Do GLP-1RAs and SGLT-2is reduce cardiovascular events in women with type 2 diabetes? A systematic review and meta-analysis.

AIMS: The risk of cardiovascular disease is often underestimated in women. This leads to a delay in controlling the risk factors for cardiovascular disease and even delays in prescribing medications with cardiovascular benefit. Our aim was to explore if glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter-2 inhibitor (SGLT-2i) medications would reduce cardiovascular events in women with type 2 diabetes when atherosclerotic cardiovascular disease (ASCVD) predominates. MATERIALS AND METHODS: We searched for randomized trials comparing GLP-1RA or SGLT-2i to placebo in people with type 2 diabetes and had a primary outcome exploring major adverse cardiovascular events (MACE). Data concerning women were then extracted. A sensitivity and subgroup analyses were performed according to the class of diabetes medication. RESULTS: A total of 9 trials (GLP-1RA in 6 trials and SGLT-2i in 3) were included. Of the 84,258 participants enrolled, 30,784 (37%) participants were women. Pooled results showed a statistically significant lower incidence of MACE favouring diabetes medications (GLP-1RA or SGLT-2i) compared to placebo (RR [95%CI]=0.87 [0.80, 0.94]). On restricting the analysis to GLP-1RA then to SGLT-2i, results remained significant with GLP-1RA but not SGLT-2i. CONCLUSIONS: In women with type 2 diabetes who either have increased cardiovascular risk or established cardiovascular disease and ASCVD predominates, GLP-1RA significantly reduce the incidence of MACE while SGLT-2i result in a non-significant reduction. SGLT-2i may have comparable effect when examined in more studies. GLP-1RA and SGLT-2i should be considered without delay in women with type 2 diabetes and increased risk for cardiovascular disease.

Utilizing general human movement models to predict the spread of emerging infectious diseases in resource poor settings.

Human mobility is an important driver of geographic spread of infectious pathogens. Detailed information about human movements during outbreaks are, however, difficult to obtain and may not be available during future epidemics. The Ebola virus disease (EVD) outbreak in West Africa between 2014-16 demonstrated how quickly pathogens can spread to large urban centers following one cross-species transmission event. Here we describe a flexible transmission model to test the utility of generalised human movement models in estimating EVD cases and spatial spread over the course of the outbreak. A transmission model that includes a general model of human mobility significantly improves prediction of EVD's incidence compared to models without this component. Human movement plays an important role not only to ignite the epidemic in locations previously disease free, but over the course of the entire epidemic. We also demonstrate important differences between countries in population mixing and the improved prediction attributable to movement metrics. Given their relative rareness, locally derived mobility data are unlikely to exist in advance of future epidemics or pandemics. Our findings show that transmission patterns derived from general human movement models can improve forecasts of spatio-temporal transmission patterns in places where local mobility data is unavailable.

Comparing once-weekly semaglutide to incretin-based therapies in patients with type 2 diabetes: a systematic review and meta-analysis.

AIMS: Our aim was to compare once-weekly semaglutide to incretin-based therapies - defined as either dipeptidyl peptidase-4 inhibitors (DPP-4i) or other glucagon-like peptide-1 receptor agonist (GLP-1RA) - in patients with type 2 diabetes. METHODS: We searched for randomized trials comparing once-weekly semaglutide to other incretin-based therapies in patients with type 2 diabetes. We pooled trials that compared semaglutide to other GLP-1RA together, and those comparing semaglutide to DPP-4i together. The primary outcome was the change in haemoglobin A1c over time. RESULTS: Five trials met our inclusion criteria. There was a significantly greater reduction in haemoglobin A1c favouring semaglutide when compared to other GLP-1RA or DPP-4i [MD (95% CI) = -0.38% (-0.62, -0.15) and -1.14% (-1.53, -0.75) respectively]. There was a significantly greater weight loss favouring semaglutide when compared to other GLP-1RA or DPP-4i [MD (95% CI) = -2.50 kg (-3.91, -1.09) and -3.19 kg (-3.66, -2.72) respectively]. The proportion of patients achieving glycaemic goals and goal weight loss was greater in semaglutide-treated patients when compared to either other GLP-1RA or DPP-4i. However, semaglutide-treated patients had a significantly higher incidence of gastrointestinal side effects. CONCLUSIONS: While both once-weekly semaglutide and other incretin-based therapies can reduce haemoglobin A1c, semaglutide causes a more potent haemoglobin A1c reduction and greater weight loss when compared to other incretin-based therapies. However, this potent effect of semaglutide was associated with a higher incidence of gastrointestinal side effects. Additional studies are needed to determine whether this marked reduction in both haemoglobin A1c and body weight may translate into improved cardiovascular outcomes.

Reconstruction and prediction of viral disease epidemics.

A growing number of infectious pathogens are spreading among geographic regions. Some pathogens that were previously not considered to pose a general threat to human health have emerged at regional and global scales, such as Zika and Ebola Virus Disease. Other pathogens, such as yellow fever virus, were previously thought to be under control but have recently re-emerged, causing new challenges to public health organisations. A wide array of new modelling techniques, aided by increased computing capabilities, novel diagnostic tools, and the increased speed and availability of genomic sequencing allow researchers to identify new pathogens more rapidly, assess the likelihood of geographic spread, and quantify the speed of human-to-human transmission. Despite some initial successes in predicting the spread of acute viral infections, the practicalities and sustainability of such approaches will need to be evaluated in the context of public health responses.

Quantifying potentially infectious sharing patterns among people who inject drugs in Baltimore, USA.

Mixing matrices quantify how people with similar or different characteristics make contact with each other, creating potential for disease transmission. Little empirical data on mixing patterns among persons who inject drugs (PWID) are available to inform models of blood-borne disease such as HIV and hepatitis C virus. Egocentric drug network data provided by PWID in Baltimore, Maryland between 2005 and 2007 were used to characterise drug equipment-sharing patterns according to age, race and gender. Black PWID and PWID who were single (i.e. no stable sexual partner) self-reported larger equipment-sharing networks than their white and non-single counterparts. We also found evidence of assortative mixing according to age, gender and race, though to a slightly lesser degree in the case of gender. Highly assortative mixing according to race and gender highlights the existence of demographically isolated clusters, for whom generalised treatment interventions may have limited benefits unless targeted directly. These findings provide novel insights into mixing patterns of PWID for which little empirical data are available. The age-specific assortativity we observed is also significant in light of its role as a key driver of transmission for other pathogens such as influenza and tuberculosis.

Travel distance and human movement predict paths of emergence and spatial spread of chikungunya in Thailand.

Human movement contributes to the probability that pathogens will be introduced to new geographic locations. Here we investigate the impact of human movement on the spatial spread of Chikungunya virus (CHIKV) in Southern Thailand during a recent re-emergence. We hypothesised that human movement, population density, the presence of habitat conducive to vectors, rainfall and temperature affect the transmission of CHIKV and the spatiotemporal pattern of cases seen during the emergence. We fit metapopulation transmission models to CHIKV incidence data. The dates at which incidence in each of 151 districts in Southern Thailand exceeded specified thresholds were the target of model fits. We confronted multiple alternative models to determine which factors were most influential in the spatial spread. We considered multiple measures of spatial distance between districts and adjacency networks and also looked for evidence of long-distance translocation (LDT) events. The best fit model included driving-distance between districts, human movement, rubber plantation area and three LDT events. This work has important implications for predicting the spatial spread and targeting resources for control in future CHIKV emergences. Our modelling framework could also be adapted to other disease systems where population mobility may drive the spatial advance of outbreaks.

Time Course of Cerebral Perfusion Changes in Children with Migraine with Aura Mimicking Stroke.

Hemiplegic migraine is a common cause of acute brain attack in pediatrics. MR imaging sequences useful in differentiating hemiplegic migraine from other entities include arterial spin-labeling, SWI, MRA, and DWI. There has been limited exploration on the simultaneous use of these sequences in pediatrics. We present 12 pediatric patients with acute hemiplegic migraine or migraine with aura who underwent MR imaging within 12 hours of symptom onset. Quantitative and qualitative analyses were performed on arterial spin-labeling; and qualitative analysis, on SWI and MRA sequences. All 12 patients had normal DWI and abnormal arterial spin-labeling findings. Furthermore, we observed a more rapid transition from hypoperfusion to rebound hyperperfusion in 3 patients compared with prior reports. These findings support the use of multimodal MR imaging to distinguish migraine with aura from stroke and the simultaneous use of these MR imaging sequences to improve understanding of perfusion changes during migraine with aura.

Understanding dengue virus evolution to support epidemic surveillance and counter-measure development.

Dengue virus (DENV) causes a profound burden of morbidity and mortality, and its global burden is rising due to the co-circulation of four divergent DENV serotypes in the ecological context of globalization, travel, climate change, urbanization, and expansion of the geographic range of the Ae.aegypti and Ae.albopictus vectors. Understanding DENV evolution offers valuable opportunities to enhance surveillance and response to DENV epidemics via advances in RNA virus sequencing, bioinformatics, phylogenetic and other computational biology methods. Here we provide a scoping overview of the evolution and molecular epidemiology of DENV and the range of ways that evolutionary analyses can be applied as a public health tool against this arboviral pathogen.

Comparing SGLT-2 inhibitors to DPP-4 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes: A systematic review and meta-analysis.

AIMS: Our aim was to compare Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) to Dipeptidyl peptidase-4 inhibitors (DPP-4i) as add-on therapy to metformin. METHODS: We searched for randomized trials comparing SGLT-2i to DPP-4i as add-on therapy to metformin in Type 2 diabetes.We pooled trials reporting outcomes between 12 and 26 weeks together while trials reporting results ≥52 weeks were pooled together. The primary outcomes were the change in haemoglobin A1c (A1c) at ≤26 and ≥52 weeks. Sensitivity analyses were performed according to the dose of SGLT-2i and according to baseline A1c for the primary outcomes. RESULTS: Seven trials met our inclusion criteria. There was a statistically significant reduction in A1c at ≥52 weeks favouring SGLT-2i compared to DPP-4i (MD [95% CI]=-0.11% [-0.20, -0.03]) but no significant difference at ≤26 weeks (MD [95% CI]=-0.05% [-0.16, 0.05]). SGLT-2i caused significantly more weight loss compared to DPP-4i at ≤26 weeks and ≥52 weeks (MD [95% CI]=-2.31kg [-2.66, -1.96] and -2.45kg [-2.83, -2.07], respectively). SGLT-2i treated patients had a significantly more genital infection compared to DPP-4i. On restricting the analysis according to the SGLT-2i FDA-approved dose, only higher doses at ≥52 weeks showed a statistically significant reduction in A1c compared to DPP-4i. On restricting the analysis according to baseline A1c, results favoured DPP-4i if baseline A1c was<8.5%, but favoured SGLT-2i if ≥8.5%. CONCLUSION: While both SGLT-2i and DPP-4i can reduce A1c, SGLT-2i causes a more robust A1c reduction and more weight loss but with more genital infections. Higher doses of SGLT-2i showed more efficacy when compared to DPP-4i; however, this data should be interpreted cautiously given the limited number of trials.

Impact of a peri-operative quality improvement programme on postoperative pulmonary complications.

Postoperative pulmonary complications are common, with a reported incidence of 2-40%, and are associated with adverse outcomes that include death, longer hospital stay and reduced long-term survival. Enhanced recovery is now a standard of care for patients undergoing elective major surgery. Despite the high prevalence of pulmonary complications in this population, few elements of enhanced recovery specifically address reducing these complications. In 2013, a prevalence audit confirmed a postoperative pulmonary complication rate of 16/83 (19.3%) in patients undergoing elective major surgery who were admitted to critical care postoperatively. A quality improvement team developed and implemented ERAS+, an innovative model of peri-operative care combining elements of enhanced recovery with specific measures aimed at reducing pulmonary complications. ERAS+ was introduced in June 2014, with full implementation in September 2014. Patients were screened during full ERAS+ implementation and again one year following implementation. Following ERAS+ implementation, postoperative pulmonary complications reduced to 24/228 (10.5%). Sustained improvement was evident one year after implementation, with a pulmonary complication rate of 16/183 (8.7%). Median (IQR [range]) length of hospital stay one year after implementation of ERAS+ also improved from 12 (9-15 [4-101]) to 9 (5.5-10.5 [3-81]) days. The ERAS+ pathway is applicable to patients undergoing elective major surgery and appears effective in reducing postoperative pulmonary complications.

Using age-stratified incidence data to examine the transmission consequences of pertussis vaccination.

Pertussis is a highly infectious respiratory disease that has been on the rise in many countries worldwide over the past several years. The drivers of this increase in pertussis incidence remain hotly debated, with a central and long-standing hypothesis that questions the ability of vaccines to eliminate pertussis transmission rather than simply modulate the severity of disease. In this paper, we present age-structured case notification data from all provinces of Thailand between 1981 and 2014, a period during which vaccine uptake rose substantially, permitting an evaluation of the transmission impacts of vaccination. Our analyses demonstrate decreases in incidence across all ages with increased vaccine uptake - an observation that is at odds with pertussis case notification data in a number of other countries. To explore whether these observations are consistent with a rise in herd immunity and a reduction in bacterial transmission, we analyze an age-structured model that incorporates contrasting hypotheses concerning the immunological and transmission consequences of vaccines. Our results lead us to conclude that the most parsimonious explanation for the combined reduction in incidence and the shift to older age groups in the Thailand data is vaccine-induced herd immunity.

Big city, small world: density, contact rates, and transmission of dengue across Pakistan.

Macroscopic descriptions of populations commonly assume that encounters between individuals are well mixed; i.e. each individual has an equal chance of coming into contact with any other individual. Relaxing this assumption can be challenging though, due to the difficulty of acquiring detailed knowledge about the non-random nature of encounters. Here, we fitted a mathematical model of dengue virus transmission to spatial time-series data from Pakistan and compared maximum-likelihood estimates of 'mixing parameters' when disaggregating data across an urban-rural gradient. We show that dynamics across this gradient are subject not only to differing transmission intensities but also to differing strengths of nonlinearity due to differences in mixing. Accounting for differences in mobility by incorporating two fine-scale, density-dependent covariate layers eliminates differences in mixing but results in a doubling of the estimated transmission potential of the large urban district of Lahore. We furthermore show that neglecting spatial variation in mixing can lead to substantial underestimates of the level of effort needed to control a pathogen with vaccines or other interventions. We complement this analysis with estimates of the relationships between dengue transmission intensity and other putative environmental drivers thereof.

Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome.

Hippocampal pathology is likely to contribute to cognitive disability in Down syndrome, yet the neural network basis of this pathology and its contributions to different facets of cognitive impairment remain unclear. Here we report dysfunctional connectivity between dentate gyrus and CA3 networks in the transchromosomic Tc1 mouse model of Down syndrome, demonstrating that ultrastructural abnormalities and impaired short-term plasticity at dentate gyrus-CA3 excitatory synapses culminate in impaired coding of new spatial information in CA3 and CA1 and disrupted behavior in vivo. These results highlight the vulnerability of dentate gyrus-CA3 networks to aberrant human chromosome 21 gene expression and delineate hippocampal circuit abnormalities likely to contribute to distinct cognitive phenotypes in Down syndrome.

Ghrelin.

BACKGROUND: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

Close encounters of the infectious kind: methods to measure social mixing behaviour.

A central tenet of close-contact or respiratory infection epidemiology is that infection patterns within human populations are related to underlying patterns of social interaction. Until recently, few researchers had attempted to quantify potentially infectious encounters made between people. Now, however, several studies have quantified social mixing behaviour, using a variety of methods. Here, we review the methodologies employed, suggest other appropriate methods and technologies, and outline future research challenges for this rapidly advancing field of research.

The population ecology of infectious diseases: pertussis in Thailand as a case study.

Many of the fundamental concepts in studying infectious diseases are rooted in population ecology. We describe the importance of population ecology in exploring central issues in infectious disease research including identifying the drivers and dynamics of host-pathogen interactions and pathogen persistence, and evaluating the success of public health policies. The use of ecological concepts in infectious disease research is demonstrated with simple theoretical examples in addition to an analysis of case notification data of pertussis, a childhood respiratory disease, in Thailand as a case study. We stress that further integration of these fields will have significant impacts in infectious diseases research.

A long-lasting measles epidemic in Maroua, Cameroon 2008-2009: mass vaccination as response to the epidemic.

BACKGROUND: A measles outbreak occurred in Maroua, Cameroon, from January 2008 to April 2009. In accordance with recent World Health Organization guidelines, an outbreak-response immunization (ORI) was conducted in January 2009. The aim of this study was to investigate the causes of the epidemic in order to guide vaccination strategies. METHODS: We performed a stratified household-based survey using cluster sampling to determine measles vaccination coverage in children aged 9 months to 15 years. We defined 3 strata based on measles incidence. Next, we performed a case-control study to measure vaccine effectiveness (VE). Cases were obtained from health center registries. Controls were selected among respondents to the coverage survey. RESULTS: The vaccination-coverage survey included 2963 children in total. The overall routine vaccination coverage was 74.1% (95% confidence interval [CI]: 70.0%-78.3%). Measles incidence was inversely proportional to routine vaccination coverage, with high incidence associated with coverage of 71% and low incidence associated with coverage of 84%. The overall VE was 94% (95% CI, 86.7%-97.4%). After the ORI in January 2009, the coverage was >90% in all strata and measles incidence declined rapidly. DISCUSSION: Our results confirm that insufficient vaccination coverage was the main reason for this epidemic. The ORI conducted in January 2009 contributed both to control the epidemic and to increase the vaccination coverage to desirable levels.

Impaired long-term potentiation in the prefrontal cortex of Huntington's disease mouse models: rescue by D1 dopamine receptor activation.

BACKGROUND: The introduction of gene testing for Huntington's disease (HD) has enabled the neuropsychiatric and cognitive profiling of human gene carriers prior to the onset of overt motor and cognitive symptoms. Such studies reveal an early decline in working memory and executive function, altered EEG and a loss of striatal dopamine receptors. Working memory is processed in the prefrontal cortex and modulated by extrinsic dopaminergic inputs. OBJECTIVE: We sought to study excitatory synaptic function and plasticity in the medial prefrontal cortex of mouse models of HD. METHODS: We have used 2 mouse models of HD, carrying 89 and 116 CAG repeats (corresponding to a preclinical and symptomatic state, respectively) and performed electrophysiological field recording in coronal slices of the medial prefrontal cortex. RESULTS: We report that short-term synaptic plasticity and long-term potentiation (LTP) are impaired and that the severity of impairment is correlated with the size of the CAG repeat. Remarkably, the deficits in LTP and short-term plasticity are reversed in the presence of a D(1) dopamine receptor agonist (SKF38393). CONCLUSION: In a previous study, we demonstrated that a deficit in long-term depression (LTD) in the perirhinal cortex could also be reversed by a dopamine agonist. These and our current data indicate that inadequate dopaminergic modulation of cortical synaptic function is an early event in HD and may provide a route for the alleviation of cognitive dysfunction.

Maintaining high rates of measles immunization in Africa.

Supplementary immunization activities (SIAs) are important in achieving high levels of population immunity to measles virus. Using data from a 2006 survey of measles vaccination in Lusaka, Zambia, we developed a model to predict measles immunity following routine vaccination and SIAs, and absent natural infection. Projected population immunity was compared between the current programme and alternatives, including supplementing routine vaccination with a second dose, or SIAs at 1-, 2-, 3-, 4- and 5-year intervals. Current routine vaccination plus frequent SIAs could maintain high levels of population immunity in children aged <5 years, even if each frequent SIA has low coverage (e.g. ≥ 72% for bi-annual 60% coverage SIAs vs. ≥ 69% for quadrennial 95% coverage SIAs). A second dose at 12 months with current coverage could achieve 81% immunity. Circulating measles virus will only increase population immunity. Public health officials should consider frequent SIAs when resources for a two-dose strategy are unavailable.