Circulating CD8+ mucosal-associated invariant T cells correlate with improved treatment responses and overall survival in anti-PD-1-treated melanoma patients.

OBJECTIVES: While much of the research concerning factors associated with responses to immune checkpoint inhibitors (ICIs) has focussed on the contributions of conventional peptide-specific T cells, the role of unconventional T cells, such as mucosal-associated invariant T (MAIT) cells, in human melanoma remains largely unknown. MAIT cells are an abundant population of innate-like T cells expressing a semi-invariant T-cell receptor restricted to the MHC class I-like molecule, MR1, presenting vitamin B metabolites derived from bacteria. We sought to characterise MAIT cells in melanoma patients and determined their association with treatment responses and clinical outcomes. METHODS: In this prospective clinical study, we analysed the frequency and functional profile of circulating and tumor-infiltrating MAIT cells in human melanoma patients. Using flow cytometry, we compared these across metastatic sites and between ICI responders vs. non-responders as well as healthy donors. RESULTS: We identified tumor-infiltrating MAIT cells in melanomas across metastatic sites and found that the number of circulating MAIT cells is reduced in melanoma patients compared to healthy donors. However, circulating MAIT cell frequencies are restored by ICI treatment in responding patients, correlating with treatment responses, in which patients with high frequencies of MAIT cells exhibited significantly improved overall survival. CONCLUSION: Our results suggest that MAIT cells may be a potential predictive marker of responses to immunotherapies and provide rationale for testing MAIT cell-directed therapies in combination with current and next-generation ICIs.

The Lake Erie HABs Grab: A binational collaboration to characterize the western basin cyanobacterial harmful algal blooms at an unprecedented high-resolution spatial scale.

Monitoring of cyanobacterial bloom biomass in large lakes at high resolution is made possible by remote sensing. However, monitoring cyanobacterial toxins is only feasible with grab samples, which, with only sporadic sampling, results in uncertainties in the spatial distribution of toxins. To address this issue, we conducted two intensive "HABs Grabs" of microcystin (MC)-producing Microcystis blooms in the western basin of Lake Erie. These were one-day sampling events during August of 2018 and 2019 in which 100 and 172 grab samples were collected, respectively, within a six-hour window covering up to 2,270 km2 and analyzed using consistent methods to estimate the total mass of MC. The samples were analyzed for 57 parameters, including toxins, nutrients, chlorophyll, and genomics. There were an estimated 11,513 kg and 30,691 kg of MCs in the western basin during the 2018 and 2019 HABs Grabs, respectively. The bloom boundary poses substantial issues for spatial assessments because MC concentration varied by nearly two orders of magnitude over very short distances. The MC to chlorophyll ratio (MC:chl) varied by a factor up to 5.3 throughout the basin, which creates challenges for using MC:chl to predict MC concentrations. Many of the biomass metrics strongly correlated (r > 0.70) with each other except chlorophyll fluorescence and phycocyanin concentration. While MC and chlorophyll correlated well with total phosphorus and nitrogen concentrations, MC:chl correlated with dissolved inorganic nitrogen. More frequent MC data collection can overcome these issues, and models need to account for the MC:chl spatial heterogeneity when forecasting MCs.

Prevalence and patterns of multimorbidity in Australian baby boomers: the Busselton healthy ageing study.

BACKGROUND AND OBJECTIVE: Chronic medical conditions accumulate within individuals with age. However, knowledge concerning the trends, patterns and determinants of multimorbidity remains limited. This study assessed the prevalence and patterns of multimorbidity using extensive individual phenotyping in a general population of Australian middle-aged adults. METHODS: Participants (n = 5029, 55% female), born between 1946 and 1964 and attending the cross-sectional phase of the Busselton Healthy Ageing Study (BHAS) between 2010 and 2015, were studied. Prevalence of 21 chronic conditions was estimated using clinical measurement, validated instrument scores and/or self-reported doctor-diagnosis. Non-random patterns of multimorbidity were explored using observed/expected (O/E) prevalence ratios and latent class analysis (LCA). Variables associated with numbers of conditions and class of multimorbidity were investigated. RESULTS: The individual prevalence of 21 chronic conditions ranged from 2 to 54% and multimorbidity was common with 73% of the cohort having 2 or more chronic conditions. (mean ± SD 2.75 ± 1.84, median = 2.00, range 0-13). The prevalence of multimorbidity increased with age, obesity, physical inactivity, tobacco smoking and family history of asthma, diabetes, myocardial infarct or cancer. There were 13 pairs and 27 triplets of conditions identified with a prevalence > 1.5% and O/E > 1.5. Of the triplets, arthritis (> 50%), bowel disease (> 33%) and depression-anxiety (> 33%) were observed most commonly. LCA modelling identified 4 statistically and clinically distinct classes of multimorbidity labelled as: 1) "Healthy" (70%) with average of 1.95 conditions; 2) "Respiratory and Atopy" (11%, 3.65 conditions); 3) "Non-cardiometabolic" (14%, 4.77 conditions), and 4) "Cardiometabolic" (5%, 6.32 conditions). Predictors of multimorbidity class membership differed between classes and differed from predictors of number of co-occurring conditions. CONCLUSION: Multimorbidity is common among middle-aged adults from a general population. Some conditions associated with ageing such as arthritis, bowel disease and depression-anxiety co-occur in clinically distinct patterns and at higher prevalence than expected by chance. These findings may inform further studies into shared biological and environmental causes of co-occurring conditions of ageing. Recognition of distinct patterns of multimorbidity may aid in a holistic approach to care management in individuals presenting with multiple chronic conditions, while also guiding health resource allocation in ageing populations.

Elucidating controls on cyanobacteria bloom timing and intensity via Bayesian mechanistic modeling.

The adverse impacts of harmful algal blooms (HABs) are increasing worldwide. Lake Erie is a North American Great Lake highly affected by cultural eutrophication and summer cyanobacterial HABs. While phosphorus loading is a known driver of bloom size, more nuanced yet crucial questions remain. For example, it is unclear what mechanisms are primarily responsible for initiating cyanobacterial dominance and subsequent biomass accumulation. To address these questions, we develop a mechanistic model describing June-October dynamics of chlorophyll a, nitrogen, and phosphorus near the Maumee River outlet, where blooms typically initiate and are most severe. We calibrate the model to a new, geostatistically-derived dataset of daily water quality spanning 2008-2017. A Bayesian framework enables us to embed prior knowledge on system characteristics and test alternative model formulations. Overall, the best model formulation explains 42% of the variability in chlorophyll a and 83% of nitrogen, and better captures bloom timing than previous models. Our results, supported by cross validation, show that onset of the major midsummer bloom is associated with about a month of water temperatures above 20 °C (occurring 19 July to 6 August), consistent with when cyanobacteria dominance is usually reported. Decreased phytoplankton loss rate is the main factor enabling biomass accumulation, consistent with reduced zooplankton grazing on cyanobacteria. The model also shows that phosphorus limitation is most severe in August, and nitrogen limitation tends to occur in early autumn. Our results highlight the role of temperature in regulating bloom initiation and subsequent loss rates, and suggest that a 2 °C increase could lead to blooms that start about 10 days earlier and grow 23% more intense.

Complementary and alternative medicine beliefs in type 2 diabetes: The Fremantle Diabetes Study Phase II.

Complementary medicine (CM) treatment beliefs of people with type 2 diabetes were assessed using a validated three-domain questionnaire. Belief in holistic health, but not natural treatments or participation in treatment, was independently associated with CM use (P = 0.003). Strong holistic health beliefs could identify present/future CM use, with potential management implications.

Discovery and Development of S6821 and S7958 as Potent TAS2R8 Antagonists.

In humans, bitter taste is mediated by 25 TAS2Rs. Many compounds, including certain active pharmaceutical ingredients, excipients, and nutraceuticals, impart their bitter taste (or in part) through TAS2R8 activation. However, effective TAS2R8 blockers that can either suppress or reduce the bitterness of these compounds have not been described. We are hereby reporting a series of novel 3-(pyrazol-4-yl) imidazolidine-2,4-diones as potent and selective TAS2R8 antagonists. In human sensory tests, S6821 and S7958, two of the most potent analogues from the series, demonstrated efficacy in blocking TAS2R8-mediated bitterness and were selected for development. Following data evaluation by expert panels of a number of national and multinational regulatory bodies, including the US, the EU, and Japan, S6821 and S7958 were approved as safe under conditions of intended use as bitter taste blockers.

Recent Patterns in Lake Erie Phosphorus and Chlorophyll a Concentrations in Response to Changing Loads.

Despite the initial success of extensive efforts to reduce phosphorus (P) loading to Lake Erie as a part of the Great Lakes Water Quality Agreement, Lake Erie appears to be undergoing a re-eutrophication and it is plagued by harmful algal blooms. To offer insights into potential lake responses under differing Maumee River loads and reveal recent changes with time, we explored patterns in phosphorus and chlorophyll a data from 2008 to 2018 collected in western Lake Erie near the mouth of the Maumee River. We found high, but relatively stable Maumee River and lake concentrations of total P (TP) and soluble reactive P (SRP) with no discernable annual or seasonal patterns. Maumee spring TP load was not strongly related to lake TP, and lake SRP concentrations were positively but weakly related to SRP loads. Lake TP was a strong predictor of chlorophyll a, but the relationship was weaker at sites closer to the Maumee. These results highlight spatial differences both in P concentration and the relationship between TP and chlorophyll a, and these indicate that spring phosphorus loads are a weak algal biomass predictor in the portion of the western basin of Lake Erie represented by these sampling stations.

Complementary medicine use and its cost in Australians with type 2 diabetes: the Fremantle Diabetes Study Phase II.

BACKGROUND: Few studies have examined complementary medicine (CM) use in diabetes. Australian data are inconsistent, limited in scope and have not considered cost. AIMS: To evaluate the prevalence, associates and costs of CM in a contemporary Australian urban, community-based cohort of people with type 2 diabetes. METHODS: Baseline CM use was determined as part of a detailed assessment in 1543 of 1551 Fremantle Diabetes Study Phase II (FDS2) participants with type 2 diabetes (mean age 65.7 years, 51.8% males, median diabetes duration 9.0 years) recruited to the FDS2 between 2008 and 2011 who self-reported medication use including CM defined as non-prescription medicinal products. RESULTS: A total of 672 FDS2 type 2 participants (43.6%) used at least one type of CM, 92% of which were nutritional supplements (omega-3 fatty acids/fish oil in 24% of CM users followed by calcium in 11%, glucosamine in 10% and others in <10%). Independent associates of CM use included older age, female sex, any mobility problem, and, inversely, Southern European or Indigenous Australian background, lack of English fluency, ex/current smoking status, taking oral glucose-lowering medications and higher HbA1c . The total annual estimated cost of CM used by FDS2 participants with type 2 diabetes was A$121 640 or A$79 ± 208 per person (range A$0-2993). Extrapolating these data, the 1 million Australians with type 2 diabetes spend A$79 million/year on CM. CONCLUSIONS: CM use in type 2 diabetes is both common and costly. Healthcare professionals should consider discussing safe and cost-effective use of CM with their patients with type 2 diabetes.

Reduced forms of nitrogen are a driver of non-nitrogen-fixing harmful cyanobacterial blooms and toxicity in Lake Erie.

Western Lake Erie (WLE) experiences anthropogenic eutrophication and annual, toxic cyanobacterial blooms of non-nitrogen (N) fixing Microcystis. Numerous studies have shown that bloom biomass is correlated with an increased proportion of soluble reactive phosphorus loading from the Maumee River. Long term monitoring shows that the proportion of the annual Maumee River N load of non-nitrate N, or total Kjeldahl nitrogen (TKN), has also increased significantly (Spearman's ρ = 0.68, p = 0.001) over the last few decades and is also significantly correlated to cyanobacterial bloom biomass (Spearman's ρ = 0.64, p = 0.003). The ratio of chemically reduced N to oxidized N (TKN:NO3) concentrations was also compared to extracted chlorophyll and phycocyanin concentrations from all weekly sampling stations within WLE from 2009 to 2015. Both chlorophyll (Spearman's ρ = 0.657, p < 0.0001) and phycocyanin (Spearman's ρ = 0.714, p < 0.0001) were significantly correlated with TKN:NO3. This correlation between the increasing fraction of chemically reduced N from the Maumee River and increasing bloom biomass demonstrates the urgent need to control N loading, in addition to current P load reductions, to WLE and similar systems impacted by non-N-fixing, toxin-producing cyanobacteria.

The Neuromodulation Appropriateness Consensus Committee on Best Practices for Dorsal Root Ganglion Stimulation.

INTRODUCTION: The Neuromodulation Appropriateness Consensus Committee (NACC) is dedicated to improving the safety and efficacy of neuromodulation and thus improving the lives of patients undergoing neuromodulation therapies. With continued innovations in neuromodulation comes the need for evolving reviews of best practices. Dorsal root ganglion (DRG) stimulation has significantly improved the treatment of complex regional pain syndrome (CRPS), among other conditions. Through funding and organizational leadership by the International Neuromodulation Society (INS), the NACC reconvened to develop the best practices consensus document for the selection, implantation and use of DRG stimulation for the treatment of chronic pain syndromes. METHODS: The NACC performed a comprehensive literature search of articles about DRG published from 1995 through June, 2017. A total of 2538 article abstracts were then reviewed, and selected articles graded for strength of evidence based on scoring criteria established by the US Preventive Services Task Force. Graded evidence was considered along with clinical experience to create the best practices consensus and recommendations. RESULTS: The NACC achieved consensus based on peer-reviewed literature and experience to create consensus points to improve patient selection, guide surgical methods, improve post-operative care, and make recommendations for management of patients treated with DRG stimulation. CONCLUSION: The NACC recommendations are intended to improve patient care in the use of this evolving therapy for chronic pain. Clinicians who choose to follow these recommendations may improve outcomes.

DRG FOCUS: A Multicenter Study Evaluating Dorsal Root Ganglion Stimulation and Predictors for Trial Success.

INTRODUCTION: Dorsal root ganglion stimulation (DRGS) is a powerful tool in the treatment of chronic, neuropathic pain. The premise of DRGS is similar to that of conventional spinal cord stimulation (cSCS), however, there is more variability in how it can be utilized. While it is this variability that likely gives it its versatility, DRGS is not as straightforward to implement as cSCS. The purpose of this study was to assess the efficacy of DRGS on a broad number of diagnoses, determine which dorsal root ganglia were associated with better outcomes for particular body parts/diagnoses, and evaluate what factors/parameters were associated with higher rates of trial success. METHODS: This is a physician initiated, multicenter retrospective registry of 217 patients trialed with DRGS. Data were collected via an online questionnaire that assessed specifics regarding the patient's pain, distribution, size, and response to treatment. The data were analyzed to see if there were certain diagnoses and/or parameters that were more or less associated with trial success. RESULTS: DRGS was found to be an effective treatment in all diagnoses evaluated within this study, most of which had statistically significant improvements in pain. The most important predictor of trial success was the amount of painful area covered by paresthesias during the programing phase. The number of leads utilized had a direct and indirect impact on trial success. Pain in the distribution of a specific peripheral nerve responded best and there was no statistical difference based on what body part was being treated. CONCLUSION: DRGS can be an effective treatment for a variety of neuropathic pain syndromes, in addition to CRPS. It is recommended that a minimum of 2 leads should be utilized per area being treated. In addition, this therapy was shown to be equally efficacious in any body part/region so long as the area being treated is focal and not widespread.

Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: a randomized comparative trial.

Animal and human studies indicate that electrical stimulation of dorsal root ganglion (DRG) neurons may modulate neuropathic pain signals. ACCURATE, a pivotal, prospective, multicenter, randomized comparative effectiveness trial, was conducted in 152 subjects diagnosed with complex regional pain syndrome or causalgia in the lower extremities. Subjects received neurostimulation of the DRG or dorsal column (spinal cord stimulation, SCS). The primary end point was a composite of safety and efficacy at 3 months, and subjects were assessed through 12 months for long-term outcomes and adverse events. The predefined primary composite end point of treatment success was met for subjects with a permanent implant who reported 50% or greater decrease in visual analog scale score from preimplant baseline and who did not report any stimulation-related neurological deficits. No subjects reported stimulation-related neurological deficits. The percentage of subjects receiving ≥50% pain relief and treatment success was greater in the DRG arm (81.2%) than in the SCS arm (55.7%, P < 0.001) at 3 months. Device-related and serious adverse events were not different between the 2 groups. Dorsal root ganglion stimulation also demonstrated greater improvements in quality of life and psychological disposition. Finally, subjects using DRG stimulation reported less postural variation in paresthesia (P < 0.001) and reduced extraneous stimulation in nonpainful areas (P = 0.014), indicating DRG stimulation provided more targeted therapy to painful parts of the lower extremities. As the largest prospective, randomized comparative effectiveness trial to date, the results show that DRG stimulation provided a higher rate of treatment success with less postural variation in paresthesia intensity compared to SCS.

Validation and Application of a Dried Blood Spot Assay for Biofilm-Active Antibiotics Commonly Used for Treatment of Prosthetic Implant Infections.

Dried blood spot (DBS) antibiotic assays can facilitate pharmacokinetic (PK)/pharmacodynamic (PD) studies in situations where venous blood sampling is logistically difficult. We sought to develop, validate, and apply a DBS assay for rifampin (RIF), fusidic acid (FUS), and ciprofloxacin (CIP). These antibiotics are considered active against organisms in biofilms and are therefore commonly used for the treatment of infections associated with prosthetic implants. A liquid chromatography-mass spectroscopy DBS assay was developed and validated, including red cell partitioning and thermal stability for each drug and the rifampin metabolite desacetyl rifampin (Des-RIF). Plasma and DBS concentrations in 10 healthy adults were compared, and the concentration-time profiles were incorporated into population PK models. The limits of quantification for RIF, Des-RIF, CIP, and FUS in DBS were 15 µg/liter, 14 µg/liter, 25 µg/liter, and 153 µg/liter, respectively. Adjusting for hematocrit, red cell partitioning, and relative recovery, DBS-predicted plasma concentrations were comparable to measured plasma concentrations for each antibiotic (r > 0.95; P < 0.0001), and Bland-Altman plots showed no significant bias. The final population PK estimates of clearance, volume of distribution, and time above threshold MICs for measured and DBS-predicted plasma concentrations were comparable. These drugs were stable in DBSs for at least 10 days at room temperature and 1 month at 4°C. The present DBS antibiotic assays are robust and can be used as surrogates for plasma concentrations to provide valid PK and PK/PD data in a variety of clinical situations, including therapeutic drug monitoring or studies of implant infections.

The dual role of nitrogen supply in controlling the growth and toxicity of cyanobacterial blooms.

Historically, phosphorus (P) has been considered the primary limiting nutrient for phytoplankton assemblages in freshwater ecosystems. This review, supported by new findings from Lake Erie, highlights recent molecular, laboratory, and field evidence that the growth and toxicity of some non-diazotrophic blooms of cyanobacteria can be controlled by nitrogen (N). Cyanobacteria such as Microcystis possess physiological adaptations that allow them to dominate low-P surface waters, and in temperate lakes, cyanobacterial densities can be controlled by N availability. Beyond total cyanobacterial biomass, N loading has been shown to selectively promote the abundance of Microcystis and Planktothrix strains capable of synthesizing microcystins over strains that do not possess this ability. Among strains of cyanobacteria capable of synthesizing the N-rich microcystins, cellular toxin quotas have been found to depend upon exogenous N supplies. Herein, multi-year observations from western Lake Erie are presented demonstrating that microcystin concentrations peak in parallel with inorganic N, but not orthophosphate, concentrations and are significantly lower (p<0.01) during years of reduced inorganic nitrogen loading and concentrations. Collectively, this information underscores the importance of N as well as P in controlling toxic cyanobacteria blooms. Furthermore, it supports the premise that management actions to reduce P in the absence of concurrent restrictions on N loading may not effectively control the growth and/or toxicity of non-diazotrophic toxic cyanobacteria such as the cosmopolitan, toxin-producing genus, Microcystis.

Relationship Between Electrode-to-Modiolus Distance and Current Levels for Adults With Cochlear Implants.

HYPOTHESIS: Electrode-to-modiolus distance is correlated with clinically programmed stimulation levels. BACKGROUND: Conventional wisdom has long supposed a significant relationship between cochlear implant (CI) stimulation levels and electrode-to-modiolus distance; however, to date, no such formal investigation has been completed. Thus, the purpose of this project was to investigate the relationship between stimulation levels and electrode-to-modiolus distance. A strong correlation between the two would suggest that stimulation levels might be used to estimate electrode-to-modiolus geometry. METHODS: Electrode-to-modiolus distance was determined via CT imaging using validated CI position analysis software in 137 implanted ears from the three manufacturers holding FDA approval in the United States. Analysis included 2,365 total electrodes, with 1,472 from precurved arrays. Distances were compared to clinically programmed C/M levels that were converted to charge units. RESULTS: Mean modiolar distance with perimodiolar and lateral wall electrodes was 0.47 and 1.15 mm, respectively. Mean suprathreshold charge values were significantly different between each manufacturer. When combining all data, we found a moderate positive correlation (r = 0.367, p < 0.01) that was driven both by the different charge values across companies, and that the company with the highest mean charge values only offers straight electrode arrays. When grouped by electrode type, however, we found a weak correlation (r = 0.12, p < 0.01) for perimodiolar array electrodes only. When considering a single array type from any one manufacturer, only one was observed where distance mildly predicted charge. CONCLUSION: Our results suggest that electrode distance minimally contributes to the current level required for suprathreshold stimulation.

Nutrient-Controlled Niche Differentiation of Western Lake Erie Cyanobacterial Populations Revealed via Metatranscriptomic Surveys.

Although toxic cyanobacterial blooms in western Lake Erie threaten drinking water supplies and are promoted by nutrient loading, the precise nutrient regime that selects specific cyanobacteria populations is poorly understood. Here, we assess shifts in cyanobacterial abundances and global gene-expression patterns in response to natural and manipulated gradients in nitrogen and phosphorus to identify gene pathways that facilitate dominance by different cyanobacteria. Gradients in soluble reactive phosphorus shaped cyanobacterial communities and elicited the largest transcriptomic responses. Under high-P conditions (closest to the mouth of the Maumee River), Anabaena and Planktothrix were the dominant cyanobacterial populations, and experimental P and ammonium enrichment promoted nitrogen fixation gene (nifH) expression in Anabaena. For Microcystis, experimental additions of P up-regulated genes involved in phage defense, genomic rearrangement, and nitrogen acquisition but led to lower abundances. Within offshore, low-P regions of the western basin of Lake Erie, Microcystis up-regulated genes associated with P scavenging (pstSCAB, phoX) and dominated cyanobacterial communities. Experimental additions of ammonium and urea did not alter Microcystis abundances but did up-regulate protease inhibitors (aer and mcn gene sets) and microcystin synthetase genes (mcy), with urea enrichment yielding significant increases in microcystin concentrations. Our findings suggest that management plans that reduce P loads alone may not significantly reduce the risk of cyanobacterial blooms in western Lake Erie but rather may promote a shift among cyanobacterial populations (Microcystis, Anabaena, and Planktothrix) toward a greater dominance by toxic strains of Microcystis.

Effects of increasing nitrogen and phosphorus concentrations on phytoplankton community growth and toxicity during Planktothrix blooms in Sandusky Bay, Lake Erie.

Sandusky Bay experiences annual toxic cyanobacterial blooms dominated by Planktothrix agardhii/suspensa. To further understand the environmental drivers of these events, we evaluated changes in the growth response and toxicity of the Planktothrix-dominated blooms to nutrient amendments with orthophosphate (PO4) and inorganic and organic forms of dissolved nitrogen (N; ammonium (NH4), nitrate (NO3) and urea) over the bloom season (June - October). We complemented these with a metagenomic analysis of the planktonic microbial community. Our results showed that bloom growth and microcystin (MC) concentrations responded more frequently to additions of dissolved N than PO4, and that the dual addition of NH4 + PO4 and Urea + PO4 yielded the highest MC concentrations in 54% of experiments. Metagenomic analysis confirmed that P. agardhii/suspensa was the primary MC producer. The phylogenetic distribution of nifH revealed that both heterocystous cyanobacteria and heterotrophic proteobacteria had the genetic potential for N2 fixation in Sandusky Bay. These results suggest that as best management practices are developed for P reductions in Sandusky Bay, managers must be aware of the negative implications of not managing N loading into this system as N may significantly impact cyanobacterial bloom size and toxicity.

Nutrient-related changes in the toxicity of field blooms of the cyanobacterium, Cylindrospermopsis raciborskii.

Nutrients have the capacity to change cyanobacterial toxin loads via growth-related toxin production, or shifts in the dominance of toxic and nontoxic strains. This study examined the effect of nitrogen (N) and phosphorus on cell division and strain-related changes in production of the toxins, cylindrospermopsins (CYNs) by the cyanobacterium, Cylindrospermopsis raciborskii. Two short-term experiments were conducted with mixed phytoplankton populations dominated by C. raciborskii in a subtropical reservoir where treatments had nitrate (NO3 ), urea (U) and inorganic phosphorus (P) added alone or in combination. Cell division rates of C. raciborskii were only statistically higher than the control on day 5 when U and P were co-supplied. In contrast, cell quotas of CYNs (QCYNS ) increased significantly in treatments where P was supplied, irrespective of whether N was supplied, and this increase was not necessarily related to cell division rates. Increased QCYNS did correlate with an increase in the proportion of the cyrA toxin gene to 16S genes in the C. raciborskii-dominated cyanobacterial population. Therefore, changes in strain dominance are the most likely factor driving differences in toxin production between treatments. Our study has demonstrated differential effects of nutrients on cell division and strain dominance reflecting a C. raciborskii population with a range of strategies in response to environmental conditions.

Localization and interaural time difference (ITD) thresholds for cochlear implant recipients with preserved acoustic hearing in the implanted ear.

The purpose of this study was to investigate horizontal plane localization and interaural time difference (ITD) thresholds for 14 adult cochlear implant recipients with hearing preservation in the implanted ear. Localization to broadband noise was assessed in an anechoic chamber with a 33-loudspeaker array extending from -90 to +90°. Three listening conditions were tested including bilateral hearing aids, bimodal (implant + contralateral hearing aid) and best aided (implant + bilateral hearing aids). ITD thresholds were assessed, under headphones, for low-frequency stimuli including a 250-Hz tone and bandpass noise (100-900 Hz). Localization, in overall rms error, was significantly poorer in the bimodal condition (mean: 60.2°) as compared to both bilateral hearing aids (mean: 46.1°) and the best-aided condition (mean: 43.4°). ITD thresholds were assessed for the same 14 adult implant recipients as well as 5 normal-hearing adults. ITD thresholds were highly variable across the implant recipients ranging from the range of normal to ITDs not present in real-world listening environments (range: 43 to over 1600 µs). ITD thresholds were significantly correlated with localization, the degree of interaural asymmetry in low-frequency hearing, and the degree of hearing preservation related benefit in the speech reception threshold (SRT). These data suggest that implant recipients with hearing preservation in the implanted ear have access to binaural cues and that the sensitivity to ITDs is significantly correlated with localization and degree of preserved hearing in the implanted ear.