High-Specificity Imaging Mass Spectrometry.

Imaging mass spectrometry (IMS) enables highly multiplexed, untargeted tissue mapping for a broad range of molecular classes, facilitating in situ biological discovery. Yet, challenges persist in molecular specificity, which is the ability to discern one molecule from another, and spatial specificity, which is the ability to link untargeted imaging data to specific tissue features. Instrumental developments have dramatically improved IMS spatial resolution, allowing molecular observations to be more readily associated with distinct tissue features across spatial scales, ranging from larger anatomical regions to single cells. High-performance mass analyzers and systems integrating ion mobility technologies are also becoming more prevalent, further improving molecular coverage and the ability to discern chemical identity. This review provides an overview of recent advancements in high-specificity IMS that are providing critical biological context to untargeted molecular imaging, enabling integrated analyses, and addressing advanced biomedical research applications.

Experiences of children's self-wetting (including urinary incontinence) in Cox's Bazar's Rohingya refugee camps, Bangladesh.

Self-wetting is the leakage of urine, either due to the medical condition of urinary incontinence (UI), or because a person does not want to, or cannot, access a toileting facility in time. This study explored the attitudes towards self-wetting and experiences of children (aged five to 11), their caregivers, community leaders and humanitarian practitioners in the Rohingya refugee camps in Cox's Bazar, Bangladesh. We particularly focused on how water, sanitation and hygiene (WASH) and protection interventions might assist in improving these experiences. We purposively selected participants from two camps where our partner organisation works. We conducted Key Informant Interviews (KIIs) with community leaders and camp officials, Story Book (SB) sessions with Rohingya children and in-depth Interviews (IDIs) with caregivers of children who participated in the SB sessions, as well as surveying communal toilets. Self-wetting by children was common and resulted in them feeling embarrassed, upset and uncomfortable, and frightened to use the toilet at night; many children also indicated that they would be punished by their caregivers for self-wetting. Key informants indicated that caregivers have difficulty handling children's self-wetting due to a limited amount of clothing, pillows, and blankets, and difficulty cleaning these items. It was evident that the available toilets are often not appropriate and/or accessible for children. Children in the Rohingya camps appear to self-wet due to both the medical condition of UI and because the sanitation facilities are inappropriate. They are teased by their peers and punished by their caregivers. Although WASH and protection practitioners are unable to drastically alter camp conditions or treat UI, the lives of children who self-wet in these camps could likely be improved by increasing awareness on self-wetting to decrease stigma and ease the concerns of caregivers, increasing the number of child-friendly toilets and increasing the provision of continence management materials.

Gradients of glucose metabolism regulate morphogen signalling required for specifying tonotopic organisation in the chicken cochlea.

In vertebrates with elongated auditory organs, mechanosensory hair cells (HCs) are organised such that complex sounds are broken down into their component frequencies along a proximal-to-distal long (tonotopic) axis. Acquisition of unique morphologies at the appropriate position along the chick cochlea, the basilar papilla, requires that nascent HCs determine their tonotopic positions during development. The complex signalling within the auditory organ between a developing HC and its local niche along the cochlea is poorly understood. Using a combination of live imaging and NAD(P)H fluorescence lifetime imaging microscopy, we reveal that there is a gradient in the cellular balance between glycolysis and the pentose phosphate pathway in developing HCs along the tonotopic axis. Perturbing this balance by inhibiting different branches of cytosolic glucose catabolism disrupts developmental morphogen signalling and abolishes the normal tonotopic gradient in HC morphology. These findings highlight a causal link between graded morphogen signalling and metabolic reprogramming in specifying the tonotopic identity of developing HCs.

Understanding children's experiences of self-wetting in humanitarian contexts: An evaluation of the Story Book methodology.

Little is known about how children in humanitarian contexts experience self-wetting. Children can wet themselves due to having the medical condition of urinary incontinence (the involuntary leakage of urine), or due to them not wanting to or not being able to use the toilet facilities available (social or functional incontinence). Self-wetting is a global public health challenge: the physical health of children can suffer; they can miss out on educational and social opportunities; they may face increased protection risks; and the emotional effect on daily life can be significantly negative. The Story Book methodology was developed to facilitate conversations with children aged five to eleven in humanitarian contexts (specifically refugee settlements in Adjumani District, Uganda; and refugee camps in Cox's Bazar, Bangladesh) about self-wetting to understand how humanitarian professionals can best meet the needs of children that wet themselves. This paper has evaluated how far the Story Book methodology meets the specific requirements of conducting research a) in a humanitarian context; b) with young children; and c) on a personal and highly sensitive topic. Data has been used from Story Book sessions held with children in Adjumani District and Cox's Bazar, and from semi-structured interviews held with adults known to have participated in the planning and/or facilitation of the sessions. The evaluation found that although the Story Book methodology provided deep insights into how children in humanitarian contexts experience self-wetting, it was not always implemented as designed; it is not practical to implement in humanitarian settings; and it was not acceptable to all participants and facilitators as a research tool. Changes have been recommended to improve the methodology as a research tool to better understand how children experience personal health issues, but even with such changes the methodology will remain better suited to non-humanitarian contexts.

Neprilysin Inhibitors in Heart Failure: The Science, Mechanism of Action, Clinical Studies, and Unanswered Questions.

This article provides a contemporary review and a new perspective on the role of neprilysin inhibition in heart failure (HF) in the context of recent clinical trials and addresses potential mechanisms and unanswered questions in certain HF patient populations. Neprilysin is an endopeptidase that cleaves a variety of peptides such as natriuretic peptides, bradykinin, adrenomedullin, substance P, angiotensin I and II, and endothelin. It has a broad role in cardiovascular, renal, pulmonary, gastrointestinal, endocrine, and neurologic functions. The combined angiotensin receptor and neprilysin inhibitor (ARNi) has been developed with an intent to increase vasodilatory natriuretic peptides and prevent counterregulatory activation of the angiotensin system. ARNi therapy is very effective in reducing the risks of death and hospitalization for HF in patients with HF and New York Heart Association functional class II to III symptoms, but studies failed to show any benefits with ARNi when compared with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker in patients with advanced HF with reduced ejection fraction or in patients following myocardial infarction with left ventricular dysfunction but without HF. These raise the questions about whether the enzymatic breakdown of natriuretic peptides may not be a very effective solution in advanced HF patients when there is downstream blunting of the response to natriuretic peptides or among post-myocardial infarction patients in the absence of HF when there may not be a need for increased natriuretic peptide availability. Furthermore, there is a need for additional studies to determine the long-term effects of ARNi on albuminuria, obesity, glycemic control and lipid profile, blood pressure, and cognitive function in patients with HF.

Gi/o protein-coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na+/K+ ATPase activation.

Gi/o-coupled somatostatin or α2-adrenergic receptor activation stimulated ß-cell NKA activity, resulting in islet Ca2+ fluctuations. Furthermore, intra-islet paracrine activation of ß-cell Gi/o-GPCRs and NKAs by δ-cell somatostatin secretion slowed Ca2+ oscillations, which decreased insulin secretion. ß-cell membrane potential hyperpolarization resulting from Gi/o-GPCR activation was dependent on NKA phosphorylation by Src tyrosine kinases. Whereas, ß-cell NKA function was inhibited by cAMP-dependent PKA activity. These data reveal that NKA-mediated ß-cell membrane potential hyperpolarization is the primary and conserved mechanism for Gi/o-GPCR control of electrical excitability, Ca2+ handling, and insulin secretion.

Aerobic glycolysis is important for zebrafish larval wound closure and tail regeneration.

The underlying mechanisms of appendage regeneration remain largely unknown and uncovering these mechanisms in capable organisms has far-reaching implications for potential treatments in humans. Recent studies implicate a requirement for metabolic reprogramming reminiscent of the Warburg effect during successful appendage and organ regeneration. As changes are thus predicted to be highly dynamic, methods permitting direct, real-time visualisation of metabolites at the tissue and organismal level would offer a significant advance in defining the influence of metabolism on regeneration and healing. We sought to examine whether glycolytic activity was altered during larval fin regeneration, utilising the genetically encoded biosensor, Laconic, enabling the spatiotemporal assessment of lactate levels in living zebrafish. We present evidence for a rapid increase in lactate levels within min following injury, with a role of aerobic glycolysis in actomyosin contraction and wound closure. We also find a second wave of lactate production, associated with overall larval tail regeneration. Chemical inhibition of glycolysis attenuates both the contraction of the wound and regrowth of tissue following tail amputation, suggesting aerobic glycolysis is necessary at two distinct stages of regeneration.

How NHS Tayside dealt with the COVID-19 pandemic within Urgent Dental Care Centres: clinical staff views and experiences.

Introduction Dental staff are considered to be at increased risk of COVID-19 transmission, and national concerns about personal protective equipment (PPE) and staff safety have been widely reported. This study explores the views of staff working in Urgent Dental Care Centres (UDCCs) during the first COVID-19 lockdown.Aims To explore clinical staff views and experiences of PPE and personal safety while working in NHS Tayside's UDCCs during the initial months of the COVID-19 pandemic.Design Cross-sectional questionnaire survey.Materials and methods A questionnaire was emailed to staff working within NHS Tayside UDCCs during the first lockdown. The questions related to PPE, working environment, personal safety and wellbeing. This paper focuses on PPE and personal safety.Results Of the 176 invited to participate, 116 completed the questionnaire. The majority confirmed that they always had access to appropriate PPE and few had concerns about personal safety.Discussion Despite having worked in a high-risk environment throughout the lockdown, staff supporting the Tayside UDCCs felt safe and well-protected. This runs counter to widely reported anxieties about PPE and safety across the UK. Further investigation is required to understand this disparity.Conclusion The results indicate that PPE was adequate, accessible and staff felt protected.

Clinical outcomes and predictors of complications in patients undergoing leadless pacemaker implantation.

BACKGROUND: Leadless pacemakers have emerged as a viable alternative for traditional transvenous pacemakers to reduce the risk of device-related complications. OBJECTIVE: The purpose of this study was to examine the real-world clinical outcomes and complications associated with the implantation of leadless pacemaker devices. METHODS: Using the National Readmission Database (NRD), we examined patient demographics, and in-hospital and 30-day procedural outcomes after leadless pacemaker implantation from 2016-2018. Our cohort comprised adults (≥18 years) with an ICD-10 procedural code for leadless pacemaker implantation. RESULTS: Our cohort included a total of 7821 patients who underwent leadless pacemaker implantation. Overall immediate procedure-related complications, as defined broadly in this study, occurred in 7.5% of patients. Pericardial effusion without the need for pericardiocentesis occurred in 1.9% of patients, with pericardiocentesis performed in 1.0%. Vascular complications occurred in 2.3% of patients; 0.33% required repair, and device dislodgment occurred in 0.51%. The most significant predictor for procedural complications was end-stage renal disease (odds ratio [OR] 1.65; 95% confidence interval [CI] 1.17-2.32; P = .004), congestive heart failure (OR 1.28; 95% CI 1.01-1.62; P = .04), and coagulopathy (OR 1.77; 95% CI 1.34-2.34; P <.001). All-cause readmission occurred in 17.9% of patients within 30 days from device implant, with 1.36% of readmissions being procedure related. At 30 days postimplant and after discharge, 0.25% of patients needed a new pacemaker, and 0.18% had pericardial complications. CONCLUSION: In our large real-life cohort, we found the rate of serious complications after leadless pacemaker implantation to be relatively low and comparable to prior studies in a high-risk population with multiple comorbid conditions.

A qualitative analysis of dental professionals' beliefs and concerns about providing aerosol generating procedures early in the COVID-19 pandemic.

INTRODUCTION: In response to the COVID-19 pandemic, the Scottish Dental Clinical Effectiveness Programme (SDCEP) initiated a rapid review of the evidence related to the generation and mitigation of aerosols in dental practice. To support this review, a survey was distributed to better understand the provision of aerosol generating procedures (AGPs) in dentistry. METHODS: An online questionnaire was distributed to dental professionals asking about their current practice and beliefs about AGPs. Data were analysed using qualitative content analysis. RESULTS: Analysis revealed confusion and uncertainty regarding mitigation of AGPs. There was also frustration and scepticism over the risk of SARS-COV-2 transmission within dental settings, the evidence underpinning the restrictions and the leadership and guidance being provided, as well as concern over financial implications and patient and staff safety. DISCUSSION: The frustration and concerns expressed by respondents mirrored findings from other recent studies and suggest there is a need for reflection within the profession so that lessons can be learned to better support staff and patients. CONCLUSION: Understanding the profession's views about AGP provision contributed to the SDCEP rapid review and provides insights to help inform policymakers and leaders in anticipation not only of future pandemics but in considering the success of any large scale and/or rapid organisational change.

Association Between Cinnamon Consumption and Risk of Cardiovascular Health: A Systematic Review and Meta-Analysis.

BACKGROUND: Cinnamon has been used as a traditional herbal medication for decades. Several studies have investigated cinnamon consumption and cardiovascular risk. So far, the evidence remains inconclusive. Thus, we aim to systematically review the currently available literature and quantify the evidence, if possible. METHODS: We systematically searched Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Scopus, and Web of Science from database inception in 1966 through December 2020. The exposure of interest was cinnamon consumption, the outcome was cardiovascular risk defined as hemoglobin A1C, low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c). Two investigators independently reviewed the data. Conflicts were resolved through consensus. Random-effects meta-analyses were used. RESULTS: Of 23 studies (1070 subjects), the included studies were heterogeneous, generally of very poor quality. We found no difference in LDL-c levels in patients who consumed cinnamon vs those who did not, with a weighted mean difference (WMD) of 0.38 (confidence interval [CI], -6.07-6.83). We also found no difference in HDL-c between the 2 groups with WMD 0.40 (CI, -1.14-1.94). In addition, we found no statistical differences in hemoglobin A1C between the 2 groups with WMD of 0.0 (CI, -0.44-0.45). CONCLUSIONS: Our meta-analysis suggests that there is no association between cinnamon consumption and differences in LDL-c, HDL-c, and hemoglobin A1C levels. Further randomized control trials studies using a robust design with long-term cinnamon consumption are needed to further investigate any potential effect.

Canine pyoderma: mecA persists autogenous bacterin formulation from meticillin-resistant Staphylococcus pseudintermedius (MRSP) and S. aureus (MRSA).

OBJECTIVE: Autogenous Staphylococcus pseudintermedius bacterins can reduce prescribing of antimicrobials in the management of canine recurrent pyoderma. However, increasing prevalence of meticillin-resistant, mecA-positive S. pseudintermedius (MRSP) raises concern over dispersal of mecA through bacterin therapy. We investigated the presence and integrity of mecA in bacterin formulations after manufacturing. MATERIAL AND METHODS: Twenty clinical isolates (12 MRSP, 7 MR-S. aureus, 1 meticillin-susceptible SP) were investigated. Pellets from overnight growth were washed 3 times with 0.5 % phenol saline, followed by addition of 0.1 ml 10 % formal-saline to 10 ml phenol-saline. Sterility was confirmed, and DNA extracted using both a standard genomic extraction kit and one recommended for formalin-fixed tissue samples (FFPE). The presence of mecA was determined after PCR and its integrity examined in 5 randomly selected samples after sequencing. RESULTS: In all bacterins from meticillin-resistant isolates, mecA was detected following FFPE extraction; products aligned fully to a reported mecA sequence. After standard DNA extraction, mecA was seen in 16/19 samples. CONCLUSION: Persistence of mecA in MRSP bacterins suggests that dispersal of this important resistance mediator through therapy may be possible. While the ability of skin bacteria to uptake naked DNA remains unclear, it seems prudent to only formulate autogenous bacterins from mecA-negative S. pseudintermedius to avoid unnecessary spread of mecA.

Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX.

Epithelial tissues are primed to respond to insults by activating epithelial cell motility and rapid inflammation. Such responses are also elicited upon overexpression of the membrane-bound protease, Matriptase, or mutation of its inhibitor, Hai1. Unrestricted Matriptase activity also predisposes to carcinoma. How Matriptase leads to these cellular outcomes is unknown. We demonstrate that zebrafish hai1a mutants show increased H2O2, NfκB signalling, and IP3R -mediated calcium flashes, and that these promote inflammation, but do not generate epithelial cell motility. In contrast, inhibition of the Gq subunit in hai1a mutants rescues both the inflammation and epithelial phenotypes, with the latter recapitulated by the DAG analogue, PMA. We demonstrate that hai1a has elevated MAPK pathway activity, inhibition of which rescues the epidermal defects. Finally, we identify RSK kinases as MAPK targets disrupting adherens junctions in hai1a mutants. Our work maps novel signalling cascades mediating the potent effects of Matriptase on epithelia, with implications for tissue damage response and carcinoma progression.

Cancer occurs when normal processes in the cell become corrupted or unregulated. Many proteins can contribute, including one enzyme called Matriptase that cuts other proteins at specific sites. Matriptase activity is tightly controlled by a protein called Hai1. In mice and zebrafish, when Hai1 cannot adequately control Matriptase activity, invasive cancers with severe inflammation develop. However, it is unclear how unregulated Matriptase leads to both inflammation and cancer invasion. One outcome of Matriptase activity is removal of proteins called Cadherins from the cell surface. These proteins have a role in cell adhesion: they act like glue to stick cells together. Without them, cells can dissociate from a tissue and move away, a critical step in cancer cells invading other organs. However, it is unknown exactly how Matriptase triggers the removal of Cadherins from the cell surface to promote invasion. Previous work has shown that Matriptase switches on a receptor called Proteinase-activated receptor 2, or Par2 for short, which is known to activate many enzymes, including one called phospholipase C. When activated, this enzyme releases two signals into the cell: a sugar called inositol triphosphate, IP3; and a lipid or fat called diacylglycerol, DAG. It is possible that these two signals have a role to play in how Matriptase removes Cadherins from the cell surface. To find out, Ma et al. mapped the effects of Matriptase in zebrafish lacking the Hai1 protein. This revealed that Matriptase increases IP3 and DAG levels, which initiate both inflammation and invasion. IP3 promotes inflammation by switching on pro-inflammatory signals inside the cell such as the chemical hydrogen peroxide. At the same time, DAG promotes cell invasion by activating a well-known cancer signalling pathway called MAPK. This pathway activates a protein called RSK. Ma et al. show that this protein is required to remove Cadherins from the surface of cells, thus connecting Matriptase's activation of phospholipase C with its role in disrupting cell adhesion. An increase in the ratio of Matriptase to HAI-1 (the human equivalent of Hai1) is present in many cancers. For this reason, the signal cascades described by Ma et al. may be of interest in developing treatments for these cancers. Understanding how these signals work together could lead to more direct targeted anti-cancer approaches in the future.

Audit and feedback with or without training in-practice targeting antibiotic prescribing (TiPTAP): a study protocol of a cluster randomised trial in dental primary care.

BACKGROUND: Antimicrobial resistance is an increasingly serious threat to global public health and patient safety. Overuse of antibiotics has aggravated this issue. Around 7% of all antibiotics in Scotland are prescribed by dentists. Audit and feedback has been shown to decrease these prescriptions, but there is evidence that dentists still prescribe unnecessarily. Our aim is to compare the effectiveness of a theory-informed in-practice training session (TiPTAP) in addition to individualised audit and feedback, with audit and feedback alone for reducing antibiotic prescribing by NHS dentists working in NHS primary care dental practices. METHODS: We will conduct a 2-arm parallel cluster randomised trial: out of 228 practices, 114 will be randomised to the theory-informed in-practice training session targeting antibiotic prescribing and individualised audit and feedback; 114 practices will be randomised to audit and feedback alone. The theory-informed session will include (a) an introductory session including several behaviour change techniques; (b) problem solving discussion, setting and recording action plans; (c) practice-level prescribing feedback discussion. The primary outcome is the number of antibiotic items per 100 NHS treatment claims over a 1-year period post-randomisation for each dentist. Secondary outcomes are the number of amoxicillin 3 g and broad spectrum antibiotics prescribed per 100 NHS treatment claims over a 1-year period; amoxicillin 3 g and broad spectrum antibiotics defined daily doses of antibiotics per 100 claims. Process measures include fidelity, knowledge, and confidence. Primary and secondary outcomes will be obtained using routine data. DISCUSSION: This study provides the opportunity to robustly assess the effect of adding an in-practice training co-intervention to audit and feedback. Its behaviour change theory-informed content will allow replication of the different components and can inform future training interventions. TRIAL REGISTRATION: ISRCTN, ISRCTN12345678 . Registered 18 June 2020.

Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion.

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.

Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy.

Since the 1960s, a single class of agent has been licensed targeting virus-encoded ion channels, or 'viroporins', contrasting the success of channel blocking drugs in other areas of medicine. Although resistance arose to these prototypic adamantane inhibitors of the influenza A virus (IAV) M2 proton channel, a growing number of clinically and economically important viruses are now recognised to encode essential viroporins providing potential targets for modern drug discovery. We describe the first rationally designed viroporin inhibitor with a comprehensive structure-activity relationship (SAR). This step-change in understanding not only revealed a second biological function for the p7 viroporin from hepatitis C virus (HCV) during virus entry, but also enabled the synthesis of a labelled tool compound that retained biological activity. Hence, p7 inhibitors (p7i) represent a unique class of HCV antiviral targeting both the spread and establishment of infection, as well as a precedent for future viroporin-targeted drug discovery.

Using the behaviour change technique taxonomy v1 (BCTTv1) to identify the active ingredients of pharmacist interventions to improve non-hospitalised patient health outcomes.

OBJECTIVES: The aim of this study was to identify which behaviour change techniques (BCTs) were present in intervention and control groups of randomised controlled trials (RCTs) included in a Cochrane systematic review. SETTING: The RCTs included were conducted in community, primary and/or ambulatory-care settings. PARTICIPANTS: The data set was derived from 86 RCTs from an interim update of the Cochrane review of the effectiveness of pharmacist services on non-hospitalised patient outcomes. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the identification of BCTs scheduled for delivery in intervention and control groups of the RCTs. The secondary outcome measure was to identify which BCTs are not being utilised in intervention and control groups of the RCTs. RESULTS: The intervention and control groups included 31 and 12 BCTs, respectively. The number of identifiable BCTs/study ranged from 0 to 12 in the intervention groups (mean 3.01 (SD 2.4)) and 0 to 6 in the control groups (mean 0.38 (SD 0.84)). The most commonly identified BCTs in the intervention groups were: instruction on how to perform the behaviour (55%, n=47) (also the most common BCT in control groups); problem solving (29%, n=25); information about health consequences (24%, n=21); social support (practical) (24%, n=21); and social support (unspecified) (23%, n=20) (the second most common BCT in control groups). Thirteen trials had no identifiable BCTs in either group. CONCLUSION: The pharmacist interventions presented in this study did not use the full range of available BCTs. Furthermore, the reporting of BCTs was incomplete for both intervention and control groups, thereby limiting the utility and reproducibility of the interventions. Future interventions should be designed and reported using relevant taxonomies and checklists for example, BCT taxonomy and TIDieR (the template for intervention description and replication).

Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza.

Pandemic influenza A virus (IAV) remains a significant threat to global health. Preparedness relies primarily upon a single class of neuraminidase (NA) targeted antivirals, against which resistance is steadily growing. The M2 proton channel is an alternative clinically proven antiviral target, yet a near-ubiquitous S31N polymorphism in M2 evokes resistance to licensed adamantane drugs. Hence, inhibitors capable of targeting N31 containing M2 (M2-N31) are highly desirable. Rational in silico design and in vitro screens delineated compounds favouring either lumenal or peripheral M2 binding, yielding effective M2-N31 inhibitors in both cases. Hits included adamantanes as well as novel compounds, with some showing low micromolar potency versus pandemic "swine" H1N1 influenza (Eng195) in culture. Interestingly, a published adamantane-based M2-N31 inhibitor rapidly selected a resistant V27A polymorphism (M2-A27/N31), whereas this was not the case for non-adamantane compounds. Nevertheless, combinations of adamantanes and novel compounds achieved synergistic antiviral effects, and the latter synergised with the neuraminidase inhibitor (NAi), Zanamivir. Thus, site-directed drug combinations show potential to rejuvenate M2 as an antiviral target whilst reducing the risk of drug resistance.

The association of periodontal disease with the complications of diabetes mellitus. A systematic review.

This review investigated the association of periodontal disease with diabetes mellitus (DM) and diabetic complications. PubMed/MEDLINE was searched including search terms "periodontal" OR "periodontitis" AND "diabetic complications" OR "diabetic retinopathy" OR "diabetic nephropathy" OR "diabetic neuropathy" OR "cardiovascular disease diabetes" OR "myocardial infarction diabetes" OR "cerebrovascular disease diabetes" OR "stroke diabetes" OR "peripheral vascular disease diabetes". Fourteen studies included in this review consistently reported an increased risk for diabetic complications including microvascular, macrovascular and death in the presence of periodontal disease. Higher risks for diabetic retinopathy (odds ratios: 2.8-8.7), neuropathy (3.2-6.6), nephropathy (1.9-8.5), cardiovascular complications (1.28-17.7) and mortality (2.3-8.5) were reported for people with diabetes with periodontitis compared to those with diabetes who have no periodontitis. This novel review summarizes current data providing further evidence of a link between poor oral health and DM and its complications. It has also drawn attention to major limitations of the available data linking periodontal disease and diabetic complications.

Behaviour change techniques associated with smoking cessation in intervention and comparator groups of randomized controlled trials: a systematic review and meta-regression.

AIMS: To estimate the strengths of associations between use of behaviour change techniques (BCTs) and clusters of BCTs in behavioural smoking cessation interventions and comparators with smoking cessation rates. METHOD: Systematic review and meta-regression of biochemically verified smoking cessation rates on BCTs in interventions and comparators in randomized controlled trials, adjusting for a priori-defined potential confounding variables, together with moderation analyses. Studies were drawn from the Cochrane Tobacco Addiction Group Specialised Register. Data were extracted from published and unpublished (i.e. obtained from study authors) study materials by two independent coders. Adequately described intervention (k = 143) and comparator (k = 92) groups were included in the analyses (n = 43 992 participants). Using bivariate mixed-effects meta-regressions, while controlling for key a priori confounders, we regressed smoking cessation on (a) three BCT groupings consistent with dual-process theory (i.e. associative, reflective motivational and self-regulatory), (b) 17 expert-derived BCT groupings (i.e. BCT taxonomy version 1 clusters) and (c) individual BCTs from the BCT taxonomy version 1. RESULTS: Among person-delivered interventions, higher smoking cessation rates were predicted by BCTs targeting associative and self-regulatory processes (B = 0.034, 0.041, P < 0.05), and by three individual BCTs (prompting commitment, social reward, identity associated with changed behaviour). Among written interventions, BCTs targeting taxonomy cluster 10a (rewards) predicted higher smoking cessation (B = 0.394, P < 0.05). Moderation effects were observed for nicotine dependence, mental health status and mode of delivery. CONCLUSIONS: Among person-delivered behavioural smoking cessation interventions, specific behaviour change techniques and clusters of techniques are associated with higher success rates.