A comprehensive comparison of microbial communities between aerobic granular sludge and flocculent sludge for nutrient removal in full-scale wastewater treatment plants.

Understanding the microbial community structure of sludge is crucial for improving the design, operation and optimisation of full-scale wastewater treatment plants (WWTPs). This study aimed to have a comprehensive comparison of microbial communities between aerobic granular sludge and flocculent sludge from two full-scale sequential batch reactors-based WWTPs with nutrient removal for the first time. To better understand key functional bacteria such as polyphosphate accumulating bacteria (PAOs), competitive bacteria such as glycogen accumulating bacteria (GAOs) and nitrifying bacteria for both nitrogen and phosphorus removal, another two full-scale WWTPs with only carbon (C) removal and C and nitrogen (N) removal were compared too. It was found that the richness and diversity of the microbial population in sludge increased with pollutant removal from only C, C and N, to C,N, P removal. For C, N P removal, granule structure led to a more diverse and rich microbial community structure than flocculent structure. Although more abundant nitrifying bacteria were enriched in granular sludge than flocculent sludge, the abundance of total putative PAOs was equivalent. However, the most typical putative PAOs such as Tetrasphaera and Candidatus Accumulibacter seemed to be more correlated with biological phosphorus removal performance, which might be more proper to be used as an indication for P removal potential. The higher abundance of GAOs in flocculent sludge with better phosphorus removal performance might suggest that further investigation is needed to understand the functions of GAOs. In addition, the equivalent abundances of PAOs in the WWTPs with only C removal and with C, N, and P removal, respectively, indicate that many newly reported putative PAOs might not contribute to P removal. This study provides insight into the microbial communities and functional bacteria in aerobic granular sludge and flocculent sludge in full-scale SBRs, which can provide microbes-informed optimisation of reactor operation for better nutrient removal.

Extended Pharmacologic Prophylaxis for Venous Thromboembolism after Colon Cancer Surgery is Associated with Improved Long-term Survival: A Natural Experiment in the Chemotherapeutic Benefit of Heparin Derivatives.

OBJECTIVE: This large database study assessed whether extended pharmacologic prophylaxis for venous thromboembolism after colon cancer resection was associated with improved oncologic survival. BACKGROUND: Heparin-derivatives may confer an anti-neoplastic effect via a variety of mechanisms (e.g. inhibiting angiogenesis in the tumor microenvironment). Studies evaluating the oncologic benefit of heparin and its derivatives have been limited in post-surgical patients. Multiple society guidelines recommend consideration of 30-day treatment with low molecular weight heparin to reduce venous thromboembolism risk after abdominopelvic cancer surgery. However, utilization of extended prophylaxis remains low. METHODS: Surveillance, Epidemiology, and End Results-Medicare data were used to identify patients (age 65+) undergoing resection for non-metastatic colon cancer from 2016-2017. The primary outcomes were overall and cancer-specific survival. Log-rank testing and multivariable Cox regression compared survival in patients who received extended prophylaxis versus those that did not in an inverse propensity treatment weighted cohort. RESULTS: 20,102 patients were included in propensity-weighting and analyzed. 800 (3.98%) received extended pharmacologic prophylaxis. Overall and cancer-specific survival were significantly higher in patients receiving prophylaxis on log-rank tests (P=0.0017 overall, P=0.0200 cancer-specific). Multivariable Cox regression showed improved overall survival [aHR 0.66 (0.56-0.78)] and cancer-specific survival [aHR 0.56 (0.39-0.81)] with prophylaxis after controlling for patient, treatment, and hospital factors. CONCLUSIONS: Extended pharmacologic prophylaxis after colon cancer resection was independently associated with improved overall and cancer-specific survival. These results suggest a potential anti-neoplastic effect from heparin derivatives when used in the context of preventing post-surgical venous thromboembolism.

Perioperative Malnutrition.

CASE SUMMARY: A 61-year-old man presented with penetrating Crohn's ileocolitis and neoterminal ileal fibrostenotic stricture. He developed an anastomotic leak after a redo ileocolic resection and now has a chronic low-output enterocutaneous fistula. He was transferred from an outside institution for further management and is currently without Crohn's disease (CD)-related medical therapy. The fistula output is 25 to 50 mL/day of GI contents. His weight dropped by 25 pounds in 6 months after surgery with a current BMI of 19.1, albumin of 2.0 g/dL, and hemoglobin of 9.7 g/dL. During a 3-month period, he was optimized for surgery with local wound care, initiation of infliximab, and nutritional support with exclusive enteral nutrition (EEN). He gained 9 pounds (BMI 20.4). Albumin improved to 3.4 g/dL and hemoglobin to 12.1 g/dL. He underwent a successful open takedown of the enterocutaneous fistula with ileocolic anastomosis.

Far From Home: The Role of Travel Distance and Care Fragmentation in Surgical Outcomes for Inflammatory Bowel Disease.

Background: Fragmented care for inflammatory bowel disease (IBD) is known to correlate negatively with outcomes, but it is unclear which aspects of care fragmentation are relevant and potentially modifiable. Furthermore, there is little data on the relationship between travel distance and the benefits of integrated care models. Hypothesizing care coordination in the preoperative period may have a significant impact on surgical outcomes, we explored associations between integrated care, travel distance, and surgical outcomes. Methods: A single-center retrospective cohort study of patients undergoing index abdominal surgery was done to compare the rate of surgical complications with and without long travel distance and nonintegrated preoperative care. Multivariable logistic regression was used to identify factors independently associated with complications. Results: One hundred and fifty-seven patients were included. Complications were more common among patients with travel distance >75 miles (47.6% vs 27.4%, P = .012). Integrated preoperative care was not significant on bivariate (P = .381) or multivariable analysis but had a stronger association among patients with travel distance <75 miles (20.9% integrated vs 36.7%, P = .138). After adjustment, new ileostomy, open surgical approach, and distance >75 miles were independently associated with complications. Conclusions: Patients with longer travel distances to the hospital were twice as likely to have a surgical complication after adjusting for other risk factors. Without significant accommodations for remote patients, potential benefits of an integrated model for IBD care may be limited to patients who live close to the medical center. Future efforts addressing continuity of care should consider tactics to mitigate the impact of travel distance on outcomes.

Fever After Colectomy in the Enhanced Recovery Era: Incidence and Risk Factors for Pathologic Source.

INTRODUCTION: Postoperative fever following elective colectomy is common and often results in comprehensive laboratory and radiographic testing. We hypothesized that risk factors for febrile complications may be identified with data available at the time of initial fever episode and that a significant proportion of patients exists in which additional testing is of minimal utility. METHODS: We performed a retrospective case-control study of patients undergoing elective colorectal resection at a single institution between 2015 and 2020 with postoperative fever ≥38.0°C. Febrile patients with a clinically significant fever source requiring a change in management were compared to patients with fever that resolved spontaneously. An additive risk score from 0 to 3 was generated from selected characteristics with P-value <0.001. Multivariable logistic regression was used to model the odds of infection with the risk score entered as a binary variable (0-1 versus 2-3 risk factors). RESULTS: Of 1036 elective colectomy patients, 143 (13.8%) had postoperative fever ≥38.0°C. Among the febrile patients, 27 had a positive evaluation (18.9%). Active smoking status (P = 0.018), time from surgery to fever, fever ≥38.5°C, other vital sign changes, and documented localizing signs/symptoms (all, P < 0.001) were associated with an identifiable source of fever. On multivariable regression, the presence of 2-3 risk factors and fever onset after postoperative day 1 were associated with a positive fever evaluation. CONCLUSIONS: Few patients with fever after colectomy required a change in clinical management. Those without multiple risk factors elicited from an interval history and physical exam are unlikely to benefit from additional testing.

Selective type & screen for elective colectomy based on a transfusion risk score may generate substantial cost savings.

BACKGROUND: Preoperative type and screen are currently recommended for all patients undergoing colectomy. We aimed to identify risk factors for transfusion and define a low-risk cohort of patients undergoing colectomy in whom type and screen may be safely avoided. METHODS: We identified all patients undergoing elective colectomy in the National Surgical Quality Improvement Project-Targeted Colectomy files from 2012 to 2016. Patients transfused preoperatively and those undergoing other concurrent major abdominal procedures were excluded. We compared patients who received blood transfusion on the day of surgery to those who did not. Half of the cohort was randomly selected for development of a points-based model predicting blood transfusion on the day of surgery. This model was then validated using the remaining patients. RESULTS: Of 61,964 patients undergoing colectomy, 3128 (5%) patients were transfused with 1290 (2.1%) occurring on the day of surgery. Preoperative anemia was the strongest predictor of blood transfusion on the day of surgery. Among patients with hematocrit > 35%, day of surgery transfusion risk was 0.8%; 99% of patients with hematocrit > 35% had a score 20 or less. Selective type and screen for patients with score ≤ 20 or hematocrit > 35% would avoid type and screen in 91% and 81% of patients, respectively. CONCLUSION: Transfusion following elective colectomy is rare and can be accurately predicted by preoperative patient characteristics. Selective type and screen based on these parameters have the potential to prevent operative delays and lower cost.

Surgical Outcomes Improvement and Health Inequity in a Regional Quality Collaborative.

BACKGROUND: Surgical quality improvement initiatives may impact sociodemographic groups differentially. The objective of this analysis was to assess the trajectory of surgical morbidity by race and age over time within a Regional Collaborative Quality Initiative. STUDY DESIGN: Adults undergoing eligible general surgery procedures in South Carolina Surgical Quality Collaborative hospitals were analyzed for the presence of at least 1 of 22 morbidities between August 2015 and February 2020. Surgery-level multivariable logistic regression assessed the racial differences in morbidity over time, stratified by age group (18 to 64 years, 65 years and older), and adjusting for potential patient- and surgical-level confounders. RESULTS: A total of 30,761 general surgery cases were analyzed, of which 28.4% were performed in Black patients. Mean morbidity rates were higher for Black patients than non-Black patients (8.5% vs 6.0%, p < 0.0001). After controlling for race and other confounders, a significant decrease in monthly mean morbidity through time was observed in each age group (odds ratio [95% CI]: age 18 to 64 years, 0.986 [0.981 to 0.990]; age 65 years and older, 0.991 [0.986 to 0.995]). Comparing morbidity rates from the first 4 months of the collaborative to the last 4 months reveals older Black patients had an absolute decrease in morbidity of 6.2% compared with 3.6% for older non-Black patients. Younger Black patients had an absolute decrease in morbidity of 4.7% compared with a 3.0% decrease for younger non-Black patients. CONCLUSIONS: Black patients had higher morbidity rates than non-Black patients even when controlling for confounders. The reasons for these disparities are not apparent. Morbidity improved over time in all patients with older Black patients seeing a larger absolute decrease in morbidity.

Geometrically stabilized skyrmionic vortex in FeGe tetrahedral nanoparticles.

The concept of topology has dramatically expanded the research landscape of magnetism, leading to the discovery of numerous magnetic textures with intriguing topological properties. A magnetic skyrmion is an emergent topological magnetic texture with a string-like structure in three dimensions and a disk-like structure in one and two dimensions. Skyrmions in zero dimensions have remained elusive due to challenges from many competing orders. Here, by combining electron holography and micromagnetic simulations, we uncover the real-space magnetic configurations of a skyrmionic vortex structure confined in a B20-type FeGe tetrahedral nanoparticle. An isolated skyrmionic vortex forms at the ground state and this texture shows excellent robustness against temperature without applying a magnetic field. Our findings shed light on zero-dimensional geometrical confinement as a route to engineer and manipulate individual skyrmionic metastructures.

Towards Equitable Surgical Management of Inflammatory Bowel Disease: A Systematic Review of Disparities in Surgery for Inflammatory Bowel Disease.

BACKGROUND: Existing evidence for disparities in inflammatory bowel disease is fragmented and heterogenous. Underlying mechanisms for differences in outcomes based on race and socioeconomic status remain undefined. We performed a systematic review of the literature to examine disparities in surgery for inflammatory bowel disease in the United States. METHODS: Electronic databases were searched from 2000 through June 11, 2021, to identify studies addressing disparities in surgical treatment for adults with inflammatory bowel disease. Eligible English-language publications comparing the use or outcomes of surgery by racial/ethnic, socioeconomic, geographic, and/or institutional factors were included. Studies were grouped according to whether outcomes of surgery were reported or surgery itself was the relevant end point (utilization). Quality was assessed using the Newcastle-Ottawa Scale for observational studies. RESULTS: Forty-five studies were included. Twenty-four reported surgical outcomes and 21addressed utilization. Race/ethnicity was considered in 96% of studies, socioeconomic status in 44%, geographic factors in 27%, and hospital/surgeon factors in 22%. Although study populations and end points were heterogeneous, Black and Hispanic patients were less likely to undergo abdominal surgery when hospitalized; they were more likely to have a complication when they did have surgery. Differences based on race were correlated with socioeconomic factors but frequently remained significant after adjustments for insurance and baseline health. CONCLUSIONS: Surgical disparities based on sociologic and structural factors reflect unidentified differences in multidisciplinary disease management. A broad, multidimensional approach to disparities research with more granular and diverse data sources is needed to improve health care quality and equity for inflammatory bowel disease.

Existing evidence for disparities in inflammatory bowel disease management is fragmented. In reviewing the surgical literature, differences in outcomes by race and socioeconomic status reveal opportunities for improving equity while highlighting continued knowledge gaps in understanding disparities.

P068 Racial and Socioeconomic Disparities in Acute Care Utilization in a National Cohort of Veterans With IBD.

BACKGROUND: Hospitalizations for Black patients with inflammatory bowel disease (IBD) have increased in recent decades though our understanding of disease behavior in Black patients remains limited and concerns related to healthcare equity persist. Existing data are largely drawn from small case series at IBD referral centers or national registries lacking granular longitudinal outpatient data. Our aim was to determine whether there are racial or socioeconomic disparities in acute care utilization as measured by hospitalizations and emergency department (ED) visits within a large national cohort of IBD patients. METHODS: National Veterans Heath Administration (VHA) data were used to examine baseline disease characteristics and two years of utilization following an index outpatient gastroenterology visit for Crohn's disease (CD) or ulcerative colitis (UC) in 2017. To account for patients more likely to access care outside the VHA, we excluded those with less than four unique VHA encounters per year. We compared differences in comorbidity burden [Charlson comorbidity index, (CCI)], disease duration, surgical history and modifiable IBD severity risk factors (opioid use, tobacco use, biologic agent use, anemia, malnutrition) based on race and area deprivation index (ADI), a multidimensional marker for regional socioeconomic status (SES). Negative binomial regression was used to model demographic and clinical risk factors associated with hospitalization and ED visits. RESULTS: 19,442 patients (47.4% with CD and 52.6% with UC) were included: 14% Black, 5% Hispanic and 76% White. Compared to White patients, Black patients were younger, more likely to have anemia, perianal disease, and be in the bottom quartile of ADI; they were less likely to have a history of intestinal resection. IBD type, disease duration, CCI, and rates of tobacco use, opioid use, and malnutrition were not different between Black and White patients. On bivariate analysis, Black patients had increased mean and median ED visits compared to White patients (mean 4.48 vs 3.32; p < 0.001) though no differences were seen in hospitalizations (mean 0.96 vs 0.92; p=NS). On stepwise multivariable modeling, hospitalization and ED utilization were significantly higher among Black patients when controlling for age, sex, type of IBD, and disease duration [OR for hospitalization: 1.114 (95% CI: 1.046-1.199); OR for ED visit: 1.191 (95% CI: 1.125-1.261)]. After sequential adjustment for CCI and modifiable IBD severity risk factors, no differences in hospitalizations were seen between Black and White patients. In the full model for ED visits including adjustments for modifiable IBD severity risk factors (all significant), Black race was significantly associated with increased frequency of ED access [OR: 1.261 (95% CI: 1.19-1.336)], while ADI was not. CONCLUSION: In this analysis of a large national outpatient cohort of patients with IBD, we identified significant racial differences in IBD disease behavior, anemia and subsequent acute care utilization. Racial differences in hospitalization were not significant after controlling for modifiable IBD risk factors suggesting actionable targets to mitigate the observed disparities. However, Black race was independently associated with ED utilization even in a healthcare system where access to care is theoretically similar. Future studies should investigate factors underlying increased ED utilization among Black IBD patients in further detail.

Contractile acto-myosin network on nuclear envelope remnants positions human chromosomes for mitosis.

To ensure proper segregation during mitosis, chromosomes must be efficiently captured by spindle microtubules and subsequently aligned on the mitotic spindle. The efficacy of chromosome interaction with the spindle can be influenced by how widely chromosomes are scattered in space. Here, we quantify chromosome-scattering volume (CSV) and find that it is reduced soon after nuclear envelope breakdown (NEBD) in human cells. The CSV reduction occurs primarily independently of microtubules and is therefore not an outcome of interactions between chromosomes and the spindle. We find that, prior to NEBD, an acto-myosin network is assembled in a LINC complex-dependent manner on the cytoplasmic surface of the nuclear envelope. This acto-myosin network remains on nuclear envelope remnants soon after NEBD, and its myosin-II-mediated contraction reduces CSV and facilitates timely chromosome congression and correct segregation. Thus, we find a novel mechanism that positions chromosomes in early mitosis to ensure efficient and correct chromosome-spindle interactions.

Clinical Characteristics and Longitudinal Outcomes of Primary Mycotic Aortic Aneurysms.

Medical therapy for mycotic aortic aneurysms (MAA) is almost universally fatal, while surgical and endovascular repair carry high morbidity and mortality. The purpose of this study was to compare outcomes between patients receiving treatment for MAA. Records were obtained and patients with MAA were stratified by intervention: endovascular repair, open surgery, and medical therapy. Primary outcomes were aneurysm-related mortality and survival. Risk-adjusted associations with mortality were assessed using time-to-event analysis. Thirty-eight patients were identified (median age, 67). Twenty-one underwent endovascular repair,10 had open surgery and 7 received medical therapy alone. Overall mortality was 47% (n = 18), with 94% aneurysm related. Median survival was significantly longer in the endovascular group (747.0 [161-1249]) vs open surgery and medical therapy (507.5 [34-806] and 66 [13-146] days, respectively; P = .02). The endovascular group had significantly fewer perioperative complications (43% vs 80%, P < .01). However, 4 endovascular patients experienced reinfection versus no open surgery patients. Mortality risk factors included medical therapy (hazard ratio [HR]: 5.3, P < .01) and aneurysm size (HR: 1.4 per 1-cm increase in diameter, P = .03). Endovascular repair of MAA was associated with the best long-term survival and lowest perioperative complication rate, although it is associated with greater reinfection. These tradeoffs should be considered when selecting which procedure is best for a patient.

Pulmonary-Systemic Pressure Ratio Correlates with Morbidity in Cardiac Valve Surgery.

OBJECTIVES: Pulmonary hypertension portends worse outcomes in cardiac valve surgery; however, isolated pulmonary artery pressures may not reflect patients' global cardiac function accurately. To better account for the interventricular relationship, the authors hypothesized that patients with greater pulmonary-systemic ratios (mean pulmonary arterial pressure)/(mean systemic arterial pressure) would correlate with worse outcomes after valve surgery. DESIGN: Retrospective cohort study. SETTING: Single academic hospital. PARTICIPANTS: The study comprised 314 patients undergoing valve surgery with or without coronary artery bypass grafting (2004-2016) with Society of Thoracic Surgeons predicted risk scores and preoperative right heart catheterization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The pulmonary-systemic ratio was calculated as follows: mean pulmonary arterial pressure/mean systemic arterial pressure. Patients were stratified by pulmonary-systemic ratio quartile. Logistic regression was used to assess the risk-adjusted association between pulmonary-systemic ratio or mean pulmonary arterial pressure. Median pulmonary-systemic ratio was 0.33 (Q1-Q3: 0.23-0.65); median pulmonary arterial pressure was 29 (21-30) mmHg. Patients with the highest pulmonary-systemic ratio had the highest rates of morbidity and mortality (p < 0.0001). A high pulmonary-systemic ratio was associated with longer duration in the intensive care unit (p < 0.0001) and hospital (p < 0.0001). After risk-adjustment, pulmonary-systemic ratio and pulmonary arterial pressure were independently associated with morbidity and mortality, but the pulmonary-systemic ratio (odds ratio 23.88, p = 0.008, Wald 7.1) was more strongly associated than the pulmonary arterial pressure (odds ratio 1.035, p = 0.011, Wald 6.5). CONCLUSIONS: The pulmonary-systemic ratio is more strongly associated with risk-adjusted morbidity and mortality in valve surgery than pulmonary arterial pressure. By integrating ventricular interactions, this metric may better characterize the risk of valve surgery.

Methylene Blue for Vasoplegic Syndrome.

Vasoplegic syndrome is a form of vasodilatory shock that occurs frequently in patients who undergo cardiac surgery requiring cardiopulmonary bypass (CBP). Treatment often demands high doses of vasopressors over sustained periods for hypotension that can be refractory to standard vasoactive medications. Furthermore, the development of vasoplegia greatly contributes to morbidity and mortality following cardiac surgery. Methylene blue (MB) has become a popular therapy for cardiac vasoplegia despite a paucity of prospective data to direct its use. Therefore, the aim of this study was to review available data regarding mechanisms, dosing strategies, and side effects of MB, with a focus on its applications for vasoplegia in cardiac surgery.

A dynamic microtubule cytoskeleton directs medial actomyosin function during tube formation.

The cytoskeleton is a major determinant of cell-shape changes that drive the formation of complex tissues during development. Important roles for actomyosin during tissue morphogenesis have been identified, but the role of the microtubule cytoskeleton is less clear. Here, we show that during tubulogenesis of the salivary glands in the fly embryo, the microtubule cytoskeleton undergoes major rearrangements, including a 90° change in alignment relative to the apicobasal axis, loss of centrosomal attachment, and apical stabilization. Disruption of the microtubule cytoskeleton leads to failure of apical constriction in placodal cells fated to invaginate. We show that this failure is due to loss of an apical medial actomyosin network whose pulsatile behavior in wild-type embryos drives the apical constriction of the cells. The medial actomyosin network interacts with the minus ends of acentrosomal microtubule bundles through the cytolinker protein Shot, and disruption of Shot also impairs apical constriction.

Chemical genetic analyses of quantitative changes in Cdk1 activity during the human cell cycle.

Cyclin-dependent kinase 1 (Cdk1) controls cell proliferation and is inhibited by promising anticancer agents, but its mode of action and the consequences of its inhibition are incompletely understood. Cdk1 promotes S- and M-phases during the cell-cycle but also suppresses endoreduplication, which is associated with polyploidy and genome instability. The complexity of Cdk1 regulation has made it difficult to determine whether these different roles require different thresholds of kinase activity and whether the surge of activity as inhibitory phosphates are removed at mitotic onset is essential for cell proliferation. Here, we have used chemical genetics in a human cell line to address these issues. We rescued cells lethally depleted of endogenous Cdk1 with an exogenous Cdk1 conferring sensitivity to one ATP analogue inhibitor (1NMPP1) and resistance to another (RO3306). At no 1NMPP1 concentration was mitosis in rescued clones prevented without also inducing endoreduplication, suggesting that these two key roles for Cdk1 are not simply controlled by different Cdk1 activity thresholds. We also rescued RO3306-resistant clones using exogenous Cdk1 without inhibitory phosphorylation sites, indicating that the mitotic surge of Cdk1 activity is dispensable for cell proliferation. These results suggest that the basic mammalian cycle requires at least some qualitative changes in Cdk1 activity and that quantitative increases in activity need not be rapid. Furthermore, the viability of cells that are unable to undergo rapid Cdk1 activation, and the strong association between endoreduplication and impaired proliferation, may place restrictions on the therapeutic use of a Cdk1 inhibitors.

Enhancing the chemical mixture methodology in emergency preparedness and consequence assessment analysis.

Emergency preparedness personnel at U.S. Department of Energy (DOE) facilities use the chemical mixture methodology (CMM) to estimate the potential health impacts to workers and the public from the unintended airborne release of chemical mixtures. The CMM uses a Hazard Index (HI) for each chemical in a mixture to compare a chemical's concentration at a receptor location to an appropriate concentration limit for that chemical. This limit is typically based on Protection Action Criteria (PAC) values developed and published by the DOE. As a first cut, the CMM sums the HIs for all the chemicals in a mixture to conservatively estimate their combined health impact. A cumulative HI>1.0 represents a concentration exceeding the concentration limit and indicates the potential for adverse health effects. Next, Health Code Numbers (HCNs) are used to identify the target organ systems that may be impacted by exposure to each chemical in a mixture. The sum of the HIs for the maximally impacted target organ system is used to provide a refined, though still conservative, estimate of the potential for adverse health effects from exposure to the chemical mixture. This paper explores approaches to enhance the effectiveness of the CMM by using HCN weighting factors. A series of 24 case studies have been defined to evaluate both the existing CMM and three new approaches for improving the CMM. The first approach uses a set of HCN weighting factors that are applied based on the priority ranking of the HCNs for each chemical. The second approach uses weighting factors based on the priority rankings of the HCNs established for a given type of concentration limit. The third approach uses weighting factors that are based on the exposure route used to derive PAC values and a priority ranking of the HCNs (the same ranking as used in the second approach). Initial testing indicates that applying weighting factors increases the effectiveness of the CMM in general, though care must be taken to avoid introducing non-conservative results. In the near future, additional testing and analysis will be conducted that may lead to the adoption of one of the tested approaches into the CMM.