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Introduction: Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for depression of which the acute and short-term effects have been studied extensively.However, much J o u r n a l P r e -p r o o f less is known about the long-term effectiveness of rTMS.This paper aims to investigate the long-term effects of rTMS and antidepressant medication in patients with moderate treatment-resistant depression (2 treatment trials).Methods: Naturalistic follow-up data was collected for twelve months as part of a clinical trial comparing rTMS and antidepressant medication.Response and remission based on the Hamilton Depression Rating Scale (HDRS-17) were calculated for both groups at end of treatment, as well as at four-, six-, nine-and twelve-months follow-up.Furthermore, the sustained effects of both treatments on anxiety, anhedonia, and rumination were investigated.Results: At the end of treatment, response and remission rates were higher in the rTMS group (40.9% and 29.5%) than in the medication group (18.8% and 6.3%).69% of the patients in the medication group received treatment with rTMS at some point during the follow-up period.Response and remission remained relatively stable over 12 months in both groups.Sustained response was observed in the majority of rTMS and medication responders for whom data was available for the full follow-up period.Conclusion: Our findings provide insights into the naturalistic long-term effects of rTMS and antidepressant medication in patients with moderate treatment-resistant depression.

It remains unclear to what extent long-term lithium use leads to significant eGFR decline. This study examines the course of eGFR in a 10-year prospective cohort of lithium users and the association with duration of lithium use, lithium serum concentration, and comedication. This 10-year prospective cohort study included patients using lithium at inclusion. Medical records were reviewed for lithium concentration, eGFR, discontinuation of lithium, and other medication use. Primary outcome was a description of eGFR decline, quantified as delta eGFR per year of follow-up. In total 196 patients were analyzed (42% male, mean age 51.1 ± 12.2, median follow-up time 8.8 years [IQR 1.3]). Median yearly decline was 0.79 mL/min/1.73 m2. Of the participants, 48% had a yearly decline between 0.5 and 2.5 mL/min/1.73 m2, while 11% showed a decline > 2.5 mL/min/1.73 m2. Duration of lithium use was associated with eGFR decline. A positive association between lithium serum concentration and kidney function decline was shown, when corrected for age, sex and duration of lithium use. Comedication was not associated with eGFR decline. In the participants who discontinued lithium (20%) during follow up, there was no significant difference in eGFR before and after cessation. This study provides further evidence that eGFR decline occurs in most long-term lithium users. Of this cohort, 59% of the participants had faster eGFR decline than the mean decline in the general population. Lithium exposure, quantified as mean serum lithium concentration, could be a contributing factor in this decline. eGFR trajectory was not altered by ceasing lithium.

Randomized controlled trials (RCTs) are the foundation of current clinical treatment guidelines. However, they may not reflect real-world populations, due to strict eligibility criteria. We determined the proportion of individuals with major depressive disorder (MDD) receiving maintenance antidepressant treatment in routine care who would be ineligible for RCTs, and compared their outcomes with those who were eligible. Utilizing specialized health care registers in Finland (2004-2018) and Sweden (2006-2021), we identified adults diagnosed with non-psychotic MDD (ICD-10: F32, F33) who were stabilized on maintenance antidepressant monotherapy. Through multidisciplinary expert consensus on latest meta-analytic evidence, we derived a standardized list of RCT inclusion and exclusion criteria. These criteria were systematically applied to classify individuals as RCT-eligible or RCT-ineligible. We then used Cox proportional models to derive hazard ratios (HRs) of a composite primary outcome of hospitalization due to any psychiatric reason or suicide attempt, and all-cause mortality, during a 6-month follow-up. Secondary outcomes were treatment changes (i.e., discontinuation, switch or augmentation) and psychiatric sick leave ≥2 weeks. A total of 73,720 individuals in Finland and 135,092 in Sweden were included. More than one third of patients with MDD (33.5% in Finland and 35.3% in Sweden) were found to be ineligible for RCTs. The most common reasons for ineligibility were comorbidities (serious somatic disease, other psychiatric disorders, or substance use disorder). RCT-ineligible individuals had more than twice the risk of the composite primary outcome compared to eligible individuals (HR=2.44, 95% CI: 2.15-2.76 in Finland; HR=2.61, 95% CI: 2.37-2.87 in Sweden). Approximately one third of the composite primary outcome was attributable to RCT-ineligibility factors (32.5%, 95% CI: 27.9-37.1 for Finland; 36.2%, 95% CI: 32.6-39.8 for Sweden). Risk of treatment change was slightly but significantly higher in ineligible individuals. Findings were consistent in a wide range of sensitivity analyses. We conclude that more inclusive eligibility criteria for RCTs, and their integration with real-world data, are needed to improve the generalizability of antidepressant trial evidence and MDD clinical treatment guidelines.

Are you what your mother eats? The first 1,000 days of life—from conception to age two—are critical for a child’s health. Nutrition during this time shapes growth, immunity, and gut health. While much attention has been given to diet during pregnancy, less is known about whether maternal diet while breastfeeding influences baby’s risk of developing allergies. This research explored whether a mother’s diet during lactation influences her baby’s risk of developing eczema or food allergies. Using data from the PRIMA birth cohort, which followed over 1000 mother-infant pairs in the Utrecht region, we studied up to 272 mothers’ diets and their babies’ health during the first year of life. Based on previously published studies, we generated a systematic summary and observed that the consumption of complex fatty acids like omega-3 fatty acids relates to the level of those fatty acids in breast milk. Our own analysis showed mothers’ diet is relatively stable during the first months postpartum, with the exception for some product groups, despite mother’s breastfeeding or work status. We did not observe that adherence to dietary guidelines, intake of allergenic foods (specifically eggs, milk(products), (pea)nuts), or omega-3 fatty acids associated with their babies’ risk of eczema and possible food allergies. The strongest predictor of infant eczema and food allergy symptoms in our analysis was family history, in line with findings of others. We also examined complex fiber-like sugars in breast milk, human milk oligosaccharides (HMOs), known to support immunity. The level of a specific type of glycated HMOs in breast milk did not depend on maternal dietary fiber consumption, but mostly on maternal genetics (specifically Secretor status). Nevertheless, lab experiments with different profiles of these sugars dependent on mother’s Secretor status suggest that both mother’s and baby’s genetics may influence immune responses in the presence of these oligosaccharides, and should receive intention in further research. In short, in our study population, we did not find an association between maternal diet during breastfeeding and eczema and food allergy symptoms during the first year of life. Supporting breastfeeding and healthy eating remains important for other health benefits. Additional research is needed to understand the impact of this for infant’s risk of allergic diseases.

Tumor cell plasticity drives metastasis and therapy resistance, yet its regulation by oncoprotein dosage dynamics remains poorly understood. In Ewing sarcoma (EwS), variations in EWS::FLI1 (EF) fusion oncoprotein activity have been associated with epithelial-mesenchymal plasticity (EMP). Using degron technology, we precisely modulated endogenous EF in EwS cells and linked phenotypic states to distinct oncoprotein dosages. Strikingly, modest EF depletion promoted a pro-metastatic phenotype that diminished upon near-complete EF loss, revealing a paradoxical effect of submaximal EF inhibition. Nascent RNA-sequencing uncovered distinct gene clusters with heterogenous transcriptional responses to graded EF loss. Genes most sensitive to subtle EF depletion harbored GGAA microsatellites within EF-bound enhancers, while chromatin profiling uncovered candidate cofactors regulating EF-repressed EMP programs. Transient EF depletion followed by rapid restoration, modelling oncoprotein fluctuations, caused persistent dysregulation of genes functionally linked to enhanced extravasation and metastatic burden in preclinical models. This study highlights the therapeutic challenge of incomplete EF elimination, serving a paradigm in which oncoprotein dosage dynamics act as non-genetic drivers of disease progression and reveal novel vulnerabilities of advanced disease.

Relapse prevention in bipolar disorder (BD) involves prophylactic medication, self-management, and optional adjunctive psychotherapy. Despite guideline recommendations, a significant number of patients with BD does not use prophylactic medication. How they manage their mood is unknown. We assessed the coping styles, personality traits, and the role of childhood trauma in Older Age Bipolar Disorder (OABD) living with and without prophylactic medication. Cross-sectional data from two Dutch OABD cohorts (n=280) was used to perform logistic regression analysis on coping styles (Utrecht Coping List) and personality traits (NEO Five Factor Inventory), in relation to living without prophylactic medication. The role of childhood trauma was assessed with correlation and interaction analysis. We identified the best predictors using LASSO regression. Active problem solving (OR 1.25, 95% CI [1.10-1.45]), passive reaction (OR 1.34, 95% CI [1.10-1.66]), and comforting cognitions (OR 0.80, 95% CI [0.65-0.96]) were associated with living without prophylactic medication, while personality traits were not associated. Childhood abuse interacted with active problem solving and passive reaction in prophylactic medication usage. The best predictive model accounted for 35.5% of the variance in prophylactic medication usage, with active problem solving, passive reaction, extraversion, and neuroticism being positively associated, while comforting cognitions and openness were negatively associated. In OABD, the coping styles active problem solving and passive reaction are associated with living without prophylactic medication, while comforting cognition is negatively associated. Future research should include a larger sample size of all ages and follow-up measurements to replicate our findings.

Abstract Background Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment for obsessive-compulsive disorder (OCD), but response rates are variable. Pre-treatment characteristics of the stimulated region can influence rTMS treatment outcome. Objective/hypothesis We investigated the relationship between network features of the rTMS stimulation location and treatment outcome in a randomised trial of rTMS for OCD, using graph analysis of single-layer functional and structural brain networks, and of structural-functional multilayer networks. Methods We analysed data from 58 treatment-refractory adult OCD patients. Participants received either: high frequency (HF) rTMS to the left dorsolateral prefrontal cortex (DLPFC) (n=19); HF rTMS to the left pre-supplementary motor area (preSMA) (n=21); or control rTMS to the vertex (n=18). We used pre-treatment resting state functional MRI (rs-fMRI) and diffusion MRI (dMRI) scans to construct single-layer and structural-functional multilayer networks for each participant. We computed various centrality measures of the stimulated location and connected subnetwork, and examined their relationship with treatment outcome. Results We found no associations between functional or structural single-layer network characteristics and treatment outcome. However, higher average multilayer betweenness centrality of the stimulated subnetwork in the DLPFC rTMS group (but not in the preSMA or vertex groups) was associated with greater symptom reduction (p=0.013). Conclusions Participants with greater integration of the stimulated subnetwork with the rest of the structural-functional network showed greater improvement following DLPFC rTMS. Our results give a preliminary indication that the outcome of rTMS treatment for OCD is dependent on the interplay between structural and functional networks.