COVID-19-associated costs and mortality in Germany: an incidence-based analysis from a payer's perspective.

BACKGROUND: This study aims to estimate average COVID-19-associated healthcare costs per capita in Germany from a payer perspective. In addition, insights into COVID-19-associated mortality should be gained. METHODS: For this purpose, a retrospective longitudinal analysis using health insurance claims data was performed. Patients affected by COVID-19 in Q1/2021 (investigation group (IG)) were compared to a matched non-COVID-19 control group (CG) (1:1 propensity score matching (PSM)). Mean values of healthcare costs in 2020 and 2021 were computed for both groups and then separated by age and by development of Post-COVID-19 Syndrome (PCS). Group differences were examined using Mann-Whitney U test (α = 0.05). Difference-in-Differences approach (DiD) was used to estimate average cost effects of COVID-19 in 2021. Concerning mortality, the number of deaths in 2021 was compared between IG and CG using χ2 test of independence. RESULTS: A total of 8,014 insurants were included (n = 4,007 per group; n = 536 per group examining PCS patients only). Total healthcare costs varied a lot in the sample, were comparable between IG and CG in 2020, but were significantly higher in the IG in 2021 (DiD estimate = € 1,063 (in total); € 3,242 (PCS group)). This was more pronounced in the older age groups. High hospital costs of a minority of patients were the most influential driver of COVID-19-associated healthcare costs. Mortality was more than doubled in the IG (tripled in patients aged ≥ 60). CONCLUSIONS: COVID-19 is associated with significantly increased healthcare costs and mortality, especially in older age groups. The additional development of PCS further increases the costs of COVID-19.

Influence of the Molar Activity of 203/212Pb-PSC-PEG2-TOC on Somatostatin Receptor Type 2-Binding and Cell Uptake.

(1) Background: In neuroendocrine tumors (NETs), somatostatin receptor subtype 2 is highly expressed, which can be targeted by a radioactive ligand such as [177Lu]Lu-1,4,7,10-tetraazacyclododecane-N,N',N″,N‴,-tetraacetic acid-[Tyr3,Thr8]-octreotide (177Lu-DOTA-TOC) and, more recently, by a lead specific chelator (PSC) containing 203/212Pb-PSC-PEG2-TOC (PSC-TOC). The molar activity (AM) can play a crucial role in tumor uptake, especially in receptor-mediated uptake, such as in NETs. Therefore, an investigation of the influence of different molar activities of 203/212Pb-PSC-TOC on cell uptake was investigated. (2) Methods: Optimized radiolabeling of 203/212Pb-PSC-TOC was performed with 50 µg of precursor in a NaAc/AcOH buffer at pH 5.3-5.5 within 15-45 min at 95° C. Cell uptake was studied in AR42 J, HEK293 sst2, and ZR75-1 cells. (3) Results: 203/212Pb-PSC-TOC was radiolabeled with high radiochemical purity >95% and high radiochemical yield >95%, with AM ranging from 0.2 to 61.6 MBq/nmol. The cell uptake of 203Pb-PSC-TOC (AM = 38 MBq/nmol) was highest in AR42 J (17.9%), moderate in HEK293 sstr (9.1%) and lowest in ZR75-1 (0.6%). Cell uptake increased with the level of AM. (4) Conclusions: A moderate AM of 15-40 MBq/nmol showed the highest cell uptake. No uptake limitation was found in the first 24-48 h. Further escalation experiments with even higher AM should be performed in the future. It was shown that AM plays an important role because of its direct dependence on the cellular uptake levels, possibly due to less receptor saturation with non-radioactive ligands at higher AM.

Intraoperative suggestions to prevent postoperative delirium in patients undergoing transaortic valvular replacement: a randomized placebo-controlled trial.

BACKGROUND: Postoperative delirium (POD) is a serious complication following anaesthesia and surgery and significantly influences postoperative outcome especially in the elderly population. Intraoperative music and positive suggestions influence postoperative outcomes by attenuating analgesic demand and increasing patient satisfaction. AIMS: Here, we examined the effect of intraoperative music and positive suggestions on the development of POD in aged patients undergoing transcatheter aortic valve replacement (TAVR) procedure under general anaesthesia. METHODS: For this randomized placebo-controlled study, eligible patients without cognitive deficit, indicated by a MMSE < 10 points, were anesthetized using remifentanil and sevoflurane. Anaesthetic depth was guide with bispectral index. An audiotape with positive suggestions was applied from a MP3 player via headphones. POD, pain and PONV was assessed. CAM-ICU and Nu-DESC were done twice daily for the first 5 days. RESULTS: Of 140 patients 118 patients could be analysed (57 male, 80.6 ± 5.1 years). POD was diagnosed in 16 patients (12.7%). POD was significantly more often observed in male (12, 21.1%) than in female (4, 6.6%, p = 0.02) and in patients with a low MMSE (23.6 ± 4.5 vs. 26.8 ± 2.8, p = 0.001). Anaesthetic depth did not influence the incidence of POD. Intraoperative music and suggestions did not affect the rate of POD, pain, analgesic requirement or PONV. DISCUSSION: In patients undergoing TAVR male sex and low MMSE scoring are associated with an increase in POD. CONCLUSIONS: Intraoperative music and positive suggestions do not influence the incidence of POD in this patient group. STUDY REGISTRATION: DRKS: 00024444, start of registration: 4.02.202, final registration: 17.09.2021.

Comparative Saturation Binding Analysis of 64Cu-Labeled Somatostatin Analogues Using Cell Homogenates and Intact Cells.

The development of novel ligands for G-protein-coupled receptors (GPCRs) typically entails the characterization of their binding affinity, which is often performed with radioligands in a competition or saturation binding assay format. Since GPCRs are transmembrane proteins, receptor samples for binding assays are prepared from tissue sections, cell membranes, cell homogenates, or intact cells. As part of our investigations on modulating the pharmacokinetics of radiolabeled peptides for improved theranostic targeting of neuroendocrine tumors with a high abundance of the somatostatin receptor sub-type 2 (SST2), we characterized a series of 64Cu-labeled [Tyr3]octreotate (TATE) derivatives in vitro in saturation binding assays. Herein, we report on the SST2 binding parameters measured toward intact mouse pheochromocytoma cells and corresponding cell homogenates and discuss the observed differences taking the physiology of SST2 and GPCRs in general into account. Furthermore, we point out method-specific advantages and limitations.

Patient information, communication and competence empowerment in oncology: Results and learnings from the PIKKO study.

PURPOSE: Many concepts for accompanying and supporting cancer patients exist and have been studied over time. One of them was PIKKO (a German acronym for "Patient information, communication and competence empowerment in oncology"), which combined a patient navigator, socio-legal and psychological counseling (with psychooncologists), courses dealing with various supportive aspects, and a knowledge database with validated and easy-to-understand disease-related information. The aim was to increase the patients' health-related quality of life (HRQoL), self-efficacy as well as health literacy and to reduce psychological complaints such as depression and anxiety. METHODS: To this purpose, an intervention group was given full access to the modules in addition to treatment as usual, while a control group received only treatment as usual. Over twelve months, each group was surveyed up to five times. Measurements were taken using the SF12, PHQ-9, GAD, GSE, and HLS-EU-Q47. RESULTS: No significant differences were found in scores on the mentioned metrics. However, each module was used many times and rated positively by the patients. Further analyses showed a tendency higher score in health literacy with higher intensity of use of the database and higher score in mental HRQoL with higher intensity of use of counseling. CONCLUSION: The study was affected by several limitations. A lack of randomization, difficulties in recruiting the control group, a heterogeneous sample, and the COVID-19 lockdown influenced the results. Nevertheless, the results show that the PIKKO support was appreciated by the patients and the lack of measurable effects was rather due to the mentioned limitations than to the PIKKO intervention. TRIAL REGISTRATION: This study was retrospectively registered in the German Clinical Trial Register under DRKS00016703 (21.02.2019, retrospectively registered). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016703.

The impact of the COVID-19 pandemic restrictions on the health care utilization of cancer patients.

BACKGROUND: COVID-19 has impacted both society and medical care. While Germany entered the first lockdown in spring 2020, the PIKKO study (Patient information, communication and competence empowerment in oncology) was still active. The intervention modules, patient navigator (PN), services of the Saarland Cancer Society (SCS), psycho-social counseling and different courses, and online knowledge database (ODB) continued to be offered, but in an adapted form. It was the aim of this supplementary survey to identify the restrictions and burdens of the pandemic containment strategies on the PIKKO patients and thus on the PIKKO study itself. Furthermore, this work shows how the PIKKO modules were used during the lockdown. METHODS: All patients in the PIKKO intervention group (IG) were invited to complete a questionnaire, n = 503. Furthermore, utilization of the SCS and log files of the ODB were analyzed. For socio-demographic data and contacts with the PN, data from the regular PIKKO surveys were used. In addition to descriptive statistics, chi²-tests, F-tests and linear regression analyses were performed. RESULTS: 356 patients participated in this supplemental survey. 37.6% reported restrictions. "Restrictions on accompanying persons", "ban on visits to the wards" and "protective mouth-nose-mask" were reported as the greatest burdens. 39.0% expressed fears that the restrictions would have an impact on the course of their disease. Linear regression analyses showed differences in feelings of burden among age groups (more among < 60-year-olds), gender (more among women), children in the household (more with children), and preexisting financial stress (more with financial worries). In April 2020, there was more patient contact with PNs by phone, more SCS psycho-social counseling by phone, adapted SCS course offering, but with significantly fewer participants, and high activity on the ODB. CONCLUSION: Cancer patients in the IG reported restrictions from the pandemic containment strategies and feared an impact on their recovery. However, whether a burden is perceived as heavy depends more on gender, age, or pre-existing burdens than on whether the lockdown affects PIKKO or not. The utilization of counseling, courses or the ODB despite lockdown shows the need for such services, especially in times of crisis. TRIAL REGISTRATION: This study was retrospectively registered in the German Clinical Trial Register under DRKS00016703 (21 Feb 2019, retrospectively registered). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016703 .

[Psychometric Properties of the Qualiskope-A for Measuring Patient Satisfaction with Outpatient Medical Treatment: Use in Oncology and Transferability to Inpatient Care]. / Psychometrische Eigenschaften des Qualiskope-A zur Messung der Patientenzufriedenheit mit der ambulant-ärztlichen Behandlung: Einsatz in der Onkologie und Übertragbarkeit auf die stationäre Versorgung.

AIM: The Qualiskope-A is a German-language PREM (Patient Reported Experience Measure) which, with the help of 27 items allocated to four scales, enables measurement of patient satisfaction with outpatient medical treatment along four dimensions of patient satisfaction. This study examined whether the questionnaire delivers reliable results in an oncological population and whether its application can be extended to inpatient care. METHOD: Required data was collected as part of the PIKKO study. Initially, descriptive statistics and internal consistency (Cronbach's alpha) of the PREM's scales were analyzed. In addition, a sub-sample that assessed the same doctor at two consecutive measurement time points was observed with regard to test-retest reliability (Spearman correlation (rs) between both measurement time points). The measurement model of the Qualiskope-A was then examined using confirmatory factor analysis. To test the transferability to inpatient care, measurement invariance with regard to outpatients and inpatients was computed. RESULTS: A total of 476 patients was included in the study. Every score of the Qualiskope-A showed a left-skewed distribution in the sample and revealed pronounced ceiling effects. Cronbach's alpha coefficients were consistently>0,8. Within the test-retest group (n=197), a strong correlation (rs>0,5) was observed between the measurement time points. The fit indices calculated using confirmatory factor analysis showed a good model fit (CFI=0,958; RMSEA=0,026; SRMR=0,040; every factor loadings>0,6). The fit indices, calculated as part of the investigation of measurement invariance, consistently met the defined threshold values. CONCLUSION: The Qualiscope-A shows good reliability in the examined oncological sample. It can be used in both outpatient and inpatient settings (no indications of non-invariance were found). Due to pronounced ceiling effects, however, the item scaling should be revised.

Enzymological Characterization of 64Cu-Labeled Neprilysin Substrates and Their Application for Modulating the Renal Clearance of Targeted Radiopharmaceuticals.

The applicability of radioligands for targeted endoradionuclide therapy is limited due to radiation-induced toxicity to healthy tissues, in particular to the kidneys as primary organs of elimination. The targeting of enzymes of the renal brush border membrane by cleavable linkers that permit the formation of fast eliminating radionuclide-carrying cleavage fragments gains increasing interest. Herein, we synthesized a small library of 64Cu-labeled cleavable linkers and quantified their substrate potentials toward neprilysin (NEP), a highly abundant peptidase at the renal brush border membrane. This allowed for the derivation of structure-activity relationships, and selected cleavable linkers were attached to the somatostatin receptor subtype 2 ligand [Tyr3]octreotate. Radiopharmacological characterization revealed that a substrate-based targeting of NEP in the kidneys with small peptides entails their premature cleavage in the blood circulation by soluble and endothelium-derived NEP. However, for a kidney-specific targeting of NEP, the additional targeting of albumin in the blood is highlighted.

Modulating the pharmacokinetic profile of Actinium-225-labeled macropa-derived radioconjugates by dual targeting of PSMA and albumin.

Rationale: Small 225Ac-labeled prostate-specific membrane antigen (PSMA)-targeted radioconjugates have been described for targeted alpha therapy of metastatic castration-resistant prostate cancer. Transient binding to serum albumin as a highly abundant, inherent transport protein represents a commonly applied strategy to modulate the tissue distribution profile of such low-molecular-weight radiotherapeutics and to enhance radioactivity uptake into tumor lesions with the ultimate objective of improved therapeutic outcome. Methods: Two ligands mcp-M-alb-PSMA and mcp-D-alb-PSMA were synthesized by combining a macropa-derived chelator with either one or two lysine-ureido-glutamate-based PSMA- and 4-(p-iodophenyl)butyrate albumin-binding entities using multistep peptide-coupling chemistry. Both compounds were labeled with [225Ac]Ac3+ under mild conditions and their reversible binding to serum albumin was analyzed by an ultrafiltration assay as well as microscale thermophoresis measurements. Saturation binding studies and clonogenic survival assays using PSMA-expressing LNCaP cells were performed to evaluate PSMA-mediated cell binding and to assess the cytotoxic potency of the novel radioconjugates [225Ac]Ac-mcp-M-alb-PSMA and [225Ac]Ac-mcp-D-alb-PSMA, respectively. Biodistributions of both 225Ac-radioconjugates were investigated using LNCaP tumor-bearing SCID mice. Histological examinations of selected organs were performed to analyze the occurrence of necrosis using H&E staining, DNA damage via γH2AX staining and proliferation via Ki67 expression in the tissue samples. Results: Enhanced binding to serum components in general and to human serum albumin in particular was revealed for [225Ac]Ac-mcp-M-alb-PSMA and [225Ac]Ac-mcp-D-alb-PSMA, respectively. Moreover, the novel derivatives are highly potent PSMA ligands as their KD values in the nanomolar range (23.38 and 11.56 nM) are comparable to the reference radioconjugates [225Ac]Ac-mcp-M-PSMA (30.83 nM) and [225Ac]Ac-mcp-D-PSMA (10.20 nM) without albumin binders. The clonogenic activity of LNCaP cells after treatment with the 225Ac-labeled ligands was affected in a dose- and time-dependent manner, whereas the bivalent radioconjugate [225Ac]Ac-mcp-D-alb-PSMA has a stronger impact on the clonogenic cell survival than its monovalent counterpart [225Ac]Ac-mcp-M-alb-PSMA. Biodistribution studies performed in LNCaP tumor xenografts showed prolonged blood circulation times for both albumin-binding radioconjugates and a substantially increased tumor uptake (46.04 ± 7.77 %ID/g for [225Ac]Ac-mcp-M-alb-PSMA at 128 h p.i. and 153.48 ± 37.76 %ID/g at 168 h p.i. for [225Ac]Ac-mcp-D-alb-PSMA) with favorable tumor-to-background ratios. Consequently, a clear histological indication of DNA damage was discovered in the tumor tissues, whereas DNA double-strand break formation in kidney and liver sections was less pronounced. Conclusion: The modification of the PSMA-based 225Ac-radioconjugates with one or two albumin-binding entities resulted in an improved radiopharmacological behavior including a greatly enhanced tumor accumulation combined with a rather low uptake in most non-targeted organs combined with a high excretion via the kidneys.

Toward Personalized Medicine: One Chelator for Imaging and Therapy with Lutetium-177 and Actinium-225.

We report a nonadentate bispidine (3,7-diazabicyclo[3.3.1]nonane) that unveils the potential to bind theranostically relevant radionuclides, including indium-111, lutetium-177, and actinium-225 under mild labeling conditions. This radiopharmaceutical candidate allows the simultaneous application of imaging and treatment (radionuclide theranostics) without changing the type of the bioconjugate; that is, it allows the strong binding to an imaging and a therapeutic radionuclide by the same chelator. Since sophisticated coordination chemistry is required to achieve high thermodynamic and kinetic stability (inertness), it is not surprising that only a few chelators have been reported that are able to strongly bind several radionuclides to a satisfactory extent. Bispidine-derived ligands have proven to be ideal for di- and trivalent metal ions with generally fast complexation kinetics and high in vitro and in vivo stabilities. The presented (radio)complexes are formed under mild conditions (pH 6, <40 °C) and exhibit thermodynamic stability and inertness in human serum comparable to the corresponding DOTA complexes. The bispidine-based complexing agent was conjugated to a peptide, targeting somatostatin type 2 receptors (SSTR2), overexpressed on neuroendocrine tumors. The 177Lu- and 225Ac-labeled conjugates were investigated, considering their binding to two different SSTR2-positive cell lines, including the human pancreatic carcinoid tumor (BON-SSTR2+) and the murine pheochromocytoma cell line (MPC). The biodistribution and accumulation pattern in MPC tumor-bearing mice was also evaluated. The LuIII and AcIII complexes studied show how ligand structures can be optimized in general by extending the denticity and varying the donor set in order to allow for fast complex formation and medically relevant inertness.

Exploring Nitric Oxide (NO)-Releasing Celecoxib Derivatives as Modulators of Radioresponse in Pheochromocytoma Cells.

COX-2 can be considered as a clinically relevant molecular target for adjuvant, in particular radiosensitizing treatments. In this regard, using selective COX-2 inhibitors, e.g., in combination with radiotherapy or endoradiotherapy, represents an interesting treatment option. Based on our own findings that nitric oxide (NO)-releasing and celecoxib-derived COX-2 inhibitors (COXIBs) showed promising radiosensitizing effects in vitro, we herein present the development of a series of eight novel NO-COXIBs differing in the peripheral substitution pattern and their chemical and in vitro characterization. COX-1 and COX-2 inhibition potency was found to be comparable to the lead NO-COXIBs, and NO-releasing properties were demonstrated to be mainly influenced by the substituent in 4-position of the pyrazole (Cl vs. H). Introduction of the N-propionamide at the sulfamoyl residue as a potential prodrug strategy lowered lipophilicity markedly and abolished COX inhibition while NO-releasing properties were not markedly influenced. NO-COXIBs were tested in vitro for a combination with single-dose external X-ray irradiation as well as [177Lu]LuCl3 treatment in HIF2α-positive mouse pheochromocytoma (MPC-HIF2a) tumor spheroids. When applied directly before X-ray irradiation or 177Lu treatment, NO-COXIBs showed radioprotective effects, as did celecoxib, which was used as a control. Radiosensitizing effects were observed when applied shortly after X-ray irradiation. Overall, the NO-COXIBs were found to be more radioprotective compared with celecoxib, which does not warrant further preclinical studies with the NO-COXIBs for the treatment of pheochromocytoma. However, evaluation as radioprotective agents for healthy tissues could be considered for the NO-COXIBs developed here, especially when used directly before irradiation.

Human papillomavirus vaccination of girls in the German model region Saarland: Insurance data-based analysis and identification of starting points for improving vaccination rates.

In Germany, the incidence of cervical cancer, a disease caused by human papillomaviruses (HPV), is higher than in neighboring European countries. HPV vaccination has been recommended for girls since 2007. However, it continues to be significantly less well received than other childhood vaccines, so its potential for cancer prevention is not fully realized. To find new starting points for improving vaccination rates, we analyzed pseudonymized routine billing data from statutory health insurers in the PRÄZIS study (prevention of cervical carcinoma and its precursors in women in Saarland) in the federal state Saarland serving as a model region. We show that lowering the HPV vaccination age to 9 years led to more completed HPV vaccinations already in 2015. Since then, HPV vaccination rates and the proportion of 9- to 11-year-old girls among HPV-vaccinated females have steadily increased. However, HPV vaccination rates among 15-year-old girls in Saarland remained well below 50% in 2019. Pediatricians vaccinated the most girls overall, with a particularly high proportion at the recommended vaccination age of 9-14 years, while gynecologists provided more HPV catch-up vaccinations among 15-17-year-old girls, and general practitioners compensated for HPV vaccination in Saarland communities with fewer pediatricians or gynecologists. We also provide evidence for a significant association between attendance at the children´s medical check-ups "U11" or "J1" and HPV vaccination. In particular, participation in HPV vaccination is high on the day of U11. However, obstacles are that U11 is currently not financed by all statutory health insurers and there is a lack of invitation procedures for both U11 and J1, resulting in significantly lower participation rates than for the earlier U8 or U9 screenings, which are conducted exclusively with invitations and reminders. Based on our data, we propose to restructure U11 and J1 screening in Germany, with mandatory funding for U11 and organized invitations for HPV vaccination at U11 or J1 for both boys and girls.

Nanosensors in clinical development of CAR-T cell immunotherapy.

Immunotherapy using CAR-T cells is a new technological paradigm for cancer treatment. To avoid severe side effects and tumor escape variants observed for conventional CAR-T cells approach, adaptor CAR technologies are under development, where intermediate target modules redirect immune cells against cancer. In this work, silicon nanowire field-effect transistors are used to develop target modules for an optimized CAR-T cell operation. Focusing on a library of seven variants of E5B9 peptide that is used as CAR targeting epitope, we performed multiplexed binding tests using nanosensor chips. These peptides had been immobilized onto the sensor to compare the transistor signals upon titration with anti-La 5B9 antibodies. The correlation of binding affinities and sensor sensitivities enabled a selection of candidates for the interaction between CAR and target modules. An extremely low detection limit was observed for the sensor, down to femtomolar concentration, outperforming the current assay of the same purpose. Finally, the CAR T-cells redirection capability of selected peptides in target modules was proven successful in an in-vitro cytotoxicity assay. Our results open the perspective for the nanosensors to go beyond the early diagnostics in clinical cancer research towards developing and monitoring immunotherapeutic treatment, where the quantitative analysis with the standard techniques is limited.

"Clickable" Albumin Binders for Modulating the Tumor Uptake of Targeted Radiopharmaceuticals.

The intentional binding of radioligands to albumin gains increasing attention in the context of radiopharmaceutical cancer therapy as it can lead to an enhanced radioactivity uptake into the tumor lesions and, thus, to a potentially improved therapeutic outcome. However, the influence of the radioligand's albumin-binding affinity on the time profile of tumor uptake has been only partly addressed so far. Based on the previously identified Nε-4-(4-iodophenyl)butanoyl-lysine scaffold, we designed "clickable" lysine-derived albumin binders (cLABs) and determined their dissociation constants toward albumin by novel assay methods. Structure-activity relationships were derived, and selected cLABs were applied for the modification of the somatostatin receptor subtype 2 ligand (Tyr3)octreotate. These novel conjugates were radiolabeled with copper-64 and subjected to a detailed in vitro and in vivo radiopharmacological characterization. Overall, the results of this study provide an incentive for further investigations of albumin binders for applications in endoradionuclide therapies.

Correlation between the Incontinence Severity Index (ISI) and the quality of life dimensions of the King's Health Questionnaire (KHQ) in German-speaking urinary incontinent women.

BACKGROUND: The Incontinence Severity Index (ISI) is a patient questionnaire to ascertain severity of urinary incontinence (UI) via two items. The aim of this study was to translate the ISI into German, to compare it with the German-language King's Health Questionnaire (KHQ), an already validated German-language questionnaire within the scope of UI to measure condition-specific quality of life (QoL), and to gain more insights into association between symptom severity and QoL in German-speaking women affected. METHODS: A total of 161 urinary incontinent women completed the ISI and the KHQ. Mean scores of the KHQ domains were computed and separated into severity-groups ascertained by the ISI (slight, moderate, severe, and very severe). Differences between severity-groups were examined using Kruskal-Wallis and Mann-Whitney U test. Correlation between ISI and KHQ were computed using Spearman's correlation coefficient to investigate construct validity of the ISI as well as association between symptom severity and QoL. RESULTS: Overall, mean scores of the KHQ domains increased with increasing severity level. A consistent significant increase was found in role, physical, and social limitations (p < 0.05). Furthermore, the ISI showed moderate to strong correlations with related domains (convergent validity) and weak correlations with non-related domains of the KHQ (discriminant validity). CONCLUSIONS: Construct validity of the German-language ISI is acceptable. Therefore this study supports its use in German-speaking women but further studies have to be done to gain more comprehensive insights into its psychometric properties. Moreover, increasing symptom severity is associated with decreasing QoL, especially concerning role, physical, and social limitations. TRIAL REGISTRATION NUMBER: DRKS00018777.

Psychometric properties of the German-language questionnaire for urinary incontinence diagnosis (QUID) in women with urinary incontinence.

PURPOSE: The aim of this study was to translate the questionnaire for urinary incontinence diagnosis (QUID) into German and to assess its psychometric properties in German-speaking women with urinary incontinence (UI). The QUID contains two subscales to measure symptom severity of stress urinary incontinence (SUI) and urge urinary incontinence (UUI) and to distinguish between both forms. METHODS: A total of 161 women with UI completed the QUID and the King's Health Questionnaire (KHQ), each in the German version. To examine construct validity Spearman's correlation coefficients between both questionnaires were computed. Furthermore, the internal consistency (Cronbach's alpha) of the QUID and its criterion validity were examined. Looking at criterion validity, sensitivity, specificity, ROC curves, and Youden-indexes were computed for both subscales. RESULTS: The QUID showed good construct validity by strong correlations with related domains of the KHQ. Cronbach's alpha values were good for both subscales of the QUID (SUI-subscale: 0.76; UUI-subscale: 0.86). Sensitivity and specificity were 83% (95% CI, 0.72-0.9) and 45% (95% CI, 0.25-0.67) for the SUI-subscale and 83% (95% CI, 0.7-0.91) and 56% (95% CI, 0.4-0.72) for the UUI-subscale. Youden-index was 0.28 for the SUI-subscale and 0.39 for the UUI-subscale at the given cut-off values. CONCLUSION: Psychometric properties of the German-language QUID are principally good and support its use in the German-speaking area. However, the modest specificity when distinguishing between SUI and UUI should be taken into account. TRIAL REGISTRATION NUMBER: DRKS00018777 (date of registration: 16-January-2020).

Patient information, communication and competence empowerment in oncology (PIKKO) - evaluation of a supportive care intervention for overall oncological patients. Study protocol of a non-randomized controlled trial.

BACKGROUND: Cancer patients have to undergo a difficult medical therapy and are also confronted with various psychological, social and economic problems. Support is available from many providers, but patients often gain no access to it. Accordingly, there is a need for a single point of contact that can provide advice, information and assistance. In the state of Saarland, Germany, a supportive new consulting and information path (PIKKO) for all types of cancer is currently evaluated by the German Cancer Society, the Cancer Society of the Saarland, three statutory health insurances and the Jena University Hospital. PIKKO is designed to improve quality of life, self-efficacy, health literacy and patient satisfaction and to reduce psychological distress, related health care costs and the days of inability to work. This methodical work presents the process and analysis planning of this evaluation. METHODS: The study population includes all cancer types, both new and existing diseases. PIKKO (with patient navigator, oncological knowledge database, specialized oncological counseling) is evaluated within a controlled, non-randomized, comparative, multicenter, longitudinal design. In addition to patient surveys, data from statutory health insurances and utilization data from the web database are collected, and interviews with patient navigators and doctors are carried out. Patients are assigned to a control (usual care) or an intervention group (u. c. + PIKKO). Primary outcome is the health related quality of life (SF-12) six months after baseline. Secondary outcomes are self-efficacy (GSE), psychological distress such as depression (PHQ-9) or anxiety (GAD-7), health literacy (HLS-EU-Q47) and patient satisfaction in health care (Qualiskope-A). Furthermore, the time course of direct costs of medical care (e.g. work disability days) and usage data of the intervention modules are analyzed. Among other statistical procedures, we use t-tests, univariate tests and growth curve models. DISCUSSION: If PIKKO proves to be effective, recommendations can be made to health organizations, which should lead to the concept being rolled out throughout Germany and included into oncological guidelines. We expect PIKKO to be a useful addition to usual cancer care, helping to improve the quality of life of cancer patients and reduce healthcare costs. TRIAL REGISTRATION: This study was retrospectively registered in the German Clinical Trial Register under DRKS00016703 (21.02.2019, the reason for the delay was the prioritization of the study management in the first year to establish the new approach into practice). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016703.

Measuring azimuthal and radial modes of photons.

With the emergence of the field of quantum communications, the appropriate choice of photonic degrees of freedom used for encoding information is of paramount importance. Highly precise techniques for measuring the polarisation, frequency, and arrival time of a photon have been developed. However, the transverse spatial degree of freedom still lacks a measurement scheme that allows the reconstruction of its full transverse structure with a simple implementation and a high level of accuracy. Here we show a method to measure the azimuthal and radial modes of Laguerre-Gaussian beams with a greater than 99 % accuracy, using a single phase screen. We compare our technique with previous commonly used methods and demonstrate the significant improvements it presents for quantum key distribution and state tomography of high-dimensional quantum states of light. Moreover, our technique can be readily extended to any arbitrary family of spatial modes, such as mutually unbiased bases, Hermite-Gauss, and Ince-Gauss. Our scheme will significantly enhance existing quantum and classical communication protocols that use the spatial structure of light, as well as enable fundamental experiments on spatial-mode entanglement to reach their full potential.

Structure and 3D arrangement of endoplasmic reticulum membrane-associated ribosomes.

In eukaryotic cells, cotranslational protein translocation across the endoplasmic reticulum (ER) membrane requires an elaborate macromolecular machinery. While structural details of ribosomes bound to purified and solubilized constituents of the translocon have been elucidated in recent years, little structural knowledge of ribosomes bound to the complete ER protein translocation machinery in a native membrane environment exists. Here, we used cryoelectron tomography to provide a three-dimensional reconstruction of 80S ribosomes attached to functional canine pancreatic ER microsomes in situ. In the resulting subtomogram average at 31 Å resolution, we observe direct contact of ribosomal expansion segment ES27L and the membrane and distinguish several membrane-embedded and lumenal complexes, including Sec61, the TRAP complex and another large complex protruding 90 Å into the lumen. Membrane-associated ribosomes adopt a preferred three-dimensional arrangement that is likely specific for ER-associated polyribosomes and may explain the high translation efficiency of ER-associated ribosomes compared to their cytosolic counterparts.

The three-dimensional organization of polyribosomes in intact human cells.

Structural studies have provided detailed insights into different functional states of the ribosome and its interaction with factors involved in nascent peptide folding, processing, and targeting. However, how the translational machinery is organized spatially in native cellular environments is not yet well understood. Here we have mapped individual ribosomes in electron tomograms of intact human cells by template matching and determined the average structure of the ribosome in situ. Characteristic features of active ribosomes in the cellular environment were assigned to the tRNA channel, elongation factors, and additional densities near the peptide tunnel. Importantly, the relative spatial configuration of neighboring ribosomes in the cell is clearly nonrandom. The preferred configurations are specific for active polysomes and were largely abrogated in puromycin-treated control cells. The distinct neighbor orientations found in situ resemble configurations of bacterial polysomes in vitro, indicating a conserved supramolecular organization with implications for nascent polypeptide folding.