Evaluation of traditional uses, phytochemical constituents, therapeutic uses and future prospects of Pyracantha genus: a systematic review.

The Pyracantha genus consists of evergreen shrubs distributed from Southeast Europe to South-East Asia. They are found in geographical regions of India, China, and South West Europe. They are used in traditional medicines against earache, menstrual cycles, constipation etc. The genus is pharmacologically significant because of its antioxidant and antimicrobial effects. The genus also acts as a biomonitor species for heavy metals and bio sorbent in wastewater treatment. The review aims to present an overview of four species of the Pyracantha genus -P. crenulata, P. fortuneana, and P. coccinea and P. angustifolia. The comparison of their geographical distribution, traditional uses, therapeutic uses, phytochemical components and future prospects has been described. In this study, 189 research and review articles were scanned to provide summarised research of phytochemical composition, pharmacological effects and future prospects of the species which can benefit the plant as a therapeutic drug or as a functional food.

Exploring the potential of Andrographis paniculata for developing novel HDAC inhibitors: an in silico approach.

Cancer is one of the dreaded diseases of the twentieth century, emerging the major global causes of human morbidity. Cancer research in the last 15 years has provided unprecedented information on the role of epigenetics in cancer initiation and progression. Histone deacetylases (HDACs) are recognized as important epigenetic markers in cancer, whose overexpression leads to increased metastasis and angiogenesis. In the current study, thirty-four (34) compounds from Andrographis paniculata were screened for the identification of potential candidate drugs, targeting three Class I HDACs (Histone deacetylases), namely HDAC1 (PDB id 5ICN), HDAC3 (PDB id 4A69) and HDAC8 (PDB id 5FCW) through computer-assisted drug discovery study. Results showed that some of the phytochemicals chosen for this study exhibited significant drug-like properties. In silico molecular docking study further revealed that out of 34 compounds, the flavonoid Andrographidine E had the highest binding affinities towards HDAC1 (-9.261 Kcal mol-1) and 3 (-9.554 Kcal mol-1) when compared with the control drug Givinostat (-8.789 and -9.448 Kcal mol-1). The diterpenoid Andrographiside displayed the highest binding affinity (-9.588 Kcal mol-1) to HDAC8 compared to Givinostat (-8.947 Kcal mol-1). Statistical analysis using Principal Component Analysis tool revealed that all 34 phytocompounds could be clustered in four statistical groups. Most of them showed high or comparable inhibitory potentials towards HDAC target protein. Finally, the stability of top-ranked complexes (Andrographidine E-HDAC1 and HDAC3; Andrographiside-HDAC8) at the physiological condition was validated by Molecular Dynamic Simulation and MM-PBSA study.Communicated by Ramaswamy H. Sarma.

Curcumin inhibits spike protein of new SARS-CoV-2 variant of concern (VOC) Omicron, an in silico study.

BACKGROUND: Omicron (B.1.1.529), a variant of SARS-CoV-2 is currently spreading globally as a dominant strain. Due to multiple mutations at its Spike protein, including 15 amino acid substitutions at the receptor binding domain (RBD), Omicron is a variant of concern (VOC) and capable of escaping vaccine generated immunity. So far, no specific treatment regime is suggested for this VOC. METHODS: The three-dimensional structure of the Spike RBD domain of Omicron variant was constructed by incorporating 15 amino acid substitutions to the Native Spike (S) structure and structural changes were compared that of the Native S. Seven phytochemicals namely Allicin, Capsaicin, Cinnamaldehyde, Curcumin, Gingerol, Piperine, and Zingeberene were docked with Omicron S protein and Omicron S-hACE2 complex. Further, molecular dynamic simulation was performed between Crcumin and Omicron S protein to evaluate the structural stability of the complex in the physiological environment and compared with that of the control drug Chloroquine. RESULTS: Curcumin, among seven phytochemicals, was found to have the most substantial inhibitory potential with Omicron S protein. Further, it was found that curcumin could disrupt the Omicron S-hACE2 complex. The molecular dynamic simulation demonstrated that Curcumin could form a stable structure with Omicron S in the physiological environment. CONCLUSION: To conclude, Curcumin can be considered as a potential therapeutic agent against the highly infectious Omicron variant of SARS-CoV-2.

In silico study of some selective phytochemicals against a hypothetical SARS-CoV-2 spike RBD using molecular docking tools.

BACKGROUND: This world is currently witnessing a pandemic outbreak of 'COVID-19' caused by a positive-strand RNA virus 'SARS-CoV-2'. Millions have succumbed globally to the disease, and the numbers are increasing day by day. The viral genome enters into the human host through interaction between the spike protein (S) and host angiotensin-converting enzyme-2 (ACE2) proteins. S is the common target for most recently rolled-out vaccines across regions. A recent surge in single/multiple mutations in S region is of great concern as it may escape vaccine induced immunity. So far, the treatment regime with repurposed drugs has not been too successful. HYPOTHESIS: Natural compounds are capable of targeting mutated spike protein by binding to its active site and destabilizing the spike-host ACE2 interaction. MATERIALS AND METHODS: A hypothetical mutated spike protein was constructed by incorporating twelve different mutations from twelve geographical locations simultaneously into the receptor-binding domain (RBD) and docked with ACE2 and seven phytochemicals namely allicin, capsaicin, cinnamaldehyde, curcumin, gingerol, piperine and zingeberene. Molecular Dynamic (MD) simulation and Principal Component Analysis (PCA) were finally used for validation of the docking results. RESULT: The docking results showed that curcumin and piperine were most potent to bind ACE2, mutated spike, and mutated spike-ACE2 complex, thereby restricting viral entry. ADME analysis also proved their drug candidature. The docking complexes were found to be stable by MD simulation. CONCLUSION: This result provides a significant insight about the phytochemicals' role, namely curcumin and piperine, as the potential therapeutic entities against mutated spike protein of SARS-CoV-2.

Phytochemicals as potential drug candidates for targeting SARS CoV 2 proteins, an in silico study.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a member of the family Coronaviridae, and the world is currently witnessing a global pandemic outbreak of this viral disease called COVID-19. With no specific treatment regime, this disease is now a serious threat to humanity and claiming several lives daily. In this work, we selected 24 phytochemicals for an in silico docking study as candidate drugs, targeting four essential proteins of SARS-CoV-2 namely Spike glycoprotein (PDB id 5WRG), Nsp9 RNA binding protein (PDB id 6W4B), Main Protease (PDB id 6Y84), and RNA dependent RNA Polymerase (PDB id 6M71). After statistical validation, the results indicated that a total of 11 phytochemicals divided into two clusters might be used as potential drug candidates against SARS-CoV-2. Supplementary Information: The online version contains supplementary material available at 10.1007/s13337-021-00654-x.

Cadmium selenide (CdSe) quantum dots cause genotoxicity and oxidative stress in Allium cepa plants.

Quantum Dots (QDs), are considered as promising tools for biomedical applications. They have potential applications in agricultural industries, novel pesticide formulations, use in bio-labels and devices to aid genetic manipulation and post-harvest management. Since interactions with higher plants are of important environmental and ecological concern we investigated the cytotoxicity and genotoxicity of CdSe QDs in a model plant (Allium cepa) and established relationships between QDs genotoxic activity and oxidative stress. Allium cepa bulbs with intact roots were exposed to three concentrations of CdSe QDs (12.5, 25 and 50 nM). Cell viability and mitotic frequencies was measured for cytotoxicity, and to assess the genotoxicity DNA lesions, chromosome aberrations and micronuclei were evaluated. We report that QDs exerted significant genotoxic effects, associated with oxidative stress. This could be correlated with the retention of Cd in Allium roots as a dose-dependent increase with the highest uptake at 50 nM of CdSe QD. Oxidative stress induced by CdSe QD treatment activated both, antioxidant (SOD, CAT) scavengers and antioxidant (GPOD, GSH) enzymes. Concentrations as low as 25 nM CdSe QDs were cytotoxic and 50 nM CdSe QDs was found to be genotoxic to the plant. These findings enable to determine the concentrations to be used when practical applications using nanodevices of this type on plants are being considered.

Iron-pulsing, a novel seed invigoration technique to enhance crop yield in rice: A journey from lab to field aiming towards sustainable agriculture.

Bulk fertilizer application is one of the easiest means of improving yield of crops however it comes with several environmental impediments and consumer health menace. In the wake of this situation, sustainable agricultural practices stand as pertinent agronomic tool to increase yield and ensure sufficient food supply from farm to fork. In the present study, efficacy of iron-pulsing in improving the rice yield has been elucidated. This technique involves seed treatment with different concentrations (2.5, 5 and 10 mM) of iron salts (FeCl3 and FeSO4) during germination. FeCl3 or FeSO4 was used to treat the sets and depending on the concentration of the salts, the sets were named as C2.5, C5, C10 and S2.5, S5, S10 (where C and S stands for FeCl3 and FeSO4 respectively and the numbers succeeding them denotes the concentration of salt in mM). Our investigation identified 72 h of treatment as ideal duration for iron-pulsing. At this time point, the seedling emergence attributes and activities of α-amylase and protease increased. The relative water uptake of the seeds also increased through upregulation of aquaporin expression. The treatment efficiently maintained the ROS balance with the aid of antioxidant enzymes and increased the iron content within the treated seeds. After transplantation in field, photosynthetic rate and chlorophyll content enhanced in the treated plants. Finally, the post-harvest agro-morphological traits (represented through panicle morphology, 1000 seed weight, harvest index) and yield showed significant improvement with treatment. Sets C5 and S5 showed optimum efficiency in terms of yield improvement. To our best knowledge, this study is the first report deciphering the efficacy of iron-pulsing as a safe, cost effective and promising technique to escalate the yield of rice crops without incurring an environmental cost. Thus, iron-pulsing is expected to serve as a potential tool to address global food security in years to come.

Effect of low-dose exposure of aluminium oxide nanoparticles in Swiss albino mice: Histopathological changes and oxidative damage.

Rapid growth in the use of aluminium oxide nanoparticles (Al2O3 NPs) in various fields such as medicine, pharmacy, cosmetic industries, and engineering creates concerns since the literature is replete with data regarding their toxicity in living organisms. The objective of the present study was to demonstrate the potential toxicological manifestations of repeated exposure to Al2O3 NP at low doses in vivo. In the present study, Al2O3 NP was orally administered at 15, 30 or 60 mg kg-1 body weight for 5 days to Swiss albino male mice. A battery of well-defined assays was undertaken to evaluate aluminium (Al) bioaccumulation, haematological and histological changes, oxidative damage and genotoxicity. Physico-chemical characterisation demonstrated increases in hydrodynamic diameter along the concentration gradient of Al2O3 NP dispersed in MilliQ water. Brain, liver, spleen, kidney and testes showed high Al retention levels. Histopathological lesions were prominent in the brain and liver. Al2O3 NP treatment increased levels of lipid peroxidation and decreased glutathione content in the test organs at all dose levels. The enzyme activities of catalase and superoxide dismutase were also significantly altered. DNA damage quantified using the comet assay was markedly increased in all the soft organs studied. Anatomical abnormalities, redox imbalance and DNA damage were positively correlated with Al retention in the respective organs. Size, zeta potential and colloidal state might have contributed to the bio-physico-chemical interactions of the NPs in vivo and were responsible for the non-linear dose response. The overall data indicate that Al2O3 NP exposure may result in adverse health consequences, inclusive of but not limited to disturbed redox homeostasis, hepatocellular toxicity, neurodegeneration and DNA damage.

Potential antigenotoxicity assessment of Ziziphus jujuba fruit.

Ziziphus jujuba Mill. fruits are nutritionally rich and have a broad spectrum of health benefits. In this work we hypothesized that this natural product rich in polyphenols might protect humans against DNA damage and its consequences. This has led to our investigation to find out if the fruit extract showed an ability to decrease the frequency of DNA damage (antigenotoxicity) induced by two known genotoxins namely an alkylating agent methyl methane sulphonate (MMS) and a reactive oxygen species (ROS) inducer hydrogen peroxide (H2O2). Human lymphocytes were incubated with the Ziziphus fruit ethanol extracts (ZFE) or betulinic acid (BA) followed by an exposure to either 50 µM of MMS or 250 µM of H2O2. Results suggest that ZFE (250, 500, 1000 µg/ml) and BA (10, 20, 40 µg/ml) were able to inhibit the DNA damaging effect caused by MMS and H2O2 indicative of their protection against the genotoxin. This could be attributed to the interactions of the phenolics, flavonoid and BA present in the fruits. Additional in vivo experiments were carried since BA is an important phytochemical detected in ample amounts in the fruit extract. Mice were primed with BA (2.5, 5.0 and 10 mg/kg body weight) for a period of 6 days. The animals were injected with MMS (10 mg/kg body weight) 24 h later and sacrificed. The genotoxic activity of MMS was inhibited in a dose - related manner by BA. BA reduced the frequency of MMS - induced DNA damage in liver, kidney and bone marrow cells of mice thereby exhibiting its antigenotoxic properties. It could also reduce total glutathione level, lipid peroxidation and hydrogen peroxide content in liver cells of mice through the up-regulation of antioxidant enzymes. Therefore taking into account the antioxidant and antigenotoxic properties, the consumption of the Ziziphus fruit should be more popularized worldwide.

Oxidative stress responses of two different ecophysiological species of earthworms (Eutyphoeus waltoni and Eisenia fetida) exposed to Cd-contaminated soil.

The aim of this study was to assess the biomarkers of oxidative stress [reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione reductase (GR), aldehyde dehydrogenase (ALDH) and lipid peroxidation (LPO)] in earthworms of different ecological categories [epigeic Eisenia fetida (E. fetida) and anecic Eutyphoeus waltoni (E. waltoni)] exposed to cadmium (Cd)-polluted soil (30, 60 and 120 mg kg-1) for 28 days. Cd accumulation in earthworms increased significantly with increasing exposure dose and duration. However, E. fetida showed a relatively higher level of Cd accumulation until day 21; thereafter, depletion in the Cd level was recorded for the highest exposure dose. In E. waltoni, the detoxification enzymes and GSH level increased significantly with increasing exposure dose and Cd accumulation for 14 days (acute phase). In contrast, in E. fetida, acute exposure to Cd increased detoxification enzymes with decrease in GSH levels. For both species, sub-chronic exposures (28 days) increased lipid peroxidation with decrease in detoxification enzymes. GPx and ALDH responses of Cd-exposed earthworms showed a similar trend. Thus, these enzymes can be used as general biomarkers in these two species. The consistent variations in GST, GPx and ALDH activities suggest that E. waltoni may be used as a bioindicator species; this further signifies the use of endemic earthworms as a bioindicator to assess the risk of soil contamination. The present investigation indicates that Cd accumulation and biomarker responses in earthworms depend on dose and duration of exposure and on the concerned species.

Betulinic acid induces DNA damage and apoptosis in SiHa cells.

Betulinic acid (BA) is a naturally occurring terpenoid found principally in the bark of birch trees as well as in numerous other plants. BA is reported to inhibit cancer progression and induce apoptosis in multiple tumor types. In the present study we have investigated the cytotoxicity and potential genotoxicity of BA in SiHa cells. The cell viability was measured by using MTT assay and the morphological changes, DNA damage, changes in cell cycle and mitochondrial membrane potential (MMP) were used for the assessment of apoptosis. BA was shown to destroy SiHa cells preferentially in a concentration dependent manner with a 50% inhibition of the cells at 39.83 µg/ml. The growth inhibition of the cells by BA was coupled with DNA strand breaks, morphological changes, disruption of MMP, reactive oxygen species (ROS) generation and the cell arrest at G0/G1 stage of cell cycle. BA induced apoptosis in SiHa cells was confirmed by positive Annexin V FITC-PI staining. Our results indicate that BA effectively induced DNA damage and apoptosis in SiHa cells. The mechanism of apoptosis was caspase independent and through mitochondrial pathways.

Malathion and dithane induce DNA damage in Vicia faba.

The increasing use of pesticides such as malathion and dithane in agriculture causes environmental mutagenicity. However, their genotoxicity in edible crops is seldom assessed. In this study, the genotoxic potential of malathion and dithane was evaluated in the roots of Vicia faba L. All three concentrations (0.05, 0.1, and 0.2%) of malathion and dithane tested resulted in a significant decrease in root length and inhibited seed germination. Cytological observations showed that the mitotic frequency in the root meristematic cells decreased parallel to the increase in concentrations, and the increase in chromosome aberrations and micronuclei frequency was concentration dependent. Alkaline comet assay revealed significant onset of DNA damage at all tested concentrations. For the randomly amplified polymorphic (RAPD)-polymerase chain reaction (PCR) analyses, 10 random RAPD primers were found to produce 116 unique polymorphic RAPD band fragments of 223-3139 bp. Each primer generated 3-15 RAPD bands on an average. The percentage of polymorphic DNA fragments was higher in malathion-exposed plants than dithane ones. The changes in RAPD profiles included disappearance and/or appearance of DNA bands in malathion and dithane treatment. Hence, DNA damage observed by the cytogenetic endpoints and comet assay corroborated with RAPD-PCR analysis. A total of 15 new protein bands of molecular weight ranging 11.894-226.669 kDa were observed in roots of Vicia plants that were exposed to the pesticides. The number of new protein bands was higher in malathion-treated DNA samples than in dithane-treated ones. Based on the results, we conclude that the pesticides can alter genomic template stability and change protein profiles. Malathion was more genotoxic than dithane. Therefore, RAPD assays can be useful in determining genotoxicity of pesticides in V. faba and other crops along with other quantitative parameters.

Cost-effectiveness of alternative colonoscopy surveillance strategies to mitigate metachronous colorectal cancer incidence.

BACKGROUND: The incidence of metachronous colorectal cancer (MCRC) among colorectal cancer (CRC) survivors varies significantly, and the optimal colonoscopy surveillance practice for mitigating MCRC incidence is unknown. METHODS: A cost-effectiveness analysis was used to compare the performances of the US Multi-Society Task Force guideline and all clinically reasonable colonoscopy surveillance strategies for 50- to 79-year-old posttreatment CRC patients with a computer simulation model. RESULTS: The US guideline [(1,3,5)] recommends the first colonoscopy 1 year after treatment, whereas the second and third colonoscopies are to be repeated at 3- and 5-year intervals. Some promising alternative cost-effective strategies were identified. In comparison with the US guideline, under various scenarios for a 20-year period, 1) reducing the surveillance interval of the guideline after the first colonoscopy by 1 year [(1,2,5)] would save up to 78 discounted life-years (LYs) and prevent 23 MCRCs per 1000 patients (incremental cost-effectiveness ratio [ICER] ≤ $23,270/LY), 2) reducing the intervals after the first and second negative colonoscopies by 1 year [(1,2,4)] would save/prevent up to 109 discounted LYs and 36 MCRCs (ICER ≤ $52,155/LY), and 3) reducing the surveillance intervals after the first and second negative colonoscopy by 1 and 2 years [(1,2,3)] would save/prevent up to 141 discounted LYs and 50 MCRCs (ICER ≤ $63,822/LY). These strategies would require up to 1100 additional colonoscopies per 1000 patients. Although the US guideline might not be cost-effective in comparison with a less intensive oncology guideline [(3,3,5); the ICER could be as high as $140,000/LY], the promising strategies would be cost-effective in comparison with such less intensive guidelines unless the cumulative MCRC incidence were very low. CONCLUSIONS: The US guideline might be improved by a slight increase in the surveillance intensity at the expense of moderately increased cost. More research is warranted to explore the benefits/harms of such practices. Cancer 2016;122:2560-70. © 2016 American Cancer Society.

Changes in utilization and costs for patients with rheumatoid arthritis, 1997 to 2006.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that often results in joint pain, inflammation and bone erosions. Perhaps the most notable change in RA treatment during the last decade is the advent of biologics, and, in particular, anti-tumour necrosis factor agents. Given these advances, it is useful to assess how healthcare and work-loss costs of patients with RA have changed. OBJECTIVE: Our objective was to assess changes in healthcare utilization and costs from 1997 to 2006 for patients diagnosed with RA. METHODS: Two cohorts (1997 and 2006) of patients with RA and matched controls were identified from two administrative claims databases along with subsamples of employed patients and matched controls. The analysis focused on the more homogeneous employee subsample. We compared annual excess co-morbidity rates, resource utilization and healthcare and work-loss costs per patient between the 1997 (n = 279) and 2006 cohorts (n = 837) with difference-in-differences methodology. Results with p < 0.05 were considered statistically significant. RESULTS: In the employee subsample, there were no statistically significant differences in the excess prevalence of non-RA co-morbidities or Charlson Co-morbidity Index results, except for cardiovascular disease, which decreased by 11.1%. Excess number of ED visits and days hospitalized decreased by 1.1 visits/patient and 0.9 days/patient, respectively, while rheumatologist visits increased by 0.9 visits/patient. Excess per-patient direct costs were unchanged. However, drug costs increased by $US633/patient, but medical costs decreased by $US618/patient (not significant) [year 2006 values]. CONCLUSION: For employed patients with RA, there were significant reductions in per-patient excess hospital days, as well as ED visits, and no changes in excess total direct costs over time. New treatments introduced during the study period may be associated with cost savings that offset changes in employee utilization of drug and medical services. In addition, the reductions in excess ED visits and hospital days suggest improvements in patient quality of life.

Cost-effectiveness analysis of roflumilast/tiotropium therapy versus tiotropium monotherapy for treating severe-to-very severe COPD.

OBJECTIVE: To conduct a cost-effectiveness analysis comparing roflumilast/tiotropium therapy vs tiotropium monotherapy in patients with severe-to-very severe COPD. METHODS: The economic evaluation applied a disease-based Markov cohort model with five health states: (1) severe COPD, (2) severe COPD with a history of severe exacerbation, (3) very severe COPD, (4) very severe COPD with a history of severe exacerbation, and (5) death. Within a given health state, a patient may have a mild/moderate or severe exacerbation or die. Data from roflumilast clinical trials and published literature were used to populate model parameters. The model calculated health outcomes and costs for roflumilast/tiotropium therapy vs tiotropium monotherapy over a 5-year horizon. Incremental cost and benefits were then calculated as cost-effectiveness ratios, including cost per exacerbation avoided and cost per quality adjusted life year ($/QALY). RESULTS: Over a 5-year horizon, the estimated incremental costs per exacerbation and per severe exacerbation avoided were $589 and $5869, respectively, and the incremental cost per QALY was $15,815. One-way sensitivity analyses varying key parameters produced an incremental cost per QALY ranging from $1963-$32,773. LIMITATIONS: A number of key parameters used in the model were obtained from studies in the literature that were conducted under different contexts. Specifically, the relative risk estimate for severe COPD patients originates from a small trial not designed to demonstrate the impact of roflumilast on frequency of exacerbations. In addition, the model extrapolates the relative risk estimates over periods of 5-30 years, even though the estimates were only observed in trials that spanned less than a year. CONCLUSIONS: The addition of roflumilast to tiotropium is cost-effective for the treatment of severe to very severe COPD patients.

Economic implications of nighttime attending intensivist coverage in a medical intensive care unit.

OBJECTIVE: Our objective was to assess the cost implications of changing the intensive care unit staffing model from on-demand presence to mandatory 24-hr in-house critical care specialist presence. DESIGN: A pre-post comparison was undertaken among the prospectively assessed cohorts of patients admitted to our medical intensive care unit 1 yr before and 1 yr after the change. Our data were stratified by Acute Physiology and Chronic Health Evaluation III quartile and whether a patient was admitted during the day or at night. Costs were modeled using a generalized linear model with log-link and γ-distributed errors. SETTING: A large academic center in the Midwest. PATIENTS: All patients admitted to the adult medical intensive care unit on or after January 1, 2005 and discharged on or before December 31, 2006. Patients receiving care under both staffing models were excluded. INTERVENTION: Changing the intensive care unit staffing model from on-demand presence to mandatory 24-hr in-house critical care specialist presence. MEASUREMENTS AND MAIN RESULTS: Total cost estimates of hospitalization were calculated for each patient starting from the day of intensive care unit admission to the day of hospital discharge. Adjusted mean total cost estimates were 61% lower in the post period relative to the pre period for patients admitted during night hours (7 pm to 7 am) who were in the highest Acute Physiology and Chronic Health Evaluation III quartile. No significant differences were seen at other severity levels. The unadjusted intensive care unit length of stay fell in the post period relative to the pre period (3.5 vs. 4.8) with no change in non-intensive care unit length of stay. CONCLUSIONS: We find that 24-hr intensive care unit intensivist staffing reduces lengths of stay and cost estimates for the sickest patients admitted at night. The costs of introducing such a staffing model need to be weighed against the potential total savings generated for such patients in smaller intensive care units, especially ones that predominantly care for lower-acuity patients.

Estimating the unknown parameters of the natural history of metachronous colorectal cancer using discrete-event simulation.

OBJECTIVES: Some aspects of the natural history of metachronous colorectal cancer (MCRC), such as the rate of progression from adenomatous polyp to MCRC, are unknown. The objective of this study is to estimate a set of parameters revealing some of these unknown characteristics of MCRC. METHODS: The authors developed a computer simulation model that mimics the progression of MCRC for a 5-year period following the treatment of primary colorectal cancer (CRC). They obtained the inputs of the simulation model using longitudinal data for 284 CRC patients from the Mayo Clinic, Rochester. RESULTS: Five-year MCRC incidence and all-cause mortality were 7.4% and 12.7% in the patient cohort, respectively. Statistical analysis showed that 5-year MCRC incidence was associated with gender (P = 0.05), whereas both all-cause and CRC-related mortalities were associated with age (P < 0.001 and P = 0.01). Estimated annual probabilities of progression from adenomatous polyp to MCRC and from MCRC to metastatic MCRC were 0.14 and 0.28, respectively. Annual probabilities of mortality after MCRC and metastatic MCRC treatments were estimated to be 0.06 and 0.26, respectively. The estimated annual probability of mortality due to undetected MCRC was 0.16. CONCLUSIONS: The results imply that MCRC, especially in women, may be more common than suggested by previous studies. In addition, statistics derived from the clinical data and results of the simulation model indicate that gender and age affect the progression of MCRC.

Impact of discontinuity in health insurance on resource utilization.

BACKGROUND: This study sought to describe the incidence of transitions into and out of Medicaid, characterize the populations that transition and determine if health insurance instability is associated with changes in healthcare utilization. METHODS: 2000-2004 Medical Expenditure Panel Survey (MEPS) was used to identify adults enrolled in Medicaid at any time during the survey period (n = 6,247). We estimate both static and dynamic panel data models to examine the effect of health insurance instability on health care resource utilization. RESULTS: We find that, after controlling for observed factors like employment and health status, and after specifying a dynamic model that attempts to capture time-dependent unobserved effects, individuals who have multiple transitions into and out of Medicaid have higher emergency room utilization, more office visits, more hospitalizations, and refill their prescriptions less often. CONCLUSIONS: Individuals with more than one transition in health insurance status over the study period were likely to have higher health care utilization than individuals with one or fewer transitions. If these effects are causal, in addition to individual benefits, there are potentially large benefits for Medicaid programs from reducing avoidable insurance instability. These results suggest the importance of including provisions to facilitate continuous enrollment in public programs as the United States pursues health reform.

Improving clinical access and continuity through physician panel redesign.

BACKGROUND: Population growth, an aging population and the increasing prevalence of chronic disease are projected to increase demand for primary care services in the United States. OBJECTIVE: Using systems engineering methods, to re-design physician patient panels targeting optimal access and continuity of care. DESIGN: We use computer simulation methods to design physician panels and model a practice's appointment system and capacity to provide clinical service. Baseline data were derived from a primary care group practice of 39 physicians with over 20,000 patients at the Mayo Clinic in Rochester, MN, for the years 2004-2006. Panel design specifically took into account panel size and case mix (based on age and gender). MEASURES: The primary outcome measures were patient waiting time and patient/clinician continuity. Continuity is defined as the inverse of the proportion of times patients are redirected to see a provider other than their primary care physician (PCP). RESULTS: The optimized panel design decreases waiting time by 44% and increases continuity by 40% over baseline. The new panel design provides shorter waiting time and higher continuity over a wide range of practice panel sizes. CONCLUSIONS: Redesigning primary care physician panels can improve access to and continuity of care for patients.

The net value of health care for patients with type 2 diabetes, 1997 to 2005.

BACKGROUND: The net economic value of increased health care spending remains unclear, especially for chronic diseases. OBJECTIVE: To assess the net value of health care for patients with type 2 diabetes. DESIGN: Economic analysis of observational cohort data. SETTING: Mayo Clinic, Rochester, Minnesota, a not-for-profit integrated health care delivery system. PATIENTS: 613 patients with type 2 diabetes. MEASUREMENTS: Changes in inflation-adjusted annual health care spending and in health status between 1997 and 2005 (with health status defined as 10-year cardiovascular risk), holding age and diabetes duration constant across the observation period ("modifiable risk"), and simulated outcomes for all diabetes complications based on the UKPDS (United Kingdom Perspective Diabetes Study) Outcomes Model. Net value was estimated as the present discounted monetary value of improved survival and avoided treatment spending for coronary heart disease minus the increase in annual spending per patient. RESULTS: Assuming that 1 life-year is worth $200,000 and accounting for changes in modifiable cardiovascular risk, the net value of changes in health care for patients with type 2 diabetes was $10,911 per patient (95% CI, -$8480 to $33,402) between 1997 and 2005, a positive dollar value that suggests the value of health care has improved despite increased spending. A second approach based on diabetes complications yielded a net value of $6931 per patient (CI, -$186,901 to $211,980). LIMITATION: The patient population was homogeneous and small, and the wide CIs of the estimates are compatible with a decrease as well as an increase in value. CONCLUSION: The economic value of improvements in health status for patients with type 2 diabetes seems to exceed or equal increases in health care spending, suggesting that those increases were worth the extra cost. However, the possibility that society is getting less value for its money could not be statistically excluded, and there is opportunity to improve the value of diabetes-related health care. PRIMARY FUNDING SOURCE: None.