Challenges of conducting an international observational study to assess immunogenicity of multiple COVID-19 vaccines.

The International Study on COVID-19 Vaccines to Assess Immunogenicity, Reactogenicity, and Efficacy is an observational study to assess the immunogenicity of COVID-19 vaccines used in Democratic Republic of Congo, Guinea, Indonesia, Liberia, Mali, Mexico, and Mongolia. The study, which has enrolled 5,401 adults, is prospectively following participants for approximately two years. This study is important as it has enrolled participants from resource-limited settings that have largely been excluded from COVID-19 research studies during the pandemic. There are significant challenges to mounting a study during an international health emergency, especially in resource-limited settings. Here we focus on challenges and hurdles encountered during the planning and implementation of the study with regard to study logistics, national vaccine policies, pandemic-induced and supply chain constraints, and cultural beliefs. We also highlight the successful mitigation of these challenges through the team's proactive thinking, collaborative approach, and innovative solutions. This study serves as an example of how established programs in resource-limited settings can be leveraged to contribute to biomedical research during a pandemic response. Lessons learned from this study can be applied to other studies mounted to respond rapidly during a global health crisis and will contribute to capacity for stronger pandemic preparedness in the future when there is a crucial need for urgent response and data collection.

Impact of therapeutic drug monitoring of antibiotics in the management of infective endocarditis.

Treatment of infective endocarditis (IE) is based on high doses of antibiotics with a prolonged duration. Therapeutic drug monitoring (TDM) allows antibiotic prescription optimization and leads to a personalized medicine, but no study evaluates its interest in the management of IE. We conducted a retrospective, bicentric, descriptive study, from January 2007 to December 2019. We included patients cared for IE, defined according to Duke's criteria, for whom a TDM was requested. Clinical and microbiological data were collected after patients' charts review. We considered a trough or steady-state concentration target of 20 to 50 mg/L. We included 322 IE episodes, corresponding to 306 patients, with 78.6% (253/326) were considered definite according to Duke's criteria. Native valves were involved in 60.5% (185/306) with aortic valve in 46.6% (150/322) and mitral in 36.3% (117/322). Echocardiography was positive in 76.7% (247/322) of cases. After TDM, a dosage modification was performed in 51.5% (166/322) (decrease in 84.3% (140/166)). After initial dosage, 46.3% (82/177) and 92.8% (52/56) were considered overdosed, when amoxicillin and cloxacillin were used, respectively. The length of hospital stay was higher for patient overdosed (25 days versus 20 days (p = 0.04)), and altered creatinine clearance was associated with overdosage (p = 0.01). Our study suggests that the use of current guidelines probably leads to unnecessarily high concentrations in most patients. TDM benefits predominate in patients with altered renal function, but probably limit adverse effects related to overdosing in most patients.

Inoculum effect of Enterobacterales co-expressing OXA-48 and CTX-M on the susceptibility to ceftazidime/avibactam and meropenem.

BACKGROUND: The treatment of infections caused by OXA-48/CTX-M-coproducing Enterobacterales may be based on new beta-lactam/beta-lactamase inhibitors, such as ceftazidime/avibactam (CZA), or on high dose of meropenem (MER). However, bacterial density at the infection site may vary widely, and the inoculum effect of such antimicrobial strategies has never been specifically investigated. To determine if CZA or MER susceptibilities are impacted by high inocula of Enterobacterales co-expressing both enzymes: OXA-48 like and CTX-M. METHODS: Determination of an inoculum effect was performed with a standard inoculum of 108 CFU/mL (0.5 McFarland) as recommended by EUCAST guidelines and compared to a twofold increase as well as a tenfold increase (1 McFarland and 5 McFarland respectively). RESULTS: Thirty-nine isolates of ceftazidime-resistant Enterobacterales were included of which 27 (70%) co-expressed OXA-48 + CTX-M-15, 6 (15%) OXA-48 + CTX-M-14, and 6 (15%) OXA-181 + CTX-M-15. The susceptibility to the CZA combination was preserved whatever the inoculum used. Regarding MER, 24 (61.5%) of the isolates were susceptible to MER with the standard inoculum, 19 (48.7%) with a twofold increase, and only 15 (38.5%) with a tenfold increase. CONCLUSION: We showed that in vitro inoculum effect was observed with meropenem but not with CZA for OXA-48- combined with CTX-M-producing Enterobacterales.

Capturing the signature of single atoms with the tiny probe of a STEM.

With their first scanning transmission electron microscope (STEM), Albert Crewe and his collaborators have succeeded 40 years ago in bringing to reality a dream for all electron microscopists, to see individual atoms. In the derivation of Crewe's pioneering work, the present review describes various historical and present steps, involving continuous instrumental and methodological developments as well as the preparation of suitable specimens. They have lead to the identification of individual atoms by electron energy-loss spectroscopy (EELS) and to the demonstration of atom-by-atom spectroscopy. Beyond these spectacular successes which open wide fields of use, most recent technical achievements, such as the introduction of monochromators on the incident electron beam or of optical spectrometers for recording spectra (in the visible as well as in the X-ray domain), will undoubtedly lead to refine the accessible signature of single atoms and molecules.

Effect of FTY720 treatment on postischemic pancreatic microhemodynamics.

CD4+ T cells contribute to disturbances of pancreatic microcirculation after cold and even after warm ischemia/reperfusion (I/R). The aim of this study was to investigate a possible protective role of FTY720 (fingolimod) in this setting. In an in vivo model (42 Wistar rats), ischemia of the pancreas was induced for 60 minutes under anesthesia with xylazin/ketanest. Sham-operated (SO) (I), untreated ischemic (II), and treatment group with FTY720 pre-treatment (1 mg/kg body weight i.v.) (III) were investigated. The effect of FTY720 on I/R injury was assessed by in vivo microscopy 30-90 minutes after reperfusion and by measurement of serum lipase. In the untreated ischemic group (II), capillary constriction to 85.3 ± 6.3% of SO diameters and a reduction of functional capillary density to 67% was found. After 30 minutes of reperfusion, the number of T cells in capillaries was increased (165.7%; P < .05 vs I). FTY720 pretreatment reduced this number to 54.2% of SO (P < .05 vs II). Likewise, the number of adherent leukocytes in capillaries (145.4 ± 11.2% of SO) was reduced in group III (109.3 ± 11.4%; P < .05 vs II), leading to an improvement in functional capillary density in the treatment group (98.2 ± 2% of SO; P < .05 vs II). According to improved microcirculation, lipase values were reduced in the therapy group (P < .05). In conclusion, FTY720 ameliorates the microcirculatory and biochemical manifestations of pancreatic I/R injury by preventing T-cell infiltration.

Multi-dimensional and multi-signal approaches in scanning transmission electron microscopes.

Developments in instrumentation are essential to open new fields of science. This clearly applies to electron microscopy, where recent progress in all hardware components and in digitally assisted data acquisition and processing has radically extended the domains of application. The demonstrated breakthroughs in electron optics, such as the successful design and practical realization and the use of correctors, filters and monochromators, and the permanent progress in detector efficiency have pushed forward the performance limits, in terms of spatial resolution in imaging, as well as for energy resolution in electron energy-loss spectroscopy (EELS) and for sensitivity to the identification of single atoms. As a consequence, the objects of the nanoworld, of natural or artificial origin, can now be explored at the ultimate atomic level. The improved energy resolution in EELS, which now encompasses the near-IR/visible/UV spectral domain, also broadens the range of available information, thus providing a powerful tool for the development of nanometre-level photonics. Furthermore, spherical aberration correctors offer an enlarged gap in the objective lens to accommodate nanolaboratory-type devices, while maintaining angström-level resolution for general characterization of the nano-object under study.

A public software for energy filtering transmission electron tomography (EFTET-J): application to the study of granular inclusions in bacteria from Riftia pachyptila.

Energy-filtering transmission electron microscopy (EFTEM) allows the determination of elemental distributions out of a sequence of energy filtered images. Combined with electron tomography, EFTEM is a powerful tool to obtain three-dimensional chemical maps from sub-cellular structures. However, there is no existing software in the public-domain for the computation and analysis of 3D-chemical maps. Here, we present a Java-based program to compute 3D-elemental distribution. This program is available as a set of plug-ins for the public-domain Java image processing program Image J inspired by NIH Image. Its implemented algorithms have been successfully applied to the three-dimensional localization of iron granules in semi thin (200 nm) epon sections from the vent worm Riftia pachyptalia.

[Does caring for a schizophrenic family member increase the risk of becoming ill? Psychological and psychosomatic troubles in caregivers of Schizophrenia patients]. / Ist die Betreuung eines schizophrenen Familienmitglieds mit einem Gesundheitsrisiko verbunden? Psychische und psychosomatische Beeinträchtigungen bei Angehörigen schizophrener Patienten.

OBJECTIVE: The aim of this study was to investigate to what extent caregivers of schizophrenia patients suffer from psychiatric and psychosomatic symptoms themselves; furthermore, whether there are differences between parents and spouses. METHOD: 51 parents and 52 spouses of people with schizophrenia were interviewed regarding psychiatric and psychosomatic troubles using standardized questionnaires and diagnostic methods. RESULTS: A considerably increased prevalence of depressive disorders was found compared to the level in the general population. As well as mothers and wives, caregivers of patients with severe impairments of psycho-social functioning were particularly affected. The severity of the patient's disease and the caregiver's mental problems are significant predictors of psychosomatic complaints in parents and spouses. In addition, caregivers visit physicians more frequently, in particular family doctors, psychiatrists and psychotherapists. DISCUSSION: The results support the hypothesis that the burden carried by caregivers of severely affected schizophrenia patients increases their risk of becoming ill, which, as a consequence, leads to a greater use of medical resources. Specific offers of health care and advice on preventative measures appear to be necessary in order to preclude health impairments to caregivers as early as possible.

[Financial burden on spouses of patients suffering from schizophrenia, depression or anxiety disorder]. / Finanzielle Belastungen von Partnern psychisch Erkrankter.

The aim of this study was to compare financial burden of spouses, whose relative suffers from schizophrenia, depression or anxiety disorder. 151 spouses filled in the questionnaire about illness related expenses and financial loss. Additionally they estimate their subjective burden according to these experienced costs. Direct cash expenditures on behalf of the patients' illness were reported by 66 % spouses. In the sampling the amount of spent money did not differ statistically, however spouses of patients with anxiety disorder emphasised experiencing financial strain and described more often subjective economic disadvantages. Although most spouses of patients with psychiatric disorders experience illness related financial disadvantages, these costs were usually not considered as serious problem or as burdensome. Based on a subjective hierarchy of burdens financial problems can be regarded as less important for spouses of patients with mental illness. Thus, not only the material, but also the immaterial costs of care giving spouses should be taken into consideration when planning health policy decisions.

[Instruments for the economical evaluation of psychiatric service systems: methodological foundations of the European standardisation and the German adaptation]. / Instrumente zur gesundheitsökonomischen Evaluation psychiatrischer Versorgungssysteme: Methodische Grundlagen der europäischen Standardisierung und der deutschsprachigen Adaptation.

OBJECTIVE: In the project "Cost-effectiveness of psychiatric service systems. A European comparison" a German version of instruments for the assessment of needs for services (CAN-EU), service satisfaction (VSSS-EU) relatives' burden of care (IEQ-EU) and costs of psychiatric services (CSSRI-EU) was developed in close cooperation with the EPSILON Study group. METHOD: The English original versions of the instruments were translated into German and a back-translation into the original language was carried out by a second translator. The back-translation was screened by the first author of the original version. The German versions of all instruments were tested for comprehensibility and practicability by means of focus groups. The internal consistency of all instruments were tested on a representative sample of 307 patients with schizophrenia according to ICD-10 F20. Test-retest reliability and inter-rater reliability was tested by a sub-sample of 50 patients. RESULTS: Psychometric properties of the translated instruments will be presented and discussed. CONCLUSIONS: Statistical methods for the assessment of the reliability coefficients were identical with those of the EPSILON study, therefore the psychometric properties of the German version of the CAN-EU are directly comparable with the other European versions of the instrument.

[The standardized assessment of the need for treatment and support in severe mental illness: the development and testing of the German version of the Camberwell assessment of Need-EU]. / Die standardisierte Erfassung des Behandlungs- und Unterstützungsbedarfs bei schweren psychischen Erkrankungen - Entwicklung und Erprobung der deutschsprachigen Version des Camberwell Assessment of Need-EU

OBJECTIVE: The development and the psychometric testing of the German version of the Camberwell Assessment of Need-EU will be presented. METHOD: The internal consistency of the subscales total needs, met needs and unmet needs was tested by the application of the CAN-EU on a representative sample of 307 patients with schizophrenia according to ICD-10 F20.0. Test-retest-reliability and inter-rater-reliability was tested with a sub-sample of 41 patients. RESULTS: The internal consistency and the test-retest-reliability of the German version of the CAN-EU is satisfying and slightly higher in comparison with the other European versions. The inter-rater-reliability is also satisfying but smaller in comparison with the other European versions. CONCLUSIONS: In general, the psychometric properties of the German version of the CAN-EU are satisfying but the lower inter-rater-reliability in comparison with the other European versions suggests that more precise coding rules for the German version of the CAN-EU must be formulated to improve the inter-rater agreement of the instrument.

[German adaptation of the client sociodemographic and service receipt inventory - an instrument for the cost of mental health care]. / Die deutsche Version des Client Sociodemographic and Service Receipt Inventory - Ein Instrument zur Erfassung psychiatrischer Versorgungskosten

AIM: Psychiatric health services research has to consider health economic points of view more than before as a result of the present-day financial problems in our health care system. Therefore an instrument was developed, which is suitable for the evaluation of cost of mental health care in Germany. METHOD: The Client Sociodemographic and Service Receipt Inventory (CSSRI-EU), which was developed in the UK, was adapted to the German situation and for the first time used in a cost-effectiveness-analysis of mental health care. The adaptation process of the instrument and the practical application are explained and pros and cons considered. RESULTS: The German adaptation of the CSSRI-EU has proven effective in practical application. The instrument offers feasible solutions for many problems with the cost of mental health care. The instrument can be used for the calculation of direct and indirect costs and gives information about service utilization and medication profiles of the clients. CONCLUSION: The German adaptation of the CSSRI-EU is a feasible instrument for the evaluation of the cost of mental health care in Germany.

[The German adaptation of the Verona Service Satisfaction Scale: an instrument for patients' satisfaction with mental health care]. / Die deutsche Version der Verona Service Satisfaction Scale (VSSS-54) - Ein Instrument zur Erfassung der Patientenzufriedenheit mit psychiatrischer Behandlung -

UNLABELLED: The German Adaptation of the Verona Service Satisfaction Scale: An Instrument for Patients' Satisfaction with Mental Health Care. AIM: Measuring effectiveness and quality of care became an important topic in psychiatry. Considering that objective criteria were not sufficient in the past, the subjective perspective gained growing interest. Client satisfaction is an important variable to evaluate psychiatric care. Patient satisfaction can influence treatment outcome as well as it determines the psychiatric system itself. METHOD: The Italian original version of the Verona Service Satisfaction Scale (VSSS-54) was translated and adapted to the German language. The instrument has been tested in the project "Cost-effectiveness of psychiatric service systems". The process of development, the psychometric testing and the practical application of the German version will be presented in this paper. Additional advantages and disadvantages are discussed. RESULTS: As psychometric properties of the instrument correspond to conventional standards, they are comparable with the results of an international study. The drop out of items cannot be controlled, therefore analysing the data is difficult. CONCLUSION: Although the VSSS shows various methodological limitations, it is at the moment an appropriate instrument for measuring patient satisfaction in the German language.

[The assessment of burden on relatives of mentally ill people: the German version of the involvement evaluation questionnaire (IEQ-EU)]. / Die Erfassung der Belastung der Angehörigen psychisch erkrankter Menschen - Die deutsche Version des Involvement Evaluation Questionnaires (IEQ-EU)

AIMS: The German Version of the Involvement Evaluation Questionnaire (IEQ-EU), developed for the assessment of burden on relatives of mentally ill people will be presented. Also the results of the reliability analysis will be presented. METHOD: After translation and adaptation of the Dutch version of the IEQ-EU into German, the instrument was tested in the study "Cost-effectiveness of psychiatric service systems". RESULTS: The internal consistency was tested on a sub-sample of 138 relatives and the Test-Retest-Reliability on a sub-sample of 37 relatives. The internal consistency (Cronbachs alpha) is moderate or good and slightly lower in comparison with the other European versions. With the exception of one subscale the results for the intraclass correlation coefficient are equal to the European versions. CONCLUSIONS: The IEQ-EU is an instrument with moderate or good psychometric properties. It covers all important domains, is easy to understand and not time-consuming.

[The analysis of the cost structures of the treatment of schizophrenia by means of standardized assessment instruments]. / Die Analyse von Kostenstrukturen im Bereich der Schizophreniebehandlung mit einem standardisierten Instrumentarium.

OBJECTIVE: Aims of the study are the analysis oft the structures and influence factors causing direct costs of schizophrenic diseases by means of international standardized assessment instruments. METHOD: Annual costs of treatment were assessed for a sample of 258 patients with the diagnosis of schizophrenia (ICD-10 F20) by means of the German version of the CSSRI. For the analysis of cost variance a regression model was computed using functional level (GAF), symptoms (BPRS 4.0), needs for care (CAN), service satisfaction (VSSS) and subjective quality of life (LQoLP) as predictors. RESULTS: The average yearly treatment costs for the study sample were 12 726,- DM. Costs for sheltered accommodation and for psychiatric inpatient treatment were found to be the largest elements of the entire costs followed by the costs for ambulant medications. Results of the regression analysis show that illness history, the severity of symptoms and the need for care explain the greatest proportion of variance. CONCLUSIONS: The standardized instruments developed in the project enable a systematic and international comparable assessment of the costs in the treatment of schizophrenic diseases. Furthermore the instruments allow to explain 38 % of the cost variance. The impact of the severity of symptoms under statistical control of the functional impairment and the needs for care suggests that an effective reduction of symptoms could lead to savings in the entire treatment costs. However, the great influence of the illness history and, irrespective of the functional impairment, the need for care show that the possibilities for cost savings in the treatment of schizophrenia are generally low.

[European standardization and German language adaptation of scales for collection of outcomes and costs of treatment for patients with severe mental disorders]. / Die europäische Standardisierung und die deutschsprachige Adaptation von Instrumenten zur Erfassung der Ergebnisse und der Kosten von Versorgungsleistungen für Menschen mit schweren psychischen Erkrankungen.

For the evaluation of the effectiveness of psychiatric service systems internationally standardised instruments for the assessment of the outcome and the costs of psychiatric and psychosocial treatment and care are increasingly needed. Beside the measurement of objective facts there is a growing importance of the consideration of the subjective perspective of patients and relatives. In the research project "Cost-effectiveness analysis of psychiatric service systems in the European comparison" of the Research association for Public Health in Saxony, developments were worked out, in close cooperation with the BIOMED-2 project "European Psychiatric Services: Inputs Linked to Outcome Domains and Needs", German versions of five European standardized instruments for the assessment of needs for care, treatment satisfaction, burden of care on relatives, quality of life and service costs. The psychometric properties of the instruments were tested within the framework of a longitudinal study with 307 patients with the diagnosis of schizophrenia. As a result of this study, German versions of all relevant European instruments for psychiatric service evaluation are now available.

Element-selective single atom imaging.

Electron energy-loss spectroscopy (EELS) is widely used to identify elemental compositions of materials studied by microscopy. We demonstrate that the sensitivity and spatial resolution of EELS can be extended to the single-atom limit. A chemical map for gadolinium (Gd) clearly reveals the distribution of Gd atoms inside a single chain of metallofullerene molecules (Gd@C82) generated within a single-wall carbon nanotube. This characterization technique thus provides the "eyes" to see and identify individual atoms in nanostructures. It is likely to find broad application in nanoscale science and technology research.

Scanning transmission electron microscopy of biological structures.

The design of the scanning transmission electron microscope (STEM) has been conceived to optimize its detection efficiency of the different elastic and inelastic signals resulting from the interaction of the high energy primary electrons with the specimen. Its potential use to visualize and measure biological objects was recognized from the first studies by Crewe and coworkers in the seventies. Later the real applications have not followed the initial hopes. The purpose of the present paper is to describe how the instrument has practically evolved and recently begun to demonstrate all its potentialities for quantitative electron microscopy of a wide range of biological specimens, from freeze-dried isolated macromolecules to unstained cryosections. Emphasis will be put on the mass-mapping, multi-signal and elemental mapping modes which are unique features of the STEM instruments.

Elemental analysis and fine structure of mitochondrial granules in growth plate chondrocytes studied by electron energy loss spectroscopy and energy dispersive X-ray microanalysis.

Electron energy loss spectrometry--EELS, and energy dispersive X-ray microanalysis--XRMA, were used to study the elemental composition of mitochondrial dense granules-mdg. The study was performed on dry cut thin sections (80-200 nm) of freeze-dried and low temperature embedded cartilage. Results obtained by means of XRMA clearly showed high phosphorus and calcium content in the mdg. Using EELS at 100 kV primary voltage we found that small concentrations of elements (i.e. below typically 1% atomic weight) are difficult to analyze and map, this especially in sections thicker than 50-60 nm. Surprisingly, analysis of calcium can be successfully performed on thicker sections though the edge lies above the carbon K edge while this is not possible for the phosphorus edge which is located at lower energies. This is likely due to the edge shapes (sharp for calcium and delayed for phosphorus), and to the more intense contribution of multiple low loss scattering in the background for phosphorus between 100 and 130 eV. By means of EELS elemental mapping a centrally located core was found in numerous mdg. In the calcium map the signal was strongest in the middle of mdg which corresponds to the area of reduced carbon signal. We found that carbon maps might be used for high resolution structural studies of chemically unfixed and anhydrously processed biological tissues. As carbon is the main constituent of Lowicryl resin its distribution is reversed to the distribution of biological tissue in which the proportion of carbon is lower, but is proportional to water content in the specimen in vivo. Use of EELS in combination with electron microscope with accelerating voltages in range of 140-200 kV together with anhydrous techniques of the tissue preparation will provide a new type of information which might lead to better understanding of the etiology and function of small structures in the cell.

EELS elemental mapping with unconventional methods. II. Applications to biological specimens.

This article presents two applications of image analysis and processing using the unconventional methods described in the companion paper (part I). Both the information analysis via relative entropy measurement and mapping and the factorial analysis of correspondence are demonstrated to be valuable tools for building an elemental map from a set of noisy energy-filtered images recorded in an analytical transmission electron microscope. Although the only technique considered here is electron energy loss spectroscopy, there is no doubt that such methods can be applied to a wide variety of similar problems: only a reduced number of underlying hypotheses are needed.