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.

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.

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.

Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4.

Ca2+/calmodulin-dependent protein kinase IV (Camk4; also known as CaMKIV), a multifunctional serine/threonine protein kinase with limited tissue distribution, has been implicated in transcriptional regulation in lymphocytes, neurons and male germ cells. In the mouse testis, however, Camk4 is expressed in spermatids and associated with chromatin and nuclear matrix. Elongating spermatids are not transcriptionally active, raising the possibility that Camk4 has a novel function in male germ cells. To investigate the role of Camk4 in spermatogenesis, we have generated mice with a targeted deletion of the gene Camk4. Male Camk4-/- mice are infertile with impairment of spermiogenesis in late elongating spermatids. The sequential deposition of sperm basic nuclear proteins on chromatin is disrupted, with a specific loss of protamine-2 and prolonged retention of transition protein-2 (Tnp2) in step-15 spermatids. Protamine-2 is phosphorylated by Camk4 in vitro, implicating a connection between Camk4 signalling and the exchange of basic nuclear proteins in mammalian male germ cells. Defects in protamine-2 have been identified in sperm of infertile men, suggesting that our results may have clinical implications for the understanding of human male infertility.

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.

Central nervous system control of food intake and body weight.

The capacity to adjust food intake in response to changing energy requirements is essential for survival. Recent progress has provided an insight into the molecular, cellular and behavioural mechanisms that link changes of body fat stores to adaptive adjustments of feeding behaviour. The physiological importance of this homeostatic control system is highlighted by the severe obesity that results from dysfunction of any of several of its key components. This new information provides a biological context within which to consider the global obesity epidemic and identifies numerous potential avenues for therapeutic intervention and future 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.

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.

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.

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.

T cell clones specific for hybrid I-A molecules. Discrimination with monoclonal anti-I-Ak antibodies.

Alloreactive and soluble antigen-reactive, I-A-restricted T cell clones were examined for their ability to recognize hybrid I-A antigens. Several clones that recognized hybrid I-A(b)/I-A(k) molecules on (C57BL/6 x A/J)F(1) [(B6A)F(1)] spleen cells were studied. We were able to distinguish clones that recognized hybrid I-A molecules of the A(b)(a)A(k)(beta) type from those that recognized A(k)(a)A(b)(beta) molecules. We reached this conclusion by considering data from three independent types of experiments. (a) Monoclonal antibodies were used to inhibit T cell stimulation. Antibodies 10.2.16 and H116.32 distinguished two mutually exclusive "families" of T cell clones. One group of clones was inhibited by 10-2.16 and not H116.32, the other group exhibited reciprocal inhibition. (b) T cell proliferation was assayed using antigen-presenting cells from B6.C-H-2(bml2) (bml2) and [bml2 x B10.A(4R)]F(1) mice. Because the bml2 strain has a mutation that results in an altered A(b)(beta) polypeptide chain (A(bm12)(beta)), we reasoned that clones that could recognize the [bm12 x B 10.A(4R)]F(1) cells were recognizing A(b)(a)A(k)(beta) molecules. Alternatively, clones not recognizing [bml2 x B10.A(4R)]F(1) cells had specificity for A(k)(a)A(b)(beta) molecules. (c) I-A molecules immunoprecipitated from radiolabeled (B6A)F(1) splenocyte extracts were analyzed by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These experiments confirmed an earlier report that antibody 10.2.16 recognized determinants on the A(k)(beta) chain (12). Antibody H116.32 immunoprecipitated products consistent with recognition of A(k)(a) determinants. Taken together, these three types of results offer conclusive evidence that T cell clones recognizing "hybrid" I-A molecules use either A(b(k)A(k)(beta) or A(k)(a)A(b)(beta) molecules as recognition or restriction sites. Clones whose proliferation was supported by [bm 12 x B10.A(4R)]F(1) cells and blocked by anti-I-A(k) antibody 10-2.16 recognized A(b)(a)A(k)(beta) B molecules. Clones that were blocked by antibody H116.32 and did not recognize [bml2 X B10.A(4R)]F(1) cells use a recognition site(s) on A(b)(a)A(k)(beta) molecules. Thus, we can demonstrate both functionally and biochemically that hybrid F(1) I-A molecules of the structure A(k)(a)A(b)(beta) and A(b)(a)A(k)(beta) both exist on (B6A)F(1) splenocytes and that both configurations are used in immune recognition phenomena.

Endocrine mechanisms mediating remission of diabetes after gastric bypass surgery.

Bariatric surgery is currently the most effective method to promote major, sustained weight loss. Roux-en-Y gastric bypass (RYGB), the most commonly performed bariatric operation, ameliorates virtually all obesity-related comorbid conditions, the most impressive being a dramatic resolution of type 2 diabetes mellitus (T2DM). After RYGB, 84% of patients with T2DM experience complete remission of this disease, and virtually all have improved glycemic control. Increasing evidence indicates that the impact of RYGB on T2DM cannot be explained by the effects of weight loss and reduced energy intake alone. Weight-independent antidiabetic actions of RYGB are apparent because of the very rapid resolution of T2DM (before weight loss occurs), the greater improvement of glucose homeostasis after RYGB than after an equivalent weight loss from other means, and the occasional development of very late-onset, pancreatic beta-cell hyperfunction. Several mechanisms probably mediate the direct antidiabetic impact of RYGB, including enhanced nutrient stimulation of L-cell peptides (for example, GLP-1) from the lower intestine, intriguing but still uncharacterized phenomena related to exclusion of the upper intestine from contact with ingested nutrients, compromised ghrelin secretion, and very probably other effects that have yet to be discovered. Research designed to prioritize these mechanisms and identify potential additional mechanisms promises to help optimize surgical design and might also reveal novel pharmaceutical targets for diabetes treatment.

Isolation and partial characterization of macro- and micronuclei from Paramecium aurella.

A method was developed for the isolation of macro- and micronuclei from Paramecium aurelia. This method utilized ionic and nonionic detergents to rupture the intact cells, calcium ions and spermidine were employed to protect the nuclei, and the nuclei were purified by centrifugation. Macronuclei consisted of 22% DNA, 10% RNA, and 68% protein. Micronuclei were composed of 9% DNA, 11% RNA, and 80% protein. DNA from both macro- and micronuclei had a density of 1.687 g/cc in CsCl and 1.417 g/cc in Cs(2)SO(4). These values corresponded to G + C content of about 23%. The RNA of macronuclei was examined by gel electrophoresis, and two high molecular weight species were identified having molecular Weights of 1.3 x 10(6) and 2.8 x 10(6) daltons. Three syngens were studied, and in each case the conditions for isolation of the nuclei were the same and no differences were observed in the properties of the nuclei.

Single-copy inverted repeats associated with regional genetic duplications in gamma fibrinogen and immunoglobulin genes.

We have found that a portion (150 base pairs) of the seventh exon of the human gamma fibrinogen gene is duplicated in the preceding intron. This duplicated sequence, termed a "pseudoexon," is flanked on each side by a single-copy inverted repeat sequence consisting of 102 base pairs. Frequencies of point substitutions indicate that both the pseudoexon and the inverted repeat sequence arose approximately 10 to 20 million years ago. The generality of this type of duplication is suggested by the occurrence of a similar duplication in the mouse immunoglobulin mu-delta region. As in the fibrinogen pseudoexon, the portion of the immunoglobulin mu-delta region containing the duplication and the inverted repeat was reported to be single-copy in the mouse genome. Since both of the first two single-copy inverted repeats to be sequenced are associated with regional duplications, it is likely that many of the single-copy inverted repeat sequences, which make up 1 to 2 percent of the genome, are also associated with regional duplications.

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.

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.