Supporting Type 1 and Type 2 Diabetes Care in the Hemodialysis Unit: A Quality-improvement Initiative Throughout the COVID-19 Pandemic.

OBJECTIVE: People living with diabetes mellitus (DM) and chronic kidney disease can have difficulty attending multiple appointments to receive DM care. We developed and studied the utility of a DM outreach program to offer in the hemodialysis (HD) unit. METHODS: We conducted a quality improvement project in a satellite HD unit in London, Ontario, Canada, between August 1, 2019, and July 31, 2022. We assessed for baseline gaps in DM care among those with DM, performed root-cause analysis with key stakeholders to identify critical drivers of gaps, and conceptualized a certified diabetes educator-led outreach program to offer in the HD unit. We aimed to improve DM self-monitoring, hypo- and hyperglycemia, and DM-related screening. We used run and control charts to track outcome measures over time and modified our outreach program iteratively. RESULTS: Fifty-eight persons with DM receiving HD participated in our program. Support spanned multiple waves of the COVID-19 pandemic. With 4 tests of change, we observed improvement in DM self-monitoring with a modest decline in self-reported hyperglycemia. There were no adverse consequences, and satisfaction with our program was high. CONCLUSIONS: Although we did not meet all measures of success during the pandemic, outreach DM support in the HD unit appeared to improve self-monitoring and self-reported hyperglycemia. Similar programs could be modified and implemented in other centres.

Conceptualizing Ecological Responses to Dam Removal: If You Remove It, What's to Come?

One of the desired outcomes of dam decommissioning and removal is the recovery of aquatic and riparian ecosystems. To investigate this common objective, we synthesized information from empirical studies and ecological theory into conceptual models that depict key physical and biological links driving ecological responses to removing dams. We define models for three distinct spatial domains: upstream of the former reservoir, within the reservoir, and downstream of the removed dam. Emerging from these models are response trajectories that clarify potential pathways of ecological transitions in each domain. We illustrate that the responses are controlled by multiple causal pathways and feedback loops among physical and biological components of the ecosystem, creating recovery trajectories that are dynamic and nonlinear. In most cases, short-term effects are typically followed by longer-term responses that bring ecosystems to new and frequently predictable ecological condition, which may or may not be similar to what existed prior to impoundment.

Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment.

Sepsis-associated encephalopathy manifesting as delirium is a common problem in critical care medicine. In this study, patients that had delirium due to sepsis had significant cognitive impairments at 12-18 months after hospital discharge when compared with controls and Cambridge Neuropsychological Automated Test Battery-standardized scores in spatial recognition memory, pattern recognition memory, and delayed-matching-to-sample tests but not other cognitive functions. A mouse model of S. pneumoniae pneumonia-induced sepsis, which modeled numerous aspects of the human sepsis-associated multiorgan dysfunction, including encephalopathy, also revealed similar deficits in spatial memory but not new task learning. Both humans and mice had large increases in chemokines for myeloid cell recruitment. Intravital imaging of the brains of septic mice revealed increased neutrophil and CCR2+ inflammatory monocyte recruitment (the latter being far more robust), accompanied by subtle microglial activation. Prevention of CCR2+ inflammatory monocyte recruitment, but not neutrophil recruitment, reduced microglial activation and other signs of neuroinflammation and prevented all signs of cognitive impairment after infection. Therefore, therapeutically targeting CCR2+ inflammatory monocytes at the time of sepsis may provide a novel neuroprotective clinical intervention to prevent the development of persistent cognitive impairments.

Comparison of sediment and nutrient export and runoff characteristics from watersheds with centralized versus distributed stormwater management.

Stormwater control measures (SCMs) are used to retain stormwater and pollutants. SCMs have traditionally been installed in a centralized manner using detention to mitigate peak flows. Recently, distributed SCM networks that treat runoff near the source have been increasingly utilized. The aim of this study was to evaluate differences among watersheds that vary in SCM arrangement by assessing differences in baseflow nutrient (NOx-N and PO4-) concentrations and fluxes, stormflow export of suspended sediments and particulate phosphorus (PP), and runoff characteristics. A paired watershed approach was used to compare export between 2004 and 2016 from one forested watershed (For-MD), one suburban watershed with centralized SCMs (Cent-MD), and one suburban watershed with distributed SCMs (Dist-MD). Results indicated baseflow nitrate (NOx-N) concentrations typically exceeded 1 mg-N/L in all watersheds and were highest in Dist-MD. Over the last 10 years in Dist-MD, nitrate concentrations in both stream baseflow and in a groundwater well declined as land use shifted from agriculture to suburban. Baseflow nitrate export temporarily increased during the construction phase of SCM development in Dist-MD. This temporary pulse of nitrate may be attributed to the conversion of sediment control facilities to SCMs and increased subsurface flushing as infiltration SCMs came on line. During storm flow, Dist-MD tended to have less runoff and lower maximum specific discharge than Cent-MD for small events (<1.3 cm), but runoff responses became increasingly similar to Cent-MD with increasing precipitation (>1.3 cm). Mass export estimated during paired storm events indicated Dist-MD exported 30% less sediment and 31% more PP than Cent-MD. For large precipitation events, export of sediment and PP was similar among all three watersheds. Results suggest that distributed SCMs can reduce runoff and sediment loads during small rain events compared to centralized SCMs, but these differences become less evident for large events when peak discharge likely leads to substantial bank erosion.

Landscape context and the biophysical response of rivers to dam removal in the United States.

Dams have been a fundamental part of the U.S. national agenda over the past two hundred years. Recently, however, dam removal has emerged as a strategy for addressing aging, obsolete infrastructure and more than 1,100 dams have been removed since the 1970s. However, only 130 of these removals had any ecological or geomorphic assessments, and fewer than half of those included before- and after-removal (BAR) studies. In addition, this growing, but limited collection of dam-removal studies is limited to distinct landscape settings. We conducted a meta-analysis to compare the landscape context of existing and removed dams and assessed the biophysical responses to dam removal for 63 BAR studies. The highest concentration of removed dams was in the Northeast and Upper Midwest, and most have been removed from 3rd and 4th order streams, in low-elevation (< 500 m) and low-slope (< 5%) watersheds that have small to moderate upstream watershed areas (10-1000 km2) with a low risk of habitat degradation. Many of the BAR-studied removals also have these characteristics, suggesting that our understanding of responses to dam removals is based on a limited range of landscape settings, which limits predictive capacity in other environmental settings. Biophysical responses to dam removal varied by landscape cluster, indicating that landscape features are likely to affect biophysical responses to dam removal. However, biophysical data were not equally distributed across variables or clusters, making it difficult to determine which landscape features have the strongest effect on dam-removal response. To address the inconsistencies across dam-removal studies, we provide suggestions for prioritizing and standardizing data collection associated with dam removal activities.

Recommendations for fluoride limits in drinking water based on estimated daily fluoride intake in the Upper East Region, Ghana.

Both dental and skeletal fluorosis caused by high fluoride intake are serious public health concerns around the world. Fluorosis is particularly pronounced in developing countries where elevated concentrations of naturally occurring fluoride are present in the drinking water, which is the primary route of exposure. The World Health Organization recommended limit of fluoride in drinking water is 1.5 mg F(-) L(-1), which is also the upper limit for fluoride in drinking water for several other countries such as Canada, China, India, Australia, and the European Union. In the United States the enforceable limit is much higher at 4 mg F(-) L(-1), which is intended to prevent severe skeletal fluorosis but does not protect against dental fluorosis. Many countries, including the United States, also have notably lower unenforced recommended limits to protect against dental fluorosis. One consideration in determining the optimum fluoride concentration in drinking water is daily water intake, which can be high in hot climates such as in northern Ghana. The results of this study show that average water intake is about two times higher in Ghana than in more temperate climates and, as a result, the fluoride intake is higher. The results also indicate that to protect the Ghanaian population against dental fluorosis, the maximum concentration of fluoride in drinking water for children under 6-8 years should be 0.6 mg F(-) L(-1) (and lower in the first two years of life), and the limit for older children and adults should be 1.0 mg F(-) L(-1). However, when considering that water treatment is not cost-free, the most widely recommended limit of 1.5 mg F(-) L(-1) - which is currently the limit in Ghana--may be appropriate for older children and adults since they are not vulnerable to dental fluorosis once the tooth enamel is formed.

Cannabinoid agonist rescues learning and memory after a traumatic brain injury.

Traumatic brain injury can cause persistent challenges including problems with learning and memory. Previous studies suggest that the activation of the cannabinoid 1 receptor after a traumatic brain injury could be beneficial. We tested the hypothesis that posttraumatic brain injury administration of a cannabinoid 1 receptor agonist can rescue deficits in learning and memory. Young adult male rats were subjected to a moderately severe controlled cortical impact brain injury, with a subset given postinjury i.p. injections of a cannabinoid receptor agonist. Utilizing novel object recognition and the morris water task, we found that the brain-injured animals treated with the agonist showed a marked recovery.

Revisiting the cholinergic hypothesis in the development of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia affecting the elderly population today; however, there is currently no accurate description of the etiology of this devastating disorder. No single factor has been demonstrated as being causative; however, an alternative co-factors theory suggests that the interaction of multiple risk factors is responsible for AD. We have used this model, in combination with the original cholinergic hypothesis of AD to propose a "new" cholinergic hypothesis that we present in this review. This new version takes into account recent findings from the literature and our reports of removal of medial septum cholinergic projections to the hippocampus reduces both behavioural and anatomical plasticity, resulting in greater cognitive impairment in response to secondary insults (stress, injury, disease, etc.). We will first summarize the experimental results and discuss some potential mechanisms that could explain our results. We will then present our 'new' version of the cholinergic hypothesis and how it relates to the field of AD research today. Finally we will discuss some of the implications for treatment that arise from this model and present directions for future study.

Pragmatic management of programmatic vaccination errors--lessons learnt from incidents in London.

Correct storage, handling and administration of vaccines are vital components of a successful immunisation programme. However, with the large number of different healthcare professionals now involved in delivering the vaccine programme on a daily basis, it is inevitable that programmatic errors will occur. Decisions as to how best to rectify these errors can be difficult however, as often they are unprecedented and there may be no hard evidence on which to base their management. These decisions must therefore be based on what is known and any available previous experience. They also often take place in an environment of concern about litigation and liability which puts pressure on health care workers to take a defensive or conservative approach. Management decisions may ultimately also have to be a pragmatic choice based on the individual situation and what is deemed to be the best way to minimise adverse reactions, ensure patients are adequately protected and maintain public confidence in the immunisation programme. Here, we describe our experiences of managing vaccine programmatic errors and some of the many factors that we had to consider.

The etiology of age-related dementia is more complicated than we think.

Alzheimer's disease (AD) is the most common form of age-related dementia (ARD). Most research directed at understanding the causes of AD is focused on the genetic-based pathology associated with the familial form of this disorder. This is important work and significant progress has been made but 85% of all AD patients have the sporadic form of the disorder. This means that a complete understanding of these complex disorders will remain elusive unless alternative approaches are developed. In this paper we want to make two main points. First, we argue that the current diagnostic distinctions between AD and ARD do not accurately reflect the heterogeneity of these disorders. Second, we present an approach to understanding the etiology of these disorders by suggesting that multiple combinations of co-factors produce variants of the sporadic form of AD. Various proof of principle experiments are presented and the mechanistic and treatment implications of this view are discussed.

Murine endometrial and decidual NK1.1+ natural killer cells display a B220+CD11c+ cell surface phenotype.

Uterine natural killer (uNK) cells accumulate at the maternal-fetal interface during gestation and are thought to have an important role during pregnancy in both mice and humans. While the cell surface phenotype of human uNK cells is increasingly well defined, less is known regarding the cell surface expression profile of murine uNK cells both before and during gestation. Herein, we demonstrate that murine NK1.1(+) (KLRB1C) endometrial NK (eNK) cells, derived from virgin mice, and NK1.1(+) decidual NK (dNK) cells, obtained from pregnant mice, belong to the B220(+) (PTPRC) CD11c(+) (ITGAX) subset of NK cells. While B220 expression was low on NK1.1(+) eNK cells, it was increased on a subset of NK1.1(+) dNK cells at Embryonic Day 10.5. Endometrial NK and dNK cells also differed somewhat in their expression patterns of two activation markers, namely, CD69 and inducible costimulator (ICOS). The eNK cells acquired a B220(hi)ICOS(+) dNK cell surface phenotype when cultured in vitro in the presence of uterine cells and murine interleukin 15. Thus, the cell surface profiles generated for both NK1.1(+) eNK cells and dNK cells demonstrate that they belong to the recently described B220(+)CD11c(+) subset of NK cells, which are potent cytokine producers.

Cholinergic depletion of the medial septum followed by phase shifting does not impair memory or rest-activity rhythms measured under standard light/dark conditions in rats.

The robustness of an individual's circadian rhythms has been correlated with the quality of their cognitive aging. This has been observed in both human and non-human animals and circadian rhythms are especially disrupted in patients with Alzheimer's disease (AD). It is possible that the circadian disruption observed in AD contributes to the cognitive decline in these patients; however, this has not been conclusively proven. A common observation in AD patients is the loss of basal forebrain cholinergic neurons, some of which project to the suprachiasmatic nucleus (SCN) responsible for maintaining circadian rhythms. We were interested to see if cholinergic depletion increased susceptibility to circadian disruption, and to explore possible interactions between these two factors on measures of learning and memory. We lesioned the cholinergic neurons of the medial septum in rats using the specific immunotoxin 192 IgG Saporin and then disrupted circadian rhythms using a six day phase shifting procedure. We looked at measures of circadian rhythmicity, as well as behaviour on tasks designed to test hippocampal dependent (water maze) or hippocampal independent (fear conditioning) learning and memory. We found no difference between the groups on any of the measures examined suggesting that the cholinergic depletion of the medial septum does not increase susceptibility to circadian disruption, and that this combination of risk factors does not contribute to learning and memory impairments.

Selective lesion of medial septal cholinergic neurons followed by a mini-stroke impairs spatial learning in rats.

Reduced levels of hippocampal acetylcholine are a common finding in patients diagnosed with Alzheimer's disease, but it remains unclear what role this depletion plays in the development of dementia. It is possible that the reduced levels of acetylcholine increases the vulnerability of hippocampal neurons to future insults which could lead to neuronal death and cognitive impairment. One insult that is commonly observed in the demented elderly and often co-exists with Alzheimer's disease is stroke. In the current experiment, we used the immunotoxin 192 IgG-Saporin to specifically lesion the cholinergic neurons of the medial septum that project to the hippocampus. We then explored the effects of small, localised strokes in the hippocampus on spatial learning and memory. The combination of cholinergic depletion and stroke resulted in significant impairment on the spatial water maze compared to the performance of rats receiving either factor alone. Quantification of hippocampal damage revealed no difference in the overall lesion size of stroke-only or combined (cholinergic depletion and stroke) rats, suggesting that a more subtle mechanism is responsible for the observed impairment. We propose that healthy hippocampal neurons may normally be able to withstand, and compensate for a small ischemic insult. However, in the absence of cholinergic projections from the medial septum, these compensatory processes in the hippocampus may be compromised resulting in the spatial learning impairment reported here. This suggests an association between the cholinergic depletion observed during aging and the potential for functional recovery following stroke.

The effects of perceived parenting style on the propensity for illicit drug use: the importance of parental warmth and control.

INTRODUCTION AND AIMS: Research in adolescents has shown that parental warmth and control are important factors in drug use. The present study focused upon investigating perceived parental warmth and control in a sample of post-adolescent ecstasy/polydrug users, and investigating their relationship to severity of drug use. DESIGN AND METHODS: A total of 128 (65 male) ecstasy/polydrug users, 51 (17 male), cannabis-only users and 54 (13 male) non-users were recruited from a university population. All participants completed the parenting styles and drug use questionnaires. RESULTS: Compared to non-users, a greater proportion of ecstasy/polydrug users characterised their parents' style as neglectful. The modal style endorsed by non-users was authoritative. Those who rated their parents' style as authoritative had significantly lower lifetime consumption and average dose of ecstasy relative to those describing their parents as neglectful. Again, relative to those describing their parents as neglectful, participants from authoritarian backgrounds had significantly smaller lifetime consumption of ecstasy and cocaine and significantly smaller average doses of cannabis, ecstasy and cocaine. Contrary to expectation, there was no significant association between perceived parental warmth and the severity of ecstasy use. DISCUSSION AND CONCLUSIONS: The present study is, to our knowledge, the first to quantify drug use, and relate it to perceived parental practices in a post-adolescent sample of ecstasy/polydrug users. The results provide further support for the relationship between perceived parental control and drug use.

Reduced cholinergic status in hippocampus produces spatial memory deficits when combined with kainic acid induced seizures.

Alzheimer's disease is the most common form of dementia in North America today. Though many risk factors have been suggested to increase the likelihood of developing this disease, an accurate etiology has yet to be described. One of these risk factors commonly associated with Alzheimer's disease is the loss of cholinergic neurons of the medial septum that project to the hippocampus, leading to depletion in cholinergic activity. A second risk factor is the presence of seizures, which can increase the risk of excitotoxic cell death. To examine the interaction between these two common risk factors, we gave rats a focal cholinergic lesion of the medial septum using the specific immunotoxin 192-IgG Saporin, followed 2 weeks later by a non-convulsive dose of kainic acid. We then assessed the rats for seizure severity, hippocampal damage and performance on a spatial memory task. The combination of the two factors resulted in a trend towards increased seizure severity in the cholinergic depleted rats, but more importantly, the lesioned rats that had non-convulsive seizures were significantly impaired on a spatial version of the Morris water maze when compared with either the rats with a cholinergic depletion or non-convulsive seizure alone. This result could not be explained by seizure severity or the extent of hippocampal damage, suggesting a more subtle interaction between these two risk factors in the development of a hippocampal based memory impairment.

Emergence of spatial impairment in rats following specific cholinergic depletion of the medial septum combined with chronic stress.

A consistent finding in patients suffering from Alzheimer's disease is a loss of the cholinergic neurons of the basal forebrain that project to the hippocampus. However, the role this depletion plays in the development of Alzheimer's disease remains unclear. The loss of this ascending neurotransmitter system could potentially render hippocampal neurons more susceptible to further insult, such as chronic stress, ultimately resulting in neuronal death and memory loss. We explored this possibility by using the highly specific toxin 192 IgG-Saporin to destroy the majority of cholinergic activity in the septo-hippocampal pathway in rats. Following depletion, rats were subjected to 2 weeks of restraint stress. Rats were divided into two groups and were tested either on a hippocampal-dependent (water maze) task or a hippocampal-independent task (fear conditioning to tone and context). We showed that cholinergic depletion or stress alone had no effect on the successful performance of either of the tasks. However, rats with a combination of cholinergic depletion and stress were significantly impaired on the water-maze task. No deficits were apparent in the combined group that was tested on fear conditioning to tone or context, suggesting that this impairment is specific to spatial working memory. These rats had no obvious hippocampal neuronal loss or damage; however, there were likely subtle changes in hippocampal processing that led to the observed deficit on the hippocampal-dependent task. These findings support our theory that cholinergic depletion of the medial septum increases hippocampal vulnerability to further insults such as stress.

Enhanced cell death in hippocampus and emergence of cognitive impairments following a localized mini-stroke in hippocampus if preceded by a previous episode of acute stress.

This series of experiments represents a test of a theory concerning the etiology of age-related cognitive decline, including Alzheimer's disease (AD). The theory suggests that multiple combinations of cofactors produce variants of these disorders. Two factors that have been linked to the etiology of AD, that are of interest to our laboratories, are stress and vascular strokes. The current experiments tested the cofactors theory by evaluating the neuronal and functional effects of localized subthreshold strokes in the hippocampus of different groups of rats. One group experienced episodes of stress prior to stroke induction while the other did not. The results showed that a low dose of endothelin-1 (ET-1) injected into the hippocampus of groups of rats that had previously experienced stressful episodes showed enhanced hippocampal cell death and neurodegeneration that did not occur in the rats that did not experience stress prior to stroke induction. The results also showed that the stressed rats given subthreshold ET-1 injections into the hippocampus showed hippocampal-based learning and memory deficits that were not present in the non-stressed group given the same injections. This pattern of results suggests that individuals that are under stress are more vulnerable to insults to the hippocampus that have little effect on an individual that is not stressed. This vulnerability might be due to the actions of stress hormones, like the glucocorticoids, that have been previously shown to endanger hippocampal neurons.

Chronic disruption of circadian rhythms impairs hippocampal memory in the rat.

Circadian related disorders and alterations in sleep-wake patterns are common complaints in the elderly, especially those diagnosed with Alzheimer's disease. The negative physical and psychological effects resulting from chronic circadian disruption are numerous and appear to be positively correlated with the length of time an individual has suffered from a circadian disorder. In the current paper, we explore the effects of acute and chronic disruption of circadian rhythms on memory using a phase shifting schedule that can continually challenge the rats' circadian system by using repeated phase shifts and recovery sessions. We demonstrate a significant learning and memory deficit on a spatial version of the water maze task in the chronically phase shifted, but not in the acutely phase shifted animals. Moreover, we find no impairment in fear conditioning suggesting that chronic phase shifting predominantly affects hippocampal memory. We propose that chronic circadian disruption may play a role in the development of age-related cognitive deficits and dementia in the elderly.

Enhanced cell death and learning deficits after a mini-stroke in aged hippocampus.

One view of the etiology of age-related pathology is that a single genetic abnormality or some other single factor causes the disorder. An alternative view is that multiple combinations of factors produce variants of pathology. For example, the occurrence of stroke increases with age and has been linked to neurodegenerative disorders like Alzheimer's disease (AD). The current experiments test the hypothesis that a vascular insult and aging are co-factors that contribute to dementia by evaluating the neuronal and functional integrity of the hippocampus following small, localized strokes induced by the potent vasoconstrictor, endothelin-1 (ET-1) in the rat model of hippocampal aging. The neurotoxic effects of a low dose of ET-1 injected into the hippocampus measured by lesion size (volumetrics) and cell death (Fluorojade-B) were amplified in aged rats. The aged rats also showed hippocampal-dependent memory deficits that were not present in young rats. Overall, our pattern of results suggest that the aged hippocampus is more vulnerable to the same insult that has little or no effect on the young hippocampus.

Mechanotransduction of extracellular signal-regulated kinases 1 and 2 mitogen-activated protein kinase activity in smooth muscle is dependent on the extracellular matrix and regulated by matrix metalloproteinases.

Excessive wall stretch of distensible hollow organs in cardiovascular and urinary systems can activate matrix metalloproteinases (MMPs), thereby releasing matrix neoepitopes and growth factor ligands, leading to ERK1/2 activation. However, the role of MMPs in mechanotransduction of ERK1/2 signaling in the bladder is unknown. We examined bladders undergoing sustained distension over time, which provides a novel platform for smooth muscle mechanotransduction studies. Bladder distension ex vivo caused increased proliferation and MMP activity. Conditioned medium from distended compared with undistended bladders induced proliferation in bladder smooth muscle cells (BSMCs). When conditioned medium from distended bladders was used to proteolyze collagen type I matrices, matrices augmented BSMC proliferation, which was inhibited if bladders were distended in presence of broad-spectrum MMP inhibitors. Distension of ex vivo bladders also induced ERK1/2 phosphorylation in situ, which was dependent on MMP activity in the intact bladder. Similarly, stretching BSMCs in vitro induced increases in ERK1/2 activation and ERK1/2-dependent proliferation under discrete mechanical conditions, and distension conditioned medium itself induced MMP-dependent ERK1/2 activation in BSMCs. Overall, stretch-induced proliferation and ERK1/2 signaling in bladder tissue and BSMCs likely depend on secreted MMP activity. Identification of intermediaries between MMPs and ERK1/2 may elaborate novel mechanisms underlying mechanotransduction in bladder smooth muscle.