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ZusammenfassungDer Klimawandel hat negative Auswirkungen auf unser Leben, die Gesellschaft und unsere Gesundheit, wobei die Schwächsten unter uns unverhältnismäßig stark betroffen sind. In diesem Beitrag werden die Auswirkungen des Klimawandels mit Fokus auf die Lungengesundheit untersucht. Die Ergebnisse zeigen, dass es 4 Hauptauswirkungen gibt: Luftverschmutzung, Aeroallergene (Pollen und Schimmelpilze), extreme Hitze und Kälte und Extremwetterereignisse, wie z. B. Überschwemmungen. Diese werden jedes Jahr schlimmer und betreffen außerdem eine immer größere Gruppe an Menschen. Zweitens werden Beispiele für Fälle von bestehender und zunehmender sozialer und gesundheitlicher Ungleichheit und Ungerechtigkeit im Zusammenhang mit dem Klimawandel und seinen Folgen erläutert mit einem Fokus auf die Lungengesundheit. Drittens geben wir einen Überblick über transformative Veränderungen und soziale Gerechtigkeit, um Wege zur Lösung der Klimakrise aufzuzeigen.

The Sustainable Development Goals aim to improve access to resources and services, reduce environmental degradation, eradicate poverty and reduce inequality. However, the magnitude of the environmental burden that would arise from meeting the needs of the poorest is under debate—especially when compared to much larger burdens from the rich. We show that the ‘Great Acceleration’ of human impacts was characterized by a ‘Great Inequality’ in using and damaging the environment. We then operationalize ‘just access’ to minimum energy, water, food and infrastructure. We show that achieving just access in 2018, with existing inequalities, technologies and behaviours, would have produced 2–26% additional impacts on the Earth’s natural systems of climate, water, land and nutrients—thus further crossing planetary boundaries. These hypothetical impacts, caused by about a third of humanity, equalled those caused by the wealthiest 1–4%. Technological and behavioural changes thus far, while important, did not deliver just access within a stable Earth system. Achieving these goals therefore calls for a radical redistribution of resources.

Natural killer (NK) cell genome editing promises to enhance the innate and alloreactive anti-tumor potential of NK cell adoptive transfer. DNA transposons are versatile non-viral gene vectors now being adapted to primary NK cells, representing important tools for research and clinical product development.We set out to generate donor-derived, primary chimeric antigen receptor (CAR)-NK cells by combining the TcBuster transposon system with Epstein-Barr virus-transformed lymphoblastoid feeder cell-mediated activation and expansion.This approach allowed for clinically relevant NK-cell expansion capability and CAR expression, which was further enhanced by immunomagnetic selection based on binding to the CAR target protein.The resulting CAR-NK cells targeting the myeloid associated antigen CLL-1 efficiently targeted CLL-1-positive AML cell lines and primary AML populations, including a population enriched for leukemia stem cells. Subsequently, concurrent delivery of CRISPR/Cas9 cargo was applied to knockout the NK cell cytokine checkpoint cytokine-inducible SH2-containing protein (CIS, product of the CISH gene), resulting in enhanced cytotoxicity and an altered NK cell phenotype.This report contributes a promising application of transposon engineering to donor-derived NK cells and emphasizes the importance of feeder mediated NK cell activation and expansion to current protocols.

The Earth’s population of seven billion consume varying amounts of planetary resources with varying impacts on the environment. We combine the analytical tools offered by the socio-ecological metabolism and class theory and contribute to a novel social stratification theory to identify the differences in individual resource and energy use. This approach is applied to German society, we use per capita greenhouse gas emissions (GHG) as a proxy for resource and energy use and investigate socio-metabolic characteristics of individuals from an economic, social and cultural perspective. The results show large disparities and inequalities in emission patterns in the German society. For example, the GHG in the lowest and highest emission groups can differ by a magnitude of ten. Income, education, age, gender and regional differences (Eastern vs. Western Germany) result in distinct emission profiles. We question the focus on individual behavioral changes and consumption choices to reduce carbon emissions instead of structural changes through political decisions. We argue that emission differences are directly linked to the effects of inequalities and class differences in capitalist societies. Our research results show that natural resource and energy consumption are important for explaining social differentiation in modern societies.

Landing kinetics and kinematics have historically been correlated with potential injury. A factor that requires more attention associated with its correlation to injury risk includes the impact of physiological fatigue. Fatigue is a multifaceted phenomenon involving central and peripheral factors resulting in a slowing or cessation of motor unit firing and a decrease in maximal force and power. Sports participation rarely results in momentary muscular failure occurring, as many sports consist of intermittent periods of activity that are interspersed with short rest periods that allow for recovery to take place. However, over the course of the competition, fatigue can still accumulate and can result in impaired performance. Current literature on the topic struggles to replicate the peripheral and central metabolic stresses required to induce a state of fatigue that would be equivalent to athletic exposure. Furthermore, the current literature fails to demonstrate consistency regarding the kinetic implications associated with fatigue, which may be secondary to the inconsistencies associated with fatigue protocols utilized. This article focuses on providing an overview of the current literature associated with fatigue’s impact on the kinetics associated with landing from a jump. The article will provide a prospective methodology utilizing repeat bouts of the Wingate Anaerobic Power Test. The proposed protocol may help further our understanding of the relationship between fatigue and lower extremity biomechanics.

Zusammenfassung Hintergrund Medikamentenvernebler im Rettungsdienst sollten eine hohe Vernebelungsleistung haben, um schnell eine therapeutische Wirkstoffkonzentration des vernebelten Medikaments zu erreichen. Eine Umfrage im süddeutschen Rettungsdienst zeigte allerdings, dass fast ausschließlich die wenig effizienten Jet-Vernebler zum Einsatz kommen. Ziel der Arbeit Ziel der vorliegenden In-vitro-Studie war es herauszufinden, ob der Einsatz von Mesh-Verneblern die prähospitale Aerosoltherapie verbessern könnte. Material und Methoden Die Vernebelungsleistung eines Jet-Verneblers (Cirrus™ 2, Fa. Intersurgical®) und 2 mobil einsatzbarer Mesh-Vernebler (Aerogen Solo®, Fa. Aerogen Limited, M‑Neb® mobile, NEBU-TEC International med. Produkte Eike Kern GmbH) wurde in einem In-vitro-Modell spontan atmender Notfallpatient*innen mit 4 unterschiedlichen Atemmustern bei verschiedenen Sauerstoffflussraten getestet. Ergebnisse Die Mesh-Vernebler zeigten im Vergleich zum Jet-Vernebler eine signifikant höhere Verneblungsleistung und Salbutamol-Filterdeposition, wobei der M‑Neb® mobile die höchsten Werte für Leistung und Deposition erreichte. Der Sauerstofffluss hatte den größten Einfluss auf die Leistung des Jet-Verneblers, wirkte sich aber kaum auf die Mesh-Vernebler aus. Die Deposition wurde zudem stark vom Atemmuster beeinflusst. Diskussion Der Einsatz von Mesh-Verneblern mit hoher Verneblungsleistung konnte in einem In-vitro-Modell die Aerosoltherapie von prähospitalen Notfallpatient*innen verbessern. Sie waren dem Jet-Vernebler in Bezug auf die Verneblungsleistung und die Lungendeposition überlegen und ermöglichten zudem eine bedarfsangepasste Sauerstofftherapie. Die höchste Medikamentendeposition wurde bei den tachypnoischen Patient*innen erreicht, welche in der praktischen Anwendung auch am meisten von einem erhöhten Medikamentenspiegel profitieren würden.

This article highlights the recommendations and considerations for maintaining a healthy canine lifestyle. A key component of a healthy lifestyle is the enhancement and optimization of mobility. Mobility is essential in maintaining a high quality of life and involves the interplay of a dog's structure, posture, body condition score, physical exercise, and a healthy human-animal bond throughout a dog's lifetime.

Heatwaves and Heat Stress are an increasing risk on a global scale with our changing climate. For Southern Africa, it has been demonstrated that the number of heatwaves and heat stress days have increased since the 1980s. Consequently, a greater proportion of people in the region are exposed to extreme heat for longer periods of time. Extreme heat has been shown to have negative effects on maternal health and birth outcomes and is compounded by existing vulnerabilities such as age and lower socio-economic status. Limited previous research in Africa has demonstrated that exposure to extreme heat in the first weeks of pregnancy can cause complications during and after pregnancy such as pre-eclampsia and gestational diabetes. In addition, it has been found that exposure to extreme heat in the region increases the risk of low birth weight, pre-term birth and in some cases stillbirth. In this study, maternal health data from tertiary hospitals in Johannesburg is analysed against local weather station observations for temperature and heat stress. We assess the threshold at which extreme heat has adverse health outcomes during pregnancy and childbirth (intra-partum) and suggest potential interventions to mitigate against this. This work contributes to calls to improve the understanding of the impacts of extreme heat on maternal and child health in Africa. It also supports work to create global maternal and child climate change health indicators, to better inform adaptation and mitigation efforts. This research is part of HIGH horizons which is funded by the European Union’s Horizon Research and Innovation programme under grant agreement no 101057843

Intradural-intramedullary intervertebral disc extrusion (IIVDE) is a subtype of herniation of the hydrated nucleus pulposus and occurs after extreme exercise or traumatic events. IIVDE is a rare condition, and its diagnosis can be complex since its clinical characteristics and images are poorly characterized. The case of a six-month-old Schnauzer who suffered a fall from a height of two stories is reported. The patient developed spastic tetraplegia and was diagnosed as a fourth-degree acute cervical spinal cord injury. The radiographic and computed tomography studies only reported a simple fracture in the vertebral body of C3. The magnetic resonance study reported intramedullary linear tracts, parenchymal lesions and reduced disc volume in C3-C4. The clinical condition and its evolution, as well as the imaging findings were compatible with IIVDE., La extrusión de disco intervertebral intradural-intramedular es un subtipo de herniación del núcleo pulposo hidratado y se presenta luego de ejercicio extremo o eventos traumáticos. Esta es una condición rara y su diagnóstico puede ser complejo ya que sus características clínicas e imágenes están pobremente caracterizados. Se comunica el caso de un Schnauzer de seis meses que sufrió una caída desde una altura de dos pisos. El paciente desarrolló tetraplejía espástica y se diagnosticó como lesión medular aguda cervical de cuarto grado. Los estudios por radiografías y tomografía computarizada solo reportaron una fractura simple en cuerpo vertebral de C3. El estudio de resonancia magnética reportó tractos lineales intramedulares, lesiones parenquimatosas y volumen de disco reducido en C3-C4. La condición clínica y su evolución, así como los hallazgos por imágenes fueron compatibles con extrusión de disco intervertebral intradural-intramedular.

Follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) are the most common non-Hodgkin lymphomas distinguishable by unique mutations, chromosomal rearrangements, and gene expression patterns. Here, it is demonstrated that early B-cell progenitors express 2′,3′-cyclic-nucleotide 3′ phosphodiesterase (CNP) and that when targeted with Sleeping Beauty (SB) mutagenesis, Trp53R270H mutation or Pten loss gave rise to highly penetrant lymphoid diseases, predominantly follicular lymphoma and DLBCL. In efforts to identify the genetic drivers and signaling pathways that are functionally important in lymphomagenesis, SB transposon insertions were analyzed from splenomegaly specimens of SB-mutagenized mice (n = 23) and SB-mutagenized mice on a Trp53R270H background (n = 7) and identified 48 and 12 sites with statistically recurrent transposon insertion events, respectively. Comparison with human data sets revealed novel and known driver genes for B-cell development, disease, and signaling pathways: PI3K–AKT–mTOR, MAPK, NFκB, and B-cell receptor (BCR). Finally, functional data indicate that modulating Ras-responsive element-binding protein 1 (RREB1) expression in human DLBCL cell lines in vitro alters KRAS expression, signaling, and proliferation; thus, suggesting that this proto-oncogene is a common mechanism of RAS/MAPK hyperactivation in human DLBCL.Implications:A forward genetic screen identified new genetic drivers of human B-cell lymphoma and uncovered a RAS/MAPK–activating mechanism not previously appreciated in human lymphoid disease. Overall, these data support targeting the RAS/MAPK pathway as a viable therapeutic target in a subset of human patients with DLBCL.

Top genotyped SNP associations with metastasis at diagnosis in the discovery and all replication studies.

Top 30 loci associated with metastasis at diagnosis in the discovery set of 541 European osteosarcoma cases.

Relationship of variables to metastasis at diagnosis in the discovery set.

SNPs in the NFIB locus associated with metastasis at diagnosis with P{less than or equal to}1x10-5 in the discovery stage, and functionally annotated with information from the ENCODE and 1000 Genomes Project data.

Associations of the top GWAS and imputed SNP with metastasis at diagnosis in the discovery stage (European ancestry) by inheritance model.

Supplementary Figure 1. Manhattan plot of the Discovery stage. SNPs in the NFIB risk locus are highlighted in green. Supplementary Figure 2. LD structure of the NFIB risk locus. Plot was made using the CEU population of the 1000 Genomes Project data with LDlink (ref 54). Supplementary Figure 3. Significant relationship between the genotype of the metastasis associated SNP rs7034162, and expression of NFIB and IGFBP5 in osteosarcoma cell lines and tumors. Significance is based on linear regression comparing the distribution of expression of NFIBbetween the TT homozygous non-risk genotype (combined N=34) of rs7034162 genotypes to the heterozygous risk AT (combined N=10) and the homozygous risk AA genotypes (combined N=2). The green triangle represents the expression levels in the OSA cell line, the blue circle is expression levels in the HOS cell line, and the red square the U2OS cell line expression. These analyses were based on the publically available genotype and expression data from 17 osteosarcoma cell lines and 29 osteosarcoma tumors (ref 20). Supplementary Figure 4. No significant relationship between the genotype of the metastasis associated SNP, rs7034162, and expression of protein-encoding genes FREM1, ZDHHC1, and MPDZ in the neighborhood of NFIB in osteosarcoma cell lines and tumors. Significance is based on linear regression comparing the distribution of expression of FREM1, ZDHHC1, and MPDZ between the TT homozygous non-risk genotype (combined N=34) of rs7034162 genotypes to the heterozygous risk AT (combined N=10) and the homozygous risk AA genotypes (combined N=2). The green triangle represents the expression levels in the OSA cell line, the blue circle is expression levels in the HOS cell line, and the red square the U2OS cell line expression. These analyses were based on the publically available genotype and expression data from 17 osteosarcoma cell lines and 29 osteosarcoma tumors (ref 20). Supplementary Figure 5. The human osteosarcoma cell lines, U2OS and HOS, had higher NFIB protein levels then OSA cells. NFIB levels were determined using immunoblot analysis in the OSA, HOS and U2OS cells both basal (A) and after treatment with siRNA against NFIB (B). Supplementary Figure 6. NFIB expression significantly correlates with IGFBP5 expression in osteosarcoma cell lines and tumors. Significance is based on linear regression comparing the expression levels of NFIB with the corresponding IGFBP5 expression levels. Supplementary Figure 7. Expression levels of IGFBP5 decreases after NFIB suppression of human osteosarcoma cell lines. IGFBP5 expression of OSA, HOS and U2OS cells was determined 48 hours after transfection with control siRNA (si-NEG) or siRNA targeting NFIB (si-NFIB). Graph showing relative expression compared to control treated U2OS cells. Supplementary Figure 8. A model of how the NFIB risk locus leads to changes in NFIB expression and potentially may affect osteosarcoma metastatic potential. The risk allele (right panel) leads to lowered expression of NFIB and NFIB-mediated lower expression of IGFPB5, which then leads to less IGFBP5-mediated inhibition of IGF-1 (right panel, grey arrows), leading to an increase in proliferation, survival and metastasis of osteosarcoma cells (right panel, black arrows). The reference allele (left panel) leads to both higher expression of NFIB and higher expression of NFIB-mediated IGFPB5. In turn, higher IGFBP5 levels leads to increased inhibition of IGF-1 (left panel, black arrows), leading to a decrease in proliferation, survival and metastasis of osteosarcoma cells (left panel, grey arrows). Supplementary Figure 9. Plot of the PCA Eigenvectors of the Discovery stage. Supplementary Figure 10. QQ-plot of the Discovery stage.

Description of participating case studies.

PDF with supplemental figures 1-10 with each containing a figure legend at the bottom fo the figure.

PURPOSE: Racial and ethnic disparities have included a lack of access to both genetic testing and research, resulting in poor understanding of the genomic architecture in under-represented populations. The South Texas population is primarily of Hispanic background and has been largely devoid of genetic services. We extended access to this underserved population and uncovered genetic variants previously not observed, emphasizing the need to continually improve both genomic databases and clarification of variant significance to provide meaningful patient counseling. METHODS: This study consisted of a retrospective cohort review of patients seen through a cancer genetics education and service program across 24 counties in South Texas. In total, 1,595 individuals were identified as appropriate for cancer genetic counseling and 1,377 completed genetic testing. RESULTS: Eighty percent of those receiving genetic counseling self-identified as Hispanic, 16% as non-Hispanic White (NHW), 3% as African American, and 1% as other race/ethnicity. Of reported variants, 18.8% were pathogenic and 13.7% were reported as a variant of uncertain significance (VUS). VUS was reported in 17.2% of the Hispanic individuals compared with 9% NHW ( P = .005). CONCLUSION: Individuals of Hispanic ethnicity were significantly more likely to harbor a VUS compared with NHW. The extended reach into our regional communities revealed a gap in the ability to accurately interpret genomic variation with implications for advising patients on screening, prevention, and management strategies. A higher percentage of VUS also emphasizes the challenge of continued follow-up amid existing barriers that led to disparities in access. As understanding of the variants develops, hopefully gaps in knowledge of the genomic landscape will be lessened with increased clarity to provide accurate cancer risk assessment and recommendations for implementing prevention initiatives.

Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET.Significance:A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.

Figure S4. Shows ARHGAP36 expression in mouse and human neural tissue. Figure S5. Shows characterization of ARHGAP36 and Megf10 in C17.2 cells Figures S6-S7 show mechanistic analysis of FOXR2 in C17.2 and HSC1L cells

Characterization of SB-induced medulloblastomas and CNS-PNETs.

Living within planetary limits requires attention to justice as biophysical boundaries are not inherently just. Through collaboration between natural and social scientists, the Earth Commission defines and operationalizes Earth system justice to ensure that boundaries reduce harm, increase well-being, and reflect substantive and procedural justice. Such stringent boundaries may also affect ‘just access’ to food, water, energy and infrastructure. We show how boundaries may need to be adjusted to reduce harm and increase access, and challenge inequality to ensure a safe and just future for people, other species and the planet. Earth system justice may enable living justly within boundaries.

Hereditary proximal spinal muscular atrophy causes weakness and increased fatigability of repetitive motor functions. The neuromuscular junction is anatomically and functionally abnormal in patients with spinal muscular atrophy. Pharmacological improvement of neuromuscular transmission may therefore represent a promising additional treatment strategy. We conducted a Phase II, monocentre, placebo-controlled, double-blind, cross-over trial with the acetylcholinesterase inhibitor pyridostigmine in treatment-naïve patients with spinal muscular atrophy types 2–4. We investigated the safety and efficacy of pyridostigmine on fatigability and motor function. Each participant received pyridostigmine and a placebo for 8 weeks, in random order. Primary outcomes were the repeated nine-hole peg test for fatigability and motor function measure. Secondary outcomes were patient-reported effects, endurance shuttle test combined scores and adverse events. We included 35 patients. For the repeated nine-hole peg test, the mean difference was 0.17 s/trial (95% confidence interval: −1.17–1.49; P = 0.8), favouring placebo, and for the motor function measure, 0.74% (95% confidence interval: 0.00–1.49; P = 0.05), favouring pyridostigmine. Around 74% of patients reported medium-to-large beneficial effects of pyridostigmine on fatigability, compared with 29.7% in the placebo arm. This was paralleled by a reduced dropout risk of 70% on the endurance shuttle test combined scores (hazard ratio: 0.30; 95% confidence interval: 0.15–0.58) under pyridostigmine. Adverse events, mostly mild and self-limiting, occurred more frequently under pyridostigmine. No serious adverse events related to the study medication were observed. Patients with spinal muscular atrophy tolerated pyridostigmine well. There were no significant differences in primary outcomes, but the self-reported reduction of fatigability and improved endurance shuttle test combined score performance suggest that pyridostigmine may be useful as an additional therapy to survival motor neuron-augmenting drugs.Trial registration number: EudraCT: 2011–004369-34, NCT02941328

Despite numerous promising therapeutic targets, there are no proven medical treatments for calcific aortic stenosis (AS). Multiple stakeholders need to come together and several scientific, operational, and trial design challenges must be addressed to capitalize on the recent and emerging mechanistic insights into this prevalent heart valve disease. This review briefly discusses the pathobiology and most promising pharmacologic targets, screening, diagnosis and progression of AS, identification of subgroups that should be targeted in clinical trials, and the need to elicit the patient voice earlier rather than later in clinical trial design and implementation. Potential trial end points and tools for assessment and approaches to implementation and design of clinical trials are reviewed. The efficiencies and advantages offered by a clinical trial network and platform trial approach are highlighted. The objective is to provide practical guidance that will facilitate a series of trials to identify effective medical therapies for AS resulting in expansion of therapeutic options to complement mechanical solutions for late-stage disease.

In adults with severe aortic stenosis, sex and age differences in symptoms and diagnosis may lead to delays in intervention. Choice of intervention partly depends on expected longevity because bioprosthetic valves have limited durability, particularly in younger patients. Current guidelines recommend the following: a mechanical valve in younger adults (aged 80 years based on lower mortality and morbidity compared to SAVR and adequate valve durability. For patients aged 65–80 years, the choice between TAVI and a bioprosthetic SAVR depends on expected longevity, which is greater in women than men, as well as associated cardiac and noncardiac conditions, valvular and vascular anatomy, estimated risk of SAVR versus TAVI and expected complications and patient preferences.

We report on a 69-year-old man suffering from chronic progressive oligoarthritis (localized in metacarpal and knee joints), which clinically was interpreted as steroid-sensitive seronegative chronic arthritis. The patient died from sudden death at the emergency department after a 4-week history of increasing cough and dyspnea (meanwhile obtaining negative testing results for SARS-CoV-2). During the autopsy, we found massive pancarditis affecting all cardiac compartments, in particular exhibiting constrictive pericarditis, myocarditis, and multivalvular endocarditis. Microscopically, interstitial myocarditis could be observed. Performing extensive molecular analyses, we detected Tropheryma whipplei in the tissue specimens of the heart, but not in various duodenal tissue probes or in the synovial membrane. Taken together, in the present case the cause of death was acute cardiac failure due to multivalvular pancarditis due to T. whipplei. Besides from classical symptoms and morphological signs, Whipple's disease may present with various features. Regarding the differential diagnosis of a chronic multisystem disorder with aspects of hitherto unknown arthralgia, Whipple's disease should be considered.Wir berichten über einen 69-jährigen Patienten mit einer chronisch fortdauernden Oligoarthritis (Hand- und Kniegelenke), die klinisch als steroidsensible seronegative chronische Arthritis eingestuft wurde. Der Patient starb in der Notaufnahme am plötzlichen Herztod, nachdem er seit 4 Wochen unter Husten und Atemnot litt (SARS-CoV-2[„severe acute respiratory syndrome coronavirus 2“]-negativ getestet). Bei der Obduktion fand sich eine massive Pankarditis mit Pericarditis constrictiva, Myokarditis und multivalvulärer Endokarditis. Histologisch zeigte sich eine interstitielle Myokarditis. In einer ausführlichen molekularen Diagnostik konnte Tropheryma whipplei aus dem Herzgewebe gesichert werden, nicht aber aus der Synovialmembran und auch nicht aus diversen Duodenalbiopsien. Abschließend diagnostizierten wir als Todesursache eine akute kardiale Dekompensation bei einer durch Tropheryma whipplei ausgelösten multivalvulären Pankarditis als Todesursache. Dieser Fall untermauert das vielgestaltige klinische und morphologische Bild des Morbus Whipple. Bei einem unklaren chronifizierten Krankheitsprozess mit Hinweis auf eine Multisystemerkrankung unter Beteiligung des Gelenksystems sollte der Morbus Whipple in die Differenzialdiagnostik mit einbezogen werden.

Background Progressive lung function decline, resulting in respiratory failure, is an important complication of spinal muscular atrophy (SMA). The ability to predict the need for mechanical ventilation is important. We assessed longitudinal patterns of lung function prior to chronic respiratory failure in a national cohort of treatment-naïve children and adults with SMA, hypothesizing an accelerated decline prior to chronic respiratory failure. Methods We included treatment-naïve SMA patients participating in a prospective national cohort study if they required mechanical ventilation because of chronic respiratory failure and if lung function test results were available from the years prior to initiation of ventilation. We analyzed Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 s (FEV1), Peak Expiratory Flow (PEF) and Maximum Expiratory Pressure (PEmax). We studied the longitudinal course using linear mixed-effects models. We compared patients who electively started mechanical ventilation compared to patients who could not be weaned after acute respiratory failure. Results We analyzed 385 lung function tests from 38 patients with SMA types 1c–3a. At initiation of ventilation median age was 18.8 years (IQR: 13.2–30.1) and median standardized FVC, FEV1 and PEF were 28.8% (95% CI: 23.5; 34.2), 28.8% (95% CI: 24.0; 33.7) and 30.0% (95% CI: 23.4; 36.7), with an average annual decline of 1.75% (95% CI: 0.86; 2.66), 1.72% (95% CI: 1.04; 2.40) and 1.65% (95% CI: 0.71; 2.59), respectively. Our data did not support the hypothesis of an accelerated decline prior to initiation of mechanical ventilation. Median PEmax was 35.3 cmH2O (95% CI: 29.4; 41.2) at initiation of mechanical ventilation and relatively stable in the years preceding ventilation. Median FVC, FEV1, PEF and PEmax were lower in patients who electively started mechanical ventilation (p Conclusions Patterns of lung function decline cannot predict impending respiratory failure: SMA is characterized by a gradual decline of lung function. We found no evidence for an accelerated deterioration. In addition, PEmax remains low and stable in the years preceding initiation of ventilation. Patients who electively started mechanical ventilation had more restrictive lung function at initiation of ventilation, compared to patients who could not be weaned after surgery or a respiratory tract infection.

Phlegmasia cerulea dolens is a rare presentation of deep venous thrombus treated with catheter directed thrombolysis and pharmacomechanical thrombectomy. This is the case of a 78-year-old woman who underwent catheter directed thrombolysis to treat phlegmasia cerulea dolens and subsequently developed left-sided hemiplegia and expressive aphasia in the setting of an international normalized ratio of 2.0. Further imaging revealed a lacunar infarct in the right thalamus with a middle cerebral artery distribution. Further workup revealed a patent foramen ovale. We highlight the unexpected enigmatic consequence from multimodal endovascular intervention, the consequence of long-term inferior vena cava filters.

Item does not contain fulltext Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E-) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E- (4/35 [13%] vs. 1/43 [2%], p = .15 and 12/48 [25%] vs. 6/53 [11.3%], p = .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E- patients, notably E-/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p = .043). Eplet mismatch also predicted anti-class-I (p = .05) and anti-DQ (p < .001) de novo DSA. Adverse events were similar, but E-/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p = .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.