Background Glycosylated hemoglobin (HbA1c) is diagnostic of and a measure of the quality of control of diabetes mellitus. Both HbA1c and perioperative hyperglycemia have been targeted as modifiable ...risk factors for postoperative complications. The HbA1c percent cutoff that best predicts major complications has not been defined. Study Design A prospective study of all abdominal operations from a single institution from 2007 to 2010 was performed. All patients with HbA1c within 3 months before surgery were included. The primary end point was major complication, using the Clavien-Dindo complication system, within 30 days of surgery. Stepwise, multivariate analysis was performed including clinically relevant variables chosen a priori. Results Among 438 patients who had a measured HbA1c, 96 (21.9%) experienced a major complication. On multivariate analysis, HbA1c ≥6.5% (odds ratio = 1.95; 95% CI, 1.17–3.24; p = 0.01) was found to be the most significant predictor of major complications. Glyosylated hemoglobin and glucose were strongly correlated (correlation coefficient 0.414, p < 0.01). Predicted probabilities demonstrated that both HbA1c and glucose together contributed to major complications; and HbA1c impacted the ability to achieve optimal perioperative glucose control. Patients with a BMI >30 kg/m2 , history of coronary artery disease, and nonwhite race were more likely to have a HbA1c ≥6.5%. Conclusions Elevated HbA1c ≥6.5% and perioperative hyperglycemia were associated with an increased rate of major complications after abdominal surgery. Elevated peak postoperative glucose levels were correlated with elevated HbA1c and were independently associated with major complications. More liberal HbA1c testing should be considered in high-risk patients before elective surgery. Safe, feasible, and effective strategies to reduce both HbA1c and perioperative hyperglycemia need to be developed to optimize patient outcomes.
The integrated stress response (ISR) tunes the rate of protein synthesis. Control is exerted by phosphorylation of the general translation initiation factor eIF2. eIF2 is a guanosine triphosphatase ...that becomes activated by eIF2B, a two-fold symmetric and heterodecameric complex that functions as eIF2's dedicated nucleotide exchange factor. Phosphorylation converts eIF2 from a substrate into an inhibitor of eIF2B. We report cryo-electron microscopy structures of eIF2 bound to eIF2B in the dephosphorylated state. The structures reveal that the eIF2B decamer is a static platform upon which one or two flexible eIF2 trimers bind and align with eIF2B's bipartite catalytic centers to catalyze nucleotide exchange. Phosphorylation refolds eIF2α, allowing it to contact eIF2B at a different interface and, we surmise, thereby sequestering it into a nonproductive complex.
Background Ventral incisional hernias (VIH) develop in up to 20% of patients after abdominal surgery. No widely applicable preoperative risk-assessment tool exists. We aimed to develop and validate a ...risk-assessment tool to predict VIH after abdominal surgery. Study Design A prospective study of all patients undergoing abdominal surgery was conducted at a single institution from 2008 to 2010. Variables were defined in accordance with the National Surgical Quality Improvement Project, and VIH was determined through clinical and radiographic evaluation. A multivariate Cox proportional hazard model was built from a development cohort (2008 to 2009) to identify predictors of VIH. The HERNIAscore was created by converting the hazards ratios (HR) to points. The predictive accuracy was assessed on the validation cohort (2010) using a receiver operator characteristic curve and calculating the area under the curve (AUC). Results Of 625 patients followed for a median of 41 months (range 0.3 to 64 months), 93 (13.9%) developed a VIH. The training cohort (n = 428, VIH = 70, 16.4%) identified 4 independent predictors: laparotomy (HR 4.77, 95% CI 2.61 to 8.70) or hand-assisted laparoscopy (HAL, HR 4.00, 95% CI 2.08 to 7.70), COPD (HR 2.35; 95% CI 1.44 to 3.83), and BMI ≥ 25 kg/m2 (HR1.74; 95% CI 1.04 to 2.91). Factors that were not predictive included age, sex, American Society of Anesthesioloigsts (ASA) score, albumin, immunosuppression, previous surgery, and suture material or technique. The predictive score had an AUC = 0.77 (95% CI 0.68 to 0.86) using the validation cohort (n = 197, VIH = 23, 11.6%). Using the HERNIAscore: HERNIAscore = 4∗Laparotomy+3∗HAL+1∗COPD+1∗ BMI ≥ 25, 3 classes stratified the risk of VIH: class I (0 to 3 points),5.2%; class II (4 to 5 points),19.6%; and class III (6 points), 55.0%. Conclusions The HERNIAscore accurately identifies patients at increased risk for VIH. Although external validation is needed, this provides a starting point to counsel patients and guide clinical decisions. Increasing the use of laparoscopy, weight-loss programs, community smoking prevention programs, and incisional reinforcement may help reduce rates of VIH.
Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via ...the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.
Laparoscopic ventral hernia repair (LVHR) has grown in popularity. Typically, this procedure is performed with a mesh bridge technique that results in high rates of seroma, eventration (bulging), and ...patient dissatisfaction. In an effort to avoid these complications, there is growing interest in the role of laparoscopic primary fascial closure with intraperitoneal mesh placement. This systematic review evaluated the outcomes of closure of the central defect during LVHR. A literature search of PubMed, Cochrane databases, and Embase was conducted using PRISMA guidelines. MINORS was used to assess the methodologic quality. Primary outcome was hernia recurrence. Secondary outcomes were surgical-site infection, seroma formation, bulging, and patient-centered items (satisfaction, chronic pain, functional status). Eleven studies were identified, eight of which were case series (level 4 data). Three comparative studies examined the difference between closure and nonclosure of the fascial defect during laparoscopic ventral incisional hernia repairs (level 3 and 4 data). These studies suggested that primary fascial closure (
n
= 138) compared to nonclosure (
n
= 255) resulted in lower recurrence rates (0–5.7 vs. 4.8–16.7 %) and seroma formation rates (5.6–11.4 vs. 4.3–27.8 %). Follow-up periods for both groups were similar (1–108 months). Only one study evaluated patient function and clinical bulging. It showed better outcomes with primary fascial closure. Closure of the central defect during LVHR resulted in less recurrence, bulging, and seroma than nonclosure. Patients with closure were more satisfied with the results and had better functional status. The quality of the data was poor, however. A randomized controlled trial to evaluate the role of closure of the central defect during LVHR is warranted.
Introduction
Dog-mediated rabies is enzootic in Vietnam, resulting in at least 70 reported human deaths and 500,000 human rabies exposures annually. In 2016, an integrated bite cases management ...(IBCM) based surveillance program was developed to improve knowledge of the dog-mediated rabies burden in Phu Tho Province of Vietnam.
Methods
The Vietnam Animal Rabies Surveillance Program (VARSP) was established in four stages: (1) Laboratory development, (2) Training of community One Health workers, (3) Paper-based-reporting (VARSP 1.0), and (4) Electronic case reporting (VARSP 2.0). Investigation and diagnostic data collected from March 2016 to December 2019 were compared with historical records of animal rabies cases dating back to January 2012. A risk analysis was conducted to evaluate the probability of a rabies exposure resulting in death after a dog bite, based on data collected over the course of an IBCM investigation.
Results
Prior to the implementation of VARSP, between 2012 and 2015, there was an average of one rabies investigation per year, resulting in two confirmed and two probable animal rabies cases. During the 46 months that VARSP was operational (2016 – 2019), 1048 animal investigations were conducted, which identified 79 (8%) laboratory-confirmed rabies cases and 233 (22%) clinically-confirmed(probable) cases. VARSP produced a 78-fold increase in annual animal rabies case detection (one cases detected per year pre-VARSP vs 78 cases per year under VARSP). The risk of succumbing to rabies for bite victims of apparently healthy dogs available for home quarantine, was three deaths for every 10,000 untreated exposures.
Discussion
A pilot IBCM model used in Phu Tho Province showed promising results for improving rabies surveillance, with a 26-fold increase in annual case detection after implementation of a One Health model. The risk for a person bitten by an apparently healthy dog to develop rabies in the absence of rabies PEP was very low, which supports the WHO recommendations to delay PEP for this category of bite victims, when trained animal assessors are available and routinely communicate with the medical sector. Recent adoption of an electronic IBCM system is likely to expedite adoption of VARSP 2.0 to other Provinces and improve accuracy of field decisions and data collection.
Nature offers inspiration for developing technologies that integrate the capture, conversion, and storage of solar energy. In this review article, we highlight principles of natural photosynthesis ...and artificial photosynthesis, drawing comparisons between solar energy transduction in biology and emerging solar-to-fuel technologies. Key features of the biological approach include use of earth-abundant elements and molecular interfaces for driving photoinduced charge separation reactions that power chemical transformations at global scales. For the artificial systems described in this review, emphasis is placed on advancements involving hybrid photocathodes that power fuel-forming reactions using molecular catalysts interfaced with visible-light-absorbing semiconductors.
E-cigarette aerosol is a complex mixture of gases and particles with a composition that is dependent on the e-liquid formulation, puffing regimen, and device operational parameters. This work ...investigated mainstream aerosols from a third generation device, as a function of coil temperature (315–510 °F, or 157–266 °C), puff duration (2–4 s), and the ratio of propylene glycol (PG) to vegetable glycerin (VG) in e-liquid (100:0–0:100). Targeted and untargeted analyses using liquid chromatography high-resolution mass spectrometry, gas chromatography, in situ chemical ionization mass spectrometry, and gravimetry were used for chemical characterizations. PG and VG were found to be the major constituents (>99%) in both phases of the aerosol. Most e-cigarette components were observed to be volatile or semivolatile under the conditions tested. PG was found almost entirely in the gas phase, while VG had a sizable particle component. Nicotine was only observed in the particle phase. The production of aerosol mass and carbonyl degradation products dramatically increased with higher coil temperature and puff duration, but decreased with increasing VG fraction in the e-liquid. An exception is acrolein, which increased with increasing VG. The formation of carbonyls was dominated by the heat-induced dehydration mechanism in the temperature range studied, yet radical reactions also played an important role. The findings from this study identified open questions regarding both pathways. The vaping process consumed PG significantly faster than VG under all tested conditions, suggesting that e-liquids become more enriched in VG and the exposure to acrolein significantly increases as vaping continues. It can be estimated that a 30:70 initial ratio of PG:VG in the e-liquid becomes almost entirely VG when 60–70% of e-liquid remains during the vaping process at 375 °F (191 °C). This work underscores the need for further research on the puffing lifecycle of e-cigarettes.
Smooth muscle cells and pericytes display remarkable plasticity during injury and disease progression. Here, we tested the hypothesis that perivascular cells give rise to
-dependent macrophage-like ...cells that augment adipose tissue (AT) inflammation and metabolic dysfunction associated with diet-induced obesity (DIO). Approach and Results: Using
eYFP (enhanced yellow fluorescent protein) mice and flow cytometry of the stromovascular fraction of epididymal AT, we observed a large fraction of smooth muscle cells and pericytes lineage traced eYFP
cells expressing macrophage markers. Subsequent single-cell RNA sequencing, however, showed that the majority of these cells had no detectable eYFP transcript. Further exploration revealed that intraperitoneal injection of tamoxifen in peanut oil, used for generating conditional knockout or reporter mice in thousands of previous studies, resulted in large increase in the autofluorescence and false identification of macrophages within epididymal AT as being eYFP
; and unintended proinflammatory consequences. Using newly generated
tdTomato mice given oral tamoxifen, we virtually eliminated the problem with autofluorescence and identified 8 perivascular cell dominated clusters, half of which were altered upon DIO. Given that perivascular cell KLF4 (kruppel-like factor 4) can have beneficial or detrimental effects, we tested its role in obesity-associated AT inflammation. While smooth muscle cells and pericytes-specific
knockout (smooth muscle cells and pericytes
) mice were not protected from DIO, they displayed improved glucose tolerance upon DIO, and showed marked decreases in proinflammatory macrophages and increases in LYVE1
lymphatic endothelial cells in the epididymal AT.
Perivascular cells within the AT microvasculature dynamically respond to DIO and modulate tissue inflammation and metabolism in a KLF4-dependent manner.
The inflammatory bowel diseases IBD, including Crohn's disease CD and ulcerative colitis UC, frequently lead to bowel surgery. Hypoalbuminaemia has been shown to be a prognostic factor for outcomes ...following surgery for other indications, and we sought to determine its role in predicting IBD-related postoperative outcomes.
We included patients who underwent IBD-related major abdominal surgery in the American College of Surgeons' National Surgical Quality Improvement Program ACS-NSQIP between 2005 and 2012. We assessed the impact of indicators of protein-energy malnutrition PEM including hypoalbuminaemia, weight loss, and body mass index on postoperative outcomes.
We identified 10 913 IBD patients 6082 Crohn's disease and 4831 ulcerative colitis who underwent bowel surgery. The prevalence of modest and severe hypoalbuminaemia was 17% and 24%, respectively; 30-day mortality was higher in Crohn's patients with modest and severe hypoalbuminaemia compared with those with normal albumin levels preoperatively 0.7% vs 0.2%, p <0.05; 2.4% vs 0.2%, p <0.01. The same was true for patients with UC with modest and severe hypoalbuminaemia 0.9% vs 0.1%, p <0.01; 5.6% vs 0.1%, p <0.01. Overall infectious complications were more common in the presence of severe hypoalbuminaemia for CD 20% vs 13%, p <0.01. and UC 28% vs 15%, p <0.01 patients. Last, there were higher rates of extra-intestinal, non-septic complications in both CD and UC patients with hypoalbuminaemia compared with those with normal albumin levels.
This study suggests that moderate-severe hypoalbuminaemia is associated with worse IBD-related postoperative outcomes and may have a role in preoperative risk stratification.
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