Cardio-renal-metabolic disease in primary care setting.

In the primary care setting providers have more tools available than ever before to impact positively obesity, diabetes, and their complications, such as renal and cardiac diseases. It is important to recognise what is available for treatment taking into account diabetes heterogeneity. For those who develop type 2 diabetes (T2DM), effective treatments are available that for the first time have shown a benefit in reducing mortality and macrovascular complications, in addition to the well-established benefits of glucose control in reducing microvascular complications. Some of the newer medications for treating hyperglycaemia have also a positive impact in reducing heart failure (HF). Technological advances have also contributed to improving the quality of care in patients with diabetes. The use of technology, such as continuous glucose monitoring systems (CGM), has improved significantly glucose and glycated haemoglobin A1c (HbA1c) values, while limiting the frequency of hypoglycaemia. Other technological support derives from the use of predictive algorithms that need to be refined to help predict those subjects who are at great risk of developing the disease and/or its complications, or who may require care by other specialists. In this review we also provide recommendations for the optimal use of the new medications; sodium-glucose co-transporter-2 inhibitors (SGLT2i) and Glucagon-like peptide-receptor agonists 1 (GLP1RA) in the primary care setting considering the relevance of these drugs for the management of T2DM also in its early stage.

COVID-19 mitigation for high-risk populations in Springfield Massachusetts USA: a health systems approach.

BACKGROUND: Numerous reports have demonstrated the disproportionate impact that COVID-19 has had on vulnerable populations. Our purpose is to describe our health care system's response to this impact. METHODS: We convened a Workgroup with the goal to mitigate the impact of COVID-19 on the most medically vulnerable people in Springfield, Massachusetts, USA, particularly those with significant social needs. We did this through (1) identifying vulnerable patients in high-need geographic areas, (2) developing and implementing a needs assessment/outreach tool tailored to meet cultural, linguistic and religious backgrounds, (3) surveying pharmacies for access to medication delivery, (4) gathering information about sources of food delivery, groceries and/or prepared food, (5) gathering information about means of travel, and (6) assessing need for testing. We then combined these six elements into a patient-oriented branch and a community outreach/engagement branch. CONCLUSIONS: Our highly intentional and methodical approach to patient and community outreach with a strong geographic component has led to fruitful efforts in COVID-19 mitigation. Our patient-level outreach engages our health centers' clinical teams, particularly community health workers, and is providing the direct benefit of material and service resources for our at-risk patients and their families. Our community efforts leveraged existing relationships and created new partnerships that continue to inform us-healthcare entities, healthcare employees, and clinical teams-so that we can grow and learn in order to authentically build trust and engagement.

Telemedicine Can Replace the Neurologist on a Mobile Stroke Unit.

BACKGROUND AND PURPOSE: The BEST-MSU study (Benefits of Stroke Treatment Delivered Using a Mobile Stroke Unit) is a comparative effectiveness trial in patients randomized to mobile stroke unit or standard management. A substudy tested interrater agreement for tissue-type plasminogen activator eligibility between a telemedicine vascular neurologist and onboard vascular neurologist. METHODS: On scene, both the telemedicine vascular neurologist and onboard vascular neurologist independently evaluated the patient, documenting their tissue-type plasminogen activator treatment decision, National Institutes of Health Stroke Scale score, and computed tomographic interpretation. Agreement was determined using Cohen κ statistic. Telemedicine-related technical failures that impeded remote assessment were recorded. RESULTS: Simultaneous and independent telemedicine vascular neurologist and onboard vascular neurologist assessment was attempted in 174 patients. In 4 patients (2%), the telemedicine vascular neurologist could not make a decision because of technical problems. The telemedicine vascular neurologist agreed with the onboard vascular neurologist on 88% of evaluations (κ=0.73). CONCLUSIONS: Remote telemedicine vascular neurologist assessment is reliable and accurate, supporting either telemedicine vascular neurologist or onboard vascular neurologist assessment on our mobile stroke unit. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02190500.

Medication Adherence Does Not Explain Black-White Differences in Cardiometabolic Risk Factor Control among Insured Patients with Diabetes.

BACKGROUND: Among patients with diabetes, racial differences in cardiometabolic risk factor control are common. The extent to which differences in medication adherence contribute to such disparities is not known. We examined whether medication adherence, controlling for treatment intensification, could explain differences in risk factor control between black and white patients with diabetes. METHODS: We identified three cohorts of black and white patients treated with oral medications and who had poor risk factor control at baseline (2009): those with glycated hemoglobin (HbA1c) >8 % (n = 37,873), low-density lipoprotein cholesterol (LDL-C) >100 mg/dl (n = 27,954), and systolic blood pressure (SBP) >130 mm Hg (n = 63,641). Subjects included insured adults with diabetes who were receiving care in one of nine U.S. integrated health systems comprising the SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) consortium. Baseline and follow-up risk factor control, sociodemographic, and clinical characteristics were obtained from electronic health records. Pharmacy-dispensing data were used to estimate medication adherence (i.e., medication refill adherence [MRA]) and treatment intensification (i.e., dose increase or addition of new medication class) between baseline and follow-up. County-level income and educational attainment were estimated via geocoding. Logistic regression models were used to test the association between race and follow-up risk factor control. Models were specified with and without medication adherence to evaluate its role as a mediator. RESULTS: We observed poorer medication adherence among black patients than white patients (p < 0.01): 50.6 % of blacks versus 39.7 % of whites were not highly adherent (i.e., MRA <80 %) to HbA1c oral medication(s); 58.4 % of blacks and 46.7 % of whites were not highly adherent to lipid medication(s); and 33.4 % of blacks and 23.7 % of whites were not highly adherent to BP medication(s). Across all cardiometabolic risk factors, blacks were significantly less likely to achieve control (p < 0.01): 41.5 % of blacks and 45.8 % of whites achieved HbA1c <8 %; 52.6 % of blacks and 60.8 % of whites achieved LDL-C <100; and 45.7 % of blacks and 53.6 % of whites achieved SBP <130. Adjusting for medication adherence/treatment intensification did not alter these patterns or model fit statistics. CONCLUSIONS: Medication adherence failed to explain observed racial differences in the achievement of HbA1c, LDL-C, and SBP control among insured patients with diabetes.

One-Pot Synthesis of Highly Substituted Nicotinic Acid Derivatives Based on a Formylation Strategy of Enamino Keto Esters.

A facile one-pot synthesis of 4-chloro or 4-bromonicotinic acid esters with optional 2- and 2,5-disubstitution on the pyridine ring has been developed from easily accessible enamino keto esters by a formylation followed by in situ intramolecular cyclization strategy under optimized Vilsmeier reaction conditions. The effect of the substituents on the ß-carbon and the nature of the keto functionality were explored in detail to understand the mechanism of pyridine ring formation under the described conditions.

Hemicraniectomy versus Conservative Treatment in Large Hemispheric Ischemic Stroke Patients: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Several small trials have inconclusively evaluated the effect of hemicraniectomy in reducing death and disability in acute ischemic stroke patients with large hemispheric infarctions. We compared the effects of hemicraniectomy on death and disability with conservative treatment in patients with large hemispheric infarctions. METHODS: We calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) using random-effects models from 7 randomized trials that compared hemicraniectomy with conservative treatment in acute ischemic stroke patients. The primary end point was a favorable outcome defined by modified Rankin Scale grades of 0 (no symptoms), 1 (no significant disability), 2 (slight disability), and 3 (moderate disability) at 6-12 months post randomization. RESULTS: Of the 341 total subjects randomized, the proportion of subjects who achieved a favorable outcome was significantly greater among those randomized to hemicraniectomy than among those randomized to conservative treatment (OR 2.04, 95% CI 1.03-4.03, P = .04). Survival was also significantly greater among those randomized to hemicraniectomy (OR 5.56, 95% CI 3.40-9.08, P < .001) than among those randomized to conservative treatment. There was a trend toward higher odds of favorable outcome among those randomized to hemicraniectomy than among those randomized to conservative treatment in trials that permitted recruitment of patients aged 60 years or older (303 subjects analyzed; OR 1.87, 95% CI .91-3.86, P = .09). CONCLUSIONS: Compared with conservative treatment, the odds of achieving a favorable outcome at 6 months is approximately 2-folds higher with hemicraniectomy in patients with large hemispheric infarctions.

Trends in diabetes incidence among 7 million insured adults, 2006-2011: the SUPREME-DM project.

An observational cohort analysis was conducted within the Surveillance, Prevention, and Management of Diabetes Mellitus (SUPREME-DM) DataLink, a consortium of 11 integrated health-care delivery systems with electronic health records in 10 US states. Among nearly 7 million adults aged 20 years or older, we estimated annual diabetes incidence per 1,000 persons overall and by age, sex, race/ethnicity, and body mass index. We identified 289,050 incident cases of diabetes. Age- and sex-adjusted population incidence was stable between 2006 and 2010, ranging from 10.3 per 1,000 adults (95% confidence interval (CI): 9.8, 10.7) to 11.3 per 1,000 adults (95% CI: 11.0, 11.7). Adjusted incidence was significantly higher in 2011 (11.5, 95% CI: 10.9, 12.0) than in the 2 years with the lowest incidence. A similar pattern was observed in most prespecified subgroups, but only the differences for persons who were not white were significant. In 2006, 56% of incident cases had a glycated hemoglobin (hemoglobin A1c) test as one of the pair of events identifying diabetes. By 2011, that number was 74%. In conclusion, overall diabetes incidence in this population did not significantly increase between 2006 and 2010, but increases in hemoglobin A1c testing may have contributed to rising diabetes incidence among nonwhites in 2011.

Design, synthesis and pharmacological evaluation of novel polycyclic heteroarene ethers as PDE10A inhibitors: Part I.

We report analogue-based rational design and synthesis of two novel series of polycyclic heteroarenes, pyrrolo[3,2-b]quinolines and pyrido[2,3-b]indoles, tethered to a biaryl system by a methyl-, ethyl- or propyl ether as PDE10A inhibitors. A number of analogues were prepared with variable chain length and evaluated for their ability to block PDE10A enzyme using a radiometric assay. Detailed SAR analyses revealed that compounds with an ethyl ether linker are superior in potency compared to compounds with methyl or propyl ether linkers. These compounds, in general, showed poor metabolic stability in rat and human liver microsomes. The metabolic profile of one of the potent compounds was studied in detail to identify metabolic liabilities of these compounds. Structural modifications were carried out that resulted in improved metabolic stability without significant loss of potency.

Design, synthesis and pharmacological evaluation of novel polycyclic heteroarene ethers as PDE10A inhibitors: part II.

We report the design and synthesis of novel pyrrolo[3,2-b]quinoline containing heteroarene ethers as PDE10A inhibitors with good to excellent potency, selectivity and metabolic stability. Further optimization of this primary series resulted in the identification of 1-methyl-3-(4-{[3-(pyridine-4-yl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-b]pyridine 13a with good hPDE10A potency (IC50: 6.3 nM), excellent selectivity over other related PDEs and desirable physicochemical properties. The compound exhibited high peripheral and adequate brain levels upon oral dosing in rodents. The compound also showed excellent efficacy in multiple preclinical animal models related to psychiatric disorders, particularly schizophrenia.

Synthesis and pharmacological evaluation of novel N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamides as TRPM8 antagonists.

A novel series of N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamides was identified as transient receptor potential melastatin 8 (TRPM8) channel blockers through analogue-based rational design, synthesis and screening. Details of the synthesis, effect of aryl groups and their substituents on in-vitro potency were studied. The effects of selected functional groups on the 4-position of the chromene ring were also studied, which showed interesting results. The 4-hydroxy derivatives showed excellent potency and selectivity. Optical resolution and screening of alcohols revealed that (R)-(-)-isomers were in general more potent than the corresponding (S)-(+)-isomers. The isomer (R)-(-)-10e (IC50: 8.9nM) showed a good pharmacokinetic profile upon oral dosing at 10mg/kg in Sprague-Dawley (SD) rats. The compound (R)-(-)-10e also showed excellent efficacy in relevant rodent models of neuropathic pain.

Unfavorable results in replantation.

Reattachment of amputated parts of the body (Replantation) has become a reality since the first arm replant was carried out six decades ago. Failures were not uncommon in the beginning, leading on to the analysis of the problem and refinements in technique. Improvements in sutures, instrumentation and better microscopes further helped the surgeons to do replantation with better finesse and functional results. Evaluation of results and particularly failure and long term results help the younger surgeons to learn from the difficulties faced earlier to do better in the future. An attempt is made to list various aspects of replantation experienced by the author during the past 30 years, particularly in reference to unfavorable results, which had been occasionally total failure, or a partial failure, with poor function and cosmesis due to infection. An insensate limb with poor function is the result of inadequate or improper nerve coaptation or infection destroying the whole repair. It is apt to mention that infection is mostly the result of poor vascularity due to devitalized tissue. Difficulties arise often in identifying the viable tissue, particularly while debriding in the distal amputated part since there is no bleeding. Experience counts in this, specifically to identify the viable muscle. The factors that may lead to complications are listed with remarks to avoid them.

Ecological security assessment at different spatial scales in central Yunnan Province, China.

Healthy ecosystems are the basis of social and economic development. It is of great significance to conduct ecological security assessments in rapidly urbanization areas. Based on the driving forces, pressure, state, impact, and response (DPSIR) model, five years (1995, 2000, 2005, 2010 and 2015) of remote sensing images, social and economic statistics, and field survey data were used to establish an ecological security assessment index system. The ecological security assessment of central Yunnan Province (CYP) urban agglomeration was conducted at the 1 km × 1 km pixel scale and at the county scale based on the multilevel weighted comprehensive index method. The results showed that: (1) With 2005 as the turning point, the ecological security situation in CYP first decreased and then increased. (2) The ecological security at the county scale was mainly categorized as unsafe. At the pixel scale, ecologically unsafe and relatively unsafe areas were mainly distributed in central, northern, and western CYP. (3) The ecological security deterioration and strengthened spatial distribution differences were caused by habitat fragmentation, different physical geographical conditions, and population agglomeration. These results can provide a basis for the coordination and sustainability of economic development and environmental protection in urban agglomerations with rapid urbanization.

Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial.

BACKGROUND: Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes. We investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in people with type 2 diabetes. METHODS: ACCORD was a parallel-group, randomised trial done in 77 clinical sites in North America. People with diabetes, high HbA(1c) concentrations (>7.5%), and cardiovascular disease (or >or=2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target haemoglobin A(1c) [HbA(1c)] of <6.0%) or standard (7.0-7.9%) glycaemic therapy. In this analysis, the prespecified composite outcomes were: dialysis or renal transplantation, high serum creatinine (>291.7 micromol/L), or retinal photocoagulation or vitrectomy (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome). 13 prespecified secondary measures of kidney, eye, and peripheral nerve function were also assessed. Investigators and participants were aware of treatment group assignment. Analysis was done for all patients who were assessed for microvascular outcomes, on the basis of treatment assignment, irrespective of treatments received or compliance to therapies. ACCORD is registered with ClinicalTrials.gov, number NCT00000620. FINDINGS: 10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the standard group (HR 1.00, 95% CI 0.88-1.14; p=1.00), and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 (0.96, 0.89-1.02; p=0.19). Results were similar at study end (first composite outcome 556 of 5119 vs 586 of 5115 [HR 0.95, 95% CI 0.85-1.07, p=0.42]; and second 1956 of 5119 vs 2046 of 5115, respectively [0.95, 0.89-1.01, p=0.12]). Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Seven secondary measures at study end favoured intensive therapy (p<0.05). INTERPRETATION: Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia. FUNDING: US National Institutes of Health; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; and General Clinical Research Centers.

Quantitative analysis of hyperpolarized 3He ventilation changes in mice challenged with methacholine.

The capability to use high-resolution (3)He MRI to depict regional ventilation changes and airway narrowing in mice challenged with methacholine (MCh) offers the opportunity to gain new insights into the study of asthma. However, to fully exploit the value of this novel technique, it is important to move beyond visual inspection of the images toward automated and quantitative analysis. To address this gap, we describe a postprocessing approach to create ventilation difference maps to better visualize and quantify regional ventilation changes before and after MCh challenge. We show that difference maps reveal subtle changes in airway caliber, and highlight both focal and diffuse regional alterations in ventilation. Ventilation changes include both hypoventilation and compensatory areas of hyperventilation. The difference maps can be quantified by a histogram plot of the ventilation changes, in which the standard deviation increases with MCh dose (R(2) = 0.89). This method of analysis is shown to be more sensitive than simple threshold-based detection of gross ventilation defects.

A robust protocol for regional evaluation of methacholine challenge in mouse models of allergic asthma using hyperpolarized 3He MRI.

Hyperpolarized (HP) (3)He magnetic resonance imaging has been recently used to produce high-resolution images of pulmonary ventilation after methacholine (MCh) challenge in mouse models of allergic inflammation. This capability presents an opportunity to gain new insights about these models and to more sensitively evaluate new drug treatments in the pre-clinical setting. In the current study, we present our initial experience using two-dimensional (2D), time-resolved (3)He MRI of MCh challenge-induced airways hyperreactivity (AHR) to compare ovalbumin-sensitized and challenged (N = 8) mice to controls (N = 8). Imaging demonstrated that ovalbumin-sensitized and challenged animals exhibited many large ventilation defects even prior to MCh challenge (four out of eight) compared to no defects in the control animals. Additionally, the ovalbumin-sensitized and challenged animals experienced a greater number of ventilation defects (4.5 +/- 0.4) following MCh infusion than did controls (3.3 +/- 0.6). However, due to variability in MCh delivery that was specific to the small animal MRI environment, the difference in mean defect number was not statistically significant. These findings are reviewed in detail and a comprehensive solution to the variability problem is presented that has greatly enhanced the magnitude and reproducibility of the MCh response. This has permitted us to develop a new imaging protocol consisting of a baseline 3D image, a time-resolved 2D series during MCh challenge, and a post-MCh 3D image that reveals persistent ventilation defects.

A new risk and issue management system to improve productivity, quality, and compliance in clinical trials.

OBJECTIVE: We present a new system to track, manage, and report on all risks and issues encountered during a clinical trial. MATERIALS AND METHODS: Our solution utilizes JIRA, a popular issue and project tracking tool for software development, augmented by third-party and custom-built plugins to provide the additional functionality missing from the core product. RESULTS: The new system integrates all issue types under a single tracking tool and offers a range of capabilities, including configurable issue management workflows, seamless integration with other clinical systems, extensive history, reporting, and trending, and an intuitive web interface. DISCUSSION AND CONCLUSION: By preserving the linkage between risks, issues, actions, decisions, and outcomes, the system allows study teams to assess the impact and effectiveness of their risk management strategies and present a coherent account of how the trial was conducted. Since the tool was put in production, we have observed an increase in the number of reported issues and a decrease in the median issue resolution time which, along with the positive user feedback, point to marked improvements in quality, transparency, productivity, and teamwork.