Non‐invasive and tracheostomy invasive ventilation in amyotrophic lateral sclerosis: Utilization and survival rates in a cohort study over 12 years in Germany

Background and purpose: The aim of this study was to investigate utilization rates, treatment pathways and survival prognosis in patients with amyotrophic lateral sclerosis (ALS) undergoing non-invasive (NIV) and tracheostomy invasive ventilation (TIV) in a real-world setting. Methods: A prospective cohort study using a single-centre register of 2702 ALS patients (2007 to 2019) was conducted. Utilization of NIV/TIV and survival data were analysed in three cohorts: (i) non-NIV; (ii) NIV (NIV without subsequent TIV); and (iii) TIV (including TIV preceded by NIV). Results: A total of 1720 patients with available data were identified, 72.0% of whom (n = 1238) did not receive ventilation therapy. NIV was performed in 20.8% of patients (n = 358). TIV was performed in 9.5% of patients (n = 164), encompassing both primary TIV (7.2%, n = 124) and TIV with preceding NIV (2.3%, n = 40). TIV was more often utilized without previous NIV (25.7% vs. 8.3% of all ventilated patients), demonstrating that primary TIV was the prevailing pathway for invasive ventilation. The median (range) survival was significantly longer in the NIV cohort (40.8 [37.2–44.3] months) and the TIV cohort (82.1 [68.7–95.6] months) as compared to the non-NIV cohort (33.6 [31.6–35.7] months). Conclusions: Although NIV represents the standard of care, its utilization rate was low. TIV was mainly started without preceding NIV, suggesting that TIV may not be confined to NIV treatment escalation. However, TIV was pursued in a minority of patients who had previously undergone NIV. The survival benefit observed in the patients with NIV was equal to that reported in a controlled pivotal trial, but the prognosis with TIV is highly variable. The determinants of utilization of NIV/TIV and of survival (bulbar syndrome, availability of ventilation-related home nursing, cultural factors) warrant further investigation

Treatment expectations and perception of therapy in adult patients with spinal muscular atrophy receiving nusinersen

Background and purpose: This was an investigation of treatment expectations and of the perception of therapy in adult patients with 5q-associated spinal muscular atrophy (5q-SMA) receiving nusinersen. Methods: A prospective, non-interventional observational study of nusinersen treatment in adult 5q-SMA patients was conducted at nine SMA centers in Germany. The functional status, treatment expectations and perceived outcomes were assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale-extended (ALS-FRS-ex), the Measure Yourself Medical Outcome Profile (MYMOP2), the Treatment Satisfaction Questionnaire for Medication (TSQM-9) and the Net Promoter Score (NPS). Results: In all, 151 patients were included with a median age of 36 years (15-69 years). SMA type 3 (n = 90, 59.6%) prevailed, followed by type 2 (33.8%) and type 1 (6.6%). In SMA types 1-3, median ALS-FRS-ex scores were 25, 33 and 46 (of 60 scale points), respectively. MYMOP2 identified distinct treatment expectations: head verticalization (n = 13), bulbar function (n = 16), arm function (n = 65), respiration (n = 15), trunk function (n = 34), leg function (n = 76) and generalized symptoms (n = 77). Median symptom severity decreased during nusinersen treatment (median observational period 6.1 months, 0.5-16 months) from 3.7 to 3.3 MYMOP2 score points (p < 0.001). The convenience of drug administration was critical (49.7 of 100 TSQM-9 points, SD 22); however, the overall treatment satisfaction was high (74.3, SD 18) and the recommendation rating very positive (NPS +66). Conclusions: Nusinersen was administered across a broad range of ages, disease durations and motor function deficits. Treatment expectations were highly differentiated and related to SMA type and functional status. Patient-reported outcomes demonstrated a positive perception of nusinersen therapy in adult patients with 5q-SMA

Benefits and risks of clofarabine in adult acute lymphoblastic leukemia investigated in depth by multi-state modeling

Background: We recently reported results of the prospective, open-label HOVON-100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first-line treatment with or without clofarabine (CLO). No improvement of event-free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. Aim: In order to investigate the effects of CLO in more depth, two multi-state models were developed to identify why CLO did not show a long-term survival benefit despite more MRD-negativity. Methods: The first model evaluated the effect of CLO on going off-protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment-related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. Results: Overall, patients receiving CLO went off-protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13–3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08–7.50], p = 0.035). Going off-protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD-negativity compared with control patients (HR MRD-negativity: 1.35 [0.95–1.91], p = 0.10), which did not translate into a significant survival benefit. Conclusion: We conclude that the intermediate states, i.e., going off-protocol and MRD-negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.</p

ICA-Derived Respiration Using an Adaptive R-peak Detector

Breathing Rate (BR) plays a key role in health deterioration monitoring. Despite that, it has been neglected due to inadequate nursing skills and insufficient equipment. ECG signal, which is always monitored in a hospital ward, is affected by respiration which makes it a highly appealing way for the BR estimation. In addition, the latter requires accurate R-peak detection, which is a continuing concern because current methods are still inaccurate and miss heart beats. This study proposes a frequency domain BR estimation method which uses a novel real-time R-peak detector based on Empirical Mode Decomposition (EMD) and a blind source ICA for separating the respiratory signal. The originality of the BR estimation method is that it takes place in the frequency domain as opposed to some of the current methods which rely on a time domain analysis, making the estimation more accurate. Moreover, our novel QRS detector uses an adaptive threshold over a sliding window and differentiates large Q-peaks from R-peaks, facilitating a more accurate BR estimation. The performance of our methods was tested on real data from Capnobase dataset. An average mean absolute error of less than 0.7 breath per minute was achieved using our frequency domain method, compared to 15 breaths per minute of the time domain analysis. Moreover, our modified QRS detector shows comparable results to other published methods, achieving a detection rate over 99.80%

Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy

Review article[Abstract] The immune system regulates angiogenesis in cancer by way of both pro- and antiangiogenic activities. A bidirectional link between angiogenesis and the immune system has been clearly demonstrated. Most antiangiogenic molecules do not inhibit only VEGF signaling pathways but also other pathways which may affect immune system. Understanding of the role of these pathways in the regulation of immunosuppressive mechanisms by way of specific inhibitors is growing. Renal cell carcinoma (RCC) is an immunogenic tumor in which angiogenesis and immunosuppression work hand in hand, and its growth is associated with impaired antitumor immunity. Given the antitumor activity of selected TKIs in metastatic RCC (mRCC), it seems relevant to assess their effect on the immune system. The confirmation that TKIs improve cell cytokine response in mRCC provides a basis for the rational combination and sequential treatment of TKIs and immunotherapy

Expression Profiling of Major Histocompatibility and Natural Killer Complex Genes Reveals Candidates for Controlling Risk of Graft versus Host Disease

Background: The major histocompatibility complex (MHC) is the most important genomic region that contributes to the risk of graft versus host disease (GVHD) after haematopoietic stem cell transplantation. Matching of MHC class I and II genes is essential for the success of transplantation. However, the MHC contains additional genes that also contribute to the risk of developing acute GVHD. It is difficult to identify these genes by genetic association studies alone due to linkage disequilibrium in this region. Therefore, we aimed to identify MHC genes and other genes involved in the pathophysiology of GVHD by mRNA expression profiling. Methodology/Principal Findings: To reduce the complexity of the task, we used genetically well-defined rat inbred strains and a rat skin explant assay, an in-vitro-model of the graft versus host reaction (GVHR), to analyze the expression of MHC, natural killer complex (NKC), and other genes in cutaneous GVHR. We observed a statistically significant and strong up or down regulation of 11 MHC, 6 NKC, and 168 genes encoded in other genomic regions, i.e. 4.9%, 14.0%, and 2.6% of the tested genes respectively. The regulation of 7 selected MHC and 3 NKC genes was confirmed by quantitative real-time PCR and in independent skin explant assays. In addition, similar regulations of most of the selected genes were observed in GVHD-affected skin lesions of transplanted rats and in human skin explant assays. Conclusions/Significance: We identified rat and human MHC and NKC genes that are regulated during GVHR in skin explant assays and could therefore serve as biomarkers for GVHD. Several of the respective human genes, including HLA-DMB, C2, AIF1, SPR1, UBD, and OLR1, are polymorphic. These candidates may therefore contribute to the genetic risk of GVHD in patients

Inferior outcome of addition of the aminopeptidase inhibitor tosedostat to standard intensive treatment for elderly patients with aml and high risk mds

Treatment results of AML in elderly patients are unsatisfactory. We hypothesized that addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy may improve outcome in this population. After establishing a safe dose in a run-in phase of the study in 22 patients, 231 eligible patients with AML above 65 years of age (median 70, range 66–81) were randomly assigned in this open label randomized Phase II study to receive standard chemotherapy (3+7) with or without tosedostat at the selected daily dose of 120 mg (n = 116), days 1–21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without tosedostat. CR/CRi rates in the 2 arms were not significantly different (69% (95% C.I. 60–77%) vs 64% (55–73%), respectively). At 24 months, event-free survival (EFS) was 20% for the standard arm versus 12% for the tosedostat arm (Cox-p = 0.01) and overall survival (OS) 33% vs 18% respectively (p = 0.006). Infectious complications accounted for an increased early death rate in the tosedostat arm. Atrial fibrillation w

The role of governance in realising the transition towards sustainable societies

It is widely known that governance is central to the successful implementation of sustainable development policies and measures. Yet, there is a paucity of research which explore the links between governance and sustainability. This paper attempts to address this research need by providing an analysis of the role of governance in enabling – and to some extent – fostering a transition towards sustainable societies. A set of indicators for assessing the capacity for and willingness and commitment to transition to a more sustainable society is presented, enabling identification of direction of change. This paper presents the results of a study, in the context of which sustainability governance has been comparatively investigated in a sample of European countries with, by methodological purpose, very different economic, environmental, political and social conditions (Denmark, Finland, Germany, Latvia, Lithuania and Poland). Lessons learnt and examples of good practice – which may be replicable elsewhere-are outlined. For instance, it is discussed that limited knowledge about sustainable development amongst municipal development planners and decision-makers, deficiencies in policy integration, intersectoral cooperation, municipality and stakeholder cooperation and urban management practices are major reasons for weak governance practices in sustainable development. Furthermore, some recommendations on the role of sustainability governance are made, so as to allow the integration of the principles of governance into sustainability practice and hence provide a more general basis upon which a transition towards sustainable societies may become a reality in different types of European countries and societies. The scientific value of this paper lies in identifying opportunities for integrating principles of governance into sustainability practice, as well as outlining the basis for sustainability transitions, providing a general picture of required policy measures. The paper offers a unique comparative analysis of sustainability governance in the Baltic Sea countries, outlining some of the challenges in sustainability governance in the Baltic Sea region

Mycorrhizal feedbacks influence global forest structure and diversity

One mechanism proposed to explain high species diversity in tropical systems is strong negative conspecific density dependence (CDD), which reduces recruitment of juveniles in proximity to conspecific adult plants. Although evidence shows that plant-specific soil pathogens can drive negative CDD, trees also form key mutualisms with mycorrhizal fungi, which may counteract these effects. Across 43 large-scale forest plots worldwide, we tested whether ectomycorrhizal tree species exhibit weaker negative CDD than arbuscular mycorrhizal tree species. We further tested for conmycorrhizal density dependence (CMDD) to test for benefit from shared mutualists. We found that the strength of CDD varies systematically with mycorrhizal type, with ectomycorrhizal tree species exhibiting higher sapling densities with increasing adult densities than arbuscular mycorrhizal tree species. Moreover, we found evidence of positive CMDD for tree species of both mycorrhizal types. Collectively, these findings indicate that mycorrhizal interactions likely play a foundational role in global forest diversity patterns and structure