Contemporary operative caries management:consensus recommendations on minimally invasive caries removal

The International Caries Consensus Collaboration (ICCC) presented recommendations on terminology, on carious tissue removal and on managing cavitated carious lesions. It identified 'dental caries' as the name of the disease that dentists should manage, and the importance of controlling the activity of existing cavitated lesions to preserve hard tissues, maintain pulp sensibility and retain functional teeth in the long term. The ICCC recommended the level of hardness (soft, leathery, firm, and hard dentine) as the criterion for determining the clinical consequences of the disease and defined new strategies for carious tissue removal: 1) Selective removal of carious tissue - including selective removal to soft dentine and selective removal to firm dentine; 2) stepwise removal - including stage 1, selective removal to soft dentine, and stage 2, selective removal to firm dentine 6 to 12 months later; and 3) non-selective removal to hard dentine - formerly known as complete caries removal (a traditional approach no longer recommended). Adoption of these terms will facilitate improved understanding and communication among researchers, within dental educators and the wider clinical dentistry community. Controlling the disease in cavitated carious lesions should be attempted using methods which are aimed at biofilm removal or control first. Only when cavitated carious dentine lesions are either non-cleansable or can no longer be sealed, are restorative interventions indicated. Carious tissue is removed purely to create conditions for long-lasting restorations. Bacterially contaminated or demineralised tissues close to the pulp do not need to be removed. The evidence and, therefore these recommendations, supports minimally invasive carious lesion management, delaying entry to, and slowing down, the destructive restorative cycle by preserving tooth tissue, maintaining pulp sensibility and retaining the functional tooth-restoration complex long-term

Pollination and biological control research: are we neglecting two billion smallholders

Food insecurity is a major world problem, with ca. 870 million people in the world being chronically undernourished. Most of these people live in tropical, developing regions and rely on smallholder farming for food security. Solving the problem of food insecurity is thought to depend, in part, on managing ecosystem services, such as the pollination of crops and the biological control of crop pests, to enhance or maintain food production. Our knowledge regarding regulating ecosystem services in smallholder-farmed (or dualistic) landscapes is limited and whilst pollination has been the focus of considerable research, the provision of natural enemy services, important for every crop worldwide, has been relatively neglected. In order to assess whether ecosystem-service research adequately represents smallholder-farmed landscapes, whilst also considering climatic region and national economic status, we examined the constituent studies of recent quantitative reviews relevant to biological control and pollination. No regulating ecosystem service meta-analysis, to our knowledge, has focussed on smallholder agriculture despite its importance to billions of peoples’ local food security. We found that whilst smallholdings contributed 16% of global farmland area and 83% of the global agricultural population (estimated using FAO’s World Census of Agriculture 2000) only 22 of 190 studies (12%), overall, came from smallholder-farmed landscapes. These smallholder studies mostly concerned coffee production (16 studies). Individual reviews of biological control were significantly and strongly biased towards data from large-scale farming in temperate regions. In contrast pollination reviews included more smallholder studies and were more balanced for climate regions. The high diversity of smallholder-farmed landscapes implies that more research will be needed to understand them compared to large-scale landscapes but we found far more research from the latter. We highlight that these skews in research effort have implications for sustainable intensification and the food security of billions in the developing world. In particular we urge for balance in future ecosystem-services research and synthesis by greater consideration of a diverse range of smallholder-farmed landscapes in Africa and continental Asia

Two decades of ART: improving on success through further research

Since the introduction of the Atraumatic Restorative Treatment (ART) approach over twenty years ago, more than 190 research publications have appeared. The last research agenda defining research priorities for ART was published in 1999. The objective of the present work was to review existing research in the context of future research priorities for ART. MATERIAL AND METHODS: An internet survey was conducted amongst those who had published on ART or were known to be working on the ART approach, to solicit their views as to areas of future ART research. Three broad categories were defined, namely: 1. Basic and laboratory research; 2. Clinical research, and, 3. Community, Public Health, Health Services Research. RESULTS: A 31% response rate was achieved. The study identified a number of new areas of research as well as areas where additional research is required. These are expressed as recommendations for future ART research. CONCLUSIONS: The ART approach is based on a robust, reliable and ever-growing evidence base concerning its clinical applications which indicates that it is a reliable and quality treatment approach. In common with all other oral health care procedures, targeted applied research is required to improve the oral health care offered

Polyglutamine tracts regulate beclin 1-dependent autophagy

Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different proteins, such as huntingtin in Huntington's disease and ataxin 3 in spinocerebellar ataxia type 3 (SCA3). Age at onset of disease decreases with increasing polyglutamine length in these proteins and the normal length also varies. PolyQ expansions drive pathogenesis in these diseases, as isolated polyQ tracts are toxic, and an N-terminal huntingtin fragment comprising exon 1, which occurs $\textit{in vivo}$ as a result of alternative splicing, causes toxicity. Although such mutant proteins are prone to aggregation, toxicity is also associated with soluble forms of the proteins. The function of the polyQ tracts in many normal cytoplasmic proteins is unclear. One such protein is the deubiquitinating enzyme ataxin 3 (refs 7, 8), which is widely expressed in the brain. Here we show that the polyQ domain enables wild-type ataxin 3 to interact with beclin 1, a key initiator of autophagy. This interaction allows the deubiquitinase activity of ataxin 3 to protect beclin 1 from proteasome-mediated degradation and thereby enables autophagy. Starvation-induced autophagy, which is regulated by beclin 1, was particularly inhibited in ataxin-3-depleted human cell lines and mouse primary neurons, and $\textit{in vivo}$ in mice. This activity of ataxin 3 and its polyQ-mediated interaction with beclin 1 was competed for by other soluble proteins with polyQ tracts in a length-dependent fashion. This competition resulted in impairment of starvation-induced autophagy in cells expressing mutant huntingtin exon 1, and this impairment was recapitulated in the brains of a mouse model of Huntington's disease and in cells from patients. A similar phenomenon was also seen with other polyQ disease proteins, including mutant ataxin 3 itself. Our data thus describe a specific function for a wild-type polyQ tract that is abrogated by a competing longer polyQ mutation in a disease protein, and identify a deleterious function of such mutations distinct from their propensity to aggregate.We thank the Wellcome Trust (Principal Research Fellowship to D.C.R. (095317/Z/11/Z), Wellcome Trust Strategic Grant to Cambridge Institute for Medical Research (100140/Z/12/Z)), National Institute for Health Research Biomedical Research Centre at Addenbrooke’s Hospital, and Addenbrooke’s Charitable Trust and Federation of European Biochemical Societies (FEBS Long-Term Fellowship to A.A.) for funding; R. Antrobus for mass spectrometry analysis; S. Luo for truncated HTT constructs; M. Jimenez-Sanchez and C. Karabiyik for assistance with the primary mouse cell cultures; and J. Lim and Z. Ignatova for reagents

The ART approach: clinical aspects reviewed

The success of ART as a caries management approach is supported by more than 20 years of scientific evidence. ART follows the contemporary concepts of modern cariology and restorative dentistry. It challenges treatment concepts such as step-wise excavation and the need for complete removal of affected dentine. The ART approach so far has mainly used high-viscosity glass-ionomer as the sealant and restorative material. Cariostatic and remineralization properties have been ascribed to this material which requires further research to establish its clinical relevance. The adhesion of high-viscosity glass-ionomer to enamel in pits and fissures is apparently strong, as its remnants, blocking the pits and fissures, have been considered a possible reason for the low prevalence of carious lesion development after the glass-ionomer has clinically disappeared from it. Encapsulated high-viscosity glass-ionomers may lead to higher restoration survival results than those of the hand-mixed version and should, therefore, not be neglected when using ART. Similarly, the use of resin-modified glass-ionomer with ART should be researched. The effectiveness of ART when compared to conventional caries management approaches has been shown in numerous studies. Proper case selection is an important factor for long-lasting ART restoration survival. This is based on the caries risk situation of the individual, the size of the cavity opening, the strategic position of the cavitated tooth and the presence of adequate caries control measures. As the operator is one of the main causes for failure of ART restorations, attending a well-conducted ART training course is mandatory for successful implementation of ART

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Why dispersal should be maximized at intermediate scales of heterogeneity

Citation: Skelsey, P., . . . & Garret, K. (2013). Why dispersal should be maximized at intermediate scales of heterogeneity. Theoretical Ecology, 6(2), 203-211. https://doi.org/10.1007/s12080-012-0171-3Dispersal is a fundamental biological process that results in the redistribution of organisms due to the interplay between the mode of dispersal, the range of scales over which movement occurs, and the scale of spatial heterogeneity, in which patchiness may occur across a broad range of scales. Despite the diversity of dispersal mechanisms and dispersal length scales in nature, we posit that a fundamental scaling relationship should exist between dispersal and spatial heterogeneity. We present both a conceptual model and mathematical formalization of this expected relationship between the scale of dispersal and the scale of patchiness, which predicts that the magnitude of dispersal (number of individuals) among patches should be maximized when the scale of spatial heterogeneity (defined in terms of patch size and isolation) is neither too fine nor too coarse relative to the gap-crossing abilities of a species. We call this the “dispersal scaling hypothesis” (DSH). We demonstrate congruence in the functional form of this relationship under fundamentally different dispersal assumptions, using well-documented isotropic dispersal kernels and empirically derived dispersal parameters from diverse species, in order to explore the generality of this finding. The DSH generates testable hypotheses as to when and under what landscape scenarios dispersal is most likely to be successful. This provides insights into what management scenarios might be necessary to either restore landscape connectivity, as in certain conservation applications, or disrupt connectivity, as when attempting to manage landscapes to impede the spread of an invasive species, pest, or pathogen