Abstract
Background
Effective care services for people whose work participation is at risk require low-threshold access, a comprehensive diagnostic clarification of intervention needs, a connection ...to the workplace and job demands, and interdisciplinary collaboration between key stakeholders at the interface of rehabilitation and occupational medicine. We have developed a comprehensive diagnostic service to clarify intervention needs for employees with health restrictions and limited work ability: this service is initiated by occupational health physicians.
Methods/design
Our randomized controlled trial tests the effectiveness of a comprehensive diagnostic service for clarifying intervention needs (GIBI: Comprehensive clarification of the need for intervention for people whose work participation is at risk). The comprehensive intervention comprises three elements: initial consultation, two-day diagnostics at a rehabilitation center and follow-up consultations. We will include 210 employees with health restrictions and limited work ability, who are identified by occupational health physicians. All individuals will receive an initial consultation with their occupational health physician to discuss their health, work ability and job demands. After this, half the individuals are randomly assigned to the intervention group and the other half to the waiting-list control group. Individuals in the intervention group start two-day diagnostics, carried out by a multi-professional rehabilitation team in a rehabilitation center, shortly after the initial consultation. The diagnostics will allow first recommendations for improving work participation. The implementation of these recommendations is supported by an occupational health physician in four follow-up consultations. The control group will receive the comprehensive two-day diagnostic service and subsequent follow-up consultations six months after the initial consultation. The primary outcome of the randomized controlled trial is self-rated work ability assessed using the Work Ability Score (0 to 10 points) six months after study inclusion. Secondary outcomes include a range of patient-reported outcomes regarding physical and mental health, impairment, and the physical and mental demands of jobs.
Discussion
This randomized controlled trial is designed to test the effects of a new complex intervention involving a comprehensive clarification of intervention needs in order to promote work participation and prevent the worsening of health and work disability.
Trial registration
German Clinical Trials Register (DRKS00027577, February 01, 2022).
According to many prognostic scenarios by the Intergovernmental Panel on Climate Change (IPCC), a scaling-up of carbon dioxide (CO2) capture and storage (CCS) by several orders-of-magnitude is ...necessary to meet the target of ≤2 °C global warming by 2100 relative to preindustrial levels. Since a large fraction of the predicted CO2 storage capacity lies offshore, there is a pressing need to develop field-tested methods to detect and quantify potential leaks in the marine environment. Here, we combine field measurements with numerical models to determine the flow rate of a controlled release of CO2 in a shallow marine setting at about 119 m water depth in the North Sea. In this experiment, CO2 was injected into the sediment at 3 m depth at 143 kg d-1. The new leakage monitoring tool predicts that 91 kg d-1 of CO2 escaped across the seafloor, and that 51 kg d-1 of CO2 were retained in the sediment, in agreement with independent field estimates. The new approach relies mostly on field data collected from ship-deployed technology (towed sensors, Acoustic Doppler current profiler—ADCP), which makes it a promising tool to monitor existing and upcoming offshore CO2 storage sites and to detect and quantify potential CO2 leakage.
•Combination of towed sensors and numerical simulations quantified the CO2 leakage.•64% of CO2 injected at 3-m depth in the sediment leaked into bottom water.•Gas-phase measurements of chemical tracers validated the bubble dissolution model.
Zusammenfassung
Einleitung
Bei Mitarbeiter*innen mit gefährdeter beruflicher Teilhabe ist eine ganzheitliche und arbeitsplatzorientierte Diagnostik erforderlich, um Gesundheitsprobleme zu verstehen ...und individuelle Lösungsansätze zu finden. Wir entwickelten eine neuartige diagnostische Leistung zur Sicherung beruflicher Teilhabe, die rehabilitative und betriebsärztliche Expertise verbindet. Ziel der Machbarkeitsstudie war die Bewertung der Implementierung sowie die Analyse von Veränderungen von Gesundheit und Arbeitsfähigkeit.
Methoden
Die Beobachtungsstudie (Deutsches Register Klinischer Studien: DRKS00024522) schloss Mitarbeiter*innen mit gesundheitlichen Einschränkungen und eingeschränkter Arbeitsfähigkeit ein. Die Teilnehmenden erhielten ein betriebsärztliches Erstgespräch, eine zweitägige ganzheitliche Diagnostik in einer Rehabilitationseinrichtung und bis zu vier betriebliche Nachsorgegespräche. Fragebogendaten, die im Erstgespräch und im letzten Nachsorgegespräch erhoben wurden, umfassten subjektive Arbeitsfähigkeit (0–10 Punkte) und allgemeine Gesundheit (0–10).
Ergebnisse
Für die Analyse wurden Daten von 27 Teilnehmenden berücksichtigt. Die Teilnehmenden waren zu 63 % weiblich und im Durchschnitt 46 Jahre alt (SD = 11,5). Vom betriebsärztlichen Erstgespräch zum letzten Nachsorgegespräch berichteten die Teilnehmenden eine Verbesserung ihrer allgemeinen Gesundheit (Differenz = 1,52; 95 % KI 0,37–2,67; d = 0,97).
Diskussion und Fazit
Das Modellvorhaben GIBI bietet einen niedrigschwelligen Zugang zu einem vertrauensvollen, ganzheitlichen und arbeitsplatzorientierten Angebot, das die berufliche Teilhabe stärken kann. Eine erfolgreiche Durchführung von GIBI erfordert eine enge und intensive Zusammenarbeit zwischen Betriebsärzt*innen und Rehabilitationseinrichtungen. Zur Bewertung der Wirksamkeit wird aktuell eine randomisierte kontrollierte Studie (
n
= 210) mit Wartekontrollgruppe durchgeführt.
For employees whose work participation is at risk, a comprehensive and workplace-oriented diagnosis is required in order to understand the health problems and to support affected persons with ...individual solutions. We developed a novel diagnostic service to ensure work participation that combines rehabilitative and occupational health medicine. The aim of this feasibility study was to evaluate the implementation and to analyze changes in health and working ability.
The observational study (German Clinical Trials Register: DRKS00024522) included employees with health restrictions and limited working ability. Participants received an initial consultation from an occupational health physician, a 2-day holistic diagnostics work-up at a rehabilitation center and up to four follow-up consultations. Questionnaire data collected at the initial consultation and at the first and last follow-up consultations included subjective working ability (0-10 points) and general health (0-10).
Data from 27 participants were analyzed. The participants were 63% female and on average 46 years old (standard deviation, SD = 11.5). From the initial consultation to the final follow-up consultation, participants reported improvement in their general health (difference = 1.52; 95% confidence interval. CI: 0.37-2.67; d = 0.97).
The model project GIBI offers low-threshold access to a confidential, comprehensive and workplace-oriented diagnostic service to support work participation. Successful implementation of GIBI requires intensive cooperation between occupational health physicians and rehabilitation centers. To evaluate the effectiveness, a randomized controlled trial (
= 210) with a waiting list control group is currently underway.
ZusammenfassungEinleitungBei Mitarbeiter*innen mit gefährdeter beruflicher Teilhabe ist eine ganzheitliche und arbeitsplatzorientierte Diagnostik erforderlich, um Gesundheitsprobleme zu verstehen und ...individuelle Lösungsansätze zu finden. Wir entwickelten eine neuartige diagnostische Leistung zur Sicherung beruflicher Teilhabe, die rehabilitative und betriebsärztliche Expertise verbindet. Ziel der Machbarkeitsstudie war die Bewertung der Implementierung sowie die Analyse von Veränderungen von Gesundheit und Arbeitsfähigkeit.MethodenDie Beobachtungsstudie (Deutsches Register Klinischer Studien: DRKS00024522) schloss Mitarbeiter*innen mit gesundheitlichen Einschränkungen und eingeschränkter Arbeitsfähigkeit ein. Die Teilnehmenden erhielten ein betriebsärztliches Erstgespräch, eine zweitägige ganzheitliche Diagnostik in einer Rehabilitationseinrichtung und bis zu vier betriebliche Nachsorgegespräche. Fragebogendaten, die im Erstgespräch und im letzten Nachsorgegespräch erhoben wurden, umfassten subjektive Arbeitsfähigkeit (0–10 Punkte) und allgemeine Gesundheit (0–10).ErgebnisseFür die Analyse wurden Daten von 27 Teilnehmenden berücksichtigt. Die Teilnehmenden waren zu 63 % weiblich und im Durchschnitt 46 Jahre alt (SD = 11,5). Vom betriebsärztlichen Erstgespräch zum letzten Nachsorgegespräch berichteten die Teilnehmenden eine Verbesserung ihrer allgemeinen Gesundheit (Differenz = 1,52; 95 % KI 0,37–2,67; d = 0,97).Diskussion und FazitDas Modellvorhaben GIBI bietet einen niedrigschwelligen Zugang zu einem vertrauensvollen, ganzheitlichen und arbeitsplatzorientierten Angebot, das die berufliche Teilhabe stärken kann. Eine erfolgreiche Durchführung von GIBI erfordert eine enge und intensive Zusammenarbeit zwischen Betriebsärzt*innen und Rehabilitationseinrichtungen. Zur Bewertung der Wirksamkeit wird aktuell eine randomisierte kontrollierte Studie (n = 210) mit Wartekontrollgruppe durchgeführt.
Post‐translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating ...protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA‐binding protein TAR DNA‐binding protein (TDP‐43), is hyperphosphorylated in disease on several C‐terminal serine residues, a process generally believed to promote TDP‐43 aggregation. Here, we however find that Casein kinase 1δ‐mediated TDP‐43 hyperphosphorylation or C‐terminal phosphomimetic mutations reduce TDP‐43 phase separation and aggregation, and instead render TDP‐43 condensates more liquid‐like and dynamic. Multi‐scale molecular dynamics simulations reveal reduced homotypic interactions of TDP‐43 low‐complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP‐43, but suppress accumulation of TDP‐43 in membrane‐less organelles and promote its solubility in neurons. We speculate that TDP‐43 hyperphosphorylation may be a protective cellular response to counteract TDP‐43 aggregation.
Synopsis
C‐terminal hyperphosphorylation of TDP‐43, a pathological hallmark of several neurodegenerative disorders, enhances the liquidity of TDP‐43 condensates and suppresses TDP‐43 condensation and aggregation, shedding a new light on this TDP‐43 disease‐linked posttranslational modification.
TDP‐43 phosphorylation by CK1δ or C‐terminal phosphomimetic mutations suppress TDP‐43 phase separation and aggregation.
C‐terminal phosphomimetic mutations enhance liquidity and dynamics of TDP‐43 condensates.
Suppression of phase separation is associated with loss of protein‐protein interactions in the C‐terminus and enhanced solvation of negatively charged groups.
TDP‐43 bearing C‐terminal phosphomimetic mutations fails to condense into stress‐induced membrane‐less compartments and remains dispersed.
C‐terminal TDP‐43 hyperphosphorylation may be a protective cellular response to counteract TDP‐43 aggregation, rather than a driver of neuropathology as previously assumed.
Mutations in the gene encoding podocin (NPHS2) cause autosomal recessive steroid-resistant nephrotic syndrome (SRNS). For addressing the possibility of a genotype-phenotype correlation between ...podocin mutations and age of onset, a worldwide cohort of 430 patients from 404 different families with SRNS were screened by direct sequencing. Recessive podocin mutations were present in 18.1% (73 of 404) of families with SRNS, and 69.9% of these mutations were nonsense, frameshift, or homozygous R138Q. Patients with these mutations manifested symptoms at a significantly earlier age (mean onset <1.75 years) than any other patient group, with or without podocin mutations, in this study (mean onset >4.17 yr). All but one patient affected by truncating or homozygous R138Q mutations developed SRNS before 6 yr of age. Patient groups with other recessive podocin mutations, with single heterozygous podocin mutations, with sequence variants, and with no podocin changes could not be distinguished from each other on the basis of age of onset. In conclusion, nephrotic syndrome in children with truncating or homozygous R138Q mutations manifests predominantly before 6 yr of life, and the onset of disease is significantly earlier than for any other podocin mutations. Because the age of onset can vary by several years among those with identical mutations, additional factors may modify the phenotype.
Background. Congenital nephrotic syndrome (CNS) is de- fined as nephrotic syndrome that manifests at birth or within the first 3 months of life. Most patients develop end-stage renal disease (ESRD) ...within 2 to 3 years of life. CNS of the Finnish-type (CNF) features a rather specific renal histology and is caused by recessive mutations in the NPHS1 gene encoding nephrin, a major structural protein of the glomerular slit-diaphragm. So far, more than 80 different mutations of NPHS1 causing CNF have been published. Methods. Here, we performed mutation analysis of NPHS1 by exon sequencing in a worldwide cohort of 32 children with CNS from 29 different families. Results. Sixteen of the 29 families (55%) were found to have two disease-causing alleles in NPHS1. Two additional patients had a single heterozygous mutation in NPHS1. Thirteen of a total of 20 different mutations detected were novel (65%). These were five missense mutations, one nonsense mutation, three deletions, one insertion and three splice-site mutations. Conclusion. Our data expand the spectrum of known NPHS1 mutations by >15% in a worldwide cohort. Surprisingly, two patients with disease-causing mutations showed a relatively mild phenotype, as one patient had a partial remission with steroid treatment and one patient had normal renal function 1 year after the onset of disease. The increased number of known mutations will facilitate future studies into genotype/phenotype correlations.
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