While studies have demonstrated an association between preoperative hypoalbuminemia and adverse clinical outcomes, the optimal serum albumin threshold for risk-stratification in the broader surgical ...population remains poorly defined. We sought define the optimal threshold of preoperative serum albumin concentration for risk-stratification of adverse post-operative outcomes. Using the American College of Surgeons National Surgical Quality Improvement Program Database, we identified 842,672 patients that had undergone a common surgical procedure in one of eight surgical specialties. An optimal serum albumin concentration threshold for risk-stratification was determined using receiver-operating characteristic analysis. Multivariable logistic regression analysis was used to evaluate the odds of adverse surgical events; a priori defined subgroup analyses were performed. A serum albumin threshold of 3.4 g/dL optimally predicted adverse surgical outcomes in the broader cohort. After multivariable analysis, patients with hypoalbuminemia had increased odds of death within 30 days of surgery (odds ratio OR 2.01, 95% confidence interval CI 1.94–2.08). Hypoalbuminemia was associated with greater odds of primary adverse events among patients with disseminated cancer (OR 2.03, 95% CI 1.88–2.20) compared to patients without disseminated cancer (OR 1.47, 95% CI 1.44–1.51). The standard clinical threshold for hypoalbuminemia is the optimal threshold for preoperative risk assessment.
Objective To investigate the proportion of hyperglycosylated human chorionic gonadotropin (hCG-H) produced at the time of implantation as a predictor of pregnancy success. Design Measuring daily ...urine hCG and hCG-H on the day of implantation. The time of implantation was assumed to be the first day of hCG detection (total hCG >1 mIU/mL). Setting Urine samples were collected at volunteers' homes throughout city of Albuquerque. Patient(s) 110 women attempting to conceive spontaneously; 62 achieved pregnancies (42 to term and 20 failed). Intervention(s) None. Main Outcome Measure(s) Measurements of the total hCG and hCG-H, and calculations of the proportion of hCG-H. Result(s) In all 42 term pregnancies, the proportion of hCG-H on the day of implantation was >50%. This was also true for 7 of the 20 failures. Statistically significant lower proportions of hCG-H (<50%) were observed in 13 of 20 pregnancies that eventually failed. The predictive values of proportion of hCG-H, concentration of hCG-H, total hCG, and regular hCG alone for detecting failures were 100%, 59%, 41%, and 21%, respectively. Conclusion(s) Hyperglycosylated is produced by cytotrophoblast cells in early pregnancy at the time of implantation. Effective proportions of hCG-H (>50%) are required for successful growth and invasion by cytotrophoblasts at the time of implantation. Low proportions of hCG-H at implantation predict failure and are likely to be the root of many pregnancy failures. The 7 of 20 failures with normal proportions of hCG-H were likely due to genetic, immune, or maternal causes. Measurement of a proportion of hCG-H <50% on the day of implantation absolutely indicates a failing pregnancy.
Ubiquitin-proteasome system (UPS) dysfunction is associated with the pathology of a wide range of human diseases, including myopathies and muscular atrophy. However, the mechanistic understanding of ...specific components of the regulation of protein turnover during development and disease progression in skeletal muscle is unclear. Mutations in
, an E3 ubiquitin ligase cullin3 (CUL3) substrate-specific adapter protein, result in severe congenital nemaline myopathy, but the events that initiate the pathology and the mechanism through which it becomes pervasive remain poorly understood. To characterize the KLHL40-regulated ubiquitin-modified proteome during skeletal muscle development and disease onset, we used global, quantitative mass spectrometry-based ubiquitylome and global proteome analyses of
mutant zebrafish during disease progression. Global proteomics during skeletal muscle development revealed extensive remodeling of functional modules linked with sarcomere formation, energy, biosynthetic metabolic processes, and vesicle trafficking. Combined analysis of
mutant muscle proteome and ubiquitylome identified thin filament proteins, metabolic enzymes, and ER-Golgi vesicle trafficking pathway proteins regulated by ubiquitylation during muscle development. Our studies identified a role for KLHL40 as a regulator of ER-Golgi anterograde trafficking through ubiquitin-mediated protein degradation of secretion-associated Ras-related GTPase1a (Sar1a). In KLHL40-deficient muscle, defects in ER exit site vesicle formation and downstream transport of extracellular cargo proteins result in structural and functional abnormalities. Our work reveals that the muscle proteome is dynamically fine-tuned by ubiquitylation to regulate skeletal muscle development and uncovers new disease mechanisms for therapeutic development in patients.
The Full Law Analysis Scattering System Hub (
FLASSH
) is an advanced code which evaluates the thermal scattering law (i.e. TSL, S(α,β)) for thermal scattering cross sections and resonance Doppler ...broadening. The ability to accurately capture these two key cross section features is dependent on accurate, high fidelity TSL evaluations.
FLASSH
1.0 provides advanced physics capabilities resulting in an improved, generalized TSL to most accurately represent the lattice dynamics within any material. This improved TSL will allow for consistent analysis in both the thermal and epithermal energy ranges. The features for TSL analysis are packaged within the
FLASSH
GUI for easy user interface along with data output in many file formats including ENDF File 7 and ACE files.
Smoking remains one of the leading preventable causes of death. Smoking leaves a strong signature on the blood methylome as shown in multiple studies using the Infinium HumanMethylation450 BeadChip. ...Here, we explore novel blood methylation smoking signals on the Illumina MethylationEPIC BeadChip (EPIC) array, which also targets novel CpG-sites in enhancers.
A smoking-methylation meta-analysis was carried out using EPIC DNA methylation profiles in 1407 blood samples from four UK population-based cohorts, including the MRC National Survey for Health and Development (NSHD) or 1946 British birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK). The overall discovery sample included 269 current, 497 former, and 643 never smokers. Replication was pursued in 3425 trans-ethnic samples, including 2325 American Indian individuals participating in the Strong Heart Study (SHS) in 1989-1991 and 1100 African-American participants in the Genetic Epidemiology Network of Arteriopathy Study (GENOA).
Altogether 952 CpG-sites in 500 genes were differentially methylated between smokers and never smokers after Bonferroni correction. There were 526 novel smoking-associated CpG-sites only profiled by the EPIC array, of which 486 (92%) replicated in a meta-analysis of the American Indian and African-American samples. Novel CpG sites mapped both to genes containing previously identified smoking-methylation signals and to 80 novel genes not previously linked to smoking, with the strongest novel signal in SLAMF7. Comparison of former versus never smokers identified that 37 of these sites were persistently differentially methylated after cessation, where 16 represented novel signals only profiled by the EPIC array. We observed a depletion of smoking-associated signals in CpG islands and an enrichment in enhancer regions, consistent with previous results.
This study identified novel smoking-associated signals as possible biomarkers of exposure to smoking and may help improve our understanding of smoking-related disease risk.
Electron microscopy has revealed an abundance of material in the clefts of synapses in the mammalian brain, and the biochemical and functional characteristics of proteins occupying synaptic clefts ...are well documented. However, the detailed spatial organization of the proteins in the synaptic clefts remains unclear. Electron microscope tomography provides a way to delineate and map the proteins spanning the synaptic cleft because freeze substitution preserves molecular details with sufficient contrast to visualize individual cleft proteins. Segmentation and rendering of electron dense material connected across the cleft reveals discrete structural elements that are readily classified into five types at excitatory synapses and four types at inhibitory synapses. Some transcleft elements resemble shapes and sizes of known proteins and could represent single dimers traversing the cleft. Some of the types of cleft elements at inhibitory synapses roughly matched the structure and proportional frequency of cleft elements at excitatory synapses, but the patterns of deployments in the cleft are quite different. Transcleft elements at excitatory synapses were often evenly dispersed in clefts of uniform (18 nm) width but some types show preference for the center or edges of the cleft. Transcleft elements at inhibitory synapses typically were confined to a peripheral region of the cleft where it narrowed to only 6 nm wide. Transcleft elements in both excitatory and inhibitory synapses typically avoid places where synaptic vesicles attach to the presynaptic membrane. These results illustrate that elements spanning synaptic clefts at excitatory and inhibitory synapses consist of distinct structures arranged by type in a specific but different manner at excitatory and inhibitory synapses.
While direct cell transplantation holds great promise in treating many debilitating diseases, poor cell survival and engraftment following injection have limited effective clinical translation. ...Though injectable biomaterials offer protection against membrane‐damaging extensional flow and supply a supportive 3D environment in vivo that ultimately improves cell retention and therapeutic costs, most are created from synthetic or naturally harvested polymers that are immunogenic and/or chemically ill‐defined. This work presents a shear‐thinning and self‐healing telechelic recombinant protein‐based hydrogel designed around XTEN – a well‐expressible, non‐immunogenic, and intrinsically disordered polypeptide previously evolved as a genetically encoded alternative to PEGylation to “eXTENd” the in vivo half‐life of fused protein therapeutics. By flanking XTEN with self‐associating coil domains derived from cartilage oligomeric matrix protein, single‐component physically crosslinked hydrogels exhibiting rapid shear thinning and self‐healing through homopentameric coiled‐coil bundling are formed. Individual and combined point mutations that variably stabilize coil association enables a straightforward method to genetically program material viscoelasticity and biodegradability. Finally, these materials protect and sustain viability of encapsulated human fibroblasts, hepatocytes, embryonic kidney (HEK), and embryonic stem‐cell‐derived cardiomyocytes (hESC‐CMs) through culture, injection, and transcutaneous implantation in mice. These injectable XTEN‐based hydrogels show promise for both in vitro cell culture and in vivo cell transplantation applications.
Shear‐thinning and self‐healing telechelic recombinant protein‐based hydrogels based on XTEN are introduced. Point mutations to self‐associating coil domains yield materials with programmable viscoelasticity and biodegradability. These materials protect and sustain viability of human fibroblasts, hepatocytes, HEK, and embryonic stem‐cell‐derived cardiomyocytes cultured within these genetically encodable biopolymer networks following in vivo injection. Such injectable hydrogels hold promise for therapeutic cell transplantation.
Posttraumatic stress disorder (PTSD) is highly prevalent among veterans. Although there are effective treatment approaches for PTSD, such as Prolonged Exposure (PE) and Cognitive Processing Therapy, ...many providers trained in these approaches do not use them, or use them without sufficient fidelity, and veterans drop out of these treatments at very high rates. The time intensive nature of these treatments is frequently cited as a barrier to receiving the treatment among veterans and delivering the treatment among providers. According, there is an urgent need to establish more efficient and effective PTSD treatment approaches in order to meet the needs of veterans seeking care. Written exposure therapy (WET) is an efficient, exposure-based treatment, and may represent a plausible alternative treatment option to address PTSD in veterans. Although WET has been found to be effective and non-inferior to more time intensive trauma-focused treatment, it has not yet been investigated with a veteran sample. In an ongoing randomized controlled trial (RCT) we are investigating whether WET is non-inferior in treating PTSD compared with the more time intensive PE. The study sample will include 150 men and women veterans diagnosed with PTSD who are randomly assigned to either WET (n = 75) or PE (n = 75). Participants are assessed prior to treatment and 10-, 20-, and 30-weeks after the first treatment session. The primary outcome is PTSD symptom severity assessed with the Clinician Administered PTSD Scale for DSM-5. Establishing that PTSD can be treated effectively with fewer treatment sessions would represent a significant advance in improving access to evidence-based care for veterans with PTSD.
Purpose
Patient-reported outcome measures (PROMs) have become an important part of routine auditing of outcomes in spinal surgery in the UK. PROMs can be used to help assess the quality of care ...provided by surgical units by determining the comparative health status of patients, before and after surgery. This study was designed to review the PROMs used to assess outcomes in spinal surgery and to determine if they are fit for the purpose.
Methods
A systematic literature search was undertaken to identify studies that reported PROMs data following lumbar spinal surgery. The PROMs that were used in each study were recorded and a separate search was undertaken to determine the evidence regarding the validity of each measure.
Results
The initial search identified 1142 abstracts, which were reduced through de-duplication, filtering and review to 58 articles, which were retrieved and reviewed in full. The search identified that the majority of studies used either the Oswestry Disability Index (ODI), SF-36, Roland–Morris Disability Questionnaire (RMDQ) and EQ-5D along with visual analogue scales or numeric rating scales for back and leg pain.
Conclusions
The consistent use of PROMs supports the comparison of outcomes from different studies, although there was minimal evidence regarding the specificity and sensitivity of these measures for use with lumbar spinal patients. Our review highlights the need to determine a consensus regarding the use and reporting of outcome measures within the lumbar spine literature.
BACKGROUND:Multi-ligament knee injury (MLKI) associated with knee dislocation can result in vascular injury. The purpose of this study was to compare knee function after MLKI between patients with a ...vascular injury requiring popliteal artery bypass grafting and patients without vascular involvement. Additionally, factors associated with poor knee function in patients who had MLKI with vascular injury were evaluated.
METHODS:This retrospective study identified patients with an MLKI between 1992 and 2014. Each patient who had a concomitant vascular injury requiring bypass grafting (vascular cohort, n = 16; mean age, 30.3 years) was matched to 2 patients without a vascular injury (control cohort, n = 32; mean age, 31.4 years) on the basis of age, knee dislocation (KD) grade, and peroneal nerve status. Fifteen patients in the vascular cohort and 26 patients in the control cohort had an isolated knee injury. Functional outcomes were assessed with physical examination of range of motion and ligamentous stability as well as patient-reported outcome scores.
RESULTS:The vascular cohort had a mean Lysholm score of 62.5 points (range, 16 to 100 points) and a mean International Knee Documentation Committee (IKDC) score of 59.7 points (range, 14.9 to 100 points) at a mean (and standard deviation) of 8.3 ± 5.0 years after surgery. The control cohort had a mean Lysholm score of 86.4 points (range, 51.0 to 100.0 points) and a mean IKDC score of 83.8 points (range, 35.6 to 100.0 points) at a mean of 6.0 ± 4.0 years. The vascular cohort had significantly lower Lysholm (p = 0.001) and IKDC (p = 0.002) scores than the control cohort. A body mass index (BMI) of >30 kg/m was predictive of lower IKDC (p = 0.0009) and Lysholm (p = 0.0008) scores.
CONCLUSIONS:Patients who sustain an MLKI with an associated popliteal artery injury requiring bypass grafting have significantly lower knee function scores than patients without vascular involvement. This information can be used to help counsel patients with combined multiple ligament and popliteal artery injuries.
LEVEL OF EVIDENCE:Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
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