Nierentransplantationen im Kindes- und Jugendalter:eine retrospektive Langzeitanalyse des Krankengutes der Kinderklinik Münster von 1976 bis 2000

In dieser Arbeit wurden alle nierentransplantierten Kinder (n=89), die von der pädiatrischen Nephrologie Münster in den Jahren 1976 bis 2000 betreut wurden, einer retrospektiven Analyse unterzogen. Alle Patienten, die sich zum Erhebungszeitpunkt nicht mehr in Behandlung der pädiatrischen Nephrologie Münster befanden, wurden angeschrieben und nach ihrer medizinischen und sozialen Rehabilitation befragt. Insgesamt wurden beim eigenen Patientengut mit sowohl nationalen als auch internationalen Zentren vergleichbare Ergebnisse erzielt. Im zeitlichen Verlauf von 1976 bis 2000 konnten aufgrund verbesserter Behandlungsmöglichkeiten die Ergebnisse nach Nierentransplantation stetig verbessert werden und vermehrt auch jüngeren Patienten die Nierentransplantation als Therapiemöglichkeit angeboten werden

SSRIs differentially modulate the effects of pro-inflammatory stimulation on hippocampal plasticity and memory via sigma 1 receptors and neurosteroids

Certain selective serotonin reuptake inhibitors (SSRIs) have anti-inflammatory effects in preclinical models, and recent clinical studies suggest that fluvoxamine can prevent deterioration in patients with COVID-19, possibly through activating sigma 1 receptors (S1Rs). Here we examined potential mechanisms contributing to these effects of fluvoxamine and other SSRIs using a well-characterized model of pro-inflammatory stress in rat hippocampal slices. When hippocampal slices are exposed acutely to lipopolysaccharide (LPS), a strong pro-inflammatory stimulus, basal synaptic transmission in the CA1 region remains intact, but induction of long-term potentiation (LTP), a form of synaptic plasticity thought to contribute to learning and memory, is completely disrupted. Administration of low micromolar concentrations of fluvoxamine and fluoxetine prior to and during LPS administration overcame this LTP inhibition. Effects of fluvoxamine required both activation of S1Rs and local synthesis of 5-alpha reduced neurosteroids. In contrast, the effects of fluoxetine did not involve S1Rs but required neurosteroid production. The ability of fluvoxamine to modulate LTP and neurosteroid production was mimicked by a selective S1R agonist. Additionally, fluvoxamine and fluoxetine prevented learning impairments induced by LPS in vivo. Sertraline differed from the other SSRIs in blocking LTP in control slices likely via S1R inverse agonism. These results provide strong support for the hypothesis that S1Rs and neurosteroids play key roles in the anti-inflammatory effects of certain SSRIs and that these SSRIs could be beneficial in disorders involving inflammatory stress including psychiatric and neurodegenerative illnesses

Chondrosarcoma of the Chest Wall: A Review of 53 Cases from Two Institutions

Background/Aim: Chondrosarcomas (CS) of the chest wall are rare, but present an aggressive biological behavior compared to CS of the extremities. The aims of the present study were to determine factors associated with oncological outcomes as well as complications. Patients and Methods: We retrospectively analyzed 53 patients (42 primary, 11 recurrent tumors). In total, 39 central CS, 10 peripheral CS, 3 dedifferentiated CS and 1 mesenchymal CS were included. The ribs were most commonly affected (68%). Overall survival and disease-free survival were estimated with Kaplan-Meier analyses and compared with log-rank test. Results: Mean follow-up was 7 years. Negative margins were achieved in 87% of patients. Thirty patients (57%) remained continuously disease-free (NED), three (5%) NED after treatment of relapse, seven (13%) were alive with disease, twelve (23%) were dead with disease and one of other cause. The 10-year survival rate was 81% and 45% in primary and recurrent tumors, respectively. Survival was significantly affected by tumor stage (p<0.001), local recurrence (p=0.025) and metastases (p=0.002). Six complications (16%) were observed. Conclusion: The outcome is rather poor, especially in patients with local recurrence. Presumably due to a high biological aggressiveness, a stricter definition of surgical margins should be considered for this location

Association of molecular senescence markers in late-life depression with clinical characteristics and treatment outcome

Importance: Many older adults with depression do not experience remission with antidepressant treatment, and markers of cellular senescence in late-life depression (LLD) are associated with greater severity of depression, greater executive dysfunction, and higher medical illness burden. Since these clinical characteristics are associated with remission in LLD, molecular and cellular senescence abnormalities could be a possible biological mechanism underlying poor treatment response in this population. Objective: To examine whether the senescence-associated secretory phenotype (SASP) index was associated with the likelihood of remission from a depressive episode in older adults. Design, Setting, and Participants: A nonrandomized, open-label clinical trial was conducted between August 2009 and August 2014 in Pittsburgh, Pennsylvania; St Louis, Missouri; and Toronto, Ontario, Canada, with older adults in a current major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnostic criteria. Data from biomarker analyses were reported according to the clinical trial archived plasma samples run in March 2021. Data were analyzed from June to November 2021. Exposure: Venlafaxine extended release (dose ranging from 37.5 mg to 300 mg daily) for up to 12 weeks. Main Outcomes and Measures: The association between a composite biomarker-based index (SASP index) and treatment remission in older adults with major depression was measured using clinical data and blood samples. Results: There were 416 participants with a mean (SD) age of 60.02 (7.13) years; 64% (265 participants) were self-reported female, and the mean (SD) Montgomery-Asberg Depression Rating Scale score was 26.6 (5.7). Higher SASP index scores were independently associated with higher rates of nonremission, with an increase of 1 unit in the SASP index score increasing the odds of nonremission by 19% (adjusted odds ratio, 1.19; 95% CI, 1.05-1.35; P = .006). In contrast, no individual SASP factors were associated with remission in LLD. Conclusions and Relevance: Using clinical data and blood samples from a nonrandomized clinical trial, the results of this study suggest that molecular and cellular senescence, as measured with the SASP index, is associated with worse treatment outcomes in LLD. Combining this index score reflecting interrelated biological processes with other molecular, clinical, and neuroimaging markers may be useful in evaluating antidepressant treatment outcomes. These findings inform a path forward for geroscience-guided interventions targeting senescence to improve remission rates in LLD. Trial Registration: ClinicalTrials.gov Identifier: NCT00892047

Patient active time during therapy sessions in postacute rehabilitation: Development and validation of a new measure

BACKGROUND AND PURPOSE: The accurate measurement of therapy intensity in postacute rehabilitation is important for research to improve outcomes in this setting. We developed and validated a measure of Patient Active Time during physical (PT) and occupational therapy (OT) sessions, as a proxy for therapy intensity. METHODS: This measurement validity study was carried out with 26 older adults admitted to a skilled nursing facility (SNF) for postacute rehabilitation with a variety of main underlying diagnoses, including hip fracture, cardiovascular diseases, stroke, and others. They were participants in a randomized controlled trial that compared an experimental high-intensity therapy to standard-of-care therapy. Patient Active Time was observed by research raters as the total number of minutes that a patient was actively engaging in therapeutic activities during PT and OT sessions. This was compared to patient movement (actigraphy) quantified during some of the same PT/OT sessions using data from three-dimensional accelerometers worn on the patient’s extremities. RESULTS: Activity measures were collected for 136 therapy sessions. Patient Active Time had high interrater reliability in both PT (r = 0.995, p < 0.001) and OT (r = 0.95, p = 0.012). Active time was significantly correlated with actigraphy in both PT (r = 0.73, p < 0.001) and OT (r = 0.60, p < 0.001) and discriminated between a high-intensity experimental condition and standard of care rehabilitation: in PT, 47.0 ± 13.5 min versus 16.7 ± 10.1 min (p < 0.001) and in OT, 46.2 ± 15.2 versus 27.7 ± 6.6 min (p < 0.001). CONCLUSIONS: Systematic observation of Patient Active Time provides an objective, reliable, and valid index of physical activity during PT and OT treatment sessions that has utility as a real-world alternative to the measurement of treatment intensity. This measure could be used to differentiate higher from lower therapy treatment intensity and to help determine the optimal level of active therapy time for patients in postacute and other settings

Effect of enhanced medical rehabilitation on functional recovery in older adults receiving skilled nursing care after acute rehabilitation: A randomized clinical trial

Importance: Enhanced medical rehabilitation (EMR) is a systematic and standardized approach for physical and occupational therapists to engage patients. Higher patient engagement in therapy might lead to improved functional recovery in rehabilitation settings, such as skilled nursing facilities (SNFs). Objective: To determine whether EMR improves older adults\u27 functional recovery. Design, Setting, and Participants: A double-blind, parallel-group, randomized clinical trial was conducted from July 29, 2014, to July 13, 2018, in 229 adults aged 65 years or older admitted to 2 US SNFs. Participants were randomized to receive EMR (n = 114) vs standard-of-care rehabilitation (n = 115). Intention-to-treat analysis was used. Interventions: The intervention group received their physical and occupational therapy from therapists trained in EMR. Based on models of motivation and behavior change, EMR is a toolkit of techniques to increase patient engagement and therapy intensity. The control group received standard-of-care rehabilitation from physical and occupational therapists not trained in EMR. Main Outcomes and Measures: The primary outcome was change in function in activities of daily living and mobility, as assessed with the Barthel Index, which measures 10 basic activities of daily living or mobility items (scale range, 0-100), from SNF admission to discharge; secondary outcomes were gait speed for 10 m, 6-minute walk test, discharge disposition, rehospitalizations, and self-reported functional status at days 30, 60, and 90. To examine the rehabilitation process, therapists\u27 engagement with patients and patient active time during therapy were measured for a sample of the sessions. Results: Of the 229 participants, 149 (65.1%) were women; 177 (77.3%) were white, and 51 (22.3%) were black; mean (SD) age was 79.3 (8.0) years. Participants assigned to EMR showed greater recovery of function than those assigned to standard of care (mean increase in Barthel Index score, 35 points; 95% CI, 31.6-38.3 vs 28 points; 95% CI, 25.2-31.7 points; P = .007). There was no evidence of a difference in the length of stay (mean [SD], 23.5 [13.1] days). However, there were no group by time differences in secondary outcome measures, including self-reported function after SNF discharge out to 90 days as measured on the Barthel Index (mean [SE] score: EMR, 83.65 [2.20]; standard of care, 84.67 [2.16]; P = .96). The EMR therapists used a median (interquartile range) of 24.4 (21.0-37.3) motivational messages per therapy session vs 2.3 (1.1-2.9) for nontrained therapists (P \u3c .001), and EMR patients were active during a mean (SD) of 52.5 (6.6%) of the therapy session time vs 41.2 (6.8%) for nontrained therapists (P = .001). Conclusions and Relevance: Enhanced medical rehabilitation modestly improved short-term functional recovery for selected older adults rehabilitating in SNFs. However, there was no evidence that the benefits persisted over the longer term. This study demonstrates the value of engaging and motivating older adults in rehabilitation therapy, but more work is needed to extend these benefits to longer-term outcomes after discharge home. Trial Registration: ClinicalTrials.gov identifier: NCT02114879

Exploratory genome-wide analyses of cortical inhibition, facilitation, and plasticity in late-life depression

Late-life depression (LLD) is a heterogenous mood disorder influenced by genetic factors. Cortical physiological processes such as cortical inhibition, facilitation, and plasticity may be markers of illness that are more strongly associated with genetic factors than the clinical phenotype. Thus, exploring the relationship between genetic factors and these physiological processes may help to characterize the biological mechanisms underlying LLD and improve diagnosis and treatment selection. Transcranial magnetic stimulation (TMS) combined with electromyography was used to measure short interval intracortical inhibition (SICI), cortical silent period (CSP), intracortical facilitation (ICF), and paired associative stimulation (PAS) in 79 participants with LLD. We used exploratory genome-wide association and gene-based analyses to assess for genetic correlations of these TMS measures. MARK4 (which encodes microtubule affinity-regulating kinase 4) and PPP1R37 (which encodes protein phosphatase 1 regulatory subunit 37) showed genome-wide significant association with SICI. EGFLAM (which encodes EGF-like fibronectin type III and laminin G domain) showed genome-wide significant association with CSP. No genes met genome-wide significant association with ICF or PAS. We observed genetic influences on cortical inhibition in older adults with LLD. Replication with larger sample sizes, exploration of clinical phenotype subgroups, and functional analysis of relevant genotypes is warranted to better characterize genetic influences on cortical physiology in LLD. This work is needed to determine whether cortical inhibition may serve as a biomarker to improve diagnostic precision and guide treatment selection in LLD