Validation of the predictive value of BDNF -87 methylation for antidepressant treatment success in severely depressed patients-a randomized rater-blinded trial.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is essential for antidepressant treatment of major depressive disorder (MDD). Our repeated studies suggest that DNA methylation of a specific CpG site in the promoter region of exon IV of the BDNF gene (CpG -87) might be predictive of the efficacy of monoaminergic antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others. This trial aims to evaluate whether knowing the biomarker is non-inferior to treatment-as-usual (TAU) regarding remission rates while exhibiting significantly fewer adverse events (AE). METHODS: The BDNF trial is a prospective, randomized, rater-blinded diagnostic study conducted at five university hospitals in Germany. The study's main hypothesis is that {1} knowing the methylation status of CpG -87 is non-inferior to not knowing it with respect to the remission rate while it significantly reduces the AE rate in patients experiencing at least one AE. The baseline assessment will occur upon hospitalization and a follow-up assessment on day 49 (± 3). A telephone follow-up will be conducted on day 70 (± 3). A total of 256 patients will be recruited, and methylation will be evaluated in all participants. They will be randomly assigned to either the marker or the TAU group. In the marker group, the methylation results will be shared with both the patient and their treating physician. In the TAU group, neither the patients nor their treating physicians will receive the marker status. The primary endpoints include the rate of patients achieving remission on day 49 (± 3), defined as a score of ≤ 10 on the Hamilton Depression Rating Scale (HDRS-24), and the occurrence of AE. ETHICS AND DISSEMINATION: The trial protocol has received approval from the Institutional Review Boards at the five participating universities. This trial holds significance in generating valuable data on a predictive biomarker for antidepressant treatment in patients with MDD. The findings will be shared with study participants, disseminated through professional society meetings, and published in peer-reviewed journals. TRIAL REGISTRATION: German Clinical Trial Register DRKS00032503. Registered on 17 August 2023.

Are Patient-Reported Outcome Scores a Reasonable Substitute for Clinical Follow-up After Surgically Managed Acromioclavicular Joint Injuries?

Background: Various clinical outcome scores have been described to evaluate postoperative shoulder function after operatively treated acromioclavicular joint (ACJ) instability. Clinical outcome scores can be divided between patient-reported outcome measures (PROMs) and examiner-dependent outcome measures (EDOMs) after a clinical examination by a physician. The correlation between PROMs and EDOMs, and thus their interchangeability with regard to operatively treated ACJ instability, has not yet been evaluated. Purpose: To investigate whether PROMs are a reasonable substitute for EDOMs. Correlations between global shoulder (GS) and ACJ-specific outcome measures were also investigated. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: Included in this study were 131 consecutive patients with operatively treated ACJ instability between 2011 and 2017. Postoperative shoulder function was measured using PROMs, including the Subjective Shoulder Value (SSV), Subjective Shoulder Test, and Nottingham Clavicle Score (NCS), and EDOMs, including the Constant-Murley score (CMS), Taft score, ACJ instability (ACJI) score, and SICK Scapula Score (SSS). Associations between PROM and EDOM scores were calculated using the Pearson and Spearman correlation coefficients for linear and nonlinear variables, respectively, and were interpreted using the Cohen classification. The scores were further stratified into GS versus ACJ-specific measures. Results: A strong correlation was observed between several PROMs and EDOMs (CMS vs SSV [r = 0.59; P = .02] and CMS vs NCS [r = 0.79; P ≤ .001]) and between several GS and ACJ-specific scores (CMS vs NCS; CMS vs ACJI [rs = 0.69; P < .001]; and CMS vs SSS [r = -0.68; P < .001]). Conclusion: Based on the results of this study, PROMs such as the SSV (a GS measure) and the NCS (an ACJ-specific measure) can substitute for EDOMs. Clinical Relevance: PROMs that can be substituted for EDOMs can enable the conduct of clinical studies in circumstances in which in-person clinical follow-up of the patient by a physician is not possible.

Maternal and neonatal outcomes of pregnancies with COVID-19 after medically assisted reproduction: results from the prospective COVID-19-Related Obstetrical and Neonatal Outcome Study.

BACKGROUND: Severe acute respiratory syndrome coronavirus type 2 infections in pregnancy have been associated with maternal morbidity, admission to intensive care, and adverse perinatal outcomes such as preterm birth, stillbirth, and hypertensive disorders of pregnancy. It is unclear whether medically assisted reproduction additionally affects maternal and neonatal outcomes in women with COVID-19. OBJECTIVE: To evaluate the effect of medically assisted reproduction on maternal and neonatal outcomes in women with COVID-19 in pregnancy. STUDY DESIGN: A total of 1485 women with COVID-19 registered in the COVID-19 Related Obstetric and Neonatal Outcome Study (a multicentric, prospective, observational cohort study) were included. The maternal and neonatal outcomes in 65 pregnancies achieved with medically assisted reproduction and in 1420 spontaneously conceived pregnancies were compared. We used univariate und multivariate (multinomial) logistic regressions to estimate the (un)adjusted odds ratios and 95% confidence intervals for adverse outcomes. RESULTS: The incidence of COVID-19-associated adverse outcomes (eg, pneumonia, admission to intensive care, and death) was not different in women after conceptions with COVID-19 than in women after medically assisted reproduction pregnancies. Yet, the risk of obstetrical and neonatal complications was higher in pregnancies achieved through medically assisted reproduction. However, medically assisted reproduction was not the primary risk factor for adverse maternal and neonatal outcomes including pregnancy-related hypertensive disorders, gestational diabetes mellitus, cervical insufficiency, peripartum hemorrhage, cesarean delivery, preterm birth, or admission to neonatal intensive care. Maternal age, multiple pregnancies, nulliparity, body mass index >30 (before pregnancy) and multiple gestation contributed differently to the increased risks of adverse pregnancy outcomes in women with COVID-19 independent of medically assisted reproduction. CONCLUSION: Although women with COVID-19 who conceived through fertility treatment experienced a higher incidence of adverse obstetrical and neonatal complications than women with spontaneous conceptions, medically assisted reproduction was not the primary risk factor.

Effects of an Interdisciplinary Integrative Oncology Group-Based Program to Strengthen Resilience and Improve Quality of Life in Cancer Patients: Results of a Prospective Longitudinal Single-Center Study.

BACKGROUND: Patients with cancer receiving oncological treatment often suffer from a reduced quality of life (QoL) and resilience. OBJECTIVES: The aim of this study was to evaluate the effect of an interdisciplinary integrative oncology group-based program on resilience and quality of life in patients with cancer during or after conventional oncological therapy. METHODS: This prospective longitudinal single-center study evaluated the resilience (Resilience Scale), quality of life (EORTC-QLQ C30), anxiety, depression (Hospital Anxiety and Depression Scale), and distress levels (Distress Thermometer) of 60 patients with cancer who participated in a 10-week interdisciplinary integrative oncology group-based program during or after cancer treatment in outpatient clinics. An average of 12 (range 11-13) patients participated in each 10-week group. The program included recommendations for diet, stress management, relaxation, and exercise, as well as naturopathic self-help strategies and psychosocial support. RESULTS: There were slight increases in global quality of life scores (week 0: 58.05 ± 20.05 vs week 10: 63.13 ± 18.51, n = 59, P = .063, d = -.25) and resilience scores (week 0: 63.50 ± 13.14 vs week 10: 66.15 ± 10.17, n = 52, P = .222, d = -.17) after the group program compared to before; however, these changes were not statistically significant and had small effect sizes. Patients with at least moderate anxiety symptoms (P = .022, d = .42) and low resilience (P = .006, d = -.54) benefited most from the program. The patients reported no relevant side effects or adverse events from the program. CONCLUSIONS: No significant effects on global quality of life or resilience were found in the general sample; notably, patients with anxiety and low initial resilience benefited the most from the program.

Pregnancy Outcomes After Frozen-Thawed Embryo Transfer in the Absence of a Corpus Luteum.

Background: Nowadays, frozen-thawed embryo transfer (FET) cycles represent a high proportion of fertility treatments worldwide. Recent studies suggest differences in pregnancy outcomes depending on the FET treatment protocol used. The reason for this is still unclear, but the number of corpora lutea (CL) at conception is discussed as a possible factor. This study aims to investigate whether maternal and neonatal outcomes for pregnancies following FET lacking a CL differ from FET with one or more CL in order to explore a potential link between CL absence and adverse pregnancy outcomes. Methods: The study was designed as a retrospective, multi-center observational study with two cohorts after singleton live birth [0 CL cohort (FET in a programmed cycle, n = 114) and ≥ 1 CL cohort (FET in a natural or stimulated cycle, n = 68)]. Participants completed a questionnaire on the outcome of pregnancy and birth records were analyzed in a descriptive way. Multivariable logistic and linear regressions were performed in order to explore associations between CL absence and pregnancy outcomes. The strength of the agreement between the information in the survey and the diagnoses extracted from the files was assessed by Cohen's Kappa. Results: The risk of hypertensive disorders of pregnancy was higher after FET in the absence of a CL compared to FET with CL presence (aOR 5.56, 95% CI 1.12 - 27.72). Birthweights and birthweight percentiles were significantly higher in the 0 CL group. CL absence was a predictor of higher birthweight (adjusted coefficient B 179.74, 95% CI 13.03 - 346.44) and higher birthweight percentiles (adjusted coefficient B 10.23, 95%, 95% CI 2.28 - 18.40) particularly in female newborns of the 0 CL cohort. While the strength of the agreement between the reported information in the survey and the actual diagnoses extracted from the files was good for the majority of outcomes of interest it was fair in terms of hypertension (κ = 0.38). Conclusion: This study supports observations suggesting a potential link between a lack of CL at conception and adverse maternal and neonatal outcomes. Further investigations on causes and pathophysiological relationships are yet to be conducted.

Evaluation of treatment-associated eye toxicity after irradiation in childhood and adolescence-results from the Registry of the Evaluation of Side Effects after Radiotherapy in Childhood and Adolescence (RiSK).

PURPOSE: The aim of the study is to evaluate treatment-related acute and late eye toxicity associated with radiation therapy in childhood and adolescence as correlated with RT (radiotherapy) doses. METHODS: From 2001 to 2016, a total of 1725 children and adolescents undergoing radiation therapy were prospectively documented in the Registry of the Evaluation of Side Effects after Radiotherapy in Childhood and Adolescence (RiSK). The RTOG/EORTC criteria were used to classify ocular acute and late effects. Uni- and multivariate analyses were carried out to evaluate the impact of patient age, pre-existing impairments, and radiation dose on ocular toxicity. RESULTS: Of all documented patients, 593 received dose to the eye and formed the basis of this analysis. In 435 patients, information on acute reaction was available and graded 1, 2, 3, and 4 in 49, 17, 0, and 2 patients, respectively. Information on late toxicity was available in 268 patients and graded 1, 2, 3, and 4 in 15, 11, 11, and 5 patients, respectively. The acute toxicity rate was significantly higher in children who received a maximum dose > 50 Gy to the eye (p < 0.001) and who had a pre-existing eye impairment (p < 0.001 in multivariate analysis). The development of late toxicity was significantly higher for patients experiencing acute toxicity and having received a radiation dose > 50 Gy. CONCLUSION: Acute and late toxicity both correlate with high radiation dose to the eye (> 50 Gy) and acute toxicity additionally with pre-existing eye impairments.

Does it help that efficacy has been proven once we start discussing (added) benefit?

Since the introduction of benefit assessment to support reimbursement decisions in Germany there seems to be the impression that totally distinct methodology and strategies for decision making would apply in the field of drug licensing and reimbursement. In this article, the position is held that, while decisions may differ due to differing mandates of drug licensing and reimbursement bodies, the underlying strategies are quite similar. For this purpose, we briefly summarize the legal basis for decision making in both fields from a methodological point of view, and review two recent decisions about reimbursement regarding grounds for approval. We comment on two examples, where decision making was based on the same pivotal studies in the licensing and reimbursement process. We conclude that strategies in the field of reimbursement are (from a methodological standpoint) until now more liberal than established rules in the field of drug licensing, but apply the same principles. Formal proof of efficacy preceding benefit assessment can thus be understood as a gatekeeper against principally wrong decision making about efficacy and risks of new drugs in full recognition that more is needed. We elaborate on the differences between formal proof of efficacy on the one hand and the assessment of benefit/risk or added benefit on the other hand, because it is important for statisticians to understand the difference between the two approaches.

Radiofrequency endometrial ablation for the treatment of heavy menstrual bleeding among women at high surgical risk.

OBJECTIVE: To evaluate quality of life (QoL) after radiofrequency endometrial ablation (RFEA) for heavy menstrual bleeding among women at high surgical risk. METHODS: An observational study was undertaken among women aged at least 18 years who underwent RFEA at Hanover Medical School, Germany, between June 2010 and November 2012. A validated menorrhagia outcomes questionnaire (MOQ) was used to evaluate QoL and global outcomes among patients at high risk and low risk of complications after major surgery. The high-risk group included women with anemia, coagulopathy, anticoagulation, thromboembolism, transplantation, malignancy, severe cardiovascular or pulmonary disease, and obesity. RESULTS: Overall, 235 women underwent RFEA during the study period. Median follow-up was 13 months (range 3-30). Questionnaire responses were received from 202 (86.0%) women, including 132 (65.3%) high-risk patients. The MOQ total outcome (mean difference 2.0; P = 0.166) and QoL/satisfaction (mean difference 0.8; P = 0.601) scores were similar in the two groups. Success (i.e. symptom relief and no further surgery) was recorded for 119 (90.2%) patients in the high-risk group and 67 (95.7%) patients in the low-risk group (P = 0.155). CONCLUSION: RFEA improved QoL and achieved a high rate of satisfaction for both high- and low-risk patients. RFEA offers a less invasive alternative to hysterectomy and its associated perioperative risks, particularly among high-risk patients.

Self-selected intensity exercise in the treatment of major depression: A pragmatic RCT.

OBJECTIVE: The purpose of the study was to determine the therapeutic effect of physical exercise for patients with unipolar depression. Participants took part in an 8-week walking/running aerobic exercise program at a local sports club. METHODS: Forty-six outpatients aged 18-65 years and diagnosed with mild to severe depression (ICD-10 criteria) were randomly assigned to an intervention group or wait list. Treatment as usual was continued. The Hamilton Rating Scale for Depression (HRSD-17) served as the main outcome measure. Secondary outcome measures were Beck Depression Inventory (BDI-II), Fitness Index (FI), and VO(2) max as estimated by Urho Kaleka Kekkonen or UKK 2-km Walk Test. RESULTS: Out of forty-six participants, 24% dropped out. Participants attended 58% of exercise sessions. All randomized participants were included in intention-to-treat (ITT) analysis. Analysis of covariance or ANCOVA showed a large reduction of depressive symptoms in HRSD-17 scores (Cohen's d: 1.8; mean change 8.2, p < .0001). BDI-II (Cohen's d: 0.50; mean change: 4.7, p = 0.09), FI scores (Cohen's d: 0.27; mean change: 5.3, p = 0.08), and VO2 max did not change significantly. CONCLUSIONS: We observed a large and clinically significant change in HRSD-17 scores. Moderate changes in BDI-II scores without clinical significance and small changes in physical fitness assessments were observed.

The implications for the biological and sociodynamic causal explanations of attitudes toward alcohol-dependent patients.

This study tested whether sole neurobiological or sociodynamic explanations of alcohol dependence altered respondents' attitudes toward alcohol-dependent patients. We investigated the effect of information leaflets on 444 participants: one group received an information leaflet with a biological explanation of AD; the other received a leaflet with a sole sociodynamic explanation of AD. A third, control group did not receive any leaflet. Afterwards, all three groups completed a questionnaire regarding their attitudes toward ADPs and their opinions of the underlying causes of AD. We found a significant group difference with regard to participants' agreement with a neurobiological explanation of AD. Moreover, respondents in the neurobiological intervention group considered the characteristics of ADP to be significantly more positive than those in the sociodynamic group. Furthermore, they were significantly less likely to accept AD as a self-inflicted disease. Correlation analysis revealed associations between accepting the sociodynamic disease model and all of the stigmatization dimensions tested in our questionnaire. In summary, stigmatization toward ADP was closely associated with the agreement with sociodynamic origins of AD in this study.