To examine for a legacy effect of early glycemic control on diabetic complications and death.
This cohort study of managed care patients with newly diagnosed type 2 diabetes and 10 years of survival ...(1997-2013, average follow-up 13.0 years,
= 34,737) examined associations between HbA
<6.5% (<48 mmol/mol), 6.5% to <7.0% (48 to <53 mmol/mol), 7.0% to <8.0% (53 to <64 mmol/mol), 8.0% to <9.0% (64 to <75 mmol/mol), or ≥9.0% (≥75 mmol/mol) for various periods of early exposure (0-1, 0-2, 0-3, 0-4, 0-5, 0-6, and 0-7 years) and incident future microvascular (end-stage renal disease, advanced eye disease, amputation) and macrovascular (stroke, heart disease/failure, vascular disease) events and death, adjusting for demographics, risk factors, comorbidities, and later HbA
.
Compared with HbA
<6.5% (<48 mmol/mol) for the 0-to-1-year early exposure period, HbA
levels ≥6.5% (≥48 mmol/mol) were associated with increased microvascular and macrovascular events (e.g., HbA
6.5% to <7.0% 48 to <53 mmol/mol microvascular: hazard ratio 1.204 95% CI 1.063-1.365), and HbA
levels ≥7.0% (≥53 mmol/mol) were associated with increased mortality (e.g., HbA
7.0% to <8.0% 53 to <64 mmol/mol: 1.290 1.104-1.507). Longer periods of exposure to HbA
levels ≥8.0% (≥64 mmol/mol) were associated with increasing microvascular event and mortality risk.
Among patients with newly diagnosed diabetes and 10 years of survival, HbA
levels ≥6.5% (≥48 mmol/mol) for the 1st year after diagnosis were associated with worse outcomes. Immediate, intensive treatment for newly diagnosed patients may be necessary to avoid irremediable long-term risk for diabetic complications and mortality.
The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single ...and combination therapies with monoclonal antibodies have received emergency use authorization
, and more treatments are under development
. Furthermore, multiple vaccine constructs have shown promise
, including two that have an approximately 95% protective efficacy against COVID-19
. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK
and B.1.351 in South Africa
is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3-12.4-fold). B.1.351 and emergent variants
with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.
The gut microbiome is the resident microbial community of the gastrointestinal tract. This community is highly diverse, but how microbial diversity confers resistance or susceptibility to intestinal ...pathogens is poorly understood. Using transplantation of human microbiomes into several animal models of infection, we show that key microbiome species shape the chemical environment of the gut through the activity of the enzyme bile salt hydrolase. The activity of this enzyme reduced colonization by the major human diarrheal pathogen Vibrio cholerae by degrading the bile salt taurocholate that activates the expression of virulence genes. The absence of these functions and species permits increased infection loads on a personal microbiome-specific basis. These findings suggest new targets for individualized preventative strategies of V. cholerae infection through modulating the structure and function of the gut microbiome.
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•Interpersonal human gut microbiome variation confers variable infection resistance•Microbiome-dependent infection resistance can be restored through co-transplantation•Colonization resistance is mediated through the bile salt hydrolase enzyme activity•Bile salt hydrolase abundance in human microbiomes correlates to final infection
Differences in the gut microbiome between individuals determine resistance to cholera infection through the effects on the activity of a bile salt enzyme.
The c-Jun N-terminal kinases (JNKs), with its members JNK1, JNK2, and JNK3, is a subfamily of (MAPK) mitogen-activated protein kinases. JNK signaling regulates a wide range of cellular processes, ...including cell proliferation, differentiation, survival, apoptosis, and inflammation. Dysregulation of JNK pathway is associated with a wide range of immune disorders and cancer. Our objective is to provide a review of JNK proteins and their upstream regulators and downstream effector molecules in common skin disorders, including psoriasis, dermal fibrosis, scleroderma, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma.
DNA-incorporating hydrophobic moieties can be synthesized by either solid-phase or solution-phase coupling. On a solid support the DNA is protected, and hydrophobic units are usually attached ...employing phosphoramidite chemistry involving a DNA synthesizer. On the other hand, solution coupling in aqueous medium results in low yields due to the solvent incompatibility of DNA and hydrophobic compounds. Hence, the development of a general coupling method for producing amphiphilic DNA conjugates with high yield in solution remains a major challenge. Here, we report an organic-phase coupling strategy for nucleic acid modification and polymerization by introducing a hydrophobic DNA–surfactant complex as a reactive scaffold. A remarkable range of amphiphile–DNA structures (DNA–pyrene, DNA–triphenylphosphine, DNA–hydrocarbon, and DNA block copolymers) and a series of new brush-type DNA side-chain homopolymers with high DNA grafting density are produced efficiently. We believe that this method is an important breakthrough in developing a generalized approach to synthesizing functional DNA molecules for self-assembly and related technological applications.
Traditionally viewed as an autodigestive pathway, autophagy also facilitates cellular secretion; however, the mechanisms underlying these processes remain unclear. Here, we demonstrate that ...components of the autophagy machinery specify secretion within extracellular vesicles (EVs). Using a proximity-dependent biotinylation proteomics strategy, we identify 200 putative targets of LC3-dependent secretion. This secretome consists of a highly interconnected network enriched in RNA-binding proteins (RBPs) and EV cargoes. Proteomic and RNA profiling of EVs identifies diverse RBPs and small non-coding RNAs requiring the LC3-conjugation machinery for packaging and secretion. Focusing on two RBPs, heterogeneous nuclear ribonucleoprotein K (HNRNPK) and scaffold-attachment factor B (SAFB), we demonstrate that these proteins interact with LC3 and are secreted within EVs enriched with lipidated LC3. Furthermore, their secretion requires the LC3-conjugation machinery, neutral sphingomyelinase 2 (nSMase2) and LC3-dependent recruitment of factor associated with nSMase2 activity (FAN). Hence, the LC3-conjugation pathway controls EV cargo loading and secretion.
In the coming decades, the population of older adults with type 2 diabetes mellitus is expected to grow substantially. Understanding the clinical course of diabetes in this population is critical for ...establishing evidence-based clinical practice recommendations, identifying research priorities, allocating resources, and setting health care policies. OBJECTIVE To contrast the rates of diabetes complications and mortality across age and diabetes duration categories.
This cohort study (2004-2010) included 72,310 older (≥ 60 years) patients with type 2 diabetes enrolled in a large, integrated health care delivery system. Incidence densities (events per 1000 person-years) were calculated for each age category (60-69, 70-79, and ≥ 80 years) and duration of diabetes (shorter 0-9 years vs longer ≥ 10 years).
Incident acute hyperglycemic events, acute hypoglycemic events (hypoglycemia), microvascular complications (end-stage renal disease, peripheral vascular disease, lower limb amputation, and diabetic eye disease), cardiovascular complications (coronary artery disease, cerebrovascular disease, and congestive heart failure), and all-cause mortality.
Among older adults with diabetes of short duration, cardiovascular complications followed by hypoglycemia were the most common nonfatal complications. For example, among individuals aged 70 to 79 years with a short duration of diabetes, coronary artery disease and hypoglycemia rates were higher (11.47 per 1000 person-years and 5.03 per 1000 person-years, respectively) compared with end-stage renal disease (2.60 per 1000 person-years), lower limb amputation (1.28 per 1000 person-years), and acute hyperglycemic events (0.82 per 1000 person-years). We observed a similar pattern among patients in the same age group with a long duration of diabetes, with some of the highest incidence rates in coronary artery disease and hypoglycemia (18.98 per 1000 person-years and 15.88 per 1000 person-years, respectively) compared with end-stage renal disease (7.64 per 1000 person-years), lower limb amputation (4.26 per 1000 person-years), and acute hyperglycemic events (1.76 per 1000 person-years). For a given age group, the rates of each outcome, particularly hypoglycemia and microvascular complications, increased dramatically with longer duration of the disease. However, for a given duration of diabetes, rates of hypoglycemia, cardiovascular complications, and mortality increased steeply with advancing age, and rates of microvascular complications remained stable or declined.
Duration of diabetes and advancing age independently predict diabetes morbidity and mortality rates. As long-term survivorship with diabetes increases and as the population ages, more research and public health efforts to reduce hypoglycemia will be needed to complement ongoing efforts to reduce cardiovascular and microvascular complications.
The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a ...method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and approaches for studying disease mechanisms, imaging agents and therapeutics targeting Asyn.
ObjectiveLoneliness is a significant and independent risk factor for depression in later life. Particularly in Asian culture, older people may find it less stigmatising to express loneliness than ...depression. This study aimed to adapt a simple loneliness screen for use in older Chinese, and to ascertain its relevance in detecting depressive symptoms as a community screening tool.Design, setting and participantsThis cross-sectional study was conducted among 1653 older adults aged 60 years or above living in the community in Hong Kong. This was a convenient sample recruited from four local non-governmental organisations providing community eldercare or mental healthcare services. All data was collected by trained social workers through face-to-face interviews.MeasuresLoneliness was measured using an adapted Chinese version of UCLA 3-item Loneliness Scale, depression symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), and social support with emotional and instrumental support proxies (number of people who can offer help). Basic demographics including age, gender, education and living arrangement were also recorded.ResultsThe average loneliness score was 3.9±3.0, and it had a moderate correlation with depressive symptoms (r=0.41, p<0.01). A loneliness score of 3 can distinguish those without depression from those with mild or more significant depressive symptoms, defined as a PHQ-9 score of ≥5 (sensitivity 76%, specificity 62%, area under the curve=0.73±0.01). Loneliness explained 18% unique variance of depressive symptoms, adding to age, living arrangement and emotional support as significant predictors.ConclusionA 3-item loneliness scale can reasonably identify older Chinese who are experiencing depressive symptoms as a quick community screening tool. Its wider use may facilitate early detection of depression, especially in cultures with strong mental health stigma.Trial registration numberClinicalTrials.gov NCT03593889
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