[Internet-based self-help for loneliness-a systematic review]. / Internetbasierte Selbsthilfe bei Einsamkeit ­ Eine systematische Übersicht.

BACKGROUND: Recently, the phenomenon of loneliness has received increasing attention. Loneliness is widespread and can have adverse consequences for mental and physical health if prolonged. Internet-based interventions (IBIs) for self-help have proven to be effective for a variety of psychological disorders. Due to several specific aspects, IBIs are also a relevant option for loneliness. This systematic review aims to present the current research on self-help IBIs for reducing loneliness. METHODS: A systematic literature search was conducted in the databases Web of Science, PubMed, Scopus, PsycInfo, MedLine, PsycIndex, Cochrane Library and PsyArXiv between December 2023 and early January 2024. We included original German or English studies that addressed IBIs for self-help to reduce loneliness. RESULTS: In total, eight studies published between 2017 and 2024 were included in the qualitative analysis. All studies were conducted in high-income countries, included predominantly well-educated female adults and were mostly satisfactory regarding their internal validity. DISCUSSION: The results of this review suggest that self-help IBIs may be a promising option for alleviating loneliness. However, the work also points to the need for further research. Future studies should consider larger samples and people of different ages, genders and education levels in order to generalise the results of the present review.

German translation, cultural adaptation for Austria and validation of the Neurological Sleep Index - Multiple Sclerosis (NSI-MS).

STUDY OBJECTIVES: To translate, culturally adapt, and validate the Neurological Sleep Index - Multiple Sclerosis (NSI-MS) for use in Austrian German-speaking populations with multiple sclerosis (pwMS). METHODS: Following established guidelines, the NSI-MS diurnal sleepiness (DS), non-restorative nocturnal sleep (NRNS), and fragmented nocturnal sleep (FNS) scales underwent forward-backward translation, with content and face validity, and cultural adaptation to Austria established. Construct validity was evaluated using Rasch analysis. Known-groups validity was examined, and comparisons were made with scales measuring MS fatigue, daytime sleepiness, sleep quality, anxiety, and depression. Reliability was assessed through Cronbach's alpha, Person Separation Index, Lin's concordance correlation coefficient, measurement error, and floor and ceiling effects. Data were merged with a historic English dataset for comparison between English/German language versions. RESULTS: The translation and cultural adaptation of the NSI-MS-G were successful. Pretesting involved 30 pwMS, while the validation included 400 pwMS with mild-to-severe disability. The DS, NRNS, and FNS scales exhibited good fit parameters, were unidimensional, and invariant. NSI-MS-G scales demonstrated excellent convergent and known-groups validity, internal consistency, person separation reliability, test-retest reliability, adequate measurement error, and low floor and ceiling effects. Pooling English and German datasets revealed that person estimates for the NRNS and FNS scales are equivalent across versions, unlike the DS scale. CONCLUSIONS: The NSI-MS-G demonstrates validity, reliability, and responsiveness in assessing DS, NRNS, and FNS in pwMS, generating interval-level data, and shows equivalence between its English and German versions. CLINICAL TRIAL REGISTRATION: Register: German Clinical Trials Register (DRKS); URL: https://drks.de/search/en/trial/DRKS00025573; Identifier: DRKS00025573.

Retinal layer thinning for monitoring disease-modifying treatment in relapsing multiple sclerosis-Evidence for applying a rebaselining concept.

BACKGROUND: Employing a rebaselining concept may reduce noise in retinal layer thinning measured by optical coherence tomography (OCT). METHODS: From an ongoing prospective observational study, we included patients with relapsing multiple sclerosis (RMS), who had OCT scans at disease-modifying treatment (DMT) start (baseline), 6-12 months after baseline (rebaseline), and ⩾12 months after rebaseline. Mean annualized percent loss (aL) rates (%/year) were calculated both from baseline and rebaseline for peripapillary-retinal-nerve-fiber-layer (aLpRNFLbaseline/aLpRNFLrebaseline) and macular-ganglion-cell-plus-inner-plexiform-layer (aLGCIPLbaseline/aLGCIPLrebaseline) by mixed-effects linear regression models. RESULTS: We included 173 RMS patients (mean age 31.7 years (SD 8.8), 72.8% female, median disease duration 15 months (12-94) median baseline-to-last-follow-up-interval 37 months (18-71); 56.6% moderately effective DMT (M-DMT), 43.4% highly effective DMT (HE-DMT)). Both mean aLpRNFLbaseline and aLGCIPLbaseline significantly increased in association with relapse (0.51% and 0.26% per relapse, p < 0.001, respectively) and disability worsening (1.10% and 0.48%, p < 0.001, respectively) before baseline, but not with DMT class. Contrarily, neither aLpRNFLrebaseline nor aLGCIPLrebaseline was dependent on relapse or disability worsening before baseline, while HE-DMT significantly lowered aLpRNFLrebaseline (by 0.31%, p < 0.001) and aLGCIPLrebaseline (0.25%, p < 0.001) compared with M-DMT. CONCLUSIONS: Applying a rebaselining concept significantly improves differentiation of DMT effects on retinal layer thinning by avoiding carry-over confounding from previous disease activity.

The Efficacy of Web-Based Cognitive Behavioral Therapy With a Shame-Specific Intervention for Social Anxiety Disorder: Randomized Controlled Trial.

Background: Social anxiety disorder (SAD) is one of the most prevalent psychological disorders and generally co-occurs with elevated shame levels. Previous shame-specific interventions could significantly improve outcomes in social anxiety treatments. Recent review suggests that integrating a more direct shame intervention could potentially increase the effectiveness of cognitive behavioral therapy. Web-based cognitive behavioral therapy (WCBT) has proven efficacy, sustaining benefits for 6 months to 4 years. Previous evidence indicated that shame predicted the reduction of social anxiety and mediated between engagements in exposure and changes in social anxiety during WCBT. Objective: This study aimed to design a shame intervention component through a longitudinal study and conduct a randomized controlled trial to investigate the effectiveness of a shame intervention component in reducing social anxiety symptoms and shame experience in a clinical sample of people with SAD. Methods: The development of a shame intervention component was informed by cognitive behavioral principles and insights from longitudinal data that measured the Experience of Shame Scale (ESS), the Coping Styles Questionnaire, and the Social Interaction Anxiety Scale (SIAS) in 153 participants. The psychoeducation, cognitive construct, and exposure sections were tailored to focus more on shame-related problem-solving and self-blame. A total of 1220 participants were recruited to complete questionnaires, including the ESS, the SIAS, the Social Phobia Scale (SPS), and diagnostic interviews. Following a 2-round screening process, 201 participants with SAD were randomly assigned into a shame WCBT group, a normal WCBT group, and a waiting group. After the 8-week WCBT intervention, the participants were asked to complete posttest evaluations, including the ESS, SIAS and SPS. Results: Participants in the shame WCBT group experienced significant reductions in shame levels after the intervention (ESS: P<.001; ηp2=0.22), and the reduction was greater in the shame intervention group compared to normal WCBT (P<.001; mean deviation -12.50). Participants in both the shame WCBT and normal WCBT groups experienced significant reductions in social anxiety symptoms (SIAS: P<.001; ηp2=0.32; SPS: P<.001; ηp2=0.19) compared to the waiting group after intervention. Furthermore, in the experience of social interaction anxiety (SIAS), the shame WCBT group showed a higher reduction compared to the normal WCBT group (P<.001; mean deviation -9.58). Problem-solving (SE 0.049, 95% CI 0.025-0.217) and self-blame (SE 0.082, 95% CI 0.024-0.339) mediated the effect between ESS and SIAS. Conclusions: This is the first study to design and incorporate a shame intervention component in WCBT and to validate its efficacy via a randomized controlled trial. The shame WCBT group showed a significant reduction in both shame and social anxiety after treatment compared to the normal WCBT and waiting groups. Problem-solving and self-blame mediated the effect of shame on social anxiety. In conclusion, this study supports previous findings that a direct shame-specific intervention component could enhance the efficacy of WCBT.

Four Versions of Transtheoretical Stances, and the Bernese View.

A brief characterization of transtheoretical stances to which existing approaches can be allocated is followed by a description of the "Bernese view", that is, what Klaus Grawe and his colleagues, including the authors of this article have developed: the origins, a model of the multiple constraint satisfaction construction of therapist action, a discussion of psychotherapy integration, the crucial role of supervisors in an integrative multiple constraint satisfaction approach, and a discussion of when and how trainees should be introduced to a transtheoretical stance.

GMP-compliant iPS cell lines show widespread plasticity in a new set of differentiation workflows for cell replacement and cancer immunotherapy.

Cell therapeutic applications based on induced pluripotent stem cells (iPSCs) appear highly promising and challenging at the same time. Good manufacturing practice (GMP) regulations impose necessary yet demanding requirements for quality and consistency when manufacturing iPSCs and their differentiated progeny. Given the scarcity of accessible GMP iPSC lines, we have established a corresponding production workflow to generate the first set of compliant cell banks. Hence, these lines met a comprehensive set of release specifications and, for instance, displayed a low overall mutation load reflecting their neonatal origin, cord blood. Based on these iPSC lines, we have furthermore developed a set of GMP-compatible workflows enabling improved gene targeting at strongly enhanced efficiencies and directed differentiation into critical cell types: A new protocol for the generation of retinal pigment epithelium (RPE) features a high degree of simplicity and efficiency. Mesenchymal stromal cells (MSCs) derived from iPSCs displayed outstanding expansion capacity. A fully optimized cardiomyocyte differentiation protocol was characterized by a particularly high batch-to-batch consistency at purities above 95%. Finally, we introduce a universal immune cell induction platform that converts iPSCs into multipotent precursor cells. These hematopoietic precursors could selectively be stimulated to become macrophages, T cells, or natural killer (NK) cells. A switch in culture conditions upon NK-cell differentiation induced a several thousand-fold expansion, which opens up perspectives for upscaling this key cell type in a feeder cell-independent approach. Taken together, these cell lines and improved manipulation platforms will have broad utility in cell therapy as well as in basic research.

Development and Evaluation of the Abdominal Pain Knowledge Questionnaire (A-PKQ) for Children and Their Parents.

BACKGROUND: Abdominal pain is a common and often debilitating issue for children and adolescents. In many cases, it is not caused by a specific somatic condition but rather emerges from a complex interplay of bio-psycho-social factors, leading to functional abdominal pain (FAP). Given the complex nature of FAP, understanding its origins and how to effectively manage this condition is crucial. Until now, however, no questionnaire exists that targets knowledge in this specific domain. To address this, the Abdominal Pain Knowledge Questionnaire (A-PKQ) was developed. METHODS: Two versions were created (one for children and one for parents) and tested in four gastroenterology clinics and one specialized pain clinic in Germany between November 2021 and February 2024. Children between 8 and 17 years of age (N = 128) and their accompanying parents (N = 131) participated in the study. Rasch analysis was used to test the performance of both versions of the questionnaire. RESULTS: The original questionnaires exhibited good model and item fit. Subsequently, both questionnaires were refined to improve usability, resulting in final versions containing 10 items each. These final versions also demonstrated good model and item fit, with items assessing a variety of relevant domains. CONCLUSION: The A-PKQ is an important contribution to improving assessment in clinical trials focused on pediatric functional abdominal pain.

The evaluation of a stepped care approach for early intervention of borderline personality disorder.

BACKGROUND: The current study evaluated the stepped care approach applied in AtR!Sk; a specialized outpatient clinic for adolescents with BPD features that offers a brief psychotherapeutic intervention (Cutting Down Program; CDP) to all patients, followed by a more intensive Dialectical Behavioral Therapy for Adolescents (DBT-A) for those whose symptoms persist. METHODS: The sample consisted of 127 patients recruited from two AtR!Sk clinics. The number of BPD criteria, psychosocial functioning, severity of overall psychopathology, number of days with non-suicidal self-injury (NSSI; past month), and the number of suicide attempts (last 3 months) were assessed at clinic entry (T0), after CDP (T1), and at 1- and 2-year follow-up (T2, T3). Based on the T1 assessment (decision criteria for DBT-A: ≥ 3 BPD criteria & ZAN-BPD ≥ 6), participants were allocated into three groups; CDP only (n = 74), CDP + DBT-A (eligible and accepted; n = 36), CDP no DBT-A (eligible, but declined; n = 17). RESULTS: CDP only showed significantly fewer BPD criteria (T2: ß = 3.42, p < 0.001; T3: ß = 1.97, p = 0.008), higher levels of psychosocial functioning (T2: ß = -1.23, p < 0.001; T3: ß = -1.66, p < 0.001), and lower severity of overall psychopathology (T2: ß = 1.47, p < 0.001; T3: ß = 1.43, p = 0.002) over two years compared with CDP no DBT-A, while no group differences were found with regard to NSSI and suicide attempts. There were no group differences between CDP + DBT-A and CDP no DBT-A, neither at T2 nor at T3. DISCUSSION: The findings support the decision criterion for the offer of a more intense therapy after CDP. However, there was no evidence for the efficacy of additional DBT-A, which might be explained by insufficient statistical power in the current analysis.

The long shadow of early-change patterns: a 3-year follow-up after the use of a web-based intervention for mild to moderate depressive symptoms.

Web-based interventions can be effective in treating depressive symptoms. Patients with risk not responding to treatment have been identified by early change patterns. This study aims to examine whether early changes are superior to baseline parameters in predicting long-term outcome. In a randomized clinical trial with 409 individuals experiencing mild to moderate depressive symptoms using the web-based intervention deprexis, three latent classes were identified (early response after registration, early response after screening and early deterioration) based on early change in the first four weeks of the intervention. Baseline variables and these classes were included in a Stepwise Cox Proportional Hazard Multiple Regression to identify predictors associated with the onset of remission over 36-months. Early change class was a significant predictor of remission over 36 months. Compared to early deterioration after screening, both early response after registration and after screening were associated with a higher likelihood of remission. In sensitivity and secondary analyses, only change class consistently emerged as a predictor of long-term outcome. Early improvement in depression symptoms predicted long-term outcome and those showing early improvement had a higher likelihood of long-term remission. These findings suggest that early changes might be a robust predictor for long-term outcome beyond baseline parameters.

HLA dependency and possible clinical relevance of intrathecally synthesized anti-IgLON5 IgG4 in anti-IgLON5 disease.

Background: Anti-IgLON5 disease is a rare chronic autoimmune disorder characterized by IgLON5 autoantibodies predominantly of the IgG4 subclass. Distinct pathogenic effects were described for anti-IgLON5 IgG1 and IgG4, however, with uncertain clinical relevance. Methods: IgLON5-specific IgG1-4 levels were measured in 46 sera and 20 cerebrospinal fluid (CSF) samples from 13 HLA-subtyped anti-IgLON5 disease patients (six females, seven males) using flow cytometry. Intervals between two consecutive serum or CSF samplings (31 and 10 intervals, respectively) were categorized with regard to the immunomodulatory treatment active at the end of the interval, changes of anti-IgLON5 IgG1 and IgG4 levels, and disease severity. Intrathecal anti-IgLON5 IgG4 synthesis (IS) was assessed using a quantitative method. Results: The median age at onset was 66 years (range: 54-75), disease duration 10 years (range: 15-156 months), and follow-up 25 months (range: 0-83). IgLON5-specific IgG4 predominance was observed in 38 of 46 (83%) serum and 11 of 20 (55%) CSF samples. Anti-IgLON5 IgG4 levels prior clinical improvement in CSF but not serum were significantly lower than in those prior stable/progressive disease. Compared to IgLON5 IgG4 levels in serum, CSF levels in HLA-DRB1*10:01 carriers were significantly higher than in non-carriers. Indeed, IgLON5-specific IgG4 IS was demonstrated not only in four of five HLA-DRB1*10:01 carriers but also in one non-carrier. Immunotherapy was associated with decreased anti-IgGLON5 IgG serum levels. In CSF, lower anti-IgLON5 IgG was associated with immunosuppressive treatments used in combination, that is, corticosteroids and/or azathioprine plus intravenous immunoglobulins or rituximab. Conclusion: Our findings might indicate that CSF IgLON5-specific IgG4 is frequently produced intrathecally, especially in HLA-DRB1*10:01 carriers. Intrathecally produced IgG4 may be clinically relevant. While many immunotherapies reduce serum IgLON5 IgG levels, more intense immunotherapies induce clinical improvement and may be able to target intrathecally produced anti-IgLON5 IgG. Further studies need to confirm whether anti-IgLON5 IgG4 IS is a suitable prognostic and predictive biomarker in anti-IgLON5 disease.

Immunophenotyping in routine clinical practice for predicting treatment response and adverse events in patients with MS.

Background: Recent studies proposed cellular immunoprofiling as a surrogate for predicting treatment response and/or stratifying the occurrence of adverse events (AEs) in persons with multiple sclerosis (pwMS). However, applicability in real-world circumstances is not sufficiently addressed. Objective: We aimed to explore whether standard routine clinical leukocyte phenotyping before treatment initiation could help stratify patients according to treatment response or AEs in a real-world MS cohort. Methods: In this retrospective study, 150 pwMS were included, who had been newly initiated on a disease-modifying drug (DMD) and had been assessed for standard immunophenotyping before DMD initiation (baseline) and at least once during the following year. Multivariate models were used to assess an association of immune subsets and the association between immune cell profiles regarding treatment response and AEs. Results: We found that the composition of T cell subsets was associated with relapse activity, as an increased proportion of CD8+ lymphocytes at baseline indicated a higher likelihood of subsequent relapse (about 9% per 1% increase in CD8+ proportion of all CD3+ cells). This was particularly driven by patients receiving anti-CD20 therapy, where also EDSS worsening was associated with a higher number of CD8+ cells at baseline (3% increase per 10 cells). In the overall cohort, an increase in the proportion of NK cells was associated with a higher risk of EDSS worsening (5% per 1% increase). Occurrence of AEs was associated with a higher percentage of T cells and a lower number of percentual NKT cells at baseline. Conclusion: Immune cell profiles are associated with treatment response and the occurrence of AEs in pwMS. Hence, immunophenotyping may serve as a valuable biomarker to enable individually tailored treatment strategies in pwMS.

Different lymphocyte counts of multiple sclerosis patients treated with ofatumumab and ocrelizumab: A retrospective observational study.

Introduction: Patients with Multiple Sclerosis (pwMS) treated with anti-CD20 (cluster of differentiation) monoclonal antibodies (mAbs) such as ocrelizumab (OCR) and ofatumumab (OFA) show a reduction mainly of B-lymphocytes, but also other lymphocyte subsets can be affected by these treatments. There is limited data on differences between lymphocyte subset counts of pwMS after treatment initiation with OCR or OFA. Objective: To compare lymphocyte subset counts after treatment initiation in pwMS treated with OCR and OFA. Methods: We analyzed 22 pwMS initiated on OFA and 56 sex-, age- and MS course matched pwMS initiated on OCR from 2 prospectively collected observational MS databases (Bern [n: OFA 14, OCR 44] and Vienna [n: OFA 8, OCR 12]) statistically comparing lymphocyte subset counts (Mann Whitney Test). Results: We found that pwMS treated with OCR showed a stronger reduction of CD20 B-lymphocytes (P = .001), and a trend towards lower counts of CD8+ T cells (P = .056) compared to pwMS treated with OFA, whereas reduction of total lymphocyte, CD4+ lymphocyte and NK cell count was equally distributed between both treatments. Conclusion: Different effects on lymphocyte subpopulations appear to be present in pwMS after treatment initiation with different anti-CD20 mAbs. Further studies are needed to determine potential effects on anti-CD20 treatment efficacy as well as treatment associated risks such as failed vaccinations and infections.

Role of Intragap States in Sensitized Sb-Doped Tin Oxide Photoanodes for Solar Fuels Production.

In view of developing photoelectrosynthetic cells which are able to store solar energy in chemical bonds, water splitting is usually the reaction of choice when targeting hydrogen production. However, alternative approaches can be considered, aimed at substituting the anodic reaction of water oxidation with more commercially capitalizable oxidations. Among them, the production of bromine from bromide ions was investigated long back in the 1980s by Texas Instruments. Herein we present optimized perylene-diimide (PDI)-sensitized antimony-doped tin oxide (ATO) photoanodes enabling the photoinduced HBr splitting with >4 mA/cm2 photocurrent densities under 0.1 W/cm2 AM1.5G illumination and 91 ± 3% faradaic efficiencies for bromine production. These remarkable results, among the best currently reported for the photoelectrochemical Br- oxidation by dye sensitized photoanodes, are strongly related to the occupancy extent of ATO's intragap (IG) states, generated upon Sb-doping, as demonstrated by comparing their performances with PDI-sensitized analogues on both undoped SnO2- and TiO2-passivated ATO scaffolds by means of (spectro)electrochemistry and electrochemical impedance spectroscopy. The architecture of the ATO-PDI photoanodic assembly was further modified via the introduction of a molecular iridium-based water oxidation catalyst, thus proving the versatility of the proposed hybrid interfaces as photoanodic platforms for photoinduced oxidations in PEC devices.

Comparison of the Working Alliance in Blended Cognitive Behavioral Therapy and Treatment as Usual for Depression in Europe: Secondary Data Analysis of the E-COMPARED Randomized Controlled Trial.

BACKGROUND: Increasing interest has centered on the psychotherapeutic working alliance as a means of understanding clinical change in digital mental health interventions in recent years. However, little is understood about how and to what extent a digital mental health program can have an impact on the working alliance and clinical outcomes in a blended (therapist plus digital program) cognitive behavioral therapy (bCBT) intervention for depression. OBJECTIVE: This study aimed to test the difference in working alliance scores between bCBT and treatment as usual (TAU), examine the association between working alliance and depression severity scores in both arms, and test for an interaction between system usability and working alliance with regard to the association between working alliance and depression scores in bCBT at 3-month assessments. METHODS: We conducted a secondary data analysis of the E-COMPARED (European Comparative Effectiveness Research on Blended Depression Treatment versus Treatment-as-usual) trial, which compared bCBT with TAU across 9 European countries. Data were collected in primary care and specialized services between April 2015 and December 2017. Eligible participants aged 18 years or older and diagnosed with major depressive disorder were randomized to either bCBT (n=476) or TAU (n=467). bCBT consisted of 6-20 sessions of bCBT (involving face-to-face sessions with a therapist and an internet-based program). TAU consisted of usual care for depression. The main outcomes were scores of the working alliance (Working Alliance Inventory-Short Revised-Client [WAI-SR-C]) and depressive symptoms (Patient Health Questionnaire-9 [PHQ-9]) at 3 months after randomization. Other variables included system usability scores (System Usability Scale-Client [SUS-C]) at 3 months and baseline demographic information. Data from baseline and 3-month assessments were analyzed using linear regression models that adjusted for a set of baseline variables. RESULTS: Of the 945 included participants, 644 (68.2%) were female, and the mean age was 38.96 years (IQR 38). bCBT was associated with higher composite WAI-SR-C scores compared to TAU (B=5.67, 95% CI 4.48-6.86). There was an inverse association between WAI-SR-C and PHQ-9 in bCBT (B=-0.12, 95% CI -0.17 to -0.06) and TAU (B=-0.06, 95% CI -0.11 to -0.02), in which as WAI-SR-C scores increased, PHQ-9 scores decreased. Finally, there was a significant interaction between SUS-C and WAI-SR-C with regard to an inverse association between higher WAI-SR-C scores and lower PHQ-9 scores in bCBT (b=-0.030, 95% CI -0.05 to -0.01; P=.005). CONCLUSIONS: To our knowledge, this is the first study to show that bCBT may enhance the client working alliance when compared to evidence-based routine care for depression that services reported offering. The working alliance in bCBT was also associated with clinical improvements that appear to be enhanced by good program usability. Our findings add further weight to the view that the addition of internet-delivered CBT to face-to-face CBT may positively augment experiences of the working alliance. TRIAL REGISTRATION: ClinicalTrials.gov NCT02542891, https://clinicaltrials.gov/study/NCT02542891; German Clinical Trials Register DRKS00006866, https://drks.de/search/en/trial/DRKS00006866; Netherlands Trials Register NTR4962, https://www.onderzoekmetmensen.nl/en/trial/25452; ClinicalTrials.Gov NCT02389660, https://clinicaltrials.gov/study/NCT02389660; ClinicalTrials.gov NCT02361684, https://clinicaltrials.gov/study/NCT02361684; ClinicalTrials.gov NCT02449447, https://clinicaltrials.gov/study/NCT02449447; ClinicalTrials.gov NCT02410616, https://clinicaltrials.gov/study/NCT02410616; ISRCTN Registry ISRCTN12388725, https://www.isrctn.com/ISRCTN12388725?q=ISRCTN12388725&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10; ClinicalTrials.gov NCT02796573, https://classic.clinicaltrials.gov/ct2/show/NCT02796573. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-016-1511-1.

Novel and Emerging Treatments to Target Pathophysiological Mechanisms in Various Phenotypes of Multiple Sclerosis.

The objective is to comprehensively review novel pharmacotherapies used in multiple sclerosis (MS) and the possibilities they may carry for therapeutic improvement. Specifically, we discuss pathophysiological mechanisms worth targeting in MS, ranging from well known targets, such as autoinflammation and demyelination, to more novel and advanced targets, such as neuroaxonal damage and repair. To set the stage, a brief overview of clinical MS phenotypes is provided, followed by a comprehensive recapitulation of both clinical and paraclinical outcomes available to assess the effectiveness of treatments in achieving these targets. Finally, we discuss various promising novel and emerging treatments, including their respective hypothesized modes of action and currently available evidence from clinical trials. SIGNIFICANCE STATEMENT: This comprehensive review discusses pathophysiological mechanisms worth targeting in multiple sclerosis. Various promising novel and emerging treatments, including their respective hypothesized modes of action and currently available evidence from clinical trials, are reviewed.

Clinical effectiveness of internet-based cognitive behavioral therapy for insomnia in routine secondary care: results of a randomized controlled trial.

Introduction: Delivering cognitive behavioral therapy for insomnia over the internet bears the advantage of accessibility and uptake to many patients suffering from chronic insomnia. In the current study, we aimed to investigate the effectiveness of internet-based cognitive behavioral therapy for insomnia (iCBT-I) in routine care. Materials and methods: We conducted a two-arm non-blinded randomized controlled trial with care as usual (CAU) as a control condition. Participants were recruited in a specialized outpatient sleep medicine department. Both arms had access to other healthcare resources, and the intervention group had access to the iCBT-I program for 2 months. The primary outcome was insomnia severity, measured by the Insomnia Severity Index (ISI). Secondary outcomes were fatigue severity, daytime sleepiness, affective symptoms, dysfunctional beliefs and attitudes about sleep, sleep locus of control, sleep hygiene, sleep efficiency (SE), sleep onset latency, wake time after sleep onset (WASO), and total sleep time (TST). Linear mixed models for repeated measures were used to analyze the longitudinal data at baseline, post-treatment, and after 3 months of follow-up. The trial was registered at www.clinicaltrials.gov (NCT04300218 21.04.2020). Results: The results showed a significant time*group interaction effect (p = 0.001) at post-treatment with between-group effect size (d = 0.51), indicating that the ISI decreased by a score of 3.8-fold in the iCBT-I group than in the CAU group. There was no significant difference in ISI between groups at follow-up. Regarding secondary outcomes, dysfunctional beliefs about sleep, SE, and WASO decreased significantly during treatment in the intervention group with between-group effect sizes d = 0.35, d = -0.51, and d = 0.47, respectively. At the follow-up, between-group effects on DBAS and SE remained significant: d = 0.36 and d = -0.63, respectively. For TST, we observed a significant time*group effect of d = -0.38 only after follow-up. Conclusion: Our findings suggest that iCBT-I has a significant effect on insomnia severity at post-treatment compared to CAU. iCBT-I further improved dysfunctional beliefs about sleep and improved subjective sleep characteristics, such as SE, WASO, and TST during 3 months after treatment. Clinical trial registration: www.clinicaltrials.gov, identifier (NCT04300218).

Alemtuzumab treatment for multiple sclerosis in Austria: An observational long-term outcome study.

BACKGROUND/OBJECTIVE: Observational real-world study to analyze the clinical effects of alemtuzumab (ALEM) and subsequent disease-modifying therapy (DMT) usage in multiple sclerosis (MS). METHODS: Data retrieved from the Austrian MS treatment registry (AMSTR) included baseline (BL) characteristics (at ALEM start), annualized relapse rate (ARR), 6-month confirmed progression independent of relapse activity (PIRA; ≥ 0.5-point Expanded Disability Status Scale (EDSS) score increase), 6-month confirmed disability improvement (CDI; ≥ 0.5-point EDSS decrease), and safety outcomes until initiation of a subsequent DMT. The EDSS was re-baselined at 30 days from ALEM start (BL EDSS). RESULTS: Eighty-seven ALEM-treated patients (median age: 32 years, 72% female, 14% treatment-naïve) were followed for a median of 55 (interquartile range 31-68) months. We found significant reductions in the ARR from 1.16 before ALEM to 0.15 throughout Years 1-9 (p < 0.001). Subsequent DMTs were initiated in 19 patients (22%, 74% anti-CD20 monoclonal antibodies). At Year 5 (n = 53), more patients achieved CDI (58%, 95% confidence interval (CI) 45%-71%) than had experienced PIRA (14%, CI 7.5%-24%), and 58% remained relapse-free. Shorter MS duration (p < 0.001, hazard ratio (HR) 0.86 (CI 0.80-0.93)) and no previous high-efficacy treatment (p < 0.001, HR 5.16 (CI 2.66-10.0)) were the best predictors of CDI, while PIRA was associated with a higher number of previous DMTs (p = 0.04, HR 3.06, CI 1.05-8.89). We found no new safety signals. INTERPRETATION: ALEM had long-lasting beneficial effects on the ARR and disability improvement, especially when initiated early in the course of the disease. Only a subset of patients received subsequent DMTs.

Managing multiple sclerosis in individuals aged 55 and above: a comprehensive review.

Multiple Sclerosis (MS) management in individuals aged 55 and above presents unique challenges due to the complex interaction between aging, comorbidities, immunosenescence, and MS pathophysiology. This comprehensive review explores the evolving landscape of MS in older adults, including the increased incidence and prevalence of MS in this age group, the shift in disease phenotypes from relapsing-remitting to progressive forms, and the presence of multimorbidity and polypharmacy. We aim to provide an updated review of the available evidence of disease-modifying treatments (DMTs) in older patients, including the efficacy and safety of existing therapies, emerging treatments such as Bruton tyrosine kinase (BTKs) inhibitors and those targeting remyelination and neuroprotection, and the critical decisions surrounding the initiation, de-escalation, and discontinuation of DMTs. Non-pharmacologic approaches, including physical therapy, neuromodulation therapies, cognitive rehabilitation, and psychotherapy, are also examined for their role in holistic care. The importance of MS Care Units and advance care planning are explored as a cornerstone in providing patient-centric care, ensuring alignment with patient preferences in the disease trajectory. Finally, the review emphasizes the need for personalized management and continuous monitoring of MS patients, alongside advocating for inclusive study designs in clinical research to improve the management of this growing patient demographic.