OBJECTIVE:To compare targeted muscle reinnervation (TMR) to “standard treatment” of neuroma excision and burying into muscle for postamputation pain.
SUMMARY BACKGROUND DATA:To date, no intervention ...is consistently effective for neuroma-related residual limb or phantom limb pain (PLP). TMR is a nerve transfer procedure developed for prosthesis control, incidentally found to improve postamputation pain.
METHODS:A prospective, randomized clinical trial was conducted. 28 amputees with chronic pain were assigned to standard treatment or TMR. Primary outcome was change between pre- and postoperative numerical rating scale (NRS, 0–10) pain scores for residual limb pain and PLP at 1 year. Secondary outcomes included NRS for all patients at final follow-up, PROMIS pain scales, neuroma size, and patient function.
RESULTS:In intention-to-treat analysis, changes in PLP scores at 1 year were 3.2 versus −0.2 (difference 3.4, adjusted confidence interval (aCI) −0.1 to 6.9, adjusted P = 0.06) for TMR and standard treatment, respectively. Changes in residual limb pain scores were 2.9 versus 0.9 (difference 1.9, aCI −0.5 to 4.4, P = 0.15). In longitudinal mixed model analysis, difference in change scores for PLP was significantly greater in the TMR group compared with standard treatment mean (aCI) = 3.5 (0.6, 6.3), P = 0.03. Reduction in residual limb pain was favorable for TMR (P = 0.10). At longest follow-up, including 3 crossover patients, results favored TMR over standard treatment.
CONCLUSIONS:In this first surgical RCT for the treatment of postamputation pain in major limb amputees, TMR improved PLP and trended toward improved residual limb pain compared with conventional neurectomy.
TRIAL REGISTRATION:NCT 02205385 at ClinicalTrials.gov.
Hospital readmissions in older adult populations are an emerging quality indicator for acute care hospitals. Recent evidence has linked functional decline during and after hospitalization with an ...elevated risk of hospital readmission. However, models of care that have been developed to reduce hospital readmission rates do not adequately address functional deficits. Physical therapists, as experts in optimizing physical function, have a strong opportunity to contribute meaningfully to care transition models and demonstrate the value of physical therapy interventions in reducing readmissions. Thus, the purposes of this perspective article are: (1) to describe the need for physical therapist input during care transitions for older adults and (2) to outline strategies for expanding physical therapy participation in care transitions for older adults, with an overall goal of reducing avoidable 30-day hospital readmissions.
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DOBA, FSPLJ, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability
. At present, it is unknown how the locations of replication origins are ...determined in the human genome. Here we dissect the role of topologically associating domains (TADs)
, subTADs
and loops
in the positioning of replication initiation zones (IZs). We stratify TADs and subTADs by the presence of corner-dots indicative of loops and the orientation of CTCF motifs. We find that high-efficiency, early replicating IZs localize to boundaries between adjacent corner-dot TADs anchored by high-density arrays of divergently and convergently oriented CTCF motifs. By contrast, low-efficiency IZs localize to weaker dotless boundaries. Following ablation of cohesin-mediated loop extrusion during G1, high-efficiency IZs become diffuse and delocalized at boundaries with complex CTCF motif orientations. Moreover, G1 knockdown of the cohesin unloading factor WAPL results in gained long-range loops and narrowed localization of IZs at the same boundaries. Finally, targeted deletion or insertion of specific boundaries causes local replication timing shifts consistent with IZ loss or gain, respectively. Our data support a model in which cohesin-mediated loop extrusion and stalling at a subset of genetically encoded TAD and subTAD boundaries is an essential determinant of the locations of replication origins in human S phase.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The influence of climate feedbacks on regional hydrological changes under warming is poorly understood. Here, a moist energy balance model (MEBM) with a Hadley Cell parameterization is used to ...isolate the influence of climate feedbacks on changes in zonal‐mean precipitation‐minus‐evaporation (P − E) under greenhouse‐gas forcing. It is shown that cloud feedbacks act to narrow bands of tropical P − E and increase P − E in the deep tropics. The surface‐albedo feedback shifts the location of maximum tropical P − E and increases P − E in the polar regions. The intermodel spread in the P − E changes associated with feedbacks arises mainly from cloud feedbacks, with the lapse‐rate and surface‐albedo feedbacks playing important roles in the polar regions. The P − E change associated with cloud feedback locking in the MEBM is similar to that of a climate model with inactive cloud feedbacks. This work highlights the unique role that climate feedbacks play in causing deviations from the “wet‐gets‐wetter, dry‐gets‐drier” paradigm.
Plain Language Summary
Climate feedbacks, which act to amplify or dampen global warming, play an important role in shaping how the climate system responds to changes in greenhouse‐gas concentrations. Here, we use an idealized climate model, which makes a simplified assumption about how energy is transported in the atmosphere, to examine how climate feedbacks influence the patterns of precipitation and evaporation change under global warming. We find that the cloud feedback acts to narrow the band of rainfall on the equator known as the Intertropical Convergence Zone and that the surface‐albedo feedback acts to shift the location of maximum rainfall. We also find that the cloud feedback accounts for most of the uncertainty associated with feedbacks in regional hydrological change under warming. The idealized model with a locked cloud feedback also simulates a change in precipitation and evaporation that is similar to a comprehensive climate model with an inactive cloud feedback.
Key Points
A moist energy balance model (MEBM) is used to investigate the influence of climate feedbacks on regional hydrological changes under warming
Cloud feedbacks act to narrow and increase tropical P − E and are the dominant source of feedback uncertainty in regional hydrological changes
The MEBM with a locked cloud feedback largely replicates a climate model with an inactive cloud feedback
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for disease, is ...poorly understood. Here, we perform comprehensive lipidomics to create a lipid network map during ZIKV infection. We find that ZIKV significantly alters host lipid composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic expression of ZIKV NS4B protein results in similar changes, demonstrating a role for NS4B in modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, including human neural progenitor cells, blocks ZIKV infection. Additionally, the sphingolipid ceramide redistributes to ZIKV replication sites, and increasing ceramide levels by multiple pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection.
Type II topoisomerase (Top2) poisoning therapy is used to treat a broad range of cancers via induction of double strand breaks (DSBs) in cells undergoing replication and transcription. Preventing the ...repair of DSBs via inhibition of DNA-PK, an inhibitor of non-homologous end-joining (NHEJ), increases cell kill with Top2 poisons and has led to the initiation of several clinical trials. To elucidate the cellular mechanisms leading to synergistic activity of dual DNA-PK/Top2 inhibition we looked at their effects in cycling versus non-cycling cells, in 3D spheroids and in xenograft models. Combined DNA-PK/Top2 inhibition was found to not only increase the cell kill in proliferating cells, the cell population that is typically most vulnerable to Top2 poisoning, but also in non-proliferative but transcriptionally active cells. This effect was observed in both cancer and normal tissue models, killing more cells than high concentrations of etoposide alone. The combination treatment delayed tumor growth in mice compared to Top2 poisoning alone, but also led to increased toxicity. These findings demonstrate sensitization of Top2β-expressing, non-cycling cells to Top2 poisoning by DNA-PK inhibition. Expansion of the target cell population of Top2 poison treatment to include non-proliferating cells via combination with DNA damage repair inhibitors has implications for efficacy and toxicity of these combinations, including for inhibitors of DNA-PK currently in clinical trial.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Understanding how biological molecules are generated, metabolized and eliminated in living systems is important for interpreting processes such as immune response and disease pathology. While genomic ...and proteomic studies have provided vast amounts of information over the last several decades, interest in lipidomics has also grown due to improved analytical technologies revealing altered lipid metabolism in type 2 diabetes, cancer, and lipid storage disease. Mass spectrometry (MS) measurements are currently the dominant approach for characterizing the lipidome by providing detailed information on the spatial and temporal composition of lipids. However, interpreting lipids' biological roles is challenging due to the existence of numerous structural and stereoisomers (i.e. distinct acyl chain and double-bond positions), which are often unresolvable using present approaches. Here we show that combining liquid chromatography (LC) and structurally-based ion mobility spectrometry (IMS) measurement with MS analyses distinguishes lipid isomers and allows insight into biological and disease processes.
Adaptation to respiration at birth depends upon the synthesis of pulmonary surfactant, a lipid-protein complex that reduces surface tension at the air-liquid interface in the alveoli and prevents ...lung collapse during the ventilatory cycle. Herein, we demonstrated that the gene encoding a subunit of the endoplasmic reticulum membrane complex, EMC3, also known as TMEM111 (Emc3/Tmem111), was required for murine pulmonary surfactant synthesis and lung function at birth. Conditional deletion of Emc3 in murine embryonic lung epithelial cells disrupted the synthesis and packaging of surfactant lipids and proteins, impaired the formation of lamellar bodies, and induced the unfolded protein response in alveolar type 2 (AT2) cells. EMC3 was essential for the processing and routing of surfactant proteins, SP-B and SP-C, and the biogenesis of the phospholipid transport protein ABCA3. Transcriptomic, lipidomic, and proteomic analyses demonstrated that EMC3 coordinates the assembly of lipids and proteins in AT2 cells that is necessary for surfactant synthesis and function at birth.
The ability to improve the data quality of ion mobility–mass spectrometry (IM-MS) measurements is of great importance for enabling modular and efficient computational workflows and gaining better ...qualitative and quantitative insights from complex biological and environmental samples. We developed the PNNL PreProcessor, a standalone and user-friendly software housing various algorithmic implementations to generate new MS-files with enhanced signal quality and in the same instrument format. Different experimental approaches are supported for IM-MS based on Drift-Tube (DT) and Structures for Lossless Ion Manipulations (SLIM), including liquid chromatography (LC) and infusion analyses. The algorithms extend the dynamic range of the detection system, while reducing file sizes for faster and memory-efficient downstream processing. Specifically, multidimensional smoothing improves peak shapes of poorly defined low-abundance signals, and saturation repair reconstructs the intensity profile of high-abundance peaks from various analyte types. Other functionalities are data compression and interpolation, IM demultiplexing, noise filtering by low intensity threshold and spike removal, and exporting of acquisition metadata. Several advantages of the tool are illustrated, including an increase of 19.4% in lipid annotations and a two-times faster processing of LC-DT IM-MS data-independent acquisition spectra from a complex lipid extract of a standard human plasma sample. The software is freely available at https://omics.pnl.gov/software/pnnl-preprocessor.
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IJS, KILJ, NUK, PNG, UL, UM
20.
Editorial: Autoimmune pre-disease Hundt, Jennifer E; Hoffmann, Markus H; Amber, Kyle T ...
Frontiers in immunology,
02/2023, Volume:
14
Journal Article
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