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Schizophrenia, a chronic disabling disease, is a complex psychiatric disorder with a global prevalence of approximately 1% [...].Schizophrenia, a chronic disabling disease, is a complex psychiatric disorder with a global prevalence of approximately 1% [...].

Background Clinical practice guidelines (CPGs) synthesize evidence to recommend which measures should or should not be taken in specific medical situations and thereby inform and shape the practice of medicine. In the context of an ageing population, monitoring has become an increasingly resource-intensive practice, underscoring the need for clear, evidence-based guidance. Accordingly, this study aimed to investigate the level of detail as well as the level of evidence of recommendations on monitoring for 10 common chronic diseases in CPGs from the Association of the Scientific Medical Societies in Germany (AWMF ) , the National Institute for Health and Care Excellence (NICE), and European medical societies. Methods Using a modified systematic review approach, a search of the relevant CPGs was conducted using the databases of the AWMF, NICE, and the Guidelines International Network (GIN). AWMF-equivalent evidence quality levels S2e and S3 CPGs were included. Recommendations on monitoring were extracted and evaluated, focusing on their level of detail regarding monitoring frequency, parameters, and consequences and their level of evidence, respectively. Results A total of 29 CPGs were reviewed, and 163 recommendations on monitoring were extracted and evaluated. Recommendations provided a low level of detail regarding monitoring frequency in 34.4% of cases ( n  = 56), regarding parameters in 25.2% of cases ( n  = 41), and regarding consequences in 84.7% of cases ( n  = 138). A level of evidence was reported for 87 of 163 recommendations only, and if available, it was often low. Only a small proportion (6.7%; n  = 11) of recommendations were formulated negatively as ‘do-not’ recommendations. Conclusions The frequent lack of evidence or low level of evidence for monitoring recommendations, as well as the lack of detail in these recommendations, may lead to medical underuse, yet also to overuse, causing uncertainty among physicians and unnecessary diagnostic cascades. This has significant implications for patient harm, as well as financial and personnel burdens on the healthcare system. One potential solution could be the implementation of more ‘do-not’ recommendations in CPGs. However, overcoming systemic barriers is essential to enable the generation of high-quality evidence on monitoring.

[This corrects the article DOI: 10.1371/journal.pone.0326031.].

Providing counsel on advance care directives is challenging for general practitioners. Counselling is done on unknown future circumstances of possible critical illness and critical care in intensive care units. Following the principles of evidence-based medicine, the physician’s task is to communicate evidence and elucidate the patient’s position on it. However, suitable evidence of chances of survival in case of critical illness is lacking. Aim of this study was to generate long-term survival rates of patients receiving critical care as evidence for general practitioners who provide counselling for patients on advance care directives. We conducted a retrospective cohort study analysing one-year survival rates of critical care using German health insurance claims data from an anonymised nationwide health claims data pool of over five million German patients. All patients over 18 years of age receiving critical care for the first time were included.Main outcome of our study were one-year survival probabilities depending on age and on acute life prolonging procedures. Procedures analysed were non-invasive and invasive mechanical ventilation (nMV, iMV), renal replacement therapy (RRT), their combinations (nMV + RRT, iMV + RRT), and cardiopulmonary resuscitation (CPR). A total of 149,144 datasets was analysed. One-year survival probability of all patients was 77.5%. Survival rates ranged from 94.5% in patients under 50 without any further acute life prolonging procedures to 16.4% in those older than 80 who received iMV + RRT. The application of at least one procedure was associated with an increased risk of death (HR 3.06, 95% CI 2.99 to 3.12) as was CPR (HR 4.22, 95% CI 4.07 to 4.37). Differences between pre- and COVID periods were modest. To enable patient’s decision-making in creating advance care directives, our results provide easily applicable external evidence for general practitioners counselling on advance care directives by providing probabilities of survival in critical care.

Corynebacterium glutamicum experiences a transient iron limitation during growth in minimal medium, which can be compensated by the external supplementation of protocatechuic acid (PCA). Although C. glutamicum is genetically equipped to form PCA from the intermediate 3‐dehydroshikimate catalysed by 3‐dehydroshikimate dehydratase (encoded by qsuB), PCA synthesis is not part of the native iron‐responsive regulon. To obtain a strain with improved iron availability even in the absence of the expensive supplement PCA, we re‐wired the transcriptional regulation of the qsuB gene and modified PCA biosynthesis and degradation. Therefore, we ushered qsuB expression into the iron‐responsive DtxR regulon by replacing the native promoter of the qsuB gene by the promoter PripA and introduced a second copy of the PripA‐qsuB cassette into the genome of C. glutamicum. Reduction of the degradation was achieved by mitigating expression of the pcaG and pcaH genes through a start codon exchange. The final strain C. glutamicum IRON+ showed in the absence of PCA a significantly increased intracellular Fe2+ availability, exhibited improved growth properties on glucose and acetate, retained a wild type‐like biomass yield but did not accumulate PCA in the supernatant. For the cultivation in minimal medium C. glutamicum IRON+ represents a useful platform strain that reveals beneficial growth properties on different carbon sources without affecting the biomass yield and overcomes the need of PCA supplementation. Corynebacterium glutamicum experiences a transient iron limitation during growth in minimal medium, which can be compensated by the external supplementation of protocatechuic acid (PCA). Although C. glutamicum is genetically equipped to form PCA, PCA synthesis is not part of the native iron‐responsive regulon. To obtain a strain with improved iron availability even in the absence of the expensive supplement PCA, we re‐wired the transcriptional regulation of the qsuB gene and modified PCA biosynthesis and degradation. The final strain C. glutamicum IRON+ showed in the absence of PCA a significantly increased intracellular Fe2+ availability, exhibited improved growth properties on glucose and acetate, retained a wild type‐like biomass yield but did not accumulate PCA in the supernatant. For the cultivation in minimal medium C. glutamicum IRON+ represents a useful platform strain that reveals beneficial growth properties on different carbon sources without affecting the biomass yield and overcomes the need of PCA supplementation.

The international collaboration study PRICOV-19 -Primary Health Care in times of COVID-19 aims to assess the impact of the COVID-19 pandemic on the organisation of primary health care. The German part focuses on the subjective perceptions of general practitioners on primary health care and the impact of political measures during the second wave of the COVID-19 pandemic. Within this survey, the \"open text field\" of the questionnaire was utilised remarkably frequently and extensively by the respondents. It became clear that the content that was named needed to be analysed in an exploratory manner. Accordingly, this paper addresses the following question: What preoccupies general practitioners in Germany during COVID-19 that we have not yet asked them enough? The data collection took place throughout Germany from 01.02.2021 to 28.02.2021with a quantitative online questionnaire consisting of 53 items arranged across six topics as well as an \"open text field\" for further comments. The questionnaire's open text field was analysed following the premises of the qualitative content analysis. The topics discussed by the respondents were: insufficient support from health policies, not being prioritised and involved in the vaccination strategy, feeling insufficient prepared, that infrastructural changes and financial concerns threatened the practice, and perceiving the own role as important, as well as that health policies affected the wellbeing of the respondents. One of the main points was the way general practitioners were not sufficiently acknowledged for their contribution to ensuring high-quality care during the pandemic. German general practitioners perceived their work and role as highly relevant during the COVID-19 pandemic. In controversy with their perception, they described political conditions in which they were the ones who contributed significantly to the fight against the pandemic but were not given enough recognition.

Cariprazine is a recently developed antipsychotic drug with a partial agonism for the D2 and D3 receptors. It shows a tenfold greater affinity for the D3 receptor. In clinical trials, its therapeutic effect has been tested in patients with an acute exacerbation of schizophrenia and in patients with acute mania in bipolar disorder. Like risperidone, cariprazine improves positive and negative schizophrenic symptoms, and ameliorates cognitive functions. Cariprazine induces extrapyramidal symptoms less often than risperidone and can cause acute akathisia. It is a prolactin-sparing antipsychotic drug and has a favorable metabolic profile. In acute mania in bipolar disorder, it treats manic symptoms significantly better than placebo. As a consequence of its improved adverse effects, cariprazine improves patients' quality of life to a greater extent than other second-generation antipsychotic drugs. Cariprazine is a promising antipsychotic drug in the treatment of schizophrenia, acute mania in bipolar disorder, and in schizophrenia with mania. In these patients, its long-term therapeutic effect and its action in comparison with other second-generation antipsychotic drugs, above all aripiprazole, remain to be tested in clinical trials.

Background Since the beginning of the COVID-19 vaccination campaigns, recommendations regarding the vaccination have been very dynamic. Although the safety and efficacy of different vaccines have been analysed, data were scarce for vaccine regimens combining different vaccines. We therefore aimed to evaluate and compare the perceived reactogenicity and need for medical consultation after the most frequently applied homologous and heterologous COVID-19 vaccination regimens. Methods In an observational cohort study, reactogenicity and safety were assessed within a maximum follow-up time of 124 days using web-based surveys. Reactogenicity was assessed for different vaccination regimens 2 weeks after a vaccination (short-term survey). The following surveys, long-term and follow-up surveys, focused on the utilisation of medical services, including those that were not suspected to be vaccine-related. Results Data of 17,269 participants were analysed. The least local reactions were seen after a ChAdOx1 − ChAdOx1 regimen (32.6%, 95% CI [28.2, 37.2]) and the most after the first dose with mRNA-1273 (73.9%, 95% CI [70.5, 77.2]). Systemic reactions were least frequent in participants with a BNT162b2 booster after a homologous primary immunisation with ChAdOx1 (42.9%, 95% CI [32.1, 54.1]) and most frequent after a ChAdOx1 − mRNA-1273 (85.5%, 95% CI [82.9, 87.8]) and mRNA-1273/mRNA-1273 regimen (85.1%, 95% CI [83.2, 87.0]). In the short-term survey, the most common consequences were medication intake and sick leave (after local reactions 0% to 9.9%; after systemic reactions 4.5% to 37.9%). In the long-term and follow-up surveys, between 8.2 and 30.9% of participants reported consulting a doctor and between 0% and 5.4% seeking hospital care. The regression analyses 124 days after the first and after the third dose showed that the odds for reporting medical consultation were comparable between the vaccination regimens. Conclusions Our analysis revealed differences in reactogenicity between the COVID-19 vaccines and vaccination regimens in Germany. The lowest reactogenicity as reported by participants was seen with BNT162b2, especially in homologous vaccination regimens. However, in all vaccination regimens reactogenicity rarely led to medical consultations. Small differences in seeking any medical consultation after 6 weeks diminished during the follow-up period. In the end, none of the vaccination regimens was associated with a higher risk for medical consultation. Trial registration DRKS DRKS00025881 ( https://drks.de/search/de/trial/DRKS00025373 ). Registered on 14 October 2021. DRKS DRKS00025373 ( https://drks.de/search/de/trial/DRKS00025881 ). Registered on 21 May 2021. Registered retrospectively.

Background In the course of the SARS-CoV-2 pandemic, multiple vaccines were developed. Little was known about reactogenicity and safety in comparison to established vaccines, e.g. influenza, pneumococcus, or herpes zoster. Therefore, the present study aimed to compare self-reported side effects in persons vaccinated against SARS-CoV-2 with the incidence of side effects in persons receiving one of the established vaccines. Methods A longitudinal observational study was conducted over a total of 124 days using web-based surveys. Persons receiving either a vaccination against SARS-CoV-2 or one of the established vaccines (comparator group) were included. In the first questionnaire (short-term survey), 2 weeks after vaccination, mainly local and systemic complaints were evaluated. The long-term survey (42 days after vaccination) and follow-up survey (124 weeks after vaccination) focused on medical consultations for any reason. Multivariate analyses were conducted to determine the influence of the vaccine type (SARS-CoV-2 vs. comparator) and demographic factors. Results In total, data from 16,636 participants were included. Self-reported reactogenicity was lowest in the comparator group (53.2%) and highest in the ChAdOx1 group (85.3%). Local reactions were reported most frequently after mRNA-1273 (73.9%) and systemic reactions mainly after vector-based vaccines (79.8%). Almost all SARS-CoV-2 vaccines showed increased odds of reporting local or systemic reactions. Approximately equal proportions of participants reported medical consultations. None in the comparator group suspected a link to vaccination, while this was true for just over one in 10 in the mRNA-1273 group. The multivariate analysis showed that people with SARS-CoV-2 vaccination were not more likely to report medical consultations; patients who had received a regimen with at least one ChAdOx1 were even less likely to report medical consultations. Younger age, female gender and higher comorbidity were mostly associated with higher odds of medical consultations. Conclusion The rate of adverse reactions after established vaccinations was roughly comparable to previous studies. Two weeks after vaccination, participants in the SARS-CoV-2 vaccination group reported more local and systemic local reactions than participants in the comparator group. In the further course, however, there were no higher odds of medical consultations in either of the two groups. Thus, altogether, we assume comparable safety. Trial registration DRKS-ID DRKS00025881 and DRKS-ID DRKS00025373.

Neural tissue is a hierarchical multiscale system with intracellular and extracellular diffusion compartments at different length scales. The normal diffusion of bulk water in tissues is not able to detect the specific features of a complex system, providing nonlocal, diffusion measurement averaged on a 10-20 µm length scale. Being able to probe tissues with sub-micrometric diffusion length and quantify new local parameters, transient anomalous diffusion (tAD) would dramatically increase the diagnostic potential of diffusion MRI (DMRI) in detecting collective and sub-micro architectural changes of human tissues due to pathological damage. In DMRI, the use of tAD parameters quantified using specific DMRI acquisition protocols and their interpretation has often aroused scepticism. Although the derived formulas may accurately fit experimental diffusion-weighted data, the relationships between the postulated dynamical feature and the underlying geometrical structure remains elusive, or at most only suggestive. This work aimed to elucidate and validate the image contrast and information that can be obtained using the tAD model in white matter (WM) through a direct comparison between different diffusion metrics and histology. Towards this goal, we compared tAD metrics extracted from pure subdiffusion (α-imaging) and super-pseudodiffusion (-imaging) in excised mouse spinal cord WM, together with T2 and T2* relaxometry, conventional (normal diffusion-based) diffusion tensor imaging (DTI), and q-space imaging (QSI), with morphologic measures obtained by optical microscopy, to determine which structural and topological characteristics of myelinated axons influenced tAD contrast. Axon diameter (AxDiam), the standard deviation of diameters (SDax.diam), axonal density (AxDens), and effective local density (eld) were extracted from optical images in several WM tracts. Among all the diffusion parameters obtained at 9.4T, γ-metrics confirmed a strong dependence on magnetic in-homogeneities quantified by R2*=1/T2* and showed the strongest associations with AxDiam and eld. On the other hand, α-metrics showed strong associations with SDax.diam and was significantly related to AxDens, suggesting its ability to quantify local heterogeneity degree in neural tissue. These results elucidate the biophysical mechanism underpinning tAD parameters and show the clinical potential of tAD-imaging, considering that both physiologic and pathologic neurodegeneration translate into alterations of WM morphometry and topology.