Effects of Two COVID-19 Lockdowns on HbA1c Levels in Patients with Type 1 Diabetes and Associations with Digital Treatment, Health Literacy, and Diabetes Self-Management: A Multicenter, Observational Cohort Study Over 3 Years.

INTRODUCTION: Short-term studies reported improved glycemic control and a decrease in eHbA1c (estimated hemoglobin A1c) in patients with type 1 diabetes during COVID-19 lockdown, but long-term changes are unknown. Therefore, the main objectives are to (1) analyze whether laboratory-measured HbA1c changed during and after two lockdowns and (2) investigate potential variables influencing HbA1c change. METHODS: In this cohort study, 291 adults with type 1 diabetes were followed over 3 years including the prepandemic phase and two lockdowns. The data from medical records and validated questionnaires assessing health literacy (HLS-EU-Q16), diabetes self-management (DSMQ-R27), general self-efficacy (GSE), and social support (F-SOZU-K14) were used to analyze associations with HbA1c levels (N = 2370) by performing multivariable linear regressions. RESULTS: The median age was 54 (38-63) years and 159 (54.6%) were male. All phases of the COVID-19 pandemic were associated with a significant increase in laboratory-measured HbA1c levels in percent (e.g., during first lockdown ß = 0.23, 95% confidence interval (CI) 0.07-0.39, p = 0.005; during the second lockdown, ß = 0.27, 95% CI 0.15-0.38, p < 0.001). HbA1c change during lockdowns was significantly affected by the number of checkups (ß = -0.03, 95% CI -0.05 to -0.01, p = 0.010), the value of HbA1c at previous observation (ß = 0.33, 95% CI 0.29-0.36, p < 0.001), educational level (secondary versus tertiary: ß = 0.22, 95% CI 0.06-0.38, p = 0.008; primary versus tertiary: ß = 0.31, 95% CI 0.10-0.52, p = 0.004), health literacy score (for each point: ß = -0.03, 95% CI -0.05 to - 0.002, p = 0.034), and diabetes self-management score (for each point: ß = -0.03, 95% CI -0.04 to -0.02, p < 0.001). The use of continuous glucose monitoring or insulin pump had no effect on HbA1c change. CONCLUSIONS: Lockdowns can lead to worsening glycemic control in patients with type 1 diabetes. Particularly patients with few check-ups, poor blood glucose values, deficits in diabetes self-management, low health literacy, and a low level of education seem to be at greater risk of worsening glycemic control during lockdowns and, therefore, require special medical care, e.g., through telemedicine. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04821921.

Concerted structural rearrangements enable RNA channeling into the cytoplasmic Ski238-Ski7-exosome assembly.

The Ski2-Ski3-Ski8 (Ski238) helicase complex directs cytoplasmic mRNAs toward the nucleolytic exosome complex for degradation. In yeast, the interaction between Ski238 and exosome requires the adaptor protein Ski7. We determined different cryo-EM structures of the Ski238 complex depicting the transition from a rigid autoinhibited closed conformation to a flexible active open conformation in which the Ski2 helicase module has detached from the rest of Ski238. The open conformation favors the interaction of the Ski3 subunit with exosome-bound Ski7, leading to the recruitment of the exosome. In the Ski238-Ski7-exosome holocomplex, the Ski2 helicase module binds the exosome cap, enabling the RNA to traverse from the helicase through the internal exosome channel to the Rrp44 exoribonuclease. Our study pinpoints how conformational changes within the Ski238 complex regulate exosome recruitment for RNA degradation. We also reveal the remarkable conservation of helicase-exosome RNA channeling mechanisms throughout eukaryotic nuclear and cytoplasmic exosome complexes.

Nuclear mRNPs are compact particles packaged with a network of proteins promoting RNA-RNA interactions.

Messenger RNAs (mRNAs) are at the center of the central dogma of molecular biology. In eukaryotic cells, these long ribonucleic acid polymers do not exist as naked transcripts; rather, they associate with mRNA-binding proteins to form messenger ribonucleoprotein (mRNP) complexes. Recently, global proteomic and transcriptomic studies have provided comprehensive inventories of mRNP components. However, knowledge of the molecular features of distinct mRNP populations has remained elusive. We purified endogenous nuclear mRNPs from Saccharomyces cerevisiae by harnessing the mRNP biogenesis factors THO and Sub2 in biochemical procedures optimized to preserve the integrity of these transient ribonucleoprotein assemblies. We found that these mRNPs are compact particles that contain multiple copies of Yra1, an essential protein with RNA-annealing properties. To investigate their molecular and architectural organization, we used a combination of proteomics, RNA sequencing, cryo-electron microscopy, cross-linking mass spectrometry, structural models, and biochemical assays. Our findings indicate that yeast nuclear mRNPs are packaged around an intricate network of interconnected proteins capable of promoting RNA-RNA interactions via their positively charged intrinsically disordered regions. The evolutionary conservation of the major mRNA-packaging factor (yeast Yra1 and Aly/REF in metazoans) points toward a general paradigm governing nuclear mRNP packaging.

Compliance and patient satisfaction with treatment settings recommended by the medical on-call service 116117 in Germany using computer-assisted structured initial assessment: a cross-sectional observational study accompanying the demand intervention.

OBJECTIVES: In order to reduce the use of emergency departments, computer-assisted initial assessment was implemented at the medical on-call service 116117. Our study assessed compliance and patient satisfaction. DESIGN: Cross-sectional observational postal survey. SETTING: Medical on-call service 116117 by eight Associations of Statutory Health Insurance Physicians in Germany. PARTICIPANTS: The intervention was observed between January 2020 and March 2021. Minors and patients with invalid contact data were excluded. A random sample of eligible patients received standardised questionnaires by mail. OUTCOME MEASURES: We analysed associations of sociodemographic data, health status, previous service use, health literacy, and recommended settings with compliance and patient satisfaction by multivariable, multilevel logistic regression. INTERVENTIONS: Based on symptoms and context factors, the computer software suggested service levels. Staff and patient discussed if higher levels were indicated, services were available and self-transport was possible. They then agreed on recommendations for treatment settings. RESULTS: Of 9473 contacted eligible patients, 1756 patients (18.5%) participated. Median age was 66 years (IQR=50-79), and 986 (59.0%) were women. At least one recommended setting was used by 1397 patients (85.4%). General practitioner (GP) practices were used by 143 patients (68.4%). Generally, better compliance was associated with lower depression levels (OR 1.59, 95% CI 1.17 to 2.17, p=0.003), fewer previous hospital stays (OR 2.02, 95% CI 1.27 to 3.23, p=0.003) and recommendations for any setting other than GP practices (OR 0.13, 95% CI 0.06 to 0.29, p<0001, to OR 0.37, 95% CI 0.19 to 0.72, p=0.003). A total of 606 patients (50.7%) were completely satisfied. Patient satisfaction was associated with higher age (OR 1.30, 95% CI 1.13 to 1.49, p<0.001), better self-rated health (OR 1.30, 95% CI 1.10 to 1.53, p=0.002), not having musculoskeletal disorders (OR 0.68, 95% CI 0.49 to 0.94, p=0.021), better health literacy (OR 0.69, 95% CI 0.54 to 0.89, p=0.005, and OR 0.49, 95% CI 0.36 to 0.67, p<0.001) and receiving no recommendation for GP practices (OR 0.61, 95% CI 0.43 to 0.87, p=0.006). CONCLUSIONS: Most patients were compliant and satisfied. Lowest compliance and satisfaction were found in GP practices, but nonetheless, two of three patients with respective recommendations were willing to use this setting. TRIAL REGISTRATION NUMBER: German Clinical Trials Register DRKS00017014.

Validation of patient- and GP-reported core sets of quality indicators for older adults with multimorbidity in primary care: results of the cross-sectional observational MULTIqual validation study.

BACKGROUND: Older adults with multimorbidity represent a growing segment of the population. Metrics to assess quality, safety and effectiveness of care can support policy makers and healthcare providers in addressing patient needs. However, there is a lack of valid measures of quality of care for this population. In the MULTIqual project, 24 general practitioner (GP)-reported and 14 patient-reported quality indicators for the healthcare of older adults with multimorbidity were developed in Germany in a systematic approach. This study aimed to select, validate and pilot core sets of these indicators. METHODS: In a cross-sectional observational study, we collected data in general practices (n = 35) and patients aged 65 years and older with three or more chronic conditions (n = 346). One-dimensional core sets for both perspectives were selected by stepwise backward selection based on corrected item-total correlations. We established structural validity, discriminative capacity, feasibility and patient-professional agreement for the selected indicators. Multilevel multivariable linear regression models adjusted for random effects at practice level were calculated to examine construct validity. RESULTS: Twelve GP-reported and seven patient-reported indicators were selected, with item-total correlations ranging from 0.332 to 0.576. Fulfilment rates ranged from 24.6 to 89.0%. Between 0 and 12.7% of the values were missing. Seventeen indicators had agreement rates between patients and professionals of 24.1% to 75.9% and one had 90.7% positive and 5.1% negative agreement. Patients who were born abroad (- 1.04, 95% CI = - 2.00/ - 0.08, p = 0.033) and had higher health-related quality of life (- 1.37, 95% CI = - 2.39/ - 0.36, p = 0.008), fewer contacts with their GP (0.14, 95% CI = 0.04/0.23, p = 0.007) and lower willingness to use their GPs as coordinators of their care (0.13, 95% CI = 0.06/0.20, p < 0.001) were more likely to have lower GP-reported healthcare quality scores. Patients who had fewer GP contacts (0.12, 95% CI = 0.04/0.20, p = 0.002) and were less willing to use their GP to coordinate their care (0.16, 95% CI = 0.10/0.21, p < 0.001) were more likely to have lower patient-reported healthcare quality scores. CONCLUSIONS: The quality indicator core sets are the first brief measurement tools specifically designed to assess quality of care for patients with multimorbidity. The indicators can facilitate implementation of treatment standards and offer viable alternatives to the current practice of combining disease-related metrics with poor applicability to patients with multimorbidity.

Association between patient-related factors and avoided consultations due to fear of COVID-19 during the first lockdown in northern Germany: Results of a cross-sectional observational study.

INTRODUCTION: During the COVID-19 pandemic, many people were anxious about a coronavirus infection due to the high infection rate and the mortality risk associated with the disease. Fear of COVID-19 might have influenced patients' utilisation of medical services, even if it meant that a postponed therapy had severe consequences. Our aims were to analyse (a) to what extent fear of COVID-19 contributes to forgone consultations, (b) if patient characteristics, health literacy and social support influence the effect of fear of COVID-19 on the utilisation behaviour and (c) whether interactions between these possible predictor variables are responsible for a higher extent of avoided consultations due to fear of COVID-19. METHODS: We conducted a retrospective, cross-sectional observational study in an emergency department. The study was based on personal standardized interviews of patients. The interviews took place between July 15 and August 5, 2020. Patients over the age of 18 were included if there was no urgent need for treatment on the day of the interview, no severe functional limitations, sufficient knowledge of German, ability to consent and health problems requiring treatment between March 13 and June 13, 2020. Differences between patient subgroups were described and analysed using the t-test and chi2 test. Data were analysed by logistic regression including socio-demographic data, health literacy and social support assessed by standardised instruments. Additionally, we assessed interactions between possible predictor variables by a descriptive tree analysis. RESULTS: 103 patients participated in personal standardized interviews. 46 patients (44.6%) reported that at least one necessary consultation did not take place in the observation period. Among those, 29 patients (63.0%) avoided consultations due to fear of COVID-19. Women had 3.36 times higher odds (95% confidence interval: 1.25 to 9.04, p = 0.017) for avoiding a consultation due to fear of COVID-19. There were no other statistically significant predictors in our analysis. DISCUSSION: Almost half of the required consultations did not take place. Avoidance of consultations needs to be closely monitored during the pandemic. Policy makers as well as health care providers should give consideration to the collateral effects of COVID-19 and COVID-19-related reactions of patients, especially women. CONCLUSION: In the course of the COVID-19 pandemic, physicians should ensure that their patients take advantage of necessary consultations in order to avoid negative effects of a delayed examination or treatment. Particular attention should be paid to anxious female patients. Studies are needed to analyse the association between health literacy, social support and avoidance of consultations triggered by fear of COVID-19.

Expectations and Prior Experiences Associated With Adverse Effects of COVID-19 Vaccination.

Importance: Uptake of vaccination against COVID-19 is strongly affected by concerns about adverse effects. Research on nocebo effects suggests that these concerns can amplify symptom burden. Objective: To investigate whether positive and negative expectations prior to COVID-19 vaccination are associated with systemic adverse effects. Design, Setting, and Participants: This prospective cohort study analyzed the association of expected benefits and risks of vaccination, adverse effects at first vaccination, and observed adverse effects in close contacts with severity of systemic adverse effects among adults receiving a second dose of messenger RNA (mRNA)-based vaccines between August 16 and 28, 2021. A total of 7771 individuals receiving the second dose at a state vaccination center in Hamburg, Germany, were invited to participate; of these, 5370 did not respond, 535 provided incomplete information, and 188 were excluded retrospectively. The mobile application m-Path was used for data collection. Main Outcomes and Measures: Primary outcome was a composite severity index of systemic adverse effects in 12 symptom areas measured once daily with an electronic symptom diary over 7 consecutive days. Data were analyzed by mixed-effects multivariable ordered logistic regression adjusted for prevaccine symptom levels and observation times. Results: A total of 10 447 observations from 1678 individuals receiving vaccinations (BNT162b2 [Pfizer BioNTech] in 1297 [77.3%] and mRNA-1273 [Moderna] in 381 [22.7%]) were collected. The participants' median age was 34 (IQR, 27-44) years, and 862 (51.4%) were women. The risk for more severe adverse effects was higher for persons expecting a lower benefit of vaccination (odds ratio [OR] for higher expectations, 0.72 [95% CI, 0.63-0.83]; P < .001), expecting higher adverse effects of vaccination (OR, 1.39 [95% CI, 1.23-1.58]; P < .001), having experienced higher symptom burden at the first vaccination (OR, 1.60 [95% CI, 1.42-1.82]; P < .001), scoring higher on the Somatosensory Amplification Scale (OR, 1.21 [95% CI, 1.06-1.38]; P = .004), and if the vaccine mRNA-1273 was given rather than BNT162b2 (OR, 2.45 [95% CI, 2.01-2.99]; P < .001). No associations were seen for observed experiences. Conclusions and Relevance: In this cohort study, several nocebo effects occurred in the first week after COVID-19 vaccination. The severity of systemic adverse effects was associated not only with vaccine-specific reactogenicity but also more negative prior experiences with adverse effects from the first COVID-19 vaccination, more negative expectations regarding vaccination, and tendency to catastrophize instead of normalize benign bodily sensations. Clinician-patient interactions and public vaccine campaigns may both benefit from these insights by optimizing and contextualizing information provided about COVID-19 vaccines.

The human CNOT1-CNOT10-CNOT11 complex forms a structural platform for protein-protein interactions.

The evolutionary conserved CCR4-NOT complex functions in the cytoplasm as the main mRNA deadenylase in both constitutive mRNA turnover and regulated mRNA decay pathways. The versatility of this complex is underpinned by its modular multi-subunit organization, with distinct structural modules actuating different functions. The structure and function of all modules are known, except for that of the N-terminal module. Using different structural approaches, we obtained high-resolution data revealing the architecture of the human N-terminal module composed of CNOT1, CNOT10, and CNOT11. The structure shows how two helical domains of CNOT1 sandwich CNOT10 and CNOT11, leaving the most conserved domain of CNOT11 protruding into solvent as an antenna. We discovered that GGNBP2, a protein identified as a tumor suppressor and spermatogenic factor, is a conserved interacting partner of the CNOT11 antenna domain. Structural and biochemical analyses thus pinpoint the N-terminal CNOT1-CNOT10-CNOT11 module as a conserved protein-protein interaction platform.

Impact of two COVID-19 lockdowns on HbA1c levels in patients with type 2 diabetes and associations with patient characteristics: a multicentre, observational cohort study over three years.

Introduction: Glycemic effects of COVID-19 lockdowns on patients with type 2 diabetes (T2D) are controversial. In this long-term observation, we aimed (1) to analyze changes in HbA1c levels during lockdowns in Germany, and (2) to investigate whether diabetes medication, comorbidities, and sociodemographic data influenced these changes. Materials and methods: This cohort study observed 1,089 patients aged ≥18 years over the years 2019 to 2021. Patients were recruited from 14 physicians specialized on diabetes. As dependent variable, 7,987 HbA1c values were analyzed by multivariable linear regression adjusted for random effects of physicians and patients. Results: Patients had a median age of 68 (60/76) years and 623 (57.2%) were male. Before the pandemic, median HbA1c level (in %) was 6.9 (6.3/7.7). Average HbA1c level increased during first lockdown (0.21,0.11/0.31,p < 0.001), after first lockdown (0.23,0.18/0.28,p < 0.001), during second lockdown (0.40,0.33/0.47,p < 0.001) and after second lockdown (0.27,0.18/0.36,p < 0.001). The increase of HbA1c levels was more pronounced in male patients (0.08,0.01/0.15,p = 0.019), if patients did not have German as native language (0.12,0.01/0.23,p = 0.041) and if they were widowed (0.19,0.05/0.32,p = 0.008). End organ damages (0.12,0.01/0.23,p = 0.039), atherosclerotic cardiovascular disease (ASCVD; 0.23,0.10/0.36,p = 0.001) and cardiovascular events (0.25,0.10/0.40,p = 0.001) as well as oral medication (0.09,0.03/0.15,p = 0.002), intermediate- or long-acting insulins (0.24,0.16/0.32,p < 0.001), and fast-acting or mixed insulins (0.30,0.23/0.36,p < 0.001) were also related to a greater increase in HbA1c levels. Conclusion: Both lockdowns resulted in a significant increase in HbA1c levels. In particular, patients with ASCVD, cardiovascular events, and insulin therapy appear to be at risk for worsening glycemic control in crisis and thus require special medical attention. Clinical Trial Registration: ClinicalTrials.gov (NCT04821921).

[Health literacy and commitment to a general practitioner in low-acuity patients of emergency departments: results of the PiNo observational study in Northern Germany]. / Gesundheitskompetenz und Hausarztbindung nicht dringlicher Patientinnen und Patienten in Notaufnahmen: Ergebnisse der PiNo-Studie in Hamburg und Schleswig-Holstein.

INTRODUCTION: High utilization of emergency departments by low-acuity patients remains a major challenge for the health care system. Surveys of treatment urgency show that a considerable part of the emergency department population could also be cared for in the outpatient sector. Little is known about the contributing circumstances of non-utilization of outpatient care (despite indication). The expression of health literacy is often called to explain non-urgent use of emergency departments. The extent to which a distinguished commitment to primary care might have a moderating effect is currently not known. METHODS: The data for this secondary evaluation of a non-urgent emergency department population were taken from the cross-sectional observational study PiNo Nord ("Patients in the emergency departments of hospitals in Northern Germany") (Scherer et al. 2017). In five hospitals in Hamburg and the federal state of Schleswig-Holstein, health literacy and 'intensity of the commitment to a general practitioner' were measured by self-assessment questionnaires (HLS-EU-Q16, F-HaBi). In addition to descriptive data analysis, linear regression was used to estimate the 'intensity of the commitment to a general practitioner' and other somatic, psychological, and sociodemographic characteristics of the population on health literacy. RESULTS: 548 non-urgent adult patients (mean age 41.5 years, 54.4% men) were included in the evaluation: 55.5% had sufficient, 31.4% problematic and 13.1% inadequate health literacy. 88.3% of the population had a general practitioner. A higher 'intensity of the commitment to a general practitioner', female gender, a higher subjective urgency for treatment, better self-efficacy and better social support were associated with higher health literacy. No associations were found with regard to age, household income, education and migration background, current pain or the degree of physical complaints. DISCUSSION: The extent of health literacy of a non-urgent sample of the PiNo North study population, responding to the HLS-EU-Q16, was comparable to the health literacy of the general population. Health literacy and intensity of commitment to a general practitioner were positively associated. However, the intensity of GP commitment was rather low. The fact that younger respondents were more likely to provide information about their health literacy and the availability of specialists in urban areas could explain these findings. CONCLUSION: Improving commitment to primary care physicians could include providing individualized information on how to navigate the health care system. This could make it easier for patients to choose an adequate level of care - and thus have a steering effect on emergency department utilization.