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

Use and subjective experience of the impact of motor-assisted movement exercisers in people with amyotrophic lateral sclerosis: a multicenter observational study

Motor-assisted movement exercisers (MME) are devices that assist with physical therapy in domestic settings for people living with ALS. This observational cross-sectional study assesses the subjective experience of the therapy and analyzes users' likelihood of recommending treatment with MME. The study was implemented in ten ALS centers between February 2019 and October 2020, and was coordinated by the research platform Ambulanzpartner. Participants assessed symptom severity, documented frequency of MME use and rated the subjective benefits of therapy on a numerical scale (NRS, 0 to 10 points, with 10 being the highest). The Net Promotor Score (NPS) determined the likelihood of a participant recommending MME. Data for 144 participants were analyzed. Weekly MME use ranged from 1 to 4 times for 41% of participants, 5 to 7 times for 42%, and over 7 times for 17%. Particularly positive results were recorded in the following domains: amplification of a sense of achievement (67%), diminution of the feeling of having rigid limbs (63%), diminution of the feeling of being immobile (61%), improvement of general wellbeing (55%) and reduction of muscle stiffness (52%). Participants with more pronounced self-reported muscle weakness were more likely to note a beneficial effect on the preservation and improvement of muscle strength during MME treatment (p < 0.05). Overall, the NPS for MME was high (+ 61). High-frequency MME-assisted treatment (defined as a minimum of five sessions a week) was administered in the majority of participants (59%) in addition to physical therapy. Most patients reported having achieved their individual therapeutic objectives, as evidenced by a high level of satisfaction with MME therapy. The results bolster the justification for extended MME treatment as part of a holistic approach to ALS care

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

Protein alterations associated with temozolomide resistance in subclones of human glioblastoma cell lines

Temozolomide (TMZ) is the standard chemotherapeutic agent for human malignant glioma, but intrinsic or acquired chemoresistance represents a major obstacle to successful treatment of this highly lethal group of tumours. Obtaining better understanding of the molecular mechanisms underlying TMZ resistance in malignant glioma is important for the development of better treatment strategies. We have successfully established a passage control line (D54-C10) and resistant variants (D54-P5 and D54-P10) from the parental TMZ-sensitive malignant glioma cell line D54-C0. The resistant sub-cell lines showed alterations in cell morphology, enhanced cell adhesion, increased migration capacities, and cell cycle arrests. Proteomic analysis identified a set of proteins that showed gradual changes in expression according to their 50% inhibitory concentration (IC50). Successful validation was provided by transcript profiling in another malignant glioma cell line U87-MG and its resistant counterparts. Moreover, three of the identified proteins (vimentin, cathepsin D and prolyl 4-hydroxylase, beta polypeptide) were confirmed to be upregulated in high-grade glioma. Our data suggest that acquired TMZ resistance in human malignant glioma is associated with promotion of malignant phenotypes, and our reported molecular candidates may serve not only as markers of chemoresistance but also as potential therapeutic targets in the treatment of TMZ-resistant human malignant glioma, providing a platform for future investigations

Should patients with hip joint prosthesis receive antibiotic prophylaxis before dental treatment?

The safety committee of the American Academy of Orthopedic Surgeons (AAOS) recommended in 2009 that clinicians should consider antibiotic prophylaxis for all patients with total joint replacement before any invasive procedure that may cause bacteremia. This has aroused confusion and anger among dentists asking for the evidence. The present review deals with different aspects of the rationale for this recommendation giving attention to views both in favor of and against it

Functional traits contribute in opposite directions to taxonomic turnover in northeastern US forests over time

Aims: Understanding the processes driving forest dynamics requires considering that species within communities do not respond in a coordinated manner to external factors. We argue that temporal turnover in species composition results from contrasting differences in species life history and functional strategies (demography and seed and wood traits) that might simultaneously promote stability and dynamism by operating on distinct subsets of species. Specifically, fast taxonomic turnover should be promoted by species that take advantage of sporadically available resources, while forest stability should be promoted by species with conservative and stress‐tolerant life histories.Location: Northeastern USA.Methods: We combine demographic information (survival, recruitment) over a 14‐year period from temperate tree communities in the northeastern United States with trait information on species seed mass and wood density as a proxy for their reproductive and resource acquisition strategies, to evaluate the differential contribution of species with contrasting ecological strategies (low vs high seed mass/wood density) to rates of compositional turnover in temperate forests.Results: The apparent dynamism of US forests is mostly driven by high mortality and low recruitment of small‐seeded species and by high mortality and recruitment of low wood density species. Simultaneously, species with the opposite traits, i.e., high seed mass and wood density, contribute more to stability. Our findings suggest that forests dynamics in the northeastern United States are the outcome of opposing contributions of life history and plant traits that simultaneously promote forest stability and rapid taxonomic turnover by operating differentially across tree species.Conclusions: Small‐seeded and low wood density species promote faster forest turnover than species with the opposite traits. Not accounting for these functional differences in community‐level analyses is likely to mask the complex dynamics of temperate forests. This study demonstrates the importance of studying forest composition and structure under a dynamic scope that accounts for differences in functional strategies across species.This study investigates the drivers of temporal shifts in community composition for forest across the northeastern United States. We found that tree taxonomic turnover hinders the contribution of two opposed ecological processes, dynamism and stability, that operate differently on groups of species with distinct functional traits. Small‐seeded and low wood density species promote faster forest turnover than species with the opposite traits. Photo legend: Acer rubrum, United States; Photo credit: Hans Reijnen.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171837/1/jvs13116-sup-0004-AppendixS4.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171837/2/jvs13116.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171837/3/jvs13116-sup-0002-AppendixS2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171837/4/jvs13116-sup-0001-AppendixS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171837/5/jvs13116-sup-0003-AppendixS3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171837/6/jvs13116_am.pd

Surface cracks—geomorphological indicators for late Quaternary halotectonic movements in Northern Germany

Loading and unloading effects of the Scandinavian Ice Sheet triggered halotectonic movements in Northern Germany. We present newly detected geomorphological features—termed surface cracks—which indicate a relation between ice sheet-induced salt movement and surface processes. As a part of the Central European Basin System, numerous Zechstein salt structures are abundant in the North German Basin. On the basis of high-resolution digital terrain data, more than 160 surface cracks were mapped in Northern Germany, which were grouped into 30 clusters. Almost all of the surface cracks occur above the top regions of Zechstein salt structures. The surface cracks can be several kilometres long, up to more than 20 m deep and more than 100 m wide. The comparison of the shape of the salt structures and the orientation of the cracks reveals a geometric dependency, indicating that the cracks preferably occur near the crest margins of the salt structures. Furthermore, 3D seismic data from two sites show that subsurface faults originating from salt movement exist beneath the surface cracks. We interpret the cracks as surface ruptures due to ice sheet-induced halotectonic movements. The cracks occur in a variety of Quaternary sediments and landforms. This indicates that widespread halokinetic movements occurred in the region after the last (Weichselian) deglaciation and likely before the thawing of the permafrost, possibly in a time frame from c. 30–20 ka until c. 15 ka

Enduring epigenetic landmarks define the cancer microenvironment

The growth and progression of solid tumors involves dynamic cross-talk between cancer epithelium and the surrounding microenvironment. To date, molecular profiling has largely been restricted to the epithelial component of tumors; therefore, features underpinning the persistent protumorigenic phenotype of the tumor microenvironment are unknown. Using whole-genome bisulfite sequencing, we show for the first time that cancer-associated fibroblasts (CAFs) from localized prostate cancer display remarkably distinct and enduring genome-wide changes in DNA methylation, significantly at enhancers and promoters, compared to nonmalignant prostate fibroblasts (NPFs). Differentially methylated regions associated with changes in gene expression have cancer-related functions and accurately distinguish CAFs from NPFs. Remarkably, a subset of changes is shared with prostate cancer epithelial cells, revealing the new concept of tumor-specific epigenome modifications in the tumor and its microenvironment. The distinct methylome of CAFs provides a novel epigenetic hallmark of the cancer microenvironment and promises new biomarkers to improve interpretation of diagnostic samples