Aims/hypothesis The risk of developing a range of solid tumours is increased in type 2 diabetes, and may be influenced by glucose-lowering therapies. We examined the risk of development of solid ...tumours in relation to treatment with oral agents, human insulin and insulin analogues. Methods This was a retrospective cohort study of people treated in UK general practices. Those included in the analysis developed diabetes >40 years of age, and started treatment with oral agents or insulin after 2000. A total of 62,809 patients were divided into four groups according to whether they received monotherapy with metformin or sulfonylurea, combined therapy (metformin plus sulfonylurea), or insulin. Insulin users were grouped according to treatment with insulin glargine, long-acting human insulin, biphasic analogue and human biphasic insulin. The outcome measures were progression to any solid tumour, or cancer of the breast, colon, pancreas or prostate. Confounding factors were accounted for using Cox proportional hazards models. Results Metformin monotherapy carried the lowest risk of cancer. In comparison, the adjusted HR was 1.08 (95% CI 0.96-1.21) for metformin plus sulfonylurea, 1.36 (95% CI 1.19-1.54) for sulfonylurea monotherapy, and 1.42 (95% CI 1.27-1.60) for insulin-based regimens. Adding metformin to insulin reduced progression to cancer (HR 0.54, 95% CI 0.43-0.66). The risk for those on basal human insulin alone vs insulin glargine alone was 1.24 (95% CI 0.90-1.70). Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69, 95% CI 1.23-2.33) or pancreatic cancer (HR 4.63, 95% CI 2.64-8.10), but did not influence the risk of breast or prostate cancer. Sulfonylureas were associated with a similar pattern of risk as insulin. Conclusions/interpretation Those on insulin or insulin secretagogues were more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk. Metformin use was associated with lower risk of cancer of the colon or pancreas, but did not affect the risk of breast or prostate cancer. Use of insulin analogues was not associated with increased cancer risk as compared with human insulin.
The self-assembly of palladium-based cages is frequently rationalized
via
the cumulative enthalpy (Δ
H
) of bonds between coordination nodes (
M
,
i.e.
, Pd) and ligand (
L
) components. This focus ...on enthalpic rationale limits the complete understanding of the Gibbs free energy (Δ
G
) for self-assembly, as entropic (Δ
S
) contributions are overlooked. Here, we present a study of the
M
2
lin
L
3
intermediate species (
M
= dinitrato(
N
,
N
,
N
′,
N
′-tetramethylethylenediamine)palladium(
ii
),
lin
L
= 4,4′-bipyridine), formed during the synthesis of triangle-shaped (
M
3
lin
L
3
) and square-shaped (
M
4
lin
L
4
) coordination macrocycles. Thermochemical analyses by variable temperature (VT)
1
H-NMR revealed that the
M
2
lin
L
3
intermediate exhibited an unfavorable (relative) Δ
S
compared to
M
3
lin
L
3
(triangle, Δ
T
Δ
S
= +5.22 kcal mol
−1
) or
M
4
lin
L
4
(square, Δ
T
Δ
S
= +2.37 kcal mol
−1
) macrocycles. Further analysis of these constructs with molecular dynamics (MD) identified that the self-assembly process is driven by Δ
G
losses facilitated by increases in solvation entropy (Δ
S
solv
,
i.e.
, depletion of solvent accessible surface area) that drives the self-assembly from "open" intermediates toward "closed" macrocyclic products. Expansion of our computational approach to the analysis of self-assembly in Pd
n
ben
L
2
n
cages (
ben
L
= 4,4'-(5-ethoxy-1,3-phenylene)dipyridine), demonstrated that Δ
S
solv
contributions drive the self-assembly of both thermodynamic cage products (
i.e.
, Pd
12
ben
L
24
) and kinetically-trapped intermediates (
i.e.
, Pd
8
c
L
16
).
These studies demonstrate that Δ
S
drives the self-assembly of supramolecular palladium-based coordination macrocycles and cages. As this Δ
S
contribution arises from solvation, these findings broadly reflect the thermodynamic drive of self-assembly to form compact structures.
The COVID-19 pandemic continues to ravage the world, with the United States being highly affected. A vaccine provides the best hope for a permanent solution to controlling the pandemic. However, to ...be effective, a vaccine must be accepted and used by a large majority of the population. The aim of this study was to understand the attitudes towards and obstacles facing vaccination with a potential COVID-19 vaccine. To measure these attitudes a survey was administered to 316 respondents across the United States by a survey corporation. Structural equation modeling was used to analyze the relationships of several factors with attitudes toward potential COVID-19 vaccination. Prior vaccine usage and attitudes predicted attitudes towards COVID-19 vaccination. Assessment of the severity of COVID-19 for the United States was also predictive. Approximately 68% of all respondents were supportive of being vaccinated for COVID-19, but side effects, efficacy and length of testing remained concerns. Longer testing, increased efficacy and development in the United States were significantly associated with increased vaccine acceptance. Messages promoting COVID-19 vaccination should seek to alleviate the concerns of those who are already vaccine-hesitant. Messaging directed at the benefits of vaccination for the United States as a country would address the second predictive factor. Enough time should be taken to allay concerns about both short- and long-term side effects before a vaccine is released.
Summary Background Results of intervention studies in patients with type 2 diabetes have led to concerns about the safety of aiming for normal blood glucose concentrations. We assessed survival as a ...function of HbA1c in people with type 2 diabetes. Methods Two cohorts of patients aged 50 years and older with type 2 diabetes were generated from the UK General Practice Research Database from November 1986 to November 2008. We identified 27 965 patients whose treatment had been intensified from oral monotherapy to combination therapy with oral blood-glucose lowering agents, and 20 005 who had changed to regimens that included insulin. Those with diabetes secondary to other causes were excluded. All-cause mortality was the primary outcome. Age, sex, smoking status, cholesterol, cardiovascular risk, and general morbidity were identified as important confounding factors, and Cox survival models were adjusted for these factors accordingly. Findings For combined cohorts, compared with the glycated haemoglobin (HbA1c ) decile with the lowest hazard (median HbA1c 7·5%, IQR 7·5–7·6%), the adjusted hazard ratio (HR) of all-cause mortality in the lowest HbA1c decile (6·4%, 6·1–6·6) was 1·52 (95% CI 1·32–1·76), and in the highest HbA1c decile (median 10·5%, IQR 10·1–11·2%) was 1·79 (95% CI 1·56–2·06). Results showed a general U-shaped association, with the lowest HR at an HbA1c of about 7·5%. HR for all-cause mortality in people given insulin-based regimens (2834 deaths) versus those given combination oral agents (2035) was 1·49 (95% CI 1·39–1·59). Interpretation Low and high mean HbA1c values were associated with increased all-cause mortality and cardiac events. If confirmed, diabetes guidelines might need revision to include a minimum HbA1c value. Funding Eli Lilly and Company.
Objective To characterise failure of antibiotic treatment in primary care in the United Kingdom in four common infection classes from 1991 to 2012.Design Longitudinal analysis of failure rates for ...first line antibiotic monotherapies associated with diagnoses for upper and lower respiratory tract infections, skin and soft tissue infections, and acute otitis media.Setting Routine primary care data from the UK Clinical Practice Research Datalink (CPRD).Main outcome measures Adjusted rates of treatment failure defined by standardised criteria and indexed to year 1 (1991=100).Results From 58 million antibiotic prescriptions in CPRD, we analysed 10 967 607 monotherapy episodes for the four indications: 4 236 574 (38.6%) for upper respiratory tract infections; 3 148 947 (28.7%) for lower respiratory tract infections; 2 568 230 (23.4%) for skin and soft tissue infections; and 1 013 856 (9.2%) for acute otitis media. In 1991, the overall failure rate was 13.9% (12.0% for upper respiratory tract infections; 16.9% for lower respiratory tract infections; 12.8% for skin and soft tissue infections; and 13.9% for acute otitis media). By 2012, the overall failure rate was 15.4%, representing an increase of 12% compared with 1991 (adjusted value indexed to first year (1991) 112, 95% confidence interval 112 to 113). The highest rate was seen in lower respiratory tract infections (135, 134 to 136). While failure rates were below 20% for most commonly prescribed antibiotics (amoxicillin, phenoxymethylpenicillin (penicillin-V), and flucloxacillin), notable increases were seen for trimethoprim in the treatment of upper respiratory tract infections (from 29.2% in 1991-95 to 70.1% in 2008-12) and for ciprofloxacin (from 22.3% in 1991-95 to 30.8% in 2008-12) and cefalexin (from 22.0% in 1991-95 to 30.8% in 2008-12) in the treatment of lower respiratory tract infections. Failure rates for broad spectrum penicillins, macrolides, and flucloxacillin remained largely stable.Conclusions From 1991 to 2012, more than one in 10 first line antibiotic monotherapies for the selected infections were associated with treatment failure. Overall failure rates increased by 12% over this period, with most of the increase occurring in more recent years, when antibiotic prescribing in primary care plateaued and then increased.
Background Bile acids (BAs) regulate cells by activating nuclear and membrane‐bound receptors. G protein coupled bile acid receptor 1 (GpBAR1) is a membrane‐bound G‐protein‐coupled receptor that can ...mediate the rapid, transcription‐independent actions of BAs. Although BAs have well‐known actions on motility and secretion, nothing is known about the localization and function of GpBAR1 in the gastrointestinal tract.
Methods We generated an antibody to the C‐terminus of human GpBAR1, and characterized the antibody by immunofluorescence and Western blotting of HEK293‐GpBAR1‐GFP cells. We localized GpBAR1 immunoreactivity (IR) and mRNA in the mouse intestine, and determined the mechanism by which BAs activate GpBAR1 to regulate intestinal motility.
Key Results The GpBAR1 antibody specifically detected GpBAR1‐GFP at the plasma membrane of HEK293 cells, and interacted with proteins corresponding in mass to the GpBAR1‐GFP fusion protein. GpBAR1‐IR and mRNA were detected in enteric ganglia of the mouse stomach and small and large intestine, and in the muscularis externa and mucosa of the small intestine. Within the myenteric plexus of the intestine, GpBAR1‐IR was localized to ∼50% of all neurons and to >80% of inhibitory motor neurons and descending interneurons expressing nitric oxide synthase. Deoxycholic acid, a GpBAR1 agonist, caused a rapid and sustained inhibition of spontaneous phasic activity of isolated segments of ileum and colon by a neurogenic, cholinergic and nitrergic mechanism, and delayed gastrointestinal transit.
Conclusions & Inferences G protein coupled bile acid receptor 1 is unexpectedly expressed in enteric neurons. Bile acids activate GpBAR1 on inhibitory motor neurons to release nitric oxide and suppress motility, revealing a novel mechanism for the actions of BAs on intestinal motility.
Nitric oxide (NO), produced by the neural nitric oxide synthase enzyme (nNOS) is a transmitter of inhibitory neurons supplying the muscle of the gastrointestinal tract. Transmission from these ...neurons is necessary for sphincter relaxation that allows the passage of gut contents, and also for relaxation of muscle during propulsive activity in the colon. There are deficiencies of transmission from NOS neurons to the lower esophageal sphincter in esophageal achalasia, to the pyloric sphincter in hypertrophic pyloric stenosis and to the internal anal sphincter in colonic achalasia. Deficits in NOS neurons are observed in two disorders in which colonic propulsion fails, Hirschsprung’s disease and Chagas’ disease. In addition, damage to NOS neurons occurs when there is stress to cells, in diabetes, resulting in gastroparesis, and following ischemia and reperfusion. A number of factors may contribute to the propensity of NOS neurons to be involved in enteric neuropathies. One of these is the failure of the neurons to maintain Ca2+ homeostasis. In neurons in general, stress can increase cytoplasmic Ca2+, causing a Ca2+ toxicity. NOS neurons face the additional problem that NOS is activated by Ca2+. This is hypothesized to produce an excess of NO, whose free radical properties can cause cell damage, which is exacerbated by peroxynitrite formed when NO reacts with oxygen free radicals.
Introduction: New York City is one of the areas most affected by the COVID-19 pandemic in the United States. Healthcare workers are among those at high risk of contracting the virus, and a vital ...source of information and trust in vaccines to the community. Methods: This study was conducted about attitudes towards COVID-19 vaccination among healthcare workers at a public hospital in New York City during the beginning of COVID-19 vaccination. 428 hospital employees responded. Results: Several factors were significantly associated with vaccine attitudes, including demographics such as gender (p = 0.002), age (p = 0.005), race (p < 0.001) and home location (p < 0.001), role within the hospital (p < 0.001), knowledge about the virus (p < 0.001) and confidence in and expectations about personal protective equipment and behaviors (p < 0.001). Structural equation modeling revealed that the most predictive factors were prior vaccine attitudes and concern with the speed of testing and approval of the vaccines (p < 0.001). Multivariate analysis reinforced these, while also identifying perceived personal risk as significant (p = 0.033). Conclusions: Several modifiable factors that reflect confidence in science, scientific knowledge, personal risk perception, experience and medical authority are correlated with vaccine attitudes, indicating that a holistic educational approach to improve trust in science is likely to be effective in long-term reduction in vaccine hesitancy.
Patients with autoimmune disorders (AD) have altered cancer risks compared to the general population. Systemic lupus erythematosus and multiple sclerosis lead to a heightened risk for hematological ...malignancies and decreased risk for breast, ovarian, and prostate malignancies. Often patients with autoimmune disease have dysregulated antiviral immune responses, including against oncogenic viruses. To uncover the relationship between viral incidence and cancer risk in the context of autoimmune disease, we extracted electronic health records (EHR) from Vanderbilt University. ICD-9/10 codes and laboratory values were collected for hematological, lung, anal-vaginal, thyroid, hepatobiliary, bladder, prostate, and breast cancers; and viruses including Epstein Barr virus (EBV), Human papilloma virus (HPV), and Hepatitis A/B/C (Hep). Only viral infections that led to a physician visit or laboratory test were entered into the EMR; therefore, only clinically relevant cases were noted and considered positive in this study. The relationship between virus infection and cancer in an SLE cohort (SLE-cases n = 2,313, and SLE-controls n = 5,702) and an MS cohort (MS-case n = 7,277, MS-control n = 7,277) was examined by multilinear logistic regression. Viral infection was strongly associated with increased risk for cancer overall. SLE and MS patients were more susceptible to all viral infections. MS patients trended toward increased risk for cancers overall, while decreased risk for hormone-based cancers in SLE patients non-significantly reduced their risk for overall cancer. Both SLE and MS patients had increased clinically relevant EBV infection, which was associated with risk for hematological cancers. Preventing viral infections by vaccination may be especially helpful in controlling risk for cancer in SLE and MS patients.
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