Human biodistribution and radiation dosimetry of the demyelination tracer [18F]3F4AP.

PURPOSE: [18F]3F4AP is a novel PET radiotracer that targets voltage-gated potassium (K+) channels and has shown promise for imaging demyelinated lesions in animal models of neurological diseases. This study aimed to evaluate the biodistribution, safety, and radiation dosimetry of [18F]3F4AP in healthy human volunteers. METHODS: Four healthy volunteers (2 females) underwent a 4-h dynamic PET scan from the cranial vertex to mid-thigh using multiple bed positions after administration of 368 ± 17.9 MBq (9.94 ± 0.48 mCi) of [18F]3F4AP. Volumes of interest for relevant organs were manually drawn guided by the CT, and PET images and time-activity curves (TACs) were extracted. Radiation dosimetry was estimated from the integrated TACs using OLINDA software. Safety assessments included measuring vital signs immediately before and after the scan, monitoring for adverse events, and obtaining a comprehensive metabolic panel and electrocardiogram within 30 days before and after the scan. RESULTS: [18F]3F4AP distributed throughout the body with the highest levels of activity in the kidneys, urinary bladder, stomach, liver, spleen, and brain and with low accumulation in muscle and fat. The tracer cleared quickly from circulation and from most organs. The clearance of the tracer was noticeably faster than previously reported in nonhuman primates (NHPs). The average effective dose (ED) across all subjects was 12.1 ± 2.2 µSv/MBq, which is lower than the estimated ED from the NHP studies (21.6 ± 0.6 µSv/MBq) as well as the ED of other fluorine-18 radiotracers such as [18F]FDG (~ 20 µSv/MBq). No differences in ED between males and females were observed. No substantial changes in safety assessments or adverse events were recorded. CONCLUSION: The biodistribution and radiation dosimetry of [18F]3F4AP in humans are reported for the first time. The average total ED across four subjects was lower than most 18F-labeled PET tracers. The tracer and study procedures were well tolerated, and no adverse events occurred.

Deep learning-based behavioral profiling of rodent stroke recovery.

BACKGROUND: Stroke research heavily relies on rodent behavior when assessing underlying disease mechanisms and treatment efficacy. Although functional motor recovery is considered the primary targeted outcome, tests in rodents are still poorly reproducible and often unsuitable for unraveling the complex behavior after injury. RESULTS: Here, we provide a comprehensive 3D gait analysis of mice after focal cerebral ischemia based on the new deep learning-based software (DeepLabCut, DLC) that only requires basic behavioral equipment. We demonstrate a high precision 3D tracking of 10 body parts (including all relevant joints and reference landmarks) in several mouse strains. Building on this rigor motion tracking, a comprehensive post-analysis (with >100 parameters) unveils biologically relevant differences in locomotor profiles after a stroke over a time course of 3 weeks. We further refine the widely used ladder rung test using deep learning and compare its performance to human annotators. The generated DLC-assisted tests were then benchmarked to five widely used conventional behavioral set-ups (neurological scoring, rotarod, ladder rung walk, cylinder test, and single-pellet grasping) regarding sensitivity, accuracy, time use, and costs. CONCLUSIONS: We conclude that deep learning-based motion tracking with comprehensive post-analysis provides accurate and sensitive data to describe the complex recovery of rodents following a stroke. The experimental set-up and analysis can also benefit a range of other neurological injuries that affect locomotion.

Linguistic predictors of symptom change in an internet-based cognitive behavioural intervention for prolonged grief symptoms.

This study investigates linguistic predictors of reduction in prolonged grief symptoms following a writing intervention in an internet-based cognitive behavioural therapy for people bereaved by cancer. Data stem from a randomized control clinical trial with 70 people. The Linguistic Inquiry and Word Count program was used to analyse patient language. Absolute change scores and reliable change index were used to calculate reduction in grief symptoms and clinical significant change. Best subset regression and Mann-Whitney U tests were conducted. A higher reduction of prolonged grief symptoms was correlated with more social words in the first module (ß = -.22, p = .042), less risk (ß = .33, p = .002) and body words (ß = .22, p = .048) in the second module and more time words in the third module (ß = -.26, p = .018). Patients with clinically significant change showed a higher median in function words in the first module (p = .019), a lower median in risk words in the second module (p = .019) and a higher median in assent words in the last module (p = .014) compared to patients without clinically significant change. Findings suggest that it may be beneficial for therapists to encourage a more detailed description of patients' relationship with their deceased relative during the first module, a change in perspective during the second module and a summary of past, present and future aspects at the end of therapy. Future studies should include mediation analyses to allow causal attribution of the studied effects.

Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2.

Recent studies suggest that synaptic lysophosphatidic acids (LPAs) augment glutamate-dependent cortical excitability and sensory information processing in mice and humans via presynaptic LPAR2 activation. Here, we studied the consequences of LPAR2 deletion or antagonism on various aspects of cognition using a set of behavioral and electrophysiological analyses. Hippocampal neuronal network activity was decreased in middle-aged LPAR2-/- mice, whereas hippocampal long-term potentiation (LTP) was increased suggesting cognitive advantages of LPAR2-/- mice. In line with the lower excitability, RNAseq studies revealed reduced transcription of neuronal activity markers in the dentate gyrus of the hippocampus in naïve LPAR2-/- mice, including ARC, FOS, FOSB, NR4A, NPAS4 and EGR2. LPAR2-/- mice behaved similarly to wild-type controls in maze tests of spatial or social learning and memory but showed faster and accurate responses in a 5-choice serial reaction touchscreen task requiring high attention and fast spatial discrimination. In IntelliCage learning experiments, LPAR2-/- were less active during daytime but normally active at night, and showed higher accuracy and attention to LED cues during active times. Overall, they maintained equal or superior licking success with fewer trials. Pharmacological block of the LPAR2 receptor recapitulated the LPAR2-/- phenotype, which was characterized by economic corner usage, stronger daytime resting behavior and higher proportions of correct trials. We conclude that LPAR2 stabilizes neuronal network excitability upon aging and allows for more efficient use of resting periods, better memory consolidation and better  performance in tasks requiring high selective attention. Therapeutic LPAR2 antagonism may alleviate aging-associated cognitive dysfunctions.

[Traumatization in the Medical Profession: Initiating Events, Roles and Process Factors]. / Traumatisierung im Arztberuf: Auslöser, Rollen und Prozessfaktoren.

BACKGROUND: Physicians show an increased prevalence of post-traumatic stress disorder (PTSD). Potentially traumatic events in the medical profession include confrontation with suffering, death, violent experiences, and medical errors. The aim of the present analysis is to record traumatic events (TE) in physicians seeking help and to qualitatively analyze the roles and process factors involved. METHOD: Using an online questionnaire, physicians who had experienced a traumatic event (TE) were surveyed regarding posttraumatic stress (PCL-5), depression (PHQ-9), alcohol abuse (CAGE test), and suicidality (BSIS). Reports of TEs were qualitatively analyzed using structured content analysis. RESULTS: N=41 physicians described at least one TE. K=54 descriptions of TEs were qualitatively analyzed. In some cases, the physicians were victims of e. g., accidents or violence; in other cases, they were involved as witnesses or helpers. The following themes could be identified: Accompaniment of and confrontation with suffering and dying, negative courses of treatment (especially complications and medical errors), and lack of support (especially lack of error management). 53,7% of physicians had PTSD, and 36,6% showed symptoms of posttraumatic stress. Harmful alcohol use was observed in 24,4% of the sample. Psychotropic medication was taken by 31,7% of the respondents. DISCUSSION: The results show a high burden of TE in the medical profession. In this context, physicians are affected by traumatization in their role as victims, witnesses, or treatment providers and confronted with the death or dying process of others. Residency presumably represents a particularly vulnerable phase. CONCLUSION: Easily accessible forms of therapy (e. g., online therapy), structural changes (e. g., adequate support for residents), and programs for functional error management in hospitals could have a positive effect on the mental health of physicians.

The Relationship Between Pre-Loss Grief, Preparedness and Psychological Health Outcomes in Relatives of People With Cancer.

The aim of this study was to examine the simultaneous effects of pre-loss grief, preparedness for death and preparedness for caregiving on different psychological health outcomes in relatives of people with cancer. Two hundred ninety-nine relatives of people with cancer participated in a cross-sectional online survey. Participants were included if they spoke German and were 18 years or older. Multivariate regression analysis was conducted. Pre-loss grief was significantly associated with depression (ß = .388, p < .001), anxiety (ß = .429, p < .001), somatization (ß = .221, p < .001) and satisfaction with life (ß = -.205, p < .001). Preparedness for death was significantly associated with somatization (ß = -.247, p < .001). Results suggest that people with high scores in pre-loss grief and low scores in preparedness for death are in need of early support. Interventions should address pre-loss grief and the various aspects of preparedness for death and take into account the psychological health in relatives of people with cancer. Future studies should investigate underlying mechanisms.

The Spinal Transcriptome after Cortical Stroke: In Search of Molecular Factors Regulating Spontaneous Recovery in the Spinal Cord.

In response to cortical stroke and unilateral corticospinal tract degeneration, compensatory sprouting of spared corticospinal fibers is associated with recovery of skilled movement in rodents. To date, little is known about the molecular mechanisms orchestrating this spontaneous rewiring. In this study, we provide insights into the molecular changes in the spinal cord tissue after large ischemic cortical injury in adult female mice, with a focus on factors that might influence the reinnervation process by contralesional corticospinal neurons. We mapped the area of cervical gray matter reinnervation by sprouting contralesional corticospinal axons after unilateral photothrombotic stroke of the motor cortex in mice using anterograde tracing. The mRNA profile of this reinnervation area was analyzed using whole-genome sequencing to identify differentially expressed genes at selected time points during the recovery process. Bioinformatic analysis revealed two phases of processes: early after stroke (4-7 d post-injury), the spinal transcriptome is characterized by inflammatory processes, including phagocytic processes as well as complement cascade activation. Microglia are specifically activated in the denervated corticospinal projection fields in this early phase. In a later phase (28-42 d post-injury), biological processes include tissue repair pathways with upregulated genes related to neurite outgrowth. Thus, the stroke-denervated spinal gray matter, in particular its intermediate laminae, represents a growth-promoting environment for sprouting corticospinal fibers originating from the contralesional motor cortex. This dataset provides a solid starting point for future studies addressing key elements of the post-stroke recovery process, with the goal to improve neuroregenerative treatment options for stroke patients.SIGNIFICANCE STATEMENT We show that the molecular changes in the spinal cord target tissue of the stroke-affected corticospinal tract are mainly defined by two phases: an early inflammatory phase during which microglia are specifically activated in the target area of reinnervating corticospinal motor neurons; and a late phase during which growth-promoting factors are upregulated which can influence the sprouting response, arborization, and synapse formation. By defining for the first time the endogenous molecular machinery in the stroke-denervated cervical spinal gray matter with a focus on promotors of axon growth through the growth-inhibitory adult CNS, this study will serve as a basis to address novel neuroregenerative treatment options for chronic stroke patients.

Interactions between Atorvastatin and the Farnesoid X Receptor Impair Insulinotropic Effects of Bile Acids and Modulate Diabetogenic Risk.

Bile acids such as chenodeoxycholic acid (CDC) acutely enhance insulin secretion via the farnesoid X receptor (FXR). Statins, which are frequently prescribed for patients with type 2 diabetes who suffer from dyslipidemia, are known for their diabetogenic risk and are reported to interact with the FXR. Our study investigates whether this interaction is relevant for beta cell signaling and plays a role for negative effects of statins on glycemic control. Experiments were performed with islets and islet cells from C57BL/6N wild-type and FXR-knockout (KO) mice. Culturing islets with atorvastatin (15 µM) for 24 hours decreased glucose-stimulated insulin secretion by approximately 30% without affecting ATP synthesis. Prolonged exposure for 7 days lowered the concentration necessary for impairment of insulin release to 150 nM. After 24-hour culture with atorvastatin, the ability of CDC (500 nM) to elevate [Ca2+]c was diminished and the potentiating effect on insulin secretion was completely lost. Mevalonate largely reduced the negative effect of atorvastatin. Nuclear activity of FXR was reduced by atorvastatin in a mouse FXR reporter assay. The atorvastatin-induced decrease in insulin release was also present in FXR-KO mice. Although not a prerequisite, FXR seems to influence the degree of damage caused by atorvastatin depending on its interaction with CDC: Preparations responding to CDC with an increase in insulin secretion under control conditions were less impaired by atorvastatin than preparations that were nonresponsive to CDC. Extended stimulation of FXR by the synthetic agonist GW4064, which is suggested to induce translocation of FXR from the cytosol into the nucleus, increased the inhibitory effect of atorvastatin. In conclusion, atorvastatin inhibits insulin release and prevents positive effects of bile acids on beta cell function. Both interactions may contribute to progression of type 2 diabetes mellitus. SIGNIFICANCE STATEMENT: This study shows that the diabetogenic risk of statins is coupled to the activity of farnesoid X receptor (FXR)-dependent signaling pathways in beta cells. On the one hand, statins abolish the insulinotropic effects of bile acids and on the other hand, FXR determines the level of impairment of islet function by the statin.

Psychosocial outcomes in cancer-bereaved children and adolescents: A systematic review.

OBJECTIVE: Due to the unique importance of parental and sibling relationships and concurrently existing developmental challenges, the loss of a parent or sibling due to cancer is a highly stressful event for children and adolescents. This is the first systematic review that integrates findings on psychosocial outcomes after parental or sibling cancer bereavement. METHODS: A systematic search of Web of Science, PubMed, PsycINFO, and PubPsych was conducted, last in December 2017. Quantitative studies on psychosocial outcomes of children and adolescents who lost a parent or sibling due to cancer were included. RESULTS: Twenty-four studies (N = 10 parental and N = 14 sibling bereavement), based on 13 projects, were included. Ten projects had cross-sectional designs. Only 2 projects used large, population-based samples and nonbereaved comparison groups. Outcomes were partially measured by single-item questions. Bereaved children and adolescents showed similar levels of depression and anxiety compared with nonbereaved or norms. Severe behavioral problems were found rarely. However, in 2 large, population-based studies, about half of the bereaved individuals reported unresolved grief. Bereaved adolescents had a higher risk for self-injury compared with the general population in one large, population-based study. Communication with health-care professionals, family, and other people; social support; distress during illness; age; gender; and time because loss were associated with psychosocial bereavement outcomes. CONCLUSIONS: Results indicate a high level of adjustment in cancer-bereaved children and adolescents. A modifiable risk factor for adverse psychosocial consequences is poor communication. Prospective designs, representative samples, and validated instruments, eg, for prolonged grief, are suggested for future research.

Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology.

Two hallmarks of chronic multiple sclerosis lesions are the absence of significant spontaneous remyelination and primary as well as secondary neurodegeneration. Both characteristics may be influenced by the presence of inhibitory factors preventing myelin and neuronal repair. We investigated the potential of antibodies against Nogo-A, a well-known inhibitory protein for neuronal growth and plasticity, to enhance neuronal regeneration and remyelination in two animal models of multiple sclerosis. We induced a targeted experimental autoimmune encephalomyelitis (EAE) lesion in the dorsal funiculus of the cervical spinal cord of adult rats resulting in a large drop of skilled forelimb motor functions. We subsequently observed improved recovery of forelimb function after anti-Nogo-A treatment. Anterograde tracing of the corticospinal tract revealed enhanced axonal sprouting and arborisation within the spinal cord gray matter preferentially targeting pre-motor and motor spinal cord laminae on lesion level and above in the anti-Nogo-A-treated animals. An important additional effect of Nogo-A-neutralization was enhanced remyelination observed after lysolecithin-induced demyelination of spinal tracts. Whereas remyelinated fiber numbers in the lesion site were increased several fold, no effect of Nogo-A-inhibition was observed on oligodendrocyte precursor proliferation, migration, or differentiation. Enhancing remyelination and promoting axonal regeneration and plasticity represent important unmet medical needs in multiple sclerosis. Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis, in particular during the chronic phase of the disease when neurodegeneration and remyelination failure determine disability evolution.

KPS/LDH index: a simple tool for identifying patients with metastatic melanoma who are unlikely to benefit from palliative whole brain radiotherapy.

PURPOSE: Low Karnofsky performance status (KPS) and elevated lactate dehydrogenases (LDHs) as a surrogate marker for tumor load and cell turnover may depict patients with a very short life expectancy. To validate this finding and compare it to other indices, namely, the recursive partitioning analysis (RPA) and diagnosis-specific graded prognostic assessment (DS-GPA), a multicenter analysis was undertaken. METHODS: A retrospective analysis of 234 metastatic melanoma patients uniformly treated with palliative whole brain radiotherapy (WBRT) was done. Univariate and multivariate analyses were used to determine the impact of patient-, tumor-, and treatment-related parameters on overall survival (OS). RESULTS: KPS and LDH emerged as independent factors predicting OS. By combining KPS and LDH values (KPS/LDH index), groups of patients with statistically significant differences in median OS (days; 95 % CI) after onset of WBRT were identified: group 1 (KPS ≥ 70/normal LDH) 234 (96-372), group 2 (KPS ≥ 70/elevated LDH) 112 (69-155), group 3 (KPS <70/normal LDH) 43 (12-74), and group 4 (KPS <70/elevated LDH) 29 (17-41). Between all four groups, statistically significant differences were observed. The RPA and DS-GPA indices failed to distinguish significantly between good and moderate prognosis and were inferior in predicting a very unfavorable prognosis. CONCLUSIONS: The parameters KPS and LDH independently impacted on OS. The combination of both (KPS/LDH index) identified patients with a very short life expectancy, who might be better served by recommending best supportive care instead of WBRT. The KPS/LDH index is simple and effective in terms of time and cost as compared to other prognostic indices.

The change of working alliance and the association to treatment outcome in an internet-based therapy after pregnancy loss.

BACKGROUND: Working alliance is a prominent non-specific factor for treatment outcomes in face-to-face and internet-based interventions. The association between working alliance and therapy outcome appears to be time- and disorder-specific, but less is known about the change of working alliance during the intervention and the impact of working alliance in grief-specific interventions. The present study examines the association between the change of working alliance and treatment outcomes in an internet-based intervention for parents who experienced pregnancy loss. METHODS: 228 participants received a grief intervention based on cognitive behavioral therapy with asynchronous text-based therapist feedback. Prolonged grief and related symptoms of traumatic stress, depression, anxiety, and general psychopathology were assessed with validated instruments before and after the intervention. The change of working alliance was assessed using the short version of the Working Alliance Inventory at mid-treatment (session 4) and the end of the treatment (session 10). RESULTS: Data for N = 146 persons was analyzed. Working alliance in total and all subscales increased significantly from sessions 4 to 10. This change in working alliance correlated significantly with a reduction in prolonged grief. Changes in subscales of working alliance also correlated with symptoms of depression and general psychopathology. Regression analysis showed that a change in working alliance predicted a reduction in prolonged grief but did not predict improvements in other grief-related symptoms. CONCLUSION: The results examine the change of working alliance during an internet-based intervention and the association with treatment outcome. A small impact of change in working alliance on treatment outcome of prolonged grief was confirmed, but not on related symptoms. Further research is needed to assess moderators of the alliance-outcome association to improve internet-based interventions. TRIAL REGISTRATION: Not applicable.

Factors Associated With Treatment Response in an Internet-Based Intervention for Prolonged Grief Disorder After Cancer Bereavement.

Internet-based psychological interventions have proven effective in the treatment of prolonged grief disorder (PGD). Yet, some patients do not benefit from treatment in a clinically significant way. We aimed to examine predictors of symptom reduction in an Internet-based intervention for PGD after cancer bereavement, in order to identify possible treatment mechanisms and discern directions for future intervention design. A secondary analysis of data from a randomized wait-list controlled trial on an Internet-based intervention for PGD after cancer bereavement was conducted. Multiple regression models were used (1) to test for the influence of pretreatment PGD, working alliance, avoidance and gender on PGD symptom reduction; and (2) to explore further predictors of treatment success with a best subset selection protocol. The regression models explained 18% (Model 1) and 34% (Model 2) of variance in symptom reduction. Participants with more favorable symptom change had more severe pretreatment PGD scores and better working alliance. Those with lower social support and less posttraumatic growth experienced more PGD symptom change. In conclusion, therapeutic alliance is an important factor that should be monitored and fostered. Findings regarding social support and posttraumatic growth need further replication and clarification.

Risk and course of COVID-19 in immunosuppressed patients with myasthenia gravis.

BACKGROUND: Patients with myasthenia gravis (MG) are potentially prone for a severe COVID-19 course, but there are limited real-world data available on the risk associated with COVID-19 for patients with MG. Here, we investigate whether current immunosuppressive therapy (IST) influences the risk of SARS-CoV-2 infection and COVID-19 severity. METHODS: Data from the German myasthenia gravis registry were analyzed from May 2020 until June 2021 and included patient demographics, MG disease duration, comorbidities, current IST use, COVID-19 characteristics, and outcomes. Propensity score matching was employed to match MG patients with IST to those without, and multivariable binary logistic regression models were used to determine associations between IST with (1) symptomatic SARS-CoV-2 infection and (2) severe COVID-19 course, as measured by hospitalization or death. RESULTS: Of 1379 patients with MG, 95 (7%) patients (mean age 58 (standard deviation [SD] 18) presented with COVID-19, of which 76 (80%) received IST at time of infection. 32 patients (34%) were hospitalized due to COVID-19; a total of 11 patients (12%) died. IST was a risk factor for hospitalization or death in the group of COVID-19-affected MG patients (odds ratio [OR] 3.04, 95% confidence interval [CI] = 1.02-9.06, p = 0.046), but current IST was not associated with a higher risk for SARS-CoV-2 infection itself. DISCUSSION: In this national MG cohort study, current IST use was a risk factor for a severe disease course of COVID-19 but not for SARS-CoV-2 infection itself. These data support the consequent implementation of effective strategies to prevent COVID-19 in this high-risk group. TRIAL REGISTRATION INFORMATION: German clinical trial registry ( https://www.drks.de ), DRKS00024099, first patient enrolled: February 4th, 2019.

Factors associated with pre-loss grief and preparedness in relatives of people with cancer during the COVID-19 pandemic: A cross-sectional study.

OBJECTIVES: Before the loss of a loved one to cancer, relatives have time to adapt to the impending death. However, due to the current COVID-19 pandemic, adjustment to an imminent death may be more difficult. This study investigates factors related to pre-loss grief and preparedness during the COVID-19 pandemic and their relationship with COVID-19 related fears. METHODS: Data of 299 participants from a cross-sectional study was used. Participants were included if they were relatives of people with cancer, spoke German and were at least 18 years. Multivariate linear regression analyses were conducted to measure the relationship between predictors (dysfunctional coping, emotion-focused coping, problem-focused coping, attachment anxiety, attachment avoidance, COVID-19 related fears, prognosis, perceived depth of the relationship, perceived conflict in the relationship, health status) and pre-loss grief, preparedness for caregiving and preparedness for death as the dependent variables. RESULTS: Perceived depth (ß = .365, p < .001), COVID-19 related fears (ß = .141, p = .002), prognosis for death (ß = .241, p < .001), dysfunctional coping strategies (ß = .281, p < .001) and emotion-focused coping strategies (ß = -.320, p < .001) significantly predicted pre-loss grief. Prognosis for death (ß = .347, p < .001), dysfunctional coping strategies (ß = -.229, p < .001), emotion-focused coping strategies (ß = .242, p < .001), COVID-19 related fears (ß = -.112, p = .037) and health status (ß = .123, p = .025) significantly predicted preparedness for death. Dysfunctional coping (ß = -.147, p = .009), problem-focused coping (ß = .162, p = .009), emotion-focused coping (ß = .148, p = .017), COVID-19 related fears (ß = -.151, p = .006), attachment anxiety (ß = -.169, p = .003), perceived conflict in the relationship with the patient with cancer (ß = -.164, p = .004), perceived depth in the relationship (ß = .116, p = .048) and health status (ß = .157, p = .003) significantly predicted preparedness for caregiving. CONCLUSIONS: This study shows COVID-19 pandemic impacts on the grieving process of relatives of patients with cancer. Consequently, screening for pre-loss grief, preparedness and their associated factors may help provide early support for relatives of people with cancer at need. However, further research is needed to help understand the stability of pre-loss grief and preparedness.

Therapist-Assisted Web-Based Intervention for Prolonged Grief Disorder After Cancer Bereavement: Randomized Controlled Trial.

BACKGROUND: Bereavement due to cancer increases the risk of prolonged grief disorder. However, specialized treatment options for prolonged grief after a loss due to illness are still scarce. OBJECTIVE: The aim of this study is to extend previous findings by evaluating a web-based cognitive behavioral intervention with asynchronous therapist support, consisting of structured writing tasks adapted specifically for prolonged grief after cancer bereavement. METHODS: The intervention was evaluated in a purely web-based randomized waitlist-controlled trial. Open-access recruitment of participants was conducted on the web. Prolonged grief (Inventory of Complicated Grief), depression, anxiety, posttraumatic stress, posttraumatic growth, somatization, sleep quality, and mental and physical health were assessed on the web via validated self-report measures. RESULTS: A total of 87 participants were randomized into the intervention group (IG; 44/87, 51%) or the waitlist control group (43/87, 49%). Of the participants, 7% (6/87) dropped out of the study (5/44, 11%, in the IG). Of the 39 completers in the IG, 37 (95%) completed all intervention tasks. The intervention reduced symptoms of prolonged grief (intention-to-treat: P<.001; η2=0.34; Cohen d=0.80) to a clinically significant extent. It had favorable effects on depression, anxiety, posttraumatic stress, posttraumatic growth, and overall mental health but not on somatization, sleep quality, or physical health. CONCLUSIONS: The web-based intervention for prolonged grief after cancer bereavement is effective in reducing symptoms of prolonged grief disorder and accompanying syndromes in a timely, easily realizable manner and addresses specific challenges of bereavement to illness. Considering web-based approaches in future mental health care policy and practice can reduce health care gaps for those who are bereaved to cancer. TRIAL REGISTRATION: German Clinical Trial Register U1111-1186-6255; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011001.

Depression Symptoms and Olfactory-related Quality of Life.

OBJECTIVES: Patients with olfactory dysfunction (OD) frequently report symptoms of depression. The objective of this study was to determine how clinical characteristics and olfactory-related quality of life (QoL) measures associate with the likelihood for major depressive disorders (MDDs). METHODS: A total of 192 OD patients were included. Olfactory function was measured using all three subtests of the Sniffn' Sticks test. Olfactory-related quality of life (QoL) was evaluated using the Questionnaires of Olfactory Dysfunction (QOD)-negative (NS) and -positive statement (PS). The likelihood for MDD was assessed using the Patients Health Questionnaire-2 (PHQ-2). Demographics and disease-specific variables (etiology and duration of OD) were collected. Univariate and multivariable analyses were used to associate disease-specific variables and the QOD with the outcome of the PHQ-2. Additionally, the predictive ability of the QOD-NS to predict depressive symptoms was calculated. RESULTS: In univariate analysis, COVID-19 related smell loss, the QOD-NS, and the QOD-PS were significantly associated with the PHQ-2. In multivariable analyses adjusting for QoL measures, the QOD-NS (ß = 0.532, p < 0.001) and sinonasal OD (compared with postinfectious OD) were significantly associated with the PHQ-2 (ß = 0.146, p = 0.047). When omitting QoL measures from multivariable analyses, only COVID-19 related OD (compared with postinfectious OD) was significantly associated with the PHQ-2 (ß = 0.287, p = 0.009). A QOD-NS score > 20.5 had 70.13% sensitivity and 76.32% specificity for detecting symptoms of depression. CONCLUSION: Our results suggest that COVID-19 related OD might be associated with a higher likelihood for MDD. Furthermore, we showed that the QOD-NS score might be helpful to predict symptoms of depression in OD patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1829-1834, 2022.

Eating behavior in patients with smell loss.

Background: The objective of this study was to determine how clinical characteristics and validated quality of life (QoL)-measures are associated with eating behavior in patients with olfactory dysfunction (OD). Methods: For this cross-sectional study, 150 OD patients of different causes were retrospectively recruited. Olfactory function was measured using the Sniffin' Sticks (TDI), while olfactory-related QoL was evaluated with the Questionnaire of OD negative and positive statements (QOD-NS and QOD-PS). The importance of olfaction was measured using the Importance of Olfaction Questionnaire (IOQ). The Dutch Eating Behavior Questionnaire (DEBQ) assessed eating behavior based on emotional, external, and restrained eating. Associations were sought between eating behavior metrics (as dependent variables) with clinical characteristics and olfactory-related outcome measures. Results: Emotional, external, and restrained eating behavior deviating from normative standards were reported in 54%, 71.3%, and 68% of patients, respectively. Multivariate regression modeling revealed that emotional eating was associated with age (ß = -0.227, p = 0.032), the body mass index (BMI, ß = 0.253, p = 0.005), the TDI (ß = 0.190, p = 0.046), and the QOD-NS (ß = 0.203, p = 0.049). External eating was associated with OD duration (ß = 0.291, p = 0.005), the TDI (ß = 0.225, p = 0.018), the QOD-PS (ß = -0.282, p = 0.008), and the IOQ (ß = 0.277, p = 0.004). Restrained eating was associated with age (ß = 0.216, p = 0.033), the BMI (ß = 0.257, p = 0.003), male gender (ß = -0.263, p = 0.002), and the IOQ (ß = 0.332, p < 0.001). Conclusion: Clinical characteristics and olfactory outcome measures differentially impact eating styles in OD patients. Our study's results highlight the importance of considering unfavorable changes in eating behavior during clinical counseling.

Acyl-Ghrelin Influences Pancreatic ß-Cell Function by Interference with KATP Channels.

The aim for this study was to elucidate how the hypothalamic hunger-inducing hormone acyl-ghrelin (AG), which is also produced in the pancreas, affects ß-cell function, with particular attention to the role of ATP-sensitive K+ (KATP) channels and the exact site of action of the hormone. AG hyperpolarized the membrane potential and decreased cytoplasmic calcium concentration [Ca2+]c and glucose-stimulated insulin secretion (GSIS). These effects were abolished in ß-cells from SUR1-knockout (KO) mice. AG increased KATP current but only in a configuration with intact metabolism. Unacylated ghrelin counteracted the effects of AG. The influence of AG on membrane potential and GSIS could only be averted in the combined presence of a ghrelin receptor (GHSR1a) antagonist and an inverse agonist. The inhibition of GSIS by AG could be prevented by dibutyryl cyclic-cAMP or 3-isobutyl-1-methylxanthine and the somatostatin (SST) receptor 2-5 antagonist H6056. These data indicate that AG indirectly opens KATP channels probably by interference with the cAMP/cAMP-dependent protein kinase pathway, resulting in a decrease of [Ca2+]c and GSIS. The experiments with SUR1-KO ß-cells point to a direct effect of AG on ß-cells and not, as earlier suggested, to an exclusive effect by AG-induced SST release from δ-cells. Nevertheless, SST receptors may be involved in the effect of AG, possibly by heteromerization of AG and SST receptors.