in patients with serious and persistent mental illness: recommendations from the Expert Consensus Guidelines.

Poor adherence to medication treatment can have devastating consequences for patients with serious mental illness. The literature review and recommendations in this article concerning assessment of adherence are reprinted from The Expert Consensus Guideline Series: Adherence Problems in Patients with Serious and Persistent Mental Illness, published in 2009. The expert consensus survey contained 39 questions (521 options) that asked about defining nonadherence, extent of adherence problems in schizophrenia and bipolar disorder, risk factors for nonadherence, assessment methods, and interventions for specific types of adherence problems. The survey was completed by 41 (85%) of the 48 experts to whom it was sent. When evaluating adherence, the experts considered it important to assess both behavior and attitude, although they considered actual behavior most important. They also noted the importance of distinguishing patients who are not willing to take medication from those who are willing but not able to take their medication as prescribed due to forgetfulness, misunderstanding of instructions, or financial or environmental problems, since this will affect the type of intervention needed. Although self- and physician report are most commonly used to clinically assess adherence, they are often inaccurate and may underestimate nonadherence. The experts believe that more accurate information will be obtained by asking about any problems patients are having or anticipate having taking medication rather than if they have been taking their medication; They also recommended speaking with family or caregivers, if the patient gives permission, as well as using more objective measures (e.g., pill counts, pharmacy records, smart pill containers if available, and, when appropriate, medication plasma levels). Use of a validated self-report scale may also help improve accuracy. For patients who appear adherent to medication, the experts recommended monthly assessments for adherence, with additional assessments if there is a noticeable symptomatic change. If there is concern about adherence, they recommended more frequent (e.g., weekly) assessments. The article concludes with suggestions for clinical interview techniques for assessing adherence.

Psychosocial treatments for bipolar disorder: cost-effectiveness, mediating mechanisms, and future directions.

OBJECTIVES: Randomized trials of adjunctive psychotherapy for bipolar disorder are reviewed, in tandem with discussion of cost-effectiveness, mediating mechanisms, and moderators of effects. METHODS: Systematic searches of the MEDLINE and PSYCHLIT databases yielded 19 randomized controlled trials of individual family and group therapies. Outcome variables included time to recovery, relapse or recurrence, symptom severity, medication adherence, and psychosocial functioning. RESULTS: Meta-analyses consistently show that disorder-specific psychotherapies [cognitive-behavioral therapy (CBT), interpersonal, family, and group] augment mood stabilizers in reducing rates of relapse (OR = 0.57; 95% CI: 0.39-0.82) over 1-2 years. Specific mediating mechanisms include, but are not limited to, increasing medication adherence, teaching self-monitoring and early intervention with emergent episodes, and enhancing interpersonal functioning and family communication. All therapies have strengths and weaknesses. One group psychoeducation trial, demonstrated effect sizes for recurrence that are at least equivalent to individual therapies, but findings await replication. Family interventions have been successfully administered in both single and multi-family formats, but no studies report the comparative cost-effectiveness of these formats. The best-studied psychotherapy modality, CBT, can have beneficial effects on depression, but findings are inconsistent across studies and vary with sample characteristics and comparison treatments. CONCLUSIONS: Adjunctive psychotherapies can be cost-effective when weighed against observed reductions in recurrence, hospitalization and functional impairments. Future trials need to (i) clarify which populations are most likely to benefit from which strategies; (ii) identify putative mechanisms of action; (iii) systematically evaluate costs, benefits, and generalizability; and (iv) record adverse effects. The application of psychosocial interventions to young-onset populations deserves further study.

Long-term mental health resource utilization and cost of care following group psychoeducation or unstructured group support for bipolar disorders: a cost-benefit analysis.

OBJECTIVE: To explore the short- and long-term mental health resource utilization and cost of care in a sample of 120 individuals with bipolar disorders who participated in a randomized controlled efficacy trial of group psychoeducation versus unstructured group support. METHOD: Prospective, independent monitoring of DSM-IV bipolar disorder type I or II patients aged 18 to 65 years was conducted during the intervention phase (6 months) and follow-up phase (5-year postintervention) of a randomized controlled trial reporting clinical outcomes and inpatient and outpatient mental health service utilization, with estimation of cost of treatment per patient. The study was conducted from October 1997 through October 2006. RESULTS: Compared with individuals with bipolar disorder receiving the control intervention, psychoeducated patients had twice as many planned outpatient appointments, but the estimated mean cost of emergency consultation utilization was significantly less. There were trends for psychoeducated patients to opt for self-funded psychotherapy after completing group psychoeducation and to utilize more medications. However, inpatient care accounted for 40% estimated total cost in the control group but only about 15% in the psychoeducation group. CONCLUSIONS: This study demonstrates the importance of taking a long-term overview of the cost versus benefits of adjunctive psychological therapy in bipolar disorders. If viewed only in the short-term, the psychoeducation group used more mental health care resources without clear additional health gain. However, extended follow-up demonstrated a long-term advantage for psychoeducated individuals, such that, compared to an unstructured support group intervention, group psychoeducation is less costly and more effective.

Are urologists fairly reimbursed for complex procedures: failure of 22 modifier?

OBJECTIVES: The 22 modifier was designed to provide surgeons with additional reimbursement for performing complex procedures. We evaluated whether urologists at a tertiary referral center are reimbursed when using the 22 modifier. METHODS: We evaluated the charts and billing data of all adult urology noncharity cases using the 22 modifier from January 2006 and September 2007. RESULTS: The 22 modifier was used in 317 of 7494 (4.2%) unique procedures performed. Of these 317 procedures, 99 (31%) were reimbursed at a greater rate than the contract level, with a mean increase greater than the contract of $388 (median $260, range $62-$3524), for a mean of 28% greater than the contract. Of the 317 cases, 114 were within $50 of the contract level and 104 were reimbursed at less than the contract level. Additionally, 56 cases were paid at the initial request and < or = 4 appeals were sent in 228 cases, with a successful result in 57 (25%). When analyzed by payor (n = 289), private insurance paid 81 of 187 (43.3%), Medicare paid 23 of 95 (24.2%), and Medicaid paid 1 of 7 (14.3%). Most payments took > 2 months to be paid. The reasons for using the 22 modifier code included extensive surgery, previous surgery, staghorn calculus, extended lymphadenectomy for bladder cancer, adhesions, difficult anatomy, complex dissection, morbid obesity, previous chemotherapy, scarring, previous radiotherapy, difficult debulking, and pregnancy. Of the 317 cases, > 121 had several confounding factors. CONCLUSIONS: The 22 modifier does not provide consistent reimbursement for urologists performing complex procedures. The long-term implications of financial disincentives to performing difficult surgeries need to be further evaluated.

The HCL-32: towards a self-assessment tool for hypomanic symptoms in outpatients.

BACKGROUND: Bipolar disorders (BP) are frequently diagnosed and treated as pure depression initially; accurate diagnosis often being delayed by 8 to 10 years. In prospective studies, the presence of hypomanic symptoms in adolescence is strongly predictive of later bipolar disorders. As such, an instrument for self-assessment of hypomanic symptoms might increase the detection of suspected and of manifest, but under-treated, cases of bipolar disorders. METHODS: The multi-lingual hypomania checklist (HCL-32) has been developed and is being tested internationally. This preliminary paper reports the performance of the scale in distinguishing individuals with BP (N=266) from those with major depressive disorder (MDD; N=160). The samples were adult psychiatry patients recruited in Italy (N=186) and Sweden (N=240). RESULTS: The samples reported similar clinical profiles and the structure for the HCL-32 demonstrated two main factors identified as "active/elated" hypomania and "risk-taking/irritable" hypomania. The HCL-32 distinguished between BP and MDD with a sensitivity of 80% and a specificity of 51%. LIMITATIONS: Although the HCL-32 is a sensitive instrument for hypomanic symptoms, it does not distinguish between BP-I and BP-II disorders. CONCLUSIONS: Future studies should test if different combinations of items, possibly recording the consequences of hypomania, can distinguish between these BP subtypes.

Use of cognitive therapy for relapse prevention in chronic depression. Cost-effectiveness study.

BACKGROUND: There is a lack of data on the cost-effectiveness of relapse prevention in depression. METHOD: A total of 158 subjects with partially remitted major depression despite adequate clinical treatment were randomly allocated to cognitive therapy in addition to antidepressants and clinical management v. antidepressants and clinical management alone. Relapse rates and health care resource utilisation were measured prospectively over 17 months. RESULTS: Cumulative relapse rates in the cognitive therapy group were significantly lower than in the control group (29% v. 47%). The incremental cost incurred in subjects receiving cognitive therapy over 17 months (pound sterling 779; 95% CI pound sterling 387- pound sterling 1170) was significantly lower than the overall mean costs of cognitive therapy (pound sterling 1164; 95% CI pound sterling 1084- pound sterling 1244). The incremental cost-effectiveness ratio ranged from pound sterling 4328 to pound sterling 5027 per additional relapse prevented. CONCLUSIONS: In individuals with depressive symptoms that are resistant to standard treatment, adjunctive cognitive therapy is more costly but more effective than intensive clinical treatment alone.