Flexible Designs für klinische Studien in Verteilungssituationen mit Störparametern

Kontrollierte klinische Studien sind eine experimentelle Methode der klinisch-epidemiologischen Forschung, mit deren Hilfe der kausale Nachweis therapeutischer Wirksamkeit erbracht und somit der Therapiefortschritt abgesichert wird. Im Laufe einer solchen Studie stellte sich nicht selten heraus, dass die Annahmen, die der Studienplanung zugrundeliegen, einer Korrektur bedürfen. Der zu erwartende Therapieunterschied oder die Varianz der Messgröße kann sich als kleiner oder größer herausstellen als ursprünglich angenommen. Mit konventionellen statistischen Verfahren, war es nur bedingt möglich eine einmal geplante Studie nachträglich zu ändern, da nach datenabhängige Änderungen die statistische Fehlerkontrolle nicht mehr gesichert ist. Dies führte dazu, dass viele Studien aufgrund falscher Planungsannahmen nicht zufriedenstellend beendet werden konnten oder die statistische Fehlerkontrolle nicht mehr in der gebotenen Strenge beachtet wurde. In den letzten Jahren wurden verschiedene Methoden entwickelt, die Änderungen in laufenden Studien ermöglichen, ohne die Integrität der Studien zu verletzen. Dies sind unter anderem die adaptiven Designs, welche erstmals von Bauer (1989) vorgeschlagen wurden. Später wurden diese Verfahren in flexible Designs umbenannt, um einen Namenskonflikt zu vermeiden. Flexible Designs ermöglichen es, an vorgegebenen Zeitpunkten im Verlaufe der Studie Designänderungen vorzunehmen und dabei das Fehlerniveau 1. Art einzuhalten. Ein weiterer Ansatz wurde von Müller und Schäfer (2004) vorgeschlagen, das sogenannte CRP-Prinzip. Im Gegensatz zu den flexiblen Designs müssen hierbei die Zeitpunkte, an denen Designänderungen möglich sind, nicht vorher (zum Zeitpunkt der Studienplanung) festgelegt werden. Dennoch ist die Kontrolle des Fehlerniveaus 1. Art sichergestellt. Damit ist es möglich, noch zeitnaher Korrekturen des Studiendesigns vorzunehmen, wenn sich Planungsannahmen als falsch herausstellen. Obwohl die Idee des CRP-Prinzip sehr allgemein formuliert ist, war eine exakte Anwendungen bisher nur in Verteilungssituationen mit nur einem unbekannten Parameter möglich, wie im Falle der Normalverteilung mit unbekanntem Erwartungswert und bekannter Varianz. War die Varianz ebenfalls unbekannt (t-Test), so konnte dieses Verfahren nur noch approximativ angewendet werden. Insbesondere für kleine Fallzahlen ist daher die Kontrolle des Fehlerniveaus 1. Art nicht mehr sichergestellt. Ziel dieser Arbeit ist eine Weiterentwicklung des von Müller und Schäfer vorgeschlagenen Verfahrens, so dass es auch in Verteilungssituationen mit mehreren unbekannten Parametern, wie dem t-Test, exakt angewandt werden kann. Im Kapitel 2 geben wir zunächst eine Einführung in die besondere Problematik klinischer Studien. Kapitel 3 enthält einen Literaturüberblick über die bisherigen Gruppensequentiellen und flexiblen Designs. Im Kapitel 4 wird ein allgemeines mathematisches Konzept zur formalen Beschreibung und Definition entwickelt, welches sowohl die flexiblen Designs als auch das CRP-Prinzip beinhaltet. Dieses Konzept stellt eine Erweiterung des bekannten Begriffs der statistischen Entscheidungsfunktion dar. Auf dieser Basis werden im Kapitel 5 die Hauptergebnisse dieser Arbeit entwickelt. Damit gelingt es, das CRP-Prinzip auf beliebige k-parametrige Exponentialfamilien zu verallgemeinern . Diese Verallgemeinerung wenden wir am Ende dieses Kapitels auf die Testung des Lageparameters einer Normalverteilung bei unbekannter Varianz (t-Test) und auf den Vergleich zweier unbekannter Binomialparameter (Fishers exakter Test) an

Exploring COVID-19 daily records of diagnosed cases and fatalities based on simple nonparametric methods

Containment strategies to combat epidemics such as SARS-CoV-2/COVID-19 require the availability of epidemiological parameters, e.g., the effective reproduction number. Parametric models such as the commonly used susceptible-infected-removed (SIR) compartment models fitted to observed incidence time series have limitations due to the time-dependency of the parameters. Furthermore, fatalities are delayed with respect to the counts of new cases, and the reproduction cycle leads to periodic patterns in incidence time series. Therefore, based on comprehensible nonparametric methods including time-delay correlation analyses, estimates of crucial parameters that characterise the COVID-19 pandemic with a focus on the German epidemic are presented using publicly available time-series data on prevalence and fatalities. The estimates for Germany are compared with the results for seven other countries (France, Italy, the United States of America, the United Kingdom, Spain, Switzerland, and Brazil). The duration from diagnosis to death resulting from delay-time correlations turns out to be 13 days with high accuracy for Germany and Switzerland. For the other countries, the time-to-death durations have wider confidence intervals. With respect to the German data, the two time series of new cases and fatalities exhibit a strong coherence. Based on the time lag between diagnoses and deaths, properly delayed asymptotic as well as instantaneous fatality–case ratios are calculated. The temporal median of the instantaneous fatality–case ratio with time lag of 13 days between cases and deaths for Germany turns out to be $\bf 0.02$. Time courses of asymptotic fatality–case ratios are presented for other countries, which substantially differ during the first half of the pandemic but converge to a narrow range with standard deviation $\bf 0.0057$ and mean $\bf 0.024.$ Similar results are obtained from comparing time courses of instantaneous fatality–case ratios with optimal delay for the 8 exemplarily chosen countries. The basic reproduction number, $R_0$, for Germany is estimated to be between $\bf 2.4$ and $\bf 3.4$ depending on the generation time, which is estimated based on a delay autocorrelation analysis. Resonances at about 4 days and 7 days are observed, partially attributable to weekly periodicity of sampling. The instantaneous (time-dependent) reproduction number is estimated from the incident (counts of new) cases, thus allowing us to infer the temporal behaviour of the reproduction number during the epidemic course. The time course of the reproduction number turns out to be consistent with the time-dependent per capita growth

Effect of transcutaneous auricular vagal nerve stimulation on the fatigue syndrome in patients with gastrointestinal cancers

$\bf Background$ Cancer-related fatigue (CRF) is defined as a "distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning." CRF is frequently observed in cancer patients even before the initiation of tumor therapy. Its cause is not clear, but in addition to primary effects of therapy, a tumor-induced elevated level of inflammatory cytokines may play a role. Transcutaneous auricular vagal nerve stimulation (taVNS) is a noninvasive way to activate central nervous pathways and modulate pain perception and the immune system. It has positive effects on autoimmune conditions and can also improve fatigue associated with Sjogren's syndrome. It is the main purpose of this feasibility study to investigate the feasibility of daily taVNS against CRF. Therefore, the stimulation protocol of the newly introduced smartphone app of the manufacturer is evaluated. Additionally, the effect taVNS on CRF and quality of life (QoL) shall be evaluated. $\bf Methods$ Thirty adult patients with gastrointestinal tumors during or after treatment, relevant CRF (Hornheide questionnaire) and life expectancy > 1 year, are enrolled. Patients are randomized to treatment or sham arm and be informed that they will either feel the stimulation or not. Treatment group will receive left-sided tragus above-threshold stimulation with 25 Hz, 250 $\mu$s pulse width, and 28-s/32-s on/off paradigm for 4 h throughout the day for 4 weeks. Sham group will receive no stimulation via a nonfunctional electrode. A daily stimulation protocol with time and average intensity is automatically created by a smartphone app connected to the stimulator via Bluetooth®. Multidimensional Fatigue Inventory-20, Short-Form 36 and Beck Depression Inventory questionnaires will be filled out before and after 4 weeks of stimulation. $\bf Discussion$ Primarily, the patients' daily stimulation time and intensity will be evaluated through the electronic protocol after 4 weeks. Secondarily, the effect of taVNS on cancer-related fatigue and QoL will be measured through the questionnaires. As taVNS seems to modulate inflammatory cytokines, this noninvasive method may — if accepted by the patients — be a promising adjunct in the treatment of cancer-related fatigue

Multiple sclerosis disease activity and disability following discontinuation of natalizumab for pregnancy

$\bf Importance$ The magnitude of risk of pregnancy-related multiple sclerosis relapses, particularly severe relapses, following natalizumab cessation is unclear, as is whether this risk is reduced by pregnancy or other modifiable factors. $\bf Objective$ To determine the association of early natalizumab withdrawal before or during pregnancy with risk of severe relapses and relapse-related disability. $\textbf {Design, Setting, and Participants}$ This prospective cohort study used data from the German Multiple Sclerosis and Pregnancy Registry, which enrolled participants between November 2006 and February 2018. Data were collected through structured telephone-administered questionnaires and review of neurologists’ notes. Registry patients who stopped natalizumab treatment within the 2 years before or in the first trimester of pregnancy were included in this analysis. Data were analyzed between January and November 2021. $\bf Exposures$ Cessation of natalizumab before pregnancy or until the first trimester. $\textbf {Main Outcomes and Measures}$ Severe and significant relapse-related disability was defined as at least a 2.0-point increase on the expanded disability status scale or new or worsening relapse-related ambulatory impairment. Multivariable models accounting for measures of disease severity and repeated events were used. $\bf Results$ The cohort comprised 255 women with 274 pregnancies (mean [SD] age at pregnancy onset, 31.25 [4.27] years) who stopped natalizumab before pregnancy (n = 85; median time before last menstrual period, 14.29 weeks [IQR, 3.14-42.43 weeks]) or in the first trimester (n = 189). During pregnancy and the postpartum year, relapses were reported in 183 pregnancies (66.78%), severe relapses in 44 pregnancies (16.05%), and potentially life-threatening relapses in 3 pregnancies (1.10%). One year post partum, significant relapse-related disability was accrued in 29 pregnancies (10.58%). Relapses during pregnancy (n = 109; 39.78%) and in the postpartum period (n = 135; 49.27%) were common. Pregnancy (as a time-dependent covariate) was not associated with a reduced relapse risk (adjusted HR, 0.90; 95% CI, 0.64-1.27). Neither exclusive breastfeeding (adjusted HR, 1.34; 95% CI, 0.86-2.10) nor restarting natalizumab within 4 weeks post partum (adjusted HR, 1.06; 95% CI, 0.48-2.36) were associated with a reduced risk of early postpartum relapses 6 months after delivery. However, the relapse rate ratio during 12 months post partum was lower (0.49; 95% CI, 0.28-0.86) when natalizumab was restarted in the first 4 weeks after birth. $\textbf {Conclusions and Relevance}$ This cohort study's finding suggest that 10% of women may retain clinically meaningful disability from pregnancy-related natalizumab cessation relapses 1 year post partum. This information should be shared with women on natalizumab who desire pregnancy to weigh the high risk of pregnancy-related relapses and disability to the partly uncertain risks of continuing natalizumab throughout pregnancy or switching to depleting agents before conception

Multiple sclerosis disease activity and disability following cessation of Fingolimod for pregnancy

$\textbf {Background and Objective}$ Discontinuation of fingolimod $\geq$2 months before pregnancy is recommended to minimize potential teratogenicity. The magnitude of MS pregnancy relapse risk, particularly severe relapses, after fingolimod cessation is unclear, as is whether this risk is reduced by pregnancy or modifiable factors. $\bf Methods$ Pregnancies who stopped fingolimod treatment within 1 year before or during pregnancy were identified from the German MS and Pregnancy Registry. Data were collected through structured telephone-administered questionnaires and neurologists' notes. Severe relapses were defined as a $\geq$2.0 increase in Expanded Disability Status Scale (EDSS) or new or worsening relapse-related ambulatory impairment. Women who continued to meet this definition 1 year postpartum were classified as reaching the Severe Relapse Disability Composite Score (SRDCS). Multivariable models accounting for measures of disease severity and repeated events were used. $\bf Results$ Of the 213 pregnancies among 201 women (mean age at pregnancy onset 32 years) identified, 56.81% (n = 121) discontinued fingolimod after conception. Relapses during pregnancy (31.46%) and the postpartum year (44.60%) were common. Nine pregnancies had a severe relapse during pregnancy and additional 3 during the postpartum year. One year postpartum, 11 of these (6.32% of n = 174 with complete EDSS information) reached the SRDCS. Adjusted relapse rates during pregnancy were slightly higher compared with the year before pregnancy (relapse rate ratio = 1.24, 95% CI 0.91–1.68). Neither exclusive breastfeeding nor resuming fingolimod within 4 weeks of delivery were associated with a reduced risk of postpartum relapses. Most pregnancies relapsed during the first 3 months postpartum (n = 55/204, 26.96%). $\bf Discussion$ Relapses during pregnancy after fingolimod cessation are common. Approximately 6% of women will retain clinically meaningful disability from these pregnancy-related, fingolimod cessation relapses 1 year postpartum. This information should be shared with women on fingolimod desiring pregnancy, and optimizing MS treatment with nonteratogenic approaches should be discussed

Internet-based self-assessment for symptoms of internet use disorder

$\bf Background:$ Internet use disorder (IUD) is a new type of behavioral addiction in the digital age. At the same time, internet applications and eHealth can also provide useful support in medical treatment. $\bf Objective:$ The purpose of this study is to examine if an internet-based eHealth service can reach individuals with IUD. In particular, it should be investigated whether both male and female individuals with more severe IUDs can be reached. $\bf Methods:$ Data were retrieved from the OMPRIS (online-based motivational intervention to reduce problematic internet use and promote treatment motivation in internet gaming disorder and internet use disorder) project (DRKS00019925), an internet-based motivational intervention to reduce problematic internet use and promote treatment motivation in internet gaming disorder and IUD. During the recruitment process (August 2020-March 2022), a total of 3007 individuals filled out the standardized scale for the assessment of internet and computer game addiction (AICA-S). The assessment was accessible via the project homepage. There was no preselection of participants at this stage of the study; however, the offer was addressed to people with hazardous internet use and IUDs. The web-based assessment was free and could be found via search engines, but attention was also drawn to the service via newspaper articles, radio reports, and podcasts. $\bf Results:$ Out of 3007 who participated in the web-based self-assessment, 1033 (34.4%) are female, 1740 (57.9%) are male, 67 (2.2%) are diverse individuals, and 167 (5.5%) did not disclose their gender. The IUD symptom severity score showed a wide range between the AICA-S extreme values of 0 and 27 points. On average, the total sample (mean 8.19, $\it SD$ 5.47) was in the range of hazardous IUD behavior (AICA-S cutoff>7.0). Furthermore, 561 individuals (18.7% of the total sample; mean 17.42, $\it SD$ 3.38) presented severe IUD (AICA-S cutoff>13.5). Focusing on female and male participants, 20.9% (363/1740) of the men and 14.9% (151/1033) of the women scored above 13.5 points, which can be considered pathological IUD behavior ($\chi^{2}_{2,2773}$=16.73, $\it P$<.001, effect size: Cramér $\it V$=0.078). Unemployment, being in vocational training or studying at a university, and being male were significantly associated with high IUD symptoms. $\bf Conclusions:$ Using a large sample, the study showed that both mildly and severely IUD-affected individuals can be reached via the internet. An internet-based eHealth offer can thus be a good way to reach patients with IUD where they are addicted—on the internet. In addition, eHealth services increase the likelihood of reaching female patients, who hardly ever come to specialized outpatient clinics and hospitals. Since social problems, especially unemployment, have a strong association with disease severity, the integration of social counseling into treatment seems advisable in terms of a multidisciplinary approach

Effects of an online-based motivational intervention to reduce problematic internet use and promote treatment motivation in internet gaming disorder and internet use disorder (OMPRIS)

$\it Introduction$ In May 2019, the WHO classified internet gaming disorder (IGD) as a mental disorder in the upcoming International Classification of Diseases 11th Revision. However, individuals affected by IGD or internet use disorders (IUDs) are often not provided with adequate therapy due to a lack of motivation or absence of adequate local treatment options. To close the gap between individuals with IUDs and the care system, we conduct an online-based motivational intervention to reduce problematic internet use and promote treatment motivation in internet gaming disorder and internet use disorder (OMPRIS). $\textit {Methods and analysis}$ Within the randomised controlled trial, a total of n=162 participants will be allocated by sequential balancing randomisation to the OMPRIS intervention or a waitlist control group. The study includes an extensive diagnostic, followed by a 4-week psychological intervention based on motivational interviewing, (internet-related) addiction therapy, behavioural therapy techniques and additional social counselling. The primary outcome is the reduction of problematic internet use measured by the Assessment of Internet and Computer Game Addiction Scale. Secondary outcomes include time spent on the internet, motivation for change (Stages of Change Readiness and Treatment Eagerness Scale for Internet Use Disorder), comorbid mental symptoms (Patient Health Questionnaire-9, Generalized Anxiety Disorder Screener-7), quality of life (EuroQoL Standardised Measure of Health-related Quality of Life–5 Dimensions, General Life Satisfaction-1), self-efficacy (General Self-Efficacy Scale), personality traits (Big Five Inventory-10), therapeutic alliance (Helping Alliance Questionnaire) and health economic costs. The diagnosis of (comorbid) mental disorders is carried out with standardised clinical interviews. The measurement will be assessed before (T0), at midpoint (T1) and after the OMPRIS intervention (T2), representing the primary endpoint. Two follow-up assessments will be conducted after 6 weeks (T3) and 6 months (T4) after the intervention. The outcomes will be analysed primarily via analysis of covariance. Both intention-to-treat and per-protocol analyses will be conducted. $\textit {Ethics and dissemination}$ Participants will provide written informed consent. The trial has been approved by the Ethics Committee of the Faculty of Medicine, Ruhr University Bochum (approval number 19-6779). Findings will be disseminated through presentations, peer-reviewed journals and conferences

Intravenous IgM-enriched immunoglobulins in critical COVID-19

$\bf Background:$ A profound inflammation-mediated lung injury with long-term acute respiratory distress and high mortality is one of the major complications of critical COVID-19. Immunoglobulin M (IgM)-enriched immunoglobulins seem especially capable of mitigating the inflicted inflammatory harm. However, the efficacy of intravenous IgM-enriched preparations in critically ill patients with COVID-19 is largely unclear. $\bf Methods:$ In this retrospective multicentric cohort study, 316 patients with laboratory-confirmed critical COVID-19 were treated in ten German and Austrian ICUs between May 2020 and April 2021. The primary outcome was 30-day mortality. Analysis was performed by Cox regression models. Covariate adjustment was performed by propensity score weighting using machine learning-based SuperLearner to overcome the selection bias due to missing randomization. In addition, a subgroup analysis focusing on different treatment regimens and patient characteristics was performed. $\bf Results:$ Of the 316 ICU patients, 146 received IgM-enriched immunoglobulins and 170 cases did not, which served as controls. There was no survival difference between the two groups in terms of mortality at 30 days in the overall cohort ($HR_{adj}$: 0.83; 95% CI: 0.55 to 1.25; $\it p$ = 0.374). An improved 30-day survival in patients without mechanical ventilation at the time of the immunoglobulin treatment did not reach statistical significance ($HR_{adj}$: 0.23; 95% CI: 0.05 to 1.08; $\it p$ = 0.063). Also, no statistically significant difference was observed in the subgroup when a daily dose of $\geq$ 15 g and a duration of $\geq$ 3 days of IgM-enriched immunoglobulins were applied ($HR_{adj}$: 0.65; 95% CI: 0.41 to 1.03; $\it p$ = 0.068). $\bf Conclusions:$ Although we cannot prove a statistically reliable effect of intravenous IgM-enriched immunoglobulins, the confidence intervals may suggest a clinically relevant effect in certain subgroups. Here, an early administration (i.e. in critically ill but not yet mechanically ventilated COVID-19 patients) and a dose of $\geq$ 15 g for at least 3 days may confer beneficial effects without concerning safety issues. However, these findings need to be validated in upcoming randomized clinical trials

Amyloid-β\beta misfolding as a plasma biomarker indicates risk for future clinical Alzheimer's disease in individuals with subjective cognitive decline

$\bf Background$ We evaluated A$\beta$ misfolding in combination with A$\beta_{42/40}$ ratio as a prognostic tool for future clinical progression to mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD) in individuals with subjective cognitive decline (SCD). $\bf Methods$ Baseline plasma samples ($\it n$ = 203) from SCD subjects in the SCIENCe project and Amsterdam Dementia Cohort (age 61 $\pm$ 9 years; 57% male, mean follow-up time 2.7 years) were analyzed using immuno-infrared-sensor technology. Within 6 years of follow-up, 22 (11%) individuals progressed to MCI or dementia due to AD. Sensor readout values > 1646 $cm^{− 1}$ reflected normal A$\beta$ folding; readouts at ≤ 1646 $cm^{− 1}$ reflected low and at < 1644 $cm^{− 1}$ high misfolding. We used Cox proportional hazard models to quantify Aβ$\beta$ misfolding as a prognostic biomarker for progression to MCI and dementia due to AD. The accuracy of the predicted development of MCI/AD was determined by time-dependent receiver operating characteristic (t-ROC) curve analyses that take individual follow-up and conversion times into account. Statistical models were adjusted for age, sex, and $APOE_{\epsilon}$4 status. Additionally, plasma A$\beta_{42/40}$ data measured by SIMOA were statistically analyzed and compared. $\bf Results$ All 22 patients who converted to MCI or AD-dementia within 6 years exhibited A$\beta$ misfolding at baseline. Cox analyses revealed a hazard ratio (HR) of 19 (95% confidence interval [CI] 2.2–157.8) for future conversion of SCD subjects with high misfolding and of 11 (95% CI 1.0–110.1) for those with low misfolding. T-ROC curve analyses yielded an area under the curve (AUC) of 0.94 (95% CI 0.86–1.00; 6-year follow-up) for A$\beta$ misfolding in an age, sex, and $APOE_{\epsilon}$4 model. A similar model with plasma A$\beta_{42/40}$ ratio yielded an AUC of 0.92 (95% CI, 0.82–1.00). The AUC increased to 0.99 (95% CI, 0.99–1.00) after inclusion of both A$\beta$ misfolding and the A$\beta_{42/40}$ ratio. $\bf Conclusions$ A panel of structure- and concentration-based plasma amyloid biomarkers may predict conversion to clinical MCI and dementia due to AD in cognitively unimpaired subjects. These plasma biomarkers provide a noninvasive and cost-effective alternative for screening early AD pathological changes. Follow-up studies and external validation in larger cohorts are in progress for further validation of our findings

Efficacy of a short-term webcam-based telemedicine treatment of internet use disorders (OMPRIS)

$\bf Background$ Evidence-based $\underline {treatments}$ for internet use disorders (IUDs) are limited, and online therapy approaches are poorly studied. We investigated the efficacy of a manualised therapist-guided online intervention (OMPRIS) to reduce IUD $\underline {symptoms}$ and improve psychological well-being. $\bf Methods$ In this multicentre, two-arm, single-blinded trial, individuals ≥16 years suffering from IUD symptoms were recruited in Germany from August 16, 2020, to March 11, 2022, through media advertisements and healthcare providers. Participants were randomly allocated by sequential balancing randomisation (1:1) to either the manualised webcam-based OMPRIS intervention or a waitlist control (WLC) group. OMPRIS provided strategies from motivational interviewing, behavioural therapy, and social counselling. The primary outcome at the end of treatment was a reduction in IUD symptoms as measured by the Assessment of Internet and Computer Scale (AICA-S). Follow-up assessments were conducted at 6 weeks and 6 months. Analyses were performed in the intention-to-treat population. This trial was registered (German $\underline {Clinical}$ $\underline {Trial}$ Register, DRKS00019925) and has been completed. $\bf Findings$ A total of 180 individuals were randomly assigned to the OMPRIS intervention (n = 89) or WLC (n = 91) arm. After treatment, 81 (91.0%) participants in the OMPRIS intervention group and 88 (96.7%) in the WLC group completed the outcome assessment. The $\underline {ANCOVA}$ model showed that OMPRIS participants had a significantly greater reduction in AICA-S scores from baseline (mean score 12.1 [SD 4.6]) to post-treatment (6.8 [5.2]) than those in the WLC group (from 12.6 [5.1] to 11.0 [5.4]; estimated mean difference −3.9; [95% CI −5.2 to −2.6]; p < 0.0001; d = 0.92). No adverse events were reported to the trial team. $\bf Interpretation$ Webcam-based OMPRIS therapy was effective and superior to waiting list conditions in reducing IUD symptoms. Webcam-based, specialised online therapy thus increases IUD treatment options