Morphological correlates of anxiety-related experiences during a ketamine infusion.

OBJECTIVES: Ketamine exerts rapid antidepressant effects by enhancing neuroplasticity, particularly in the amygdala and hippocampus-regions involved in fear processing and learning. While the role of ketamine's dissociative effects in its antidepressant response is debated, anxiety experienced during infusion has been negatively correlated with treatment outcomes. METHODS: In this single-blind, placebo-controlled study, a subset of 17 healthy volunteers (6 males, 23.12 ± 1.9 years) received intravenously a placebo in the first and 0.5 mg/kg racemic ketamine in the second session. Anxiety-related experiences were assessed by the 5D-ASC score obtained post-infusion, structural magnetic resonance imaging scans were acquired 4 h post-infusion. An anxiety-score was obtained from the 5D-ASC. Relation between post-placebo amygdala volume, hippocampal volume, and its subfields with the anxiety-score were assessed using linear regression models. RESULTS: Results showed a statistically significant negative relation between hippocampal head volume and the anxiety score (ß = -0.733, p = 0.006), with trending negative association for each subfield's head and the score. CONCLUSION: These findings suggest that anxiety-related experiences during ketamine infusion may be mediated by the hippocampus, with smaller hippocampal volumes leading to more anxiety-related experiences. Thus, hippocampal subfield volumes may be used as a predictor for anxiety-related events during ketamine use and might predict treatment outcome in future approaches.

[Curriculum "Tracheostomy management in dysphagia therapy"]. / Curriculum "Trachealkanülenmanagement in der Dysphagietherapie".

The number of tracheotomized patients with dysphagia and their need for treatment are continuously increasing in clinical and community settings. The revised version of the directive on home care and community-based intensive care of the Federal Joint Committee (G-BA) requires that tracheotomized patients are regularly evaluated with the aim of identifying and promoting the therapeutic potential after hospital discharge. Dysphagia treatment plays a crucial role as without improvement of severe dysphagia there is practically no possibility for decannulation. Tracheotomized patients with dysphagia are treated by speech and language therapists (SLT); however, the contents of tracheostomy management (TM) are not obligatory in the speech and language therapeutic training curricula, so that there is a need for further education and treatment standards must be secured. Therefore, the German Interdisciplinary Society for Dysphagia (DGD) in cooperation with the participating German medical and therapeutic societies developed a postgraduate curriculum for TM. This should serve as the basis for contents in TM and qualification of therapists within the framework of the delegation of medical services. The goals of the TM curriculum are the definition of theoretical and practical contents of TM, the qualification to perform TM according to current standards of care and quality assurance. The curriculum defines two qualification levels (user and trainer), entry requirements, curricular contents, examination and qualification criteria as well as transitional regulations for SLTs already experienced in TM.

[Curriculum "Tracheostomy management in dysphagia therapy"]. / Curriculum "Trachealkanülenmanagement in der Dysphagietherapie".

The number of tracheotomized patients with dysphagia and their need for treatment are continuously increasing in clinical and community settings. The revised version of the directive on home care and community-based intensive care of the Federal Joint Committee (G-BA) requires that tracheotomized patients are regularly evaluated with the aim of identifying and promoting the therapeutic potential after hospital discharge. Dysphagia treatment plays a crucial role as without improvement of severe dysphagia there is practically no possibility for decannulation. Tracheotomized patients with dysphagia are treated by speech and language therapists (SLT); however, the contents of tracheostomy management (TM) are not obligatory in the speech and language therapeutic training curricula, so that there is a need for further education and treatment standards must be secured. Therefore, the German Interdisciplinary Society for Dysphagia (DGD) in cooperation with the participating German medical and therapeutic societies developed a postgraduate curriculum for TM. This should serve as the basis for contents in TM and qualification of therapists within the framework of the delegation of medical services. The goals of the TM curriculum are the definition of theoretical and practical contents of TM, the qualification to perform TM according to current standards of care and quality assurance. The curriculum defines two qualification levels (user and trainer), entry requirements, curricular contents, examination and qualification criteria as well as transitional regulations for SLTs already experienced in TM.

[Genetic counselling and testing in pulmonary arterial hypertension - A consensus statement on behalf of the International Consortium for Genetic Studies in PAH - French version]. / Conseil génétique et dépistage de l'hypertension artérielle pulmonaire ­ consensus du Consortium international pour les études génétiques dans l'HTAP ­ version française.

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered.

Validation of the Munich Swallowing Score (MUCSS) in patients with neurogenic dysphagia: A preliminary study.

BACKGROUND: The Munich Swallowing Score (MUCSS) is a clinician rated scale for the assessment of the functional level of swallowing saliva/secretions, food and liquids. The MUCSS consists of two eight-point subscales, MUCSS-Saliva and MUCSS-Nutrition. In a previous article, content validity and interrater reliability were described. OBJECTIVE: The aim of the present study was to investigate criterion validity and sensitivity to change of the MUCSS. METHODS: The research was conducted at a tertiary care academic hospital. Data were collected retrospectively in a cohort of 100 acute and subacute neurologic patients. Criterion validity was judged by comparison to the Gugging Swallowing Screen (GUSS), the Barthel Index (BI), Early Rehabilitation Barthel Index (ERI), Extended Barthel Index (EBI) and also by comparison to three physiological scales drawn from FEES videos: The Penetration - Aspiration Scale (PAS), the Yale Pharyngeal Residue Severity Rating Scale (YPR) and the Murray Secretion Scale (MSS). Changes in oral intake and saliva swallowing were followed up for three months. RESULTS: Between MUCSS and scores directly reflecting dysphagic symptoms (GUSS, PAS, YPR, MSS, ERI), strong to moderate correlations were found, weaker but statistically significant associations were seen with global measures of disability (BI isolated, EBI-subscale cognitive functions). MUCSS was sensitive to positive change of saliva swallowing and oral intake during the recovery period. CONCLUSIONS: These preliminary data suggest that the MUCCS is a valid scale and may be appropriate for documenting clinical change in swallowing abilities of patients with neurogenic dysphagia.

[Types of evidence syntheses]. / Formen der Evidenzsynthese.

This manuscript outlines various types of review articles as forms of evidence synthesis with special regard to their strengths and limitations. Review articles not only present summarised data, but also offer an evaluation of the quality of the individual studies included in it. The validity and the reliability of outcomes of reviews is strongly dependent on the quality of the data included. For this reason, a comprehensive literature selection process is paramount. Fundamental knowledge of bias and literature assessment is also necessary when reading reviews. This article presents selected tools for evidence appraisal and evaluation of bias risk.

Systematic evaluation of laryngeal impairment in Sjögren's syndrome.

INTRODUCTION: Sjögren's syndrome (SjS) causes malfunction of the salivary and lacrimal glands. Consequently, patients suffer from xerostomia and keratoconjunctivitis sicca. This can further affect the voice and swallowing function resulting in an impaired quality of life. Aim of this study is the systematic evaluation of the impact on voice and swallowing-related quality of life in patients with SjS. MATERIAL AND METHODS: SjS patients were classified according to the American-European Consensus Group (AECG) criteria; antibodies to Ro (SS-A) or La (SS-B) antigens were detected, ESSPRI was completed. We used the following quality of life questionnaires: EORTC QLQ H&N 35, Anderson Dysphagia Inventory (ADI) and Voice Handicap Index (VHI). Patients additionally received a detailed phoniatric examination (auditory perception, videostroboscopy, acoustic analysis, Dysphonia Severity Index (DSI), aerodynamics measurements). RESULTS: Almost all the 54 patients (96.3%) had a limited quality of life due to their swallowing problems and 48% due to their voice problems. Both values correlated significantly with the degree of xerostomia. In the phoniatric examination, 77.8% had an increased DSI and two-thirds had abnormalities in videostroboscopy. CONCLUSIONS: A reasonable impairment of quality of life in patients with SjS due to the limitations in voice and swallowing function was observed. As SjS does not limitate life expectancy, preservation of quality of life is important. Detection of voice and swallowing problems as potential reasons for quality of life impairment should be detected and, if diagnosed, treated accordingly.

Colchicine is not effective for reducing osteoarthritic hand pain compared to placebo: a randomised, placebo-controlled trial (COLAH).

BACKGROUND: Colchicine may offer relief in osteoarthritis. This has never been investigated for hand osteoarthritis. OBJECTIVES: To investigate the effect of 1 mg daily colchicine vs placebo on hand pain and function over 12 weeks in older adults with hand osteoarthritis. METHODS: Community-dwelling adults with diagnosed osteoarthritis of the hand aged 40-80 years were randomised to receive colchicine (0.5 mg twice daily) or matching placebo. Primary outcome measure was VAS hand pain score (0-100 mm). Secondary outcome measures included tender and swollen joint count, grip strength, C-reactive protein, and Michigan Hand Questionnaire total, function and pain scores. In an exploratory assessment, we compared synovial grade and power Doppler. All outcome measures were obtained at baseline and week 12. Stata v16 was used to perform constrained longitudinal data analysis models. RESULTS: 64 adults (54 females, 10 males) aged 48-79 years of age were enrolled. 59 participants completed the study (N = 28 colchicine, N = 31 placebo) (withdrawal rate 8%). Adverse reactions to the study medication occurred in nine patients. VAS score was not significantly different at baseline (61 ± 17 mm in the colchicine, 64 ± 17 mm in the placebo group). Between-group difference for VAS score at week 12 was 7.6 mm (95% CI -3.5-18.7, p-value 0.18). There were no significant differences between groups for any secondary outcomes at baseline or week 12. CONCLUSIONS: 1 mg colchicine daily for 12 weeks was not effective for reducing pain, tender and swollen joint count or increasing grip strength in symptomatic hand osteoarthritis. Our results do not support the use of colchicine in hand osteoarthritis.

[Persistent anemia after kidney transplantation in a 36-year-old male patient-an unusual cause]. / Persistierende Anämie nach Nierentransplantation bei einem 36-jährigen Patienten ­ eine ungewöhnliche Ursache.

An allogeneic kidney transplantation (match 1­1­0, cytomegalovirus, CMV, donor, D, +/recipient, R, - high risk) was performed in a 36-year-old patient. The patient was on dialysis due to a tubulointerstitial nephritis confirmed by biopsy 11 years previously. Posttransplantation there was a gradual decrease in the hemoglobin (Hb) level from 11.4 g/dl to 7.3 g/dl during the initial hospitalization period. Initially this was explained by the kidney transplantation and chronic fibrosing antral gastritis with erosions. Despite repeated transfusion of red cell concentrates, a refractory anemia persisted, which is why the patient presented several times at our clinic for further diagnosis and treatment. The presence of giant erythroblasts in the bone marrow and quantitative detection of parvovirus B19 (>900 million IU/ml DNA replications) was consistent with a virus-associated red cell aplasia. Intravenous immunoglobulin administration was established and showed long-term therapeutic success.

Union of the European Phoniatricians' position statement on the exit strategy of phoniatric and laryngological services: staying safe and getting back to normal after the peak of coronavirus disease 2019 (issued on 25th May 2020).

BACKGROUND: The following position statement from the Union of the European Phoniatricians, updated on 25th May 2020 (superseding the previous statement issued on 21st April 2020), contains a series of recommendations for phoniatricians and ENT surgeons who provide and/or run voice, swallowing, speech and language, or paediatric audiology services. OBJECTIVES: This material specifically aims to inform clinical practices in countries where clinics and operating theatres are reopening for elective work. It endeavours to present a current European view in relation to common procedures, many of which fall under the aegis of aerosol generating procedures. CONCLUSION: As evidence continues to build, some of the recommended practices will undoubtedly evolve, but it is hoped that the updated position statement will offer clinicians precepts on safe clinical practice.

Effect of iodinated contrast media on the oxygen tension in the renal cortico-medullary region of pigs.

Repeated injections of iodinated contrast media (CM) can lead to a deterioration of the renal blood flow, can redistribute blood from the renal cortex to other parts of the kidney and can cause small decreases of the blood flow in cortical capillaries, a significant reduction in blood flow in peritubular capillaries and a significant reduction in blood flow in the vasa recta. Therefore, a study in pigs was designed, to show whether the repeated injection of CM boli, alone, can cause a reduction of oxygenation in the cortico-medullar renal tissue - the region with the highest oxygen demand in the kidney - of pigs.While the mean pO2-value had only decreased by 0.3 mmHg from 29.9±4.3 mmHg to 29.6±4.3 mmHg (p = 0.8799) after the tenth Iodixanol bolus, it decreased by 5.9 mmHg from 34.0±4.3 mmHg to 28.1±4.3 mmHg after the tenth Iopromide bolus (p = 0.044). This revealed a remarkable difference in the influence of these CM on the oxygen partial pressure in the kidney.Repeated applications of CM had a significant influence on the renal oxygen partial pressure. In line with earlier studies showing a redistribution of blood from the cortex to other renal areas, this study revealed that Iodixanol - in contrast to Iopromide - induced no changes in the pO2 in the cortico-medullar region which confirms that Iodixanol did not hinder the flow of blood through the renal micro-vessels. These results are in favor of a hypothesis from Brezis that a microcirculatory disorder might be the basis for the development of CI-AKI.

Allogeneic donor split skin grafts for treatment of refractory ulcers in cutaneous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation-a retrospective analysis on seven patients.

Refractory skin ulcers due to severe chronic graft-versus-host disease (cGVHD) remain to be associated with significant morbidity and mortality.We performed an allogeneic donor skin transplantation in seven adult patients after allogeneic hematopoietic stem cell transplantation for cGVHD-associated refractory skin ulcers. While four patients received a split skin graft (SSG), in one patient, a full thickness skin graft for two small refractory ulcers of the ankle was performed, and one patient received in vitro expanded donor keratinocyte grafts derived from hair roots of the original unrelated donor. In one additional patient, a large deep fascial defect of the lower leg was covered with an autologous greater omentum free graft before coverage with an allogeneic SSG. An additional patient was treated with an autologous scrotal skin graft for a refractory ulcer associated with deep sclerosis of cGVHD after unrelated donor transplantation.All skin grafts engrafted and resulted in permanent coverage of the grafted ulcers without any signs of immunological mediated damage. In the patient receiving in vitro expanded keratinocyte grafts, two localized ulcers were permanently covered by donor skin while this approach failed to cover extensive circular ulcers of the lower legs.Allogeneic donor skin grafts are a valuable treatment option in refractory ulcers due to cGVHD but are restricted mainly to related donors while keratinocyte grafts from unrelated donors remain experimental. In male patients lacking a related donor, autologous scrotal skin graft may be an alternative option.

Steroid-Refractory Autoimmune Myocarditis after Pembrolizumab Therapy: Failure of Equine Anti-Thymocyte Globulin to Prevent Heart Failure.

While immune checkpoint inhibitors (ICIs) are improving outcomes for many cancers, they can have severe adverse effects. Though cardiac immune-related adverse effects (irAEs) are rare, they have considerable morbidity and mortality. Prior case studies have demonstrated successful treatment of ICI induced autoimmune myocarditis with a variety of immunosuppressive regimens. This case describes steroid-refractory autoimmune myocarditis after treatment with pembrolizumab. Treatment with equine anti-thymocyte globulin, a regimen previously documented to reverse ICI induced autoimmune myocarditis, temporarily improved clinical status and cardiac biomarkers, however eventually failed to prevent progression to heart failure and cardiovascular death. This case highlights the importance of early stress-dose steroids, identifies troponin as a potential marker of treatment response, and underscores the value of collaboration between oncology and cardiology for optimal management.

Dysregulated autophagy in restrictive cardiomyopathy due to Pro209Leu mutation in BAG3.

Myofibrillary myopathies (MFM) are hereditary myopathies histologically characterized by degeneration of myofibrils and aggregation of proteins in striated muscle. Cardiomyopathy is common in MFM but the pathophysiological mechanisms are not well understood. The BAG3-Pro209Leu mutation is associated with early onset MFM and severe restrictive cardiomyopathy (RCM), often necessitating heart transplantation during childhood. We report on a young male patient with a BAG3-Pro209Leu mutation who underwent heart transplantation at eight years of age. Detailed morphological analyses of the explanted heart tissue showed intracytoplasmic inclusions, aggregation of BAG3 and desmin, disintegration of myofibers and Z-disk alterations. The presence of undegraded autophagosomes, seen by electron microscopy, as well as increased levels of p62, LC3-I and WIPI1, detected by immunohistochemistry and western blot analyses, indicated a dysregulation of autophagy. Parkin and PINK1, proteins involved in mitophagy, were slightly increased whereas mitochondrial OXPHOS activities were not altered. These findings indicate that altered autophagy plays a role in the pathogenesis and rapid progression of RCM in MFM caused by the BAG3-Pro209Leu mutation, which could have implications for future therapeutic strategies.

The AP-1 transcription factor FOSL1 causes melanocyte reprogramming and transformation.

The MAPK pathway is activated in the majority of melanomas and is the target of therapeutic approaches. Under normal conditions, it initiates the so-called immediate early response, which encompasses the transient transcription of several genes belonging to the AP-1 transcription factor family. Under pathological conditions, such as continuous MAPK pathway overactivation due to oncogenic alterations occurring in melanoma, these genes are constitutively expressed. The consequences of a permanent expression of these genes are largely unknown. Here, we show that FOSL1 is the main immediate early AP-1 member induced by melanoma oncogenes. We first examined its role in established melanoma cells. We found that FOSL1 is involved in melanoma cell migration as well as cell proliferation and anoikis-independent growth, which is mediated by the gene product of its target gene HMGA1, encoding a multipotent chromatin modifier. As FOSL1 expression is increased in patient melanoma samples compared to nevi, we investigated the effect of enhanced FOSL1 expression on melanocytes. Intriguingly, we found that FOSL1 acts oncogenic and transforms melanocytes, enabling subcutaneous tumor growth in vivo. During the process of transformation, FOSL1 reprogrammed the melanocytes and downregulated MITF in a HMGA1-dependent manner. At the same time, AXL was upregulated, leading to a shift in the MITF/AXL balance. Furthermore, FOSL1 re-enforced pro-tumorigenic transcription factors MYC, E2F3 and AP-1. Together, this led to the enhancement of several growth-promoting processes, such as ribosome biogenesis, cellular detachment and pyrimidine metabolism. Overall, we demonstrate that FOSL1 is a novel reprogramming factor for melanocytes with potent tumor transformation potential.

Effect of radiographic contrast media on renal perfusion - First results.

BACKGROUND: Intra-arterial administration of radiographic contrast media (CM) is discussed to impair renal perfusion. The pathogenesis of contrast-induced Nephropathy (CIN) is still not clarified. OBJECTIVE: This trial was performed to prove the effects of two CM with different molecular structure on renal perfusion. METHODS: A prospective, randomized study on 16 pigs was designed to compare the outcome after application of a low-osmolar iodinated CM (770 mOsm/kg H2O - Group1) and an iso-osmolar iodinated CM (290 mOsm/kg H2o - Group2).Color Coded Doppler Sonography (LOGIQ E9, GE, Milwaukee, USA) was applied for measuring the Renal Resistive Index (RRI) before and after the first, fifth, and tenth bolus of CM. Statistics was performed using analysis of variance for repeated measurements with the Factor "CM". RESULTS: All flow spectra were documented free of artifacts and Peak Systolic Velocity (PSV), Enddiastolic Velocity (EDV) and RRI respectively could be calculated. Mean PSV in Group 1 led to a decrease while in Group 2 PSV showed a significant increase after CM (p = 0,042). The course of the mean EDV in both groups deferred accordingly (p = 0,033). Mean RRI over time significantly deferred in both groups (p = 0,001). It showed a biphasic course in Group 2 and a decrease over time in Group 2. CONCLUSION: While iso-osmolar CM induced an increase of PSV and EDV together with a decrease of RRI, low-osmolar CM could not show this effect or rather led to the opposite.

Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma.

BACKGROUND: High-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined. PATIENTS AND METHODS: In this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation. RESULTS: MR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24-0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23-0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed. CONCLUSIONS: These data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials.

High resolution ion mobility-mass spectrometry for separation and identification of isomeric lipids.

Lipidomics is a particularly difficult analytical challenge due to the number and importance of isomeric species that are known or postulated in biological samples. Current separation and identification techniques are too often insufficiently powerful, slow or ambiguous. High resolution, low field ion mobility coupled to mass spectrometry is shown here to have sufficient performance to represent a new alternative for lipidomics. For the first time, drift-tube ion mobility separation of lipid isomers that differ only in position of the acyl chain, position of the double bond or double bond geometry is demonstrated. Differences in collision cross sections of less than 1% are sufficient for baseline separation. The same level of performance is maintained in complex biological mixtures. More than 130 high-precision reduced mobility and collision cross section values were also determined for a range of lipids. Such data can be the basis of a new lipidomics workflow, as the appropriate libraries are developed.