Did the prevalence of depressive symptoms change during the COVID-19 pandemic? A multilevel analysis on longitudinal data from healthcare workers.

BACKGROUND: Healthcare workers (HCW) are at high risk to develop mental health problems during the COVID-19 pandemic because of additional work load, perceived stress, and exposure to patients with COVID-19. Currently, there are few studies on change over time in the prevalence of depressive symptoms during pandemic start among HCW. Thus, the aims of the current study were to examine whether depressive symptoms increased during the pandemic and were associated with perceived stress and own COVID-19 infection and workplace exposure to virus-infected patients. METHODS: The cohort study used longitudinal data from HCW collected monthly (July 2020 till December 2020) during the first year of the pandemic before vaccination became available. The sample of n = 166 was drawn from a German hospital and included medical (e.g. nurses, therapists, and physicians) and administrative staff. Using multilevel models, we analyzed the change in depressive symptoms [assessed with General Depression Scale (GDS), a validated German version of the Center for Epidemiological Studies Depression Scale (CES-D)] and its association with perceived stress across the study period. Laboratory-confirmed own infection was tested as a potential moderator in this context. Subscales of the GDS were used to examine change over time of depressive symptom modalities (e.g. emotional, somatic, and social interactions (ß, 95% confidence interval). RESULTS: Depression scores increased significantly during the study period (ß = .03, 95% CI [0.02, 0.05]). Perceived stress was associated with depressive symptoms (ß = .12, 95% CI [0.10, 0.14]) but did not change over time. Exposure to COVID-19 infection was associated with a higher increase of depressive symptoms (ß = .12, 95% CI [0.10, .14]). Somatic symptoms of depression increased among medical HCW with workplace exposure to COVID-19 (ß = .25, 95% CI [0.13, 0.38]), but not in administrators (ß = .03, 95% CI [-0.04, 0.11]). CONCLUSION: Research is needed to identify factors that promote the reduction of depressive symptoms in medical HCW with exposition to COVID-19 patients. Awareness of infection protection measures should be increased.

An essential role of the autophagy activating kinase ULK1 in snRNP biogenesis.

The biogenesis of small uridine-rich nuclear ribonucleoproteins (UsnRNPs) depends on the methylation of Sm proteins catalyzed by the methylosome and the subsequent action of the SMN complex, which assembles the heptameric Sm protein ring onto small nuclear RNAs (snRNAs). In this sophisticated process, the methylosome subunit pICln (chloride conductance regulatory protein) is attributed to an exceptional key position as an 'assembly chaperone' by building up a stable precursor Sm protein ring structure. Here, we show that-apart from its autophagic role-the Ser/Thr kinase ULK1 (Uncoordinated [unc-51] Like Kinase 1) functions as a novel key regulator in UsnRNP biogenesis by phosphorylation of the C-terminus of pICln. As a consequence, phosphorylated pICln is no longer capable to hold up the precursor Sm ring structure. Consequently, inhibition of ULK1 results in a reduction of efficient UsnRNP core assembly. Thus ULK1, depending on its complex formation, exerts different functions in autophagy or snRNP biosynthesis.

[Outpatient GP and Specialist Care in Rural areas in Germany from the Point of View of Older residents in the District of Oberspreewald-Lausitz]. / Ambulante Haus- und Facharztversorgung im ländlichen Raum in Deutschland ­ Wie stellt sich die Versorgungssituation aus Sicht älterer Einwohner im Landkreis Oberspreewald-Lausitz dar?

AIM: In some rural areas of Germany, there is an impending danger of insufficient health care provision. One of these regions is the rural county of Oberspreewald-Lausitz (OSL) in the federal state of Brandenburg. The aim of this study was to explore the points of view of middle-aged and older inhabitants of OSL with regard to their current outpatient primary medical care as well as their expectations regarding future health care in OSL in 2030. METHODS: As part of the cross-sectional study, a questionnaire including closed and open questions was sent to a random sample of 3,006 inhabitants of OSL aged 50-56 years and 65-71 year. RESULTS: The majority of interviewees was "satisfied" or "very satisfied" with the access to and availability of their general practitioner (93.1%) and specialist medical care (83.3%). There were, however, regional differences. 27.1% of the interviewees in the region of Lauchhammer/Schwarzheide considered their access to specialist medical services as "unsatisfactory" or "very unsatisfactory". The study participants were quite receptive towards alternative and complementary services, such as community nurses. However, such new models of care are still underrepresented and cannot assure sufficient health provision in the future. CONCLUSION: Currently, respondents of the rural county OSL are mostly satisfied with the level of outpatient health provision. In some areas, however, specialist care seems to be rather insufficient. In order to assure future health care provision in these areas, the inhabitants would appreciate the implementation of alternative and complementary services such as community nurses and telemedicine.

Perspective of elderly patients on chronic use of potentially inappropriate medication - Results of the qualitative CIM-TRIAD study.

Although potentially inappropriate medication (PIM) is associated with risk of harm due to adverse effects, it is frequently prescribed for elderly patients. The aim of this qualitative multi-center study was to gain insight into contextual factors that might lead to chronic PIM use. We conducted semi-structured interviews with elderly patients with or without chronic PIM use (patient interviews: n = 52). Patients were between 86 and 96 years old. The participants were recruited from the AgeCoDe study. Interviews were audiotaped and transcribed verbatim. The transcripts of the interviews were analysed using qualitative content analysis. Deductive and inductive categories were determined. We found contextual factors related to the patient and related to patient-general practitioner (GP) communication that might lead to chronic PIM use (i.e., positive features of PIM, maintaining characteristics of medication intake, barriers to deprescribe PIM, external actors supporting PIM intake, system-related factors). Besides certain health-related behaviours (e.g., own obligation to report to GP) and medication-related attitudes and knowledge (e.g., awareness of side effects and interaction of medicines), patient-GP-interactions that were characterised by mutual agreements on drugs (e.g., concerning dosage or discontinuation of a drug) might be advantageous to reduce the probability of chronic PIM use. The results might assist in the development of guidelines and educational programs aiming to reduce PIM use in the elderly.

Informal caregivers' perspectives on health of and (potentially inappropriate) medication for (relatively) independent oldest-old people - a qualitative interview study.

BACKGROUND: Oldest-old persons frequently receive potentially inappropriate medication. Medication use takes place under the patients' informal caregivers' influence. We explored informal caregivers' perspectives on medication of (relatively) independent oldest-old persons to identify starting points for safer medication prescription/handling. METHODS: In this exploratory qualitative interview study we interviewed 45 informal caregivers of 45 oldest-old persons (23 with potentially inappropriate medication/22 without potentially inappropriate medication). Interviews were recorded, transcribed and content analyzed (deductive/inductive coding). RESULTS: Interviewees had little knowledge about/influence on oldest-old persons' medication, but declared to monitor oldest-old persons' needs for assistance. They were unaware of the concept of potentially inappropriate medication but sometimes sensitive to substance dependency. Most informal caregivers were satisfied with the oldest-old persons' medication and viewed medication as increasing the patients' quality of life. Inadequate communication was found between informal caregivers and general practitioners. CONCLUSIONS: Influence of informal caregivers on (relatively) independent oldest-old persons' medication seems low. Stakeholders need to be aware that there is a transitional period where independency of oldest-old persons decreases and support needs increase which may be missed by (in-)formal caregivers or concealed by oldest-old persons. Monitoring patients' medication competencies; measures supporting communication between informal caregivers and health care professionals; provision of educational and support resources for informal caregivers and the acceptance of oldest-old persons' increasing assistance needs may increase medication safety.

Effects of psychological eating behaviour domains on the association between socio-economic status and BMI.

OBJECTIVE: The current study investigates potential pathways from socio-economic status (SES) to BMI in the adult population, considering psychological domains of eating behaviour (restrained eating, uncontrolled eating, emotional eating) as potential mediators stratified for sex. DESIGN: Data were derived from the population-based cross-sectional LIFE-Adult-Study. Parallel-mediation models were conducted to obtain the total, direct and indirect effects of psychological eating behaviour domains on the association between SES and BMI for men and for women. SETTING: Leipzig, Germany. SUBJECTS: We studied 5935 participants aged 18 to 79 years. RESULTS: Uncontrolled eating mediated the association between SES and BMI in men only and restrained eating in both men and women. Emotional eating did not act as mediator in this relationship. The total effect of eating behaviour domains on the association between SES and BMI was estimated as ß=-0·03 (se 0·02; 95 % CI -0·062, -0·003) in men and ß=-0·18 (se 0·02; 95 % CI -0·217, -0·138) in women. CONCLUSIONS: Our findings do not indicate a strong overall mediation effect of the eating behaviour domains restrained eating, uncontrolled eating and emotional eating on the association between SES and BMI. Further research on other pathways of this association is strongly recommended. Importantly, our findings indicate that, independent from one's social position, focusing on psychological aspects in weight reduction might be a promising approach.

General practitioners' views on (long-term) prescription and use of problematic and potentially inappropriate medication for oldest-old patients-A qualitative interview study with GPs (CIM-TRIAD study).

BACKGROUND: Potentially inappropriate medication (PIM) is defined as medication with uncertain therapeutic effects and/or potential adverse drug reactions outweighing the clinical benefits. The prescription rate of PIM for oldest-old patients is high despite the existence of lists of PIM (e.g. the PRISCUS list) and efforts to raise awareness. This study aims at identifying general practitioners' views on PIM and aspects affecting the (long-term) use of PIM. METHODS: As part of the CIM-TRIAD study, we conducted semi-structured, qualitative interviews with 47 general practitioners, discussing 25 patients with and 22 without PIM (according to the PRISCUS list). The interview guideline included generic and patient-specific questions. Interviews were digitally recorded and transcribed verbatim. We content analyzed the interviews using deductive and inductive category development. RESULTS: The majority of the general practitioners were not aware of the PRISCUS list. Agents deemed potentially inappropriate from the general practitioners' point of view and the PRISCUS list are not completely superimposable. General practitioners named their criteria to identify appropriate medication for elderly patients (e.g. renal function, cognitive state) and emphasized the importance of monitoring. We identified prescription- (e.g. benzodiazepines on alternative private prescription), medication- (e.g. subjective perception that PIM has no alternative), general practitioner- (e.g. general practitioner relies on specialists), patient- (e.g. "demanding high-user", positive subjective benefit-risk-ratio) and system-related aspects (e.g. specialists lacking holistic view, interface problems) related to the (long term) use of PIM. CONCLUSIONS: While the PRISCUS list does not seem to play a decisive role in general practice, general practitioners are well aware of risks associated with PIM. Our study identifies some starting points for a safer handling of PIM, e.g. stronger dissemination of the PRISCUS list, better compensation of medication reviews, "positive lists", adequate patient information, multifaceted interventions and improved communication between general practitioners and specialists.

Type 2 diabetes and pre-diabetic abnormalities in patients with bipolar disorders.

BACKGROUND: Abnormalities in the glucose metabolism cause nervous and organic damage and are a cardiovascular risk factor. They could be a main cause for the increased morbidity and mortality rates found in patients with bipolar disorders. The exact prevalence of diabetes and pre-diabetic abnormalities, however, is not clear. METHODS: 85 euthymic outpatients with bipolar disorders from two university hospitals in Germany underwent an oral glucose tolerance test, laboratory screening and clinical measurements. Socio-demographic data, medication, severity of illness, global functioning and life quality were assessed. RESULTS: Diabetes mellitus was found in 7% of the patients, pre-diabetic abnormalities in 27%. The group of patients with abnormalities in the glucose metabolism had significantly lower quality of life and global functioning. Higher BMI, leptin, triglycerides and CRP levels significantly increased the likelihood for pre-diabetes/diabetes. LIMITATIONS: The low sample size did only allow limited assessment of impact of medication on the results. No healthy controls were assessed. CONCLUSIONS: One-third of the patients with bipolar disorders showed abnormalities in the glucose metabolism and this was associated with impaired global functioning and lower quality of life. Early detection and intervention strategies fitting the needs of patient with bipolar disorder are needed to improve both physical and mental health.

Eating Behaviour in the General Population: An Analysis of the Factor Structure of the German Version of the Three-Factor-Eating-Questionnaire (TFEQ) and Its Association with the Body Mass Index.

The Three-Factor-Eating-Questionnaire (TFEQ) is an established instrument to assess eating behaviour. Analysis of the TFEQ-factor structure was based on selected, convenient and clinical samples so far. Aims of this study were (I) to analyse the factor structure of the German version of the TFEQ and (II)--based on the refined factor structure--to examine the association between eating behaviour and the body mass index (BMI) in a general population sample of 3,144 middle-aged and older participants (40-79 years) of the ongoing population based cohort study of the Leipzig Research Center for Civilization Diseases (LIFE Health Study). The factor structure was examined in a split-half analysis with both explorative and confirmatory factor analysis. Associations between TFEQ-scores and BMI values were tested with multiple regression analyses controlled for age, gender, and education. We found a three factor solution for the TFEQ with an 'uncontrolled eating', a 'cognitive restraint' and an 'emotional eating' domain including 29 of the original 51 TFEQ-items. Scores of the 'uncontrolled eating domain' showed the strongest correlation with BMI values (partial r = 0.26). Subjects with scores above the median in both 'uncontrolled eating' and 'emotional eating' showed the highest BMI values (mean = 29.41 kg/m²), subjects with scores below the median in all three domains showed the lowest BMI values (mean = 25.68 kg/m²; F = 72.074, p<0.001). Our findings suggest that the TFEQ is suitable to identify subjects with specific patterns of eating behaviour that are associated with higher BMI values. Such information may help health care professionals to develop and implement more tailored interventions for overweight and obese individuals.

Expression of a ULK1/2 binding-deficient ATG13 variant can partially restore autophagic activity in ATG13-deficient cells.

Autophagy describes an intracellular process responsible for the lysosome-dependent degradation of cytosolic components. The ULK1/2 complex comprising the kinase ULK1/2 and the accessory proteins ATG13, RB1CC1, and ATG101 has been identified as a central player in the autophagy network, and it represents the main entry point for autophagy-regulating kinases such as MTOR and AMPK. It is generally accepted that the ULK1 complex is constitutively assembled independent of nutrient supply. Here we report the characterization of the ATG13 region required for the binding of ULK1/2. This binding site is established by an extremely short peptide motif at the C terminus of ATG13. This motif is mandatory for the recruitment of ULK1 into the autophagy-initiating high-molecular mass complex. Expression of a ULK1/2 binding-deficient ATG13 variant in ATG13-deficient cells resulted in diminished but not completely abolished autophagic activity. Collectively, we propose that autophagy can be executed by mechanisms that are dependent or independent of the ULK1/2-ATG13 interaction.

Deubiquitinase inhibition by WP1130 leads to ULK1 aggregation and blockade of autophagy.

Autophagy represents an intracellular degradation process which is involved in both regular cell homeostasis and disease settings. In recent years, the molecular machinery governing this process has been elucidated. The ULK1 kinase complex consisting of the serine/threonine protein kinase ULK1 and the adapter proteins ATG13, RB1CC1, and ATG101, is centrally involved in the regulation of autophagy initiation. This complex is in turn regulated by the activity of different nutrient- or energy-sensing kinases, including MTOR, AMPK, and AKT. However, next to phosphorylation processes it has been suggested that ubiquitination of ULK1 positively influences ULK1 function. Here we report that the inhibition of deubiquitinases by the compound WP1130 leads to increased ULK1 ubiquitination, the transfer of ULK1 to aggresomes, and the inhibition of ULK1 activity. Additionally, WP1130 can block the autophagic flux. Thus, treatment with WP1130 might represent an efficient tool to inhibit the autophagy-initiating ULK1 complex and autophagy.

Age- and gender-specific norms for the German version of the Three-Factor Eating-Questionnaire (TFEQ).

The 'Fragebogen zum Essverhalten' (FEV) is the German version of the Three-factor-Eating-Questionnaire (TFEQ). This questionnaire covers three domains of eating behaviour ('cognitive restraint', 'disinhibition' and 'hunger') as well as common problems (e.g. craving for sweets). So far, there is a lack of normative data of the FEV especially for the middle-aged and older population. Aim of this study therefore was to provide age- and gender-specific norms of the FEV for the general population aged 40-79 years. We studied 3144 participants of the ongoing large community-based Leipzig Research Center for Civilization Diseases (LIFE) Health Care Study. We provided age- (four age groups: 40-49, 50-59, 60-69, and 70-79 years) and gender-specific percentile ranks and T-scores for the three domains of the FEV as well as age- and gender-specific frequencies of the common problems in eating behaviour. Females scored significantly higher than males in all three domains of the FEV (p < 0.001). Older individuals showed significantly higher mean scores than the younger ones in the domain of cognitive restraint, but lower mean scores in disinhibition and hunger (p < 0.001). 45.1% of the males and 69.9% of the females reported specific problems in eating. The main problem in both genders was craving for sweets (38.6%). Eating in response to stress was mostly reported in younger individuals. The present study offers current normative data for the FEV in the middle-aged and older general population that can be applied in clinical and non-clinical settings. Information on eating behaviour can be helpful in understanding body weight modulation, and thus, may help to improve interventive and preventive programmes for overweight, obesity, and eating disorders.

The incredible ULKs.

Macroautophagy (commonly abbreviated as autophagy) is an evolutionary conserved lysosome-directed vesicular trafficking pathway in eukaryotic cells that mediates the lysosomal degradation of intracellular components. The cytoplasmic cargo is initially enclosed by a specific double membrane vesicle, termed the autophagosome. By this means, autophagy either helps to remove damaged organelles, long-lived proteins and protein aggregates, or serves as a recycling mechanism for molecular building blocks. Autophagy was once invented by unicellular organisms to compensate the fluctuating external supply of nutrients. In higher eukaryotes, it is strongly enhanced under various stress conditions, such as nutrient and growth factor deprivation or DNA damage. The serine/threonine kinase Atg1 was the first identified autophagy-related gene (ATG) product in yeast. The corresponding nematode homolog UNC-51, however, has additional neuronal functions. Vertebrate genomes finally encode five closely related kinases, of which UNC-51-like kinase 1 (Ulk1) and Ulk2 are both involved in the regulation of autophagy and further neuron-specific vesicular trafficking processes. This review will mainly focus on the vertebrate Ulk1/2-Atg13-FIP200 protein complex, its function in autophagy initiation, its evolutionary descent from the yeast Atg1-Atg13-Atg17 complex, as well as the additional non-autophagic functions of its components. Since the rapid nutrient- and stress-dependent cellular responses are mainly mediated by serine/threonine phosphorylation, it will summarize our current knowledge about the relevant upstream signaling pathways and the altering phosphorylation status within this complex during autophagy induction.

Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks.

Living cells are adaptive self-sustaining systems. They strictly depend on the sufficient supply of oxygen, energy, and nutrients from the outside in order to sustain their internal organization. However, as autonomous entities they are able to monitor and appropriately adapt to any critical fluctuation in their environment. In the case of insufficient external nutrient supply or augmented energy demands, cells start to extensively digest their own interior. This process, known as macroautophagy, comprises the transport of cytosolic portions and entire organelles to the lysosomal compartment via specific double-membrane vesicles, called autophagosomes. Although extensively upregulated under nutrient restriction, a low level of basal autophagy is likewise crucial in order to sustain the cellular homeostasis. On the other hand, cells have to avoid excessive and enduring self-digestion. The delicate balance between external energy and nutrient supply and internal production and consumption is a demanding task. The complex protein network that senses and precisely reacts to environmental changes is thus mainly regulated by rapid and reversible posttranslational modifications such as phosphorylation. This review focuses on the serine/threonine protein kinases AMP-activated protein kinase, mammalian target of rapamycin (mTOR), and unc-51-like kinase 1/2 (Ulk1/2), three interconnected major junctions within the autophagy regulating signaling network.

Atg13 and FIP200 act independently of Ulk1 and Ulk2 in autophagy induction.

Under normal growth conditions the mammalian target of rapamycin complex 1 (mTORC1) negatively regulates the central autophagy regulator complex consisting of Unc-51-like kinases 1/2 (Ulk1/2), focal adhesion kinase family-interacting protein of 200 kDa (FIP200) and Atg13. Upon starvation, mTORC1-mediated repression of this complex is released, which then leads to Ulk1/2 activation. In this scenario, Atg13 has been proposed as an adaptor mediating the interaction between Ulk1/2 and FIP200 and enhancing Ulk1/2 kinase activity. Using Atg13-deficient cells, we demonstrate that Atg13 is indispensable for autophagy induction. We further show that Atg13 function strictly depends on FIP200 binding. In contrast, the simultaneous knockout of Ulk1 and Ulk2 did not have a similar effect on autophagy induction. Accordingly, the Ulk1-dependent phosphorylation sites we identified in Atg13 are expendable for this process. This suggests that Atg13 has an additional function independent of Ulk1/2 and that Atg13 and FIP200 act in concert during autophagy induction.

Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: activation of caspase-9 in the absence of Apaf-1.

The protein kinase inhibitor staurosporine is one of the most potent and frequently used proapoptotic stimuli, although its mechanism of action is poorly understood. Here, we show that staurosporine as well as its analog 7-hydroxystaurosporine (UCN-01) not only trigger the classical mitochondrial apoptosis pathway but, moreover, activate an additional novel intrinsic apoptosis pathway. Unlike conventional anticancer drugs, staurosporine and UCN-01 induced apoptosis in a variety of tumor cells overexpressing the apoptosis inhibitors Bcl-2 and Bcl-x(L). Furthermore, activation of this novel intrinsic apoptosis pathway by staurosporine did not rely on Apaf-1 and apoptosome formation, an essential requirement for the mitochondrial pathway. Nevertheless, as demonstrated in caspase-9-deficient murine embryonic fibroblasts, human lymphoma cells, and chicken DT40 cells, staurosporine-induced apoptosis was essentially mediated by caspase-9. Our results therefore suggest that, in addition to the classical cytochrome c/Apaf-1-dependent pathway of caspase-9 activation, staurosporine can induce caspase-9 activation and apoptosis independently of the apoptosome. Since staurosporine derivatives have proven efficacy in clinical trials, activation of this novel pathway might represent a powerful target to induce apoptosis in multidrug-resistant tumor cells.

Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop.

Unc-51-like kinase 1 (Ulk1) plays a central role in autophagy induction. It forms a stable complex with Atg13 and focal adhesion kinase (FAK) family interacting protein of 200 kDa (FIP 200). This complex is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1) in a nutrient-dependent way. AMP-activated protein kinase (AMPK), which is activated by LKB1/Strad/Mo25 upon high AMP levels, stimulates autophagy by inhibiting mTORC1. Recently, it has been described that AMPK and Ulk1 interact and that the latter is phosphorylated by AMPK. This phosphorylation leads to the direct activation of Ulk1 by AMPK bypassing mTOR-inhibition. Here we report that Ulk1/2 in turn phosphorylates all three subunits of AMPK and thereby negatively regulates its activity. Thus, we propose that Ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of AMPK by Ulk1 represents a negative feedback circuit.