Important Role of Overland Flows and Tile Field Pathways in Nutrient Transport.

Nitrogen and phosphorus pollution is of great concern to aquatic life and human well-being. While most of these nutrients are applied to the landscape, little is known about the complex interplay among nutrient applications, transport attenuation processes, and coastal loads. Here, we enhance and apply the Spatially Explicit Nutrient Source Estimate and Flux model (SENSEflux) to simulate the total annual nitrogen and phosphorus loads from the US Great Lakes Basin to the coastline, identify nutrient delivery hotspots, and estimate the relative contributions of different sources and pathways at a high resolution (120 m). In addition to in-stream uptake, the main novelty of this model is that SENSEflux explicitly describes nutrient attenuation through four distinct pathways that are seldom described jointly in other models: runoff from tile-drained agricultural fields, overland runoff, groundwater flow, and septic plumes within groundwater. Our analysis shows that agricultural sources are dominant for both total nitrogen (TN) (58%) and total phosphorus (TP) (46%) deliveries to the Great Lakes. In addition, this study reveals that the surface pathways (sum of overland flow and tile field drainage) dominate nutrient delivery, transporting 66% of the TN and 76% of the TP loads to the US Great Lakes coastline. Importantly, this study provides the first basin-wide estimates of both nonseptic groundwater (TN: 26%; TP: 5%) and septic-plume groundwater (TN: 4%; TP: 2%) deliveries of nutrients to the lakes. This work provides valuable information for environmental managers to target efforts to reduce nutrient loads to the Great Lakes, which could be transferred to other regions worldwide that are facing similar nutrient management challenges.

Dulaglutide treatment results in effective glycaemic control in latent autoimmune diabetes in adults (LADA): A post-hoc analysis of the AWARD-2, -4 and -5 Trials.

AIMS: Patients with a type-2-diabetes (T2D) phenotype positive for glutamic acid decarboxylase antibodies (GADA) represent the majority of cases of latent autoimmune diabetes of the adult (LADA). The GLP-1 receptor agonist dulaglutide, recently introduced for treatment of T2D, has yet to be evaluated in LADA patients. Our primary objective was to evaluate the effect of dulaglutide on glycaemic control (HbA1c) in GADA-positive LADA vs GADA-negative T2D patients. METHODS: A post-hoc analysis was performed using data from 3 randomized phase 3 trials (AWARD-2,-4,-5; patients with GADA assessment) which were part of the dulaglutide clinical development programme in T2D. LADA patients were identified by GADA ≥5 IU/mL (ELISA). Changes in HbA1c during 12 months of treatment with dulaglutide or comparator were analysed using mixed-effect model repeated measures. RESULTS: Of 2466 adults tested for GADA (dulaglutide, 1710; glargine, 298; sitagliptin, 294; placebo, 164), 2278 (92.4%) were GADA-negative and 188 (7.6%) were GADA-positive, including 58 GADA-high patients (> 200 IU/mL) and 130 GADA-low patients (≤200 and ≥5 IU/mL). Overall, baseline parameters were comparable between the groups. Dulaglutide resulted in comparable HbA1c reductions in GADA-negative (LS mean change [95%CI], -1.09% [-1.15, -1.03]) and GADA-positive patients (-0.94% [-1.15, -0.72]) at 12 months. HbA1c reductions were numerically, but not statistically, significantly larger in GADA-low patients (-1.02% [-1.26, -0.78]) vs GADA-high patients (-0.72% [-1.21,-0.24]) at 12 months. Similar outcomes were observed at 3 and 6 months. CONCLUSIONS: These data are the first to indicate that dulaglutide was effective in reducing HbA1c in LADA patients.

Linking fecal bacteria in rivers to landscape, geochemical, and hydrologic factors and sources at the basin scale.

Linking fecal indicator bacteria concentrations in large mixed-use watersheds back to diffuse human sources, such as septic systems, has met limited success. In this study, 64 rivers that drain 84% of Michigan's Lower Peninsula were sampled under baseflow conditions for Escherichia coli, Bacteroides thetaiotaomicron (a human source-tracking marker), landscape characteristics, and geochemical and hydrologic variables. E. coli and B. thetaiotaomicron were routinely detected in sampled rivers and an E. coli reference level was defined (1.4 log10 most probable number⋅100 mL(-1)). Using classification and regression tree analysis and demographic estimates of wastewater treatments per watershed, septic systems seem to be the primary driver of fecal bacteria levels. In particular, watersheds with more than 1,621 septic systems exhibited significantly higher concentrations of B. thetaiotaomicron. This information is vital for evaluating water quality and health implications, determining the impacts of septic systems on watersheds, and improving management decisions for locating, constructing, and maintaining on-site wastewater treatment systems.

Regional Variations of Bovine and Porcine Fecal Pollution as a Function of Landscape, Nutrient, and Hydrological Factors.

The effects of manure application in agriculture on surface water quality has become a local to global problem because of the adverse consequences on public health and food security. This study evaluated (i) the spatial distribution of bovine (cow) and porcine (pig) genetic fecal markers, (ii) how hydrologic factors influenced these genetic markers, and (iii) their variations as a function of land use, nutrients, and other physiochemical factors. We collected 189 samples from 63 watersheds in Michigan's Lower Peninsula during baseflow, spring melt, and summer rain conditions. For each sample, we quantified the concentrations of bovine and porcine genetic markers by digital droplet polymerase chain reaction and measured , dissolved oxygen, pH, temperature, total phosphorus, total nitrogen, nitrate-nitrite (NO), ammonia (NH), soluble reactive phosphorus, streamflow, and watershed specific precipitation. Bovine and porcine manure markers were ubiquitous in rivers that drain agricultural and natural fields across the study region. This study provides baseline conditions on the state of watershed impairment, which can be used to develop best management practices that could improve water quality. Similar studies should be performed with higher spatial sampling density to elucidate detailed factors that influence the transport of manure constituents.

Comparative Modulation of Levels of Oxidative Stress in the Liver of Anti-Tuberculosis Drug Treated Wistar Rats by Vitamin B12, Beta-Carotene, and Spirulina fusiformis: Role of NF-κB, iNOS, IL-6, and IL-10.

Isoniazid (INH) and Rifampicin (RIF) are known hepatotoxic agents. We compared the efficacy of Spirulina fusiformis and its active components vitamin B12 and beta-carotene in attenuating INH and RIF induced hepatotoxicity. We also tried to elucidate the inflammatory mechanism behind anti-tuberculosis drug induced hepatotoxicity. INH and RIF were administered to Wistar albino rats for 28 days to induce hepatotoxicity. S. fusiformis, vitamin B12, and beta-carotene were co-administered with INH and RIF and their hepatoprotective, antioxidant, and immunomodulatory roles were studied through blood and liver analysis. Changes induced by INH and RIF in antioxidants, cytokines (IL-6 and IL-10) and expression of Nuclear Factor-κB (NF-κB) and Nitric Oxide Synthase (iNOS) were also studied. Supplement treatment caused restoration of liver function parameters to normal levels along with reversal of inflammatory changes in IL-6 and IL-10 levels. Liver PCNA, iNOS, and NF-κB expression were reduced in the supplement treated tissues compared to INH and RIF treated rats as evidenced by immunohistochemistry and quantitative PCR. Correlation of IL-6 levels, PCNA, and iNOS with NF-κB showed its pivotal role in the inflammatory process. Study shows the pivotal role of NF-kB and the equivalence in antioxidant efficacy of vitamin B12 and beta-carotene compared to Spirulina fusiformis. J. Cell. Biochem. 118: 3825-3833, 2017. © 2017 Wiley Periodicals, Inc.

Continuous glucose monitoring in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonist dulaglutide in combination with prandial insulin lispro: an AWARD-4 substudy.

AIM: To conduct a substudy, using 24-hour continuous glucose monitoring (CGM), of the AWARD-4 trial, which was designed to compare insulin + glucagon-like peptide-1 receptor agonist treatment with an insulin-only regimen. METHODS: The AWARD-4 trial randomized 884 conventional insulin regimen-treated patients to dulaglutide 1.5 mg, dulaglutide 0.75 mg and glargine, all in combination with prandial insulin lispro. The CGM substudy included 144 patients inserted with a Medtronic CGMS iPro CGM device to enable 3-day glucose monitoring. CGM sessions were completed at weeks 0, 13, 26 and 52. CGM measures included mean 24-hour glucose, percentage time in target glucose ranges, hyper- and hypoglycaemia and glucose variability. The primary objective was treatment comparison for percentage time spent with CGM glucose values in the 3.9-7.8 mmol/L range after 26 weeks. RESULTS: At week 26, mean CGM values decreased in all treatment groups (change from baseline -2.8 ± 0.3, -2.4 ± 0.3 and -2.5 ± 0.3 mmol/L for dulaglutide 1.5 mg, dulaglutide 0.75 mg and glargine, respectively); between-group differences were not statistically significant. Treatment groups were similar for percentage time in the 3.9-7.8 mmol/L range. Percentage time in the 3.9-10.0 mmol/L range was greater for dulaglutide 1.5 mg than for glargine (p < 0.05). Dulaglutide and glargine were associated with decreased glucose variability for all CGM variability indices. The overall within-patient standard deviation (s.d.) was significantly reduced with dulaglutide 1.5 mg versus glargine (p < 0.05). At week 52, there were no significant differences among the groups with regard to measures of normoglycaemia or near-normoglycaemia and for the overall within-patient s.d. Treatment with glargine was associated with greater increases in percentage time spent with glucose values ≤3.9 mmol/L, with statistically significant differences between the groups at 52 weeks (p < 0.05). CONCLUSIONS: In combination with prandial lispro, treatment with dulaglutide and glargine resulted in similar proportions of glucose values in the normoglycaemic range, but dulaglutide provided an improved balance between the proportion of values within the near-normoglycaemia range and values within the hypoglycaemic range.

Amelioration of anti-tuberculosis drug induced oxidative stress in kidneys by Spirulina fusiformis in a rat model.

Nephrotoxicity is a rare complication caused by anti-tuberculosis therapy-induced oxidative stress. The Cyanobacterium Spirulina fusiformis Voronikhin belonging to Oscillatoriaceae family is used traditionally as a source of antioxidants against oxidative stress. We aimed to investigate the efficacy of S. fusiformis in modifying isoniazid (INH) and rifampicin (RIF)-induced changes in Wistar rat kidneys. Animals were divided into six groups: normal control rats; toxic control (INH & RIF-50 mg/kg b.w./d each; p.o.); INH & RIF + S. fusiformis (400 mg/kg b.w./d); INH & RIF + S. fusiformis (800 mg/kg b.w./d); S. fusiformis (800 mg/kg b.w./d) alone-treated rats; INH & RIF + silymarin (25 mg/kg b.w./d). Study duration was 28 d after which blood and kidneys were analyzed. We also studied the binding and interactions of the transcription factors Liver X Receptor (LXR) and Farnesoid X Receptor (FXR) with INH, RIF, and representative active compounds of S. fusiformis by in silico methods. INH & RIF treatment caused significant (p< 0.05) decrease in antioxidant levels and significant (p< 0.05) increase in the levels of creatinine, urea, and uric acid showing impaired kidney function. Spirulina fusiformis ameliorated these effects in a dose dependent manner. Histological examination of kidneys supported these findings. Results of the in silico analyses showed that selected active components of S. fusiformis interact with LXR and FXR and could be a possible mechanism of action. S. fusiformis rendered protection against anti-tuberculosis drugs-induced oxidative stress in kidney tissues of rats.

Attenuation of anti-tuberculosis therapy induced hepatotoxicity by Spirulina fusiformis, a candidate food supplement.

Therapy using Isoniazid (INH) and Rifampicin (RIF) leads to induction of hepatotoxicity in some individuals undergoing anti-tuberculosis treatment. In this study, we assessed the effect of Spirulina fusiformis on INH and RIF induced hepatotoxicity in rats compared with hepatoprotective drug Silymarin. Induction of hepatotoxicity was measured by changes in the liver marker enzymes (aspartate transaminase, alanine transaminase, and alkaline phosphatase). The antioxidant status was also analyzed in liver tissue homogenate and plasma by measurement of superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase, and lipid peroxidation levels. We also aimed to study the binding and interactions of the transcription factors Pregnane X Receptor (PXR) and Farnesoid X Receptor (FXR) with INH, RIF, and representative active compounds of Spirulina fusiformis by in silico methods. The administration of INH and RIF resulted in significant (p < 0.05) decrease in the antioxidant levels and total protein levels. There was also a significant (p < 0.05) increase in the levels of liver marker enzymes. Spirulina fusiformis was seen to protect the parameters from significant changes upon challenge with INH and RIF in a dose-dependent manner. This was corroborated by histological examination of the liver. The results of the in silico analyses further support the wet lab results.

Single-nucleotide polymorphisms in Toll-like receptor (TLR)-2, TLR4 and heat shock protein 70 genes and susceptibility to scrub typhus.

Scrub typhus is a highly prevalent bacterial infection in India and South Asia that is caused by Orientia tsutsugamushi. The innate immune response to infections is modulated by Toll-like receptors (TLRs) and heat shock proteins (HSPs). This study was done to assess the prevalence and possible association of TLR and HSP polymorphisms in scrub typhus. TLR4 Asp299Gly, TLR4 Thr399Ile, TLR2 Arg753Gln and HSP70-2 A1267G are single-nucleotide polymorphisms (SNPs) that may modulate their activities, and these SNPs were assessed in 137 scrub typhus patients and 134 controls by PCR restriction fragment length polymorphism. We found that the two TLR4 mutations, TLR4 D299G and TLR4T399I, were present in 19.5% and 22% of the study population, respectively, and was in significant linkage disequilibrium with a D' of 0.8. The TLR2 mutation was found to be rare, whereas the HSP A>G mutation was very common (77.5%). Compared with the controls, the prevalence of heterozygous genotype of the TLR4D299G SNP, but not any of the other SNPs, was significantly higher among scrub typhus patients. Further studies using a larger sample size and more candidate genes may better enable in determining the role of these associations in susceptibility and severity of scrub typhus.

Connecting microbial, nutrient, physiochemical, and land use variables for the evaluation of water quality within mixed use watersheds.

As non-point sources of pollution begin to overtake point sources in watersheds, source identification and complicating variables such as rainfall are growing in importance. Microbial source tracking (MST) allows for identification of fecal contamination sources in watersheds; when combined with data on land use and co-occuring variables (e.g., nutrients, sediment runoff) MST can provide a basis for understanding how to effectively remediate water quality. To determine spatial and temporal trends in microbial contamination and correlations between MST and nutrients, water samples (n = 136) were collected between April 2017 and May of 2018 during eight sampling events from 17 sites in 5 mixed-use watersheds. These samples were analyzed for three MST markers (human - B. theta; bovine - CowM2; porcine - Pig2Bac) along with E. coli, nutrients (nitrogen and phosphorus species), and physiochemical paramaters. These water quality variables were then paired with data on land use, streamflow, precipitation and management practices (e.g., tile drainage, septic tank density, tillage practices) to determine if any significant relationships existed between the observed microbial contamination and these variables. The porcine marker was the only marker that was highly correlated (p value <0.05) with nitrogen and phosphorus species in multiple clustering schemes. Significant relationships were also identified between MST markers and variables that demonstrated temporal trends driven by precipitation and spatial trends driven by septic tanks and management practices (tillage and drainage) when spatial clustering was employed.

The Clinical Safety and Effectiveness Course: Ten Years of Experiential Training in Quality Improvement for Practicing Professionals.

Training in quality improvement (QI) and patient safety for clinicians are needed for continued progress in health care quality. A project-based QI curriculum training faculty, residents, and staff in an academic health center for >10 years are reviewed and evaluated. Didactic curriculum includes QI knowledge domains, and QI methods are applied to a project during the course. There are 638 graduates and 239 projects since implementation. Most projects (84%) effected behavior change, change in clinical practice, and benefit to patients. Faculty have used the training to develop formal QI programs for Graduate Medical Education (GME). Graduates value the skills for their professional and personal lives, and for career enhancement. Experiential QI training for practicing professionals is valuable and effective. Collaboration and support from stakeholders are key factors in success. The Clinical Safety & Effectiveness course is a reproducible and relevant model of interprofessional QI education for practicing professionals and staff.

Detangling Seasonal Relationships of Fecal Contamination Sources and Correlates with Indicators in Michigan Watersheds.

Despite the widely acknowledged public health impacts of surface water fecal contamination, there is limited understanding of seasonal effects on (i) fate and transport processes and (ii) the mechanisms by which they contribute to water quality impairment. Quantifying relationships between land use, chemical parameters, and fecal bacterial concentrations in watersheds can help guide the monitoring and control of microbial water quality and explain seasonal differences. The goals of this study were to (i) identify seasonal differences in Escherichia coli and Bacteroides thetaiotaomicron concentrations, (ii) evaluate environmental drivers influencing microbial contamination during baseflow, snowmelt, and summer rain seasons, and (iii) relate seasonal changes in B. thetaiotaomicron to anticipated gastrointestinal infection risks. Water chemistry data collected during three hydroclimatic seasons from 64 Michigan watersheds were analyzed using seasonal linear regression models with candidate variables including crop and land use proportions, prior precipitation, chemical parameters, and variables related to both wastewater treatment and septic usage. Adaptive least absolute shrinkage and selection operator (LASSO) linear regression with bootstrapping was used to select explanatory variables and estimate coefficients. Regardless of season, wastewater treatment plant and septic system usage were consistently selected in all primary models for B. thetaiotaomicron and E. coli. Chemistry and precipitation-related variable selection depended upon season and organism. These results suggest a link between human pollution (e.g., septic systems) and microbial water quality that is dependent on flow regime. IMPORTANCE In this study, a data set of 64 Michigan watersheds was utilized to gain insights into fecal contamination sources, drivers, and chemical correlates across seasons for general E. coli and human-specific fecal indicators. Results reaffirmed a link between human-specific sources (e.g., septic systems) and microbial water quality. While the importance of human sources of fecal contamination and fate and transport variables (e.g., precipitation) remain important across seasons, this study provides evidence that fate and transport mechanisms vary with seasonal hydrologic condition and microorganism source. This study contributes to a body of research that informs prioritization of fecal contamination source control and surveillance strategy development to reduce the public health burden of surface water fecal contamination.

Comparing hydrogeomorphic approaches to lake classification.

A classification system is often used to reduce the number of different ecosystem types that governmental agencies are charged with monitoring and managing. We compare the ability of several different hydrogeomorphic (HGM)-based classifications to group lakes for water chemistry/clarity. We ask: (1) Which approach to lake classification is most successful at classifying lakes for similar water chemistry/clarity? (2) Which HGM features are most strongly related to the lake classes? and, (3) Can a single classification successfully classify lakes for all of the water chemistry/clarity variables examined? We use univariate and multivariate classification and regression tree (CART and MvCART) analysis of HGM features to classify alkalinity, water color, Secchi, total nitrogen, total phosphorus, and chlorophyll a from 151 minimally disturbed lakes in Michigan USA. We developed two MvCART models overall and two CART models for each water chemistry/clarity variable, in each case comparing: local HGM characteristics alone and local HGM characteristics combined with regionalizations and landscape position. The combined CART models had the highest strength of evidence (ω(i) range 0.92-1.00) and maximized within class homogeneity (ICC range 36-66%) for all water chemistry/clarity variables except water color and chlorophyll a. Because the most successful single classification was on average 20% less successful in classifying other water chemistry/clarity variables, we found that no single classification captures variability for all lake responses tested. Therefore, we suggest that the most successful classification (1) is specific to individual response variables, and (2) incorporates information from multiple spatial scales (regionalization and local HGM variables).

Malnutrition and Associated Disorders in Tuberculosis and Its Therapy.

Tuberculosis (TB) has become the most important infectious disease to see resurgence worldwide. In 2014, there were 9.6 million documented cases worldwide with a mortality of almost 1.5 million (Global Tuberculosis Report 2014). One of the Millennium Development Goals set by the United Nations was the reversal of the TB epidemic, which has been achieved worldwide with an 18% lower incidence of TB globally compared to the incidence in the year 2000. Though efficient intervention has brought down the relative incidence and mortality of TB globally, the fact remains that one third of the world population has latent TB infection, and 10% of people with latent TB infection develop active TB at some point in their life (The Facts about Tuberculosis 1995). Risk factors that prompt the reactivation of latent TB into active TB are a compromised immune system, HIV, malnutrition, and use of tobacco. In developing and underdeveloped economies, malnutrition and undernutrition play a major role in subverting the immune system and reactivating the latent TB infection. Undernutrition is one of the major factors in India and Southeast Asia leading to an increase in TB infections. Once tuberculosis sets in, it leads to an increase in metabolism and a decrease in appetite that compounds the already present malnutrition. Drawing on previous studies, we have aimed at understanding the relationship between malnutrition and TB infection and making minimal recommendations for corrective action.

HDAC4 Controls Muscle Homeostasis through Deacetylation of Myosin Heavy Chain, PGC-1α, and Hsc70.

HDAC4, a class IIa histone deacetylase, is upregulated in skeletal muscle in response to denervation-induced atrophy. When HDAC4 is deleted postnatally, mice are partially protected from denervation. Despite the name "histone" deacetylase, HDAC4 demonstrably deacetylates cytosolic and non-histone nuclear proteins. We developed potent and selective class IIa HDAC inhibitors. Using these tools and genetic knockdown, we identified three previously unidentified substrates of HDAC4: myosin heavy chain, peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1α), and heat shock cognate 71 kDa protein (Hsc70). HDAC4 inhibition almost completely prevented denervation-induced loss of myosin heavy chain isoforms and blocked the action of their E3 ligase, MuRF1. PGC-1α directly interacts with class IIa HDACs; selective inhibitors increased PGC-1α protein in muscles. Hsc70 deacetylation by HDAC4 affects its chaperone activity. Through these endogenous HDAC4 substrates, we identified several muscle metabolic pathways that are regulated by class IIa HDACs, opening up new therapeutic options to treat skeletal muscle disorders and potentially other disease where these specific pathways are affected.

Kinetics of IgM and IgG antibodies after scrub typhus infection and the clinical implications.

OBJECTIVES: The serological detection of IgM antibodies is the most widely used test to diagnose scrub typhus infection. However, the kinetics of IgM and IgG antibodies post-infection remain elusive, which could contribute to false positivity. The objective of this study was to document the nature of the evolution of these antibody titres after infection. METHODS: Adult patients previously confirmed to have scrub typhus by IgM ELISA, positive PCR, or both, were included in this cross-sectional study. The levels of IgM and IgG antibodies in serum samples were tested using an ELISA and the distribution curve was plotted. RESULTS: Two hundred and three patients were included in this study. Post-infection serum sampling was done between 1 month and 46 months after documented infection. IgM levels declined gradually but remained elevated above the diagnostic cut-off for up to 12 months post-infection. However, IgG levels continued to rise reaching a peak at 10 months, followed by a gradual decline over several months. In the majority of cases, the IgG levels remained above the cut-off threshold for more than 36 months. CONCLUSIONS: Clinicians need to be cautious in using a single serum sample for the detection of IgM to diagnose scrub typhus, as it remains elevated for up to 12 months after the infection, whereas the serum IgG level could be used as an indicator of past infection.

Clinical spectrum, susceptibility profile, treatment and outcome of culture-confirmed brucellosis from South India.

Brucellosis, a common zoonosis, is under reported in India despite its endemicity and increased exposure to livestock among the population. This study was conducted to determine the clinical manifestations, antibiotic susceptibility pattern, treatment and outcome of culture confirmed brucellosis. Adult patients with culture confirmed brucellosis who presented to a large teaching hospital in South India between 2009 and 2015 were included. A diagnosis of brucellosis was confirmed on automated culture. Clinical profile, laboratory parameters, drug susceptibility, treatment and outcome were documented by reviewing the medical records. The cohort comprised of 22 patients with mean ± SD age of 42 ± 13 years. Twenty one (95.5%) was male. Thirteen (59%) patients were from rural area and risk of acquisition of brucellosis including occupational exposure or consumption of unpasteurized milk was evident in 16 (72.7%) patients. The mean duration of symptoms before presentation was 54.5 ± 52 days. The commonest clinical presentation was prolonged fever without a definite focus in 18 patients (82%), whereas 2 (9%) patients had osteoarticular involvement and one patient (4.5%) each had genital involvement and endocarditis. Eighteen patients (82%) with uncomplicated brucellosis were treated with aminoglycoside and doxycycline for 6 weeks. There was no relapse or mortality at 18 ± 9 months of follow up. Brucellosis in this cohort had acute or subacute presentation with prolonged fever and bacteremia. High index of clinical suspicion based on significant epidemiological history along with automated blood culture improves the efficiency of diagnosis. Cure with lack of relapse among these cases suggests a combination therapy with doxycycline and aminoglycoside is highly effective for the treatment.

The land-use legacy effect: Towards a mechanistic understanding of time-lagged water quality responses to land use/cover.

Numerous studies have linked land use/land cover (LULC) to aquatic ecosystem responses, however only a few have included the dynamics of changing LULC in their analysis. In this study, we explicitly recognize changing LULC by linking mechanistic groundwater flow and travel time models to a historical time series of LULC, creating a land-use legacy map. We then illustrate the utility of legacy maps to explore relationships between dynamic LULC and lake water chemistry. We tested two main concepts about mechanisms linking LULC and lake water chemistry: groundwater pathways are an important mechanism driving legacy effects; and, LULC over multiple spatial scales is more closely related to lake chemistry than LULC over a single spatial scale. We applied statistical models to twelve water chemistry variables, ranging from nutrients to relatively conservative ions, to better understand the roles of biogeochemical reactivity and solubility on connections between LULC and aquatic ecosystem response. Our study illustrates how different areas can have long groundwater pathways that represent different LULC than what can be seen on the landscape today. These groundwater pathways delay the arrival of nutrients and other water quality constituents, thus creating a legacy of historic land uses that eventually reaches surface water. We find that: 1) several water chemistry variables are best fit by legacy LULC while others have a stronger link to current LULC, and 2) single spatial scales of LULC analysis performed worse for most variables. Our novel combination of temporal and spatial scales was the best overall model fit for most variables, including SRP where this model explained 54% of the variation. We show that it is important to explicitly account for temporal and spatial context when linking LULC to ecosystem response.