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North-South variation in the supply of meat has always been present. Sharing of meat was the rule but in the multi-centric Neolithic revolution when domestication of animals and plants co-evolved class differences became pronounced-aristocrats and inferior proletariats and “lesser breeds and lower orders” started to form. The distribution of natural domesticates was uneven with the near-east and a temperate band across Europe well off compared with Africa and the Americas. The Columbian exchange changed this as meat became abundant in the New World who then exported to Europe. Wars, expropriations and genocides were over the meat supply and acquiring pastureland or water. Colonial plantation profits paid for meat imports from “settler colonies” indigenous or poor peoples on low meat pro-pellagrous diets were considered inferior whatever their colour and had poorer health and life expectancy. Attempts to correct hunger in the resultant ramshackle “Third world” concentrated on calories fuelling population booms and busts and delaying demographic, epidemiological and economic transitions. High meat variances are narrowing in China and Asia but need help elsewhere in the South. Dangers of not developing with a safe and sufficient meat supply include the emergence of zoonoses and mass migration. Reparations, rehabilitation and rejuvenation should concentrate on reconstituting a meat commons giving us a shot at redemption and survival.

Pellagra is caused by a dietary deficiency of milk and meat leading to insufficient nicotinamide (vitamin B3), the precursor to nicotinamide adenine dinucleotide (NAD). “Pellagra sine pellagra” was well recognised and may be common as supplementation was never globally implemented and a screening test never developed. Meat and milk intake varies 30-fold globally so there are perhaps 2 billion at risk of deficiency. Such patients will have physical and cognitive stunting, poor conduct and be prone to acute and chronic infections, including TB, and premature ageing, including dementia. Resilience may be poor to NAD-consuming insults whether chemical, microbial or traumatic that conspires to cause brain injury but comes with the opportunity for pre-conception dietary corrections breaking cycles of deprivation and poor educational outcomes. Such individuals may otherwise be subject to discrimination as was the pellagra ridden “Butterfly” caste causing racial and ethic tensions. Poor countries with many having to spend 50-80% of income on food and very little on animal produce cannot develop properly unlike wealthier meat rich empires, past and present. The many benefits of experiments with food programmes and basic income support are because, as Engels curves predict, more is spent on milk and meat enabling demographic, epidemiological, and economic transitions and modernity.

Glaucoma is the leading cause of irreversible blindness globally, with Primary open angle glaucoma (POAG) being the commonest subtype. POAG is characterized by an increase in intraocular pressure (IOP), leading to optic nerve damage and subsequent visual field defects. Despite the clinical burden this disease poses, current therapies aim to reduce IOP rather than targeting the underling pathogenesis. Although the pathogenesis of POAG is complex, the culprit for this increase in IOP resides in the aqueous humour (AH) outflow pathway; the trabecular meshwork (TM) and Schlemm’s canal. Dysfunction in these tissues is due to inherent mitochondrial dysfunction, calcium influx sensitivity, increase in reactive oxygen species (ROS) production, TGFβ-2 induction, leading to a sustained inflammatory response. Magnesium is the second most common intracellular cation, and is a major co-factor in over 300 reactions, being highly conserved within energy-dependent organelles such as the mitochondria. Magnesium deficiency has been observed in POAG and is linked to inflammatory and fibrotic responses, as well as increased oxidative stress (OS). Magnesium supplementation been shown to reduce cellular ROS, alleviate mitochondrial dysregulation and has further antifibrotic and anti-inflammatory properties within ocular tissues, and other soft tissues prone to fibrosis, suggesting that magnesium can improve visual fields in patients with POAG. The link between magnesium deficiency and glaucoma pathogenesis as well as the potential role of magnesium supplementation in the management of patients with POAG will be explored within this review.

We evolved from herbivores to a meat eating “commons” in hunter-gatherer days and then to a non-egalitarian meat power struggle between classes and countries. Egalitarian-ism, trans-egalitarianism and extremes of inequality and hierarchy revolve around the fair-unfair distribution of meat surpluses and ownership of the means of meat production. Poor people on poor diets with too few micronutrients may explain many inequalities of human capital, height and health and divergent development of individuals and nations. Learning from past successes and collapses from switching trophic levels the lesson is that meat moderation toward the top of Engel’s curves, not calorie-centrism, is the best recipe for countries and classes. Improved health with longer lives and higher crystallised intelligence comes with an ample supply of micronutrients from animal products namely iron, zinc, vitamin A, vitamin B12 and other methyl-donors (such as choline), and nicotinamide (vitamin B3). We concentrate on nicotinamide whose deficits cause the degenerative condition pellagra that manifests as poor emotional and degenerative cognitive states with stunted lives and complex antisocial and dysbiotic effects caused by and causing poverty.

Pellagra has largely been forgotten. This is unfortunate as important lessons are to be learnt about the diseases and social and economic consequences of poverty – and for the root cause of poverty (and of affluence) – that involve dietary nicotinamide and nicotinamide adenine dinucleotide (NAD) homeostasis. NAD disruption can occur not only from poor diet but from increased consumption from genotoxic, infectious and metabolic stresses. NAD deficiency is closely linked to poor physical and intellectual development, premature ageing and diseases of ageing. Acute infections, many with NAD-consuming toxins, that may differentially affect the NAD-depleted, now include COVID-19. Some Covid manifestations, such as myoclonic encephalopathy and “Long Covid,” resemble pellagra clinically and biochemically as both have disturbed nicotinic and tryptophan metabolism. Symbionts that supply nicotinic acid, such as TB and some gut micro-organisms, can become dysbiotic if the diet is very deficient in milk and meat, as it is for 1–2 billion or more. High doses of nicotinamide lead to inhibition of NAD-consuming enzymes and excessive induction of nicotinamide-n-methyl transferase (NNMT) with consequent effects on the methylome: this gives a mechanism for an unrecognised hypervitaminosis-B3 with adverse effects of nicotinamide overload for consumers on a high meat diet with “fortified” foods and “high energy” drinks. Methods of measuring NAD metabolism routinely for screening the populations at risk of deficiency and in metabolically ill or infectious disease patients should be developed urgently. Successful intervention should improve human capital and prevent many aspects of poverty, reduce discrimination and even the drive to emigrate.

Optical coherence tomography (OCT) provides non-invasive, high-resolution in vivo imaging of the ocular surface and anterior segment. Over the years, it has become an essential tool for evaluating the anterior segment of the eye to monitor ocular development and ocular pathologies in both the clinical and research fields of ophthalmology and optometry. In this review, the clinical applications relating to the use of anterior segment OCT for imaging and quantifying normal and pathological features of the ocular surface, cornea, anterior chamber, and aqueous outflow system are summarised in a range of human ocular diseases. Applications of anterior segment OCT technology that have improved imaging and quantitation of ocular inflammation in experimental animal models of ocular diseases, such as anterior uveitis, microbial keratitis and glaucoma, are also described. The capacity to longitudinally evaluate anterior segment anatomical changes during development, and inflammation facilitates the understanding of the dynamics of tissue responses, and further enhances the intra-operative in vivo imaging during procedures, such as corneal transplantation and drug delivery. Future developments including in vivo ultrahigh-resolution anterior segment OCT, automated analyses of anterior segment OCT images and functional extensions of the technique, may revolutionise the clinical evaluation of anterior segment, corneal and ocular surface diseases.

In the cornea, resident immune cells are in close proximity to sensory nerves, consistent with their important roles in the maintenance of nerves in both homeostasis and inflammation. Using in vivo confocal microscopy in humans, and ex vivo immunostaining and fluorescent reporter mice to visualize corneal sensory nerves and immune cells, remarkable progress has been made to advance our understanding of the physical and functional interactions between corneal nerves and immune cells. In this review, we summarize and discuss recent studies relating to corneal immune cells and sensory nerves, and their interactions in health and disease. In particular, we consider how disrupted corneal nerve axons can induce immune cell activity, including in dendritic cells, macrophages and other infiltrating cells, directly and/or indirectly by releasing neuropeptides such as substance P and calcitonin gene-related peptide. We summarize growing evidence that the role of corneal intraepithelial immune cells is likely different in corneal wound healing versus other inflammatory-dominated conditions. The role of different types of macrophages is also discussed, including how stromal macrophages with anti-inflammatory phenotypes communicate with corneal nerves to provide neuroprotection, while macrophages with pro-inflammatory phenotypes, along with other infiltrating cells including neutrophils and CD4

Our evolution and recent history can be seen as a “World Hunt” for meat as part of an omnivorous diet. Meat contains key micronutrients namely Nicotinamide (vitamin B3) and methyl-donors with deficits causing pellagra, an archetypal disease of poverty. Inequality is a leading ultimate risk factor invoked in the aetiology of common diseases let alone threats from climate change and pandemic triggered catastrophes. We hypothesize that the origin of inequality was our evolutionary and nutritional move from equal to unequal sharing of the meat supply some 10–20 thousand years ago. High meat intake may have bioengineered powerful ruling classes and lower intake the proletariat with higher fertility, but inferior (brain) health. A fairer quantity of a safer meat intake in future should moderate global variances of fertility, height, health, and prosperity. Death rates of acute infections including emergent zoonoses (such as COVID-19) and chronic infections (such as TB) should fall as might the incidence of some diseases of affluence. Meat justice by improving human capital could make redundant superficial markers, such as skin colour, used to discriminate against peoples and heal a divided world.

Age-related macular degeneration (AMD) is the most common cause of blindness in the Western world and is characterised in its latter stages by retinal cell death and neovascularisation and earlier stages with the loss of parainflammatory homeostasis. Patients with neovascular AMD (nAMD) are treated with frequent intraocular injections of anti-vascular endothelial growth factor (VEGF) therapies, which are not only unpopular with patients but carry risks of sight-threatening complications. A minority of patients are unresponsive with no alternative treatment available, and some patients who respond initially eventually develop a tolerance to treatment. New therapeutics with improved delivery methods and sustainability of clinical effects are required, in particular for non-neovascular AMD (90% of cases and no current approved treatments). There are age-related and disease-related changes that occur which can affect ocular drug delivery. Here, we review the latest emerging therapies for AMD, their delivery routes and implications for translating to clinical practice. LINKED ARTICLES: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

Heterotopic ossification (HO), the pathological formation of ectopic bone, is a debilitating condition which can cause chronic pain, limit joint movement, and prevent prosthetic limb fitting. The prevalence of this condition has risen in the military population, due to increased survivorship following blast injuries. Current prophylaxes, which aim to target the complex upstream biological pathways, are inconsistently effective ​and have a range of side-effects that make them unsuitable for combat-injured personnel. As such, many patients must undergo further surgery to remove the formed ectopic bone. In this study, a non-toxic, U.S. Food and Drug Administration (FDA) -approved calcium chelator, hexametaphosphate (HMP), is explored as a novel treatment paradigm for this condition, which targets the chemical, rather that biological, ​bone formation pathways. This approach allows not only prevention of pathological bone formation ​but also uniquely facilitates reversal, which current drugs cannot achieve. Targeted, minimally invasive delivery is achieved by loading HMP into an injectable colloidal alginate. These formulations significantly reduce ​the length of the ectopic bone formed in a rodent model of HO, with no effect on the adjacent skeletal bone. This study demonstrates the potential of localized dissolution as a new treatment ​and an alternative to surgery ​for pathological ossification and calcification conditions., Graphical abstract Image 1

Nicotinamide homeostasis is a candidate common denominator to explain smooth transitions, whether demographic, epidemiological or economic. This ‘NAD world’, dependent on hydrogen-based energy, is not widely recognised as it is neither measured nor viewed from a sufficiently multi-genomic or historical perspective. Reviewing the importance of meat and nicotinamide balances during our co-evolution, recent history suggests that populations only modernise and age well with low fertility on a suitably balanced diet. Imbalances on the low meat side lead to an excess of infectious disease, short lives and boom-bust demographics. On the high side, meat has led to an excess of degenerative, allergic and metabolic disease and low fertility. A ‘Goldilocks’ diet derived from mixed and sustainable farming (preserving the topsoil) allows for high intellectual capital, height and good health with controlled population growth resulting in economic growth and prosperity. Implementing meat equity worldwide could lead to progress for future generations on ‘spaceship’ earth by establishing control over population quality, thermostat and biodiversity, if it is not already too late.

Mitochondrial dynamics are regulated by a complex system of proteins representing the mitochondrial quality control (MQC). MQC balances antagonistic forces of fusion and fission determining mitochondrial and cell fates. In several neurological disorders, dysfunctional mitochondria show significant changes in gene and protein expression of the MQC and contribute to the pathophysiological mechanisms of cell damage. In this study, we evaluated the main gene and protein expression involved in the MQC in rats receiving traumatic brain injury (TBI) of different severities. At 6, 24, 48 and 120 hours after mild TBI (mTBI) or severe TBI (sTBI), gene and protein expressions of fusion and fission were measured in brain tissue homogenates. Compared to intact brain controls, results showed that genes and proteins inducing fusion or fission were upregulated and downregulated, respectively, in mTBI, but downregulated and upregulated, respectively, in sTBI. In particular, OPA1, regulating inner membrane dynamics, cristae remodelling, oxidative phosphorylation, was post-translationally cleaved generating differential amounts of long and short OPA1 in mTBI and sTBI. Corroborated by data referring to citrate synthase, these results confirm the transitory (mTBI) or permanent (sTBI) mitochondrial dysfunction, enhancing MQC importance to maintain cell functions and indicating in OPA1 an attractive potential therapeutic target for TBI.

Purpose Aging is a risk factor for dry eye disease. The aim of this study was to investigate if aging is associated with a range of signs of dry eye disease, including tear hyperosmolarity, reduced nerve density, and increased dendritic cell number, in mice. Method Healthy C57BL/6 female mice, aged 2 months (young, n = 10) and 22 months (aged, n = 11) were used. Clinical assessments included corneal sensitivity (Cochet-Bonnet esthesiometry), tear secretion (Phenol red thread test), tear film osmolarity (TearLab osmometer), and corneal thickness (optical coherence tomography). The sum length of the corneal superficial terminals and sub-basal nerves, density of vertical nerve projections, and density and tree area of resident epithelial dendritic cells, were assessed using immunofluorescence and confocal microscopy. Results Aged mice had significantly higher tear secretion, lower corneal sensitivity, and a thicker corneal stroma but thinner epithelium. There was no significant intergroup difference for tear osmolarity. Aged mice showed a significantly lower sum length of nerves in the superficial terminals and sub-basal plexus, relative to young mice. Dendritic cell density and morphology were similar in both groups. Conclusions In mice, aging is associated with higher tear secretion and corneal epithelial thinning, together with lower corneal nerve density and sensitivity. However, aging was not significantly associated with changes to tear osmolarity or dendritic cell density or size, despite a significant reduction in total nerve length. These findings demonstrate that aged mice exhibit some changes to ocular surface parameters that parallel the anomalies evident in dry eye disease.

BACKGROUND AIMS: Glaucoma is a leading cause of irreversible blindness involving loss of retinal ganglion cells (RGC). Mesenchymal stromal cells (MSC) have shown promise as a paracrine-mediated therapy for compromised neurons. It is, however, unknown whether dental pulp stem cells (DPSC) are effective as a cellular therapy in glaucoma and how their hypothesized influence compares with other more widely researched MSC sources. The present study aimed to compare the efficacy of adipose-derived stem cells, bone marrow-derived MSC (BMSC) and DPSC in preventing the loss of RGC and visual function when transplanted into the vitreous of glaucomatous rodent eyes. METHODS: Thirty-five days after raised intraocular pressure (IOP) and intravitreal stem cell transplantation, Brn3a(+) RGC numbers, retinal nerve fibre layer thickness (RNFL) and RGC function were evaluated by immunohistochemistry, optical coherence tomography and electroretinography, respectively. RESULTS: Control glaucomatous eyes that were sham-treated with heat-killed DPSC had a significant loss of RGC numbers, RNFL thickness and function compared with intact eyes. BMSC and, to a greater extent, DPSC provided significant protection from RGC loss and RNFL thinning and preserved RGC function. DISCUSSION: The study supports the use of DPSC as a neuroprotective cellular therapy in retinal degenerative disease such as glaucoma.

Scarring/Opacity on the surface of the eye and vascularisation following infectious diseases, inflammation and corneal trauma are often a leading cause of blindness. The 'gold standard' treatment to prevent corneal scarring is the application of amniotic membrane (AM) to the ocular surface in the acute stage of injury. Although clinically effective, the use of the AM is associated with biological variability and unpredictable responses. Potential health risks including disease transmission, significant ethical issues surrounding the tissue donation process and stringent regulations/storage conditions, preclude widespread use. Consequently, there is a demand for the development of a new, synthetic alternative, that is stable at room temperature, capable of protecting the wound and has the capacity to deliver anti-scarring and anti-inflammatory mediators. Here we have developed a micro-structured fluid gel eye drop, to deliver a potent anti-scarring molecule, decorin. We have compared the release of decorin from the formulated dressing to a typical gel film, demonstrating enhanced release for the fluid gel eye-drops. Therefore, we have investigated the effect of the fluid gel system in 2D human corneal fibroblast culture models, as well as shown the retention of the gellan fluid gel in an in vivo rat model. At the same time the efficacy of the fluid gel eye drop was studied in an organ culture model, whereby the fluid gel containing decorin, significantly (P 0.05) increased re-epithelialisation within 4 days of treatment.

Disorganization of the transparent collagenous matrix in the cornea, as a consequence of a variety of infections and inflammatory conditions, leads to corneal opacity and sight-loss. Such corneal opacities are a leading cause of blindness, according to the WHO. Public health programs target prevention of corneal scarring, but the only curative treatment of established scarring is through transplantation. Although attempts to minimize corneal scarring through aggressive control of infection and inflammation are made, there has been little progress in the development of anti-scarring therapies. This is owing to eye drop formulations using low viscosity or weak gelling materials having short retention times on the ocular surface. In this study, we report an innovative eye drop formulation that has the ability to provide sustained delivery of decorin, an anti-scarring agent. The novelty of this eye drop lies in the method of structuring during manufacture, which creates a material that can transition between solid and liquid states, allowing retention in a dynamic environment being slowly removed through blinking. In a murine model of Pseudomonas keratitis, applying the eye drop resulted in reductions of corneal opacity within 16 days. More remarkably, the addition of hrDecorin resulted in restoration of corneal epithelial integrity with minimal stromal opacity endorsed by reduced α-smooth muscle actin (αSMA), fibronectin, and laminin levels. We believe that this drug delivery system is an ideal non-invasive anti-fibrotic treatment for patients with microbial keratitis, potentially without recourse to surgery, saving the sight of many in the developing world, where corneal transplantation may not be available., Ophthalmology: novel eye drop brings sustained drug delivery to ocular surface An eye drop formulation that applies anti-scarring drugs to the surface of the eye helps reverse infection-induced corneal damage in mice. Hill et al. from the University of Birmingham, UK, formulated a fluid gel loaded with a wound-healing protein called decorin that conforms to the ocular surface and is cleared gradually through blinking. With colleagues in California, they applied the therapeutic eye drop to mice with bacterial eye infections that trigger sight-threatening corneal scarring. Within a matter of days, the team saw improvements in corneal transparency, with reductions in scar tissue and reconstitution of healthy cells. Such a drug delivery system, if successful in humans, could help save many people’s sight and reduce the need for corneal transplantation.

Aims and Scope: To further explore the role of dietary nicotinamide in both brain development and diseases, particularly those of ageing. Articles cover neurodegenerative disease and cancer. Also discussed are the effects of nicotinamide, contained in meat and supplements and derived from symbionts, on the major transitions of disease and fertility from ancient times up to the present day. A key role for the tryptophan – NAD ‘de novo’ and immune tolerance pathway are discussed at length in the context of fertility and longevity and the transitions from immune paresis to Treg-mediated immune tolerance and then finally to intolerance and their associated diseases. Abstract: Nicotinamide in human evolution increased cognitive power in a positive feedback loop originally involving hunting. As the precursor to metabolic master molecule NAD it is, as vitamin B3, vital for health. Paradoxically, a lower dose on a diverse plant then cereal-based diet fuelled population booms from the Mesolithic onwards, by upping immune tolerance of the foetus. Increased tolerance of risky symbionts, whether in the gut or TB, that excrete nicotinamide co-evolved as buffers for when diet was inadequate. High biological fertility, despite disease trade-offs, avoided the extinction of Homo sapiens and heralded the dawn of a conscious, creative, and pro-fertility culture. Nicotinamide equity now would stabilise populations and prevent NAD-based diseases of poverty and affluence.

Purpose Elevations in intraocular pressure (IOP) are associated with the development of glaucoma and loss of sight. High transforming growth factor-β (TGF-β) 1 levels in the eye’s anterior chamber can lead to dysfunctional contractions through RhoA signaling in trabecular meshwork (TM) cells and IOP spikes. Sustained high TGF-β levels leads to TM fibrosis and sustained increases in IOP. We investigated whether inhibiting RhoA, using a siRNA-mediated RhoA (siRhoA), controls IOP by altering TM expression of fibrosis and contractility-related proteins in a rodent model of glaucoma. Methods TGF-β was injected intracamerally twice a week into adult Sprague Dawley rats, and IOP was recorded with tonometry. Animals were euthanized on day 7 and 35 with TM expression of fibrosis and contractility-related proteins, as well as survival of retinal ganglion cells (RGCs) assessed with immunohistochemistry. siRNA against RhoA or enhanced green fluorescent protein (EGFP) was also injected intracamerally into select animals. Successful RhoA knockdown was determined with quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, and the effects of the knockdown on the parameters above analyzed. Results TGF-β caused increased TM contractile proteins and IOP spikes by day 7, sustained increases in IOP from day 15, and TM fibrosis at day 35. siRhoA abolished the transient 7 day IOP rise but not the later sustained IOP increase (due to fibrosis). At 35 days, TGF-β-related RGC loss was not prevented with siRhoA treatment. Conclusions We conclude that RhoA signaling mediates the early IOP rise induced by TM cellular changes associated with contractility but not the sustained IOP elevation caused by TM fibrosis. Thus, RhoA therapies offer a clinically relevant opportunity for IOP management, likely through the modulation of TM contractility, but appear to be ineffective in the amelioration of fibrosis.

The development of new materials for clinical use is limited by an onerous regulatory framework, which means that taking a completely new material into the clinic can make translation economically unfeasible. One way to get around this issue is to structure materials that are already approved by the regulator, such that they exhibit very distinct physical properties and can be used in a broader range of clinical applications. Here, the focus is on the structuring of soft materials at multiple length scales by modifying processing conditions. By applying shear to newly forming materials, it is possible to trigger molecular reorganization of polymer chains, such that they aggregate to form particles and ribbon-like structures. These structures then weakly interact at zero shear forming a solid-like material. The resulting self-healing network is of particular use for a range of different biomedical applications. How these materials are used to allow the delivery of therapeutic entities (cells and proteins) and as a support for additive layer manufacturing of larger-scale tissue constructs is discussed. This technology enables the development of a range of novel materials and structures for tissue augmentation and regeneration.

Traumatic brain injury (TBI) is set to become the leading cause of neurological disability across all age groups. Currently, no reliable biomarkers exist to help diagnose the severity of TBI to identify patients who are at risk of developing secondary injuries. Thus, the discovery of reliable biomarkers for the management of TBI would improve clinical interventions. Inflammatory markers are particularly suited for biomarker discovery as TBI leads to very early alterations in inflammatory proteins. Using the Proseek Multiplex Inflammation assay, we measured in patients that had suffered mild TBI (n = 10) or severe TBI (n = 10) with extra-cranial injury or extracranial injury only (EC) (n = 10), 92 inflammation-associated proteins in serum obtained

Purpose: To evaluate the efficacy of anti-VEGF agents for treating choroidal neovascularization (CNV) when delivered topically using novel cell-penetrating peptides (CPPs) compared with delivery by intravitreal (ivit) injection.Methods: CPP toxicity was investigated in cell cultures. Ivit concentrations of ranibizumab and bevacizumab after topical administration were measured using ELISA. The biological efficacy of topical anti-VEGF + CPP complexes was compared with ivit anti-VEGF injections using an established model of CNV.Results: CPPs were nontoxic in vitro. In vivo, after topical eye drop delivery, CPPs were present in the rat anterior chamber within 6 minutes. A single application of CPP + bevacizumab eye drop delivered clinically relevant concentrations of bevacizumab to the posterior chamber of the rat eye in vivo. Similarly, clinically relevant levels of CPP + ranibizumab and CPP + bevacizumab were detected in the porcine vitreous and retina ex vivo. In an established model of CNV, mice treated with either a single ivit injection of anti-VEGF, twice daily CPP + anti-VEGF eye drops or daily dexamethasone gavage for 10 days all had significantly reduced areas of CNV when compared with lasered eyes without treatment.Conclusions: CPPs are nontoxic to ocular cells and can be used to deliver therapeutically relevant doses of ranibizumab and bevacizumab by eye drop to the posterior segment of mouse, rat, and pig eyes. The CPP + anti-VEGF drug complexes were cleared from the retina within 24 hours, suggesting a daily eye drop dosing regimen. Daily, topically delivered anti-VEGF with CPP was as efficacious as a single ivit injection of anti-VEGF in reducing areas of CNV in vivo.

Meat and vitamin B 3 – nicotinamide – intake was high during hunter-gatherer times. Intake then fell and variances increased during and after the Neolithic agricultural revolution. Health, height, and IQ deteriorated. Low dietary doses are buffered by ‘welcoming’ gut symbionts and tuberculosis that can supply nicotinamide, but this co-evolved homeostatic metagenomic strategy risks dysbioses and impaired resistance to pathogens. Vitamin B 3 deficiency may now be common among the poor billions on a low-meat diet. Disease transitions to non-communicable inflammatory disorders (but longer lives) may be driven by positive ‘meat transitions’. High doses of nicotinamide lead to reduced regulatory T cells and immune intolerance. Loss of no longer needed symbiotic ‘old friends’ compounds immunological over-reactivity to cause allergic and auto-immune diseases. Inhibition of nicotinamide adenine dinucleotide consumers and loss of methyl groups or production of toxins may cause cancers, metabolic toxicity, or neurodegeneration. An optimal dosage of vitamin B 3 could lead to better health, but such a preventive approach needs more equitable meat distribution. Some people may require personalised doses depending on genetic make-up or, temporarily, when under stress.

Traumatic brain injury (TBI) is the leading cause of death and disability in people younger than 45 in Western countries. Despite many studies, no reliable biomarkers have been found to assess TBI severity and predict recovery. MicroRNA (miRNA) profiling has become widely used to identify biomarkers and therapeutic targets. Through use of the TaqMan Array Human MicroRNA A+B Cards, the expression of 754 miRNAs was analyzed in serum of five mild TBI (mTBI) patients with extra-cranial injury (EC), five severe TBI (sTBI) patients with EC, and five healthy volunteers (HV) at 1 day and 15 days post-injury. The aim was to find candidate biomarkers able to discriminate between mTBI and sTBI. Following this, it was possible to select 10 miRNAs for further study in an enlarged validation cohort of 120 patients by using single TaqMan assays at the following time-points: T0-1 h, T4-12 h, T48-72 h, and 15 days from the injury. Analysis revealed two miRNAs (miR-425-5p and miR-502) that were significantly downregulated (p 0.05) in mTBI at early time-points and are ideal candidates for diagnosis of mTBI, and two miRNAs (miR-21 and miR-335) that were significantly upregulated (p 0.01) and are valid biomarkers for the diagnosis of sTBI. In addition, miR-425-5p was a strong predictor of 6-month outcome at T0-1 h and T4-12 h, while miR-21 was predictive of the outcome at T4-12 h. The panel of selected miRNAs shows promise as biomarkers to discriminate mTBI from sTBI. In addition, the selected miRNAs represent new potential therapeutic targets.

Compartmentalized redox faults are common to ageing diseases. Dietary constituents are catabolized to NAD(H) donating electrons producing proton-based bioenergy in coevolved, cross-species and cross-organ networks. Nicotinamide and NAD deficiency from poor diet or high expenditure causes pellagra, an ageing and dementing disorder with lost robustness to infection and stress. Nicotinamide and stress induce Nicotinamide-N-methyltransferase (NNMT) improving choline retention but consume methyl groups. High NNMT activity is linked to Parkinson’s, cancers, and diseases of affluence. Optimising nicotinamide and choline/methyl group availability is important for brain development and increased during our evolution raising metabolic and methylome ceilings through dietary/metabolic symbiotic means but strict energy constraints remain and life-history tradeoffs are the rule. An optimal energy, NAD and methyl group supply, avoiding hypo and hyper-vitaminoses nicotinamide and choline, is important to healthy ageing and avoids utilising double-edged symbionts or uncontrolled autophagy or reversions to fermentation reactions in inflammatory and cancerous tissue that all redistribute NAD(P)(H), but incur high allostatic costs.

Serotonin syndrome (SS) (also referred to as serotonin toxicity) is a potentially life-threatening drug-induced toxidrome associated with increased serotonergic activity in both the peripheral (PNS) and central nervous systems (CNS). It is characterised by a dose-relevant spectrum of clinical findings related to the level of free serotonin (5-hydroxytryptamine [5-HT]), or 5-HT receptor activation (predominantly the 5-HT1Aand 5-HT2Asubtypes), which include neuromuscular abnormalities, autonomic hyperactivity, and mental state changes. Severe SS is only usually precipitated by the simultaneous initiation of 2 or more serotonergic drugs, but the syndrome can also occur after the initiation of a single serotonergic drug in a susceptible individual, the addition of a second or third agent to long-standing doses of a maintenance serotonergic drug, or after an overdose. The combination of a monoamine oxidase inhibitor (MAOI), in particular MAO-A inhibitors that preferentially inhibit the metabolism of 5-HT, with serotonergic drugs is especially dangerous, and may lead to the most severe form of the syndrome, and occasionally death. This review describes our current understanding of the pathophysiology, clinical presentation and management of SS, and summarises some of the drugs and interactions that may precipitate the condition. We also discuss the newer novel psychoactive substances (NPSs), a growing public health concern due to their increased availability and use, and their potential risk to evoke the syndrome. Finally, we discuss whether the inhibition of tryptophan hydroxylase (TPH), in particular the neuronal isoform (TPH2), may provide an opportunity to pharmacologically target central 5-HT synthesis, and so develop new treatments for severe, life-threatening SS.

Good health and rapid progress depend on an optimal dose of nicotinamide. Too little meat triggers the neurodegenerative condition pellagra and tolerance of symbionts such as tuberculosis (TB), risking dysbioses and impaired resistance to acute infections. Nicotinamide deficiency is an overlooked diagnosis in poor cereal-dependant economies masquerading as ‘environmental enteropathy’ or physical and cognitive stunting. Too much meat (and supplements) may precipitate immune intolerance and autoimmune and allergic disease, with relative infertility and longevity, via the tryptophan-nicotinamide pathway. This switch favours a dearth of regulatory T (Treg) and an excess of T helper cells. High nicotinamide intake is implicated in cancer and Parkinson’s disease. Pro-fertility genes, evolved to counteract high-nicotinamide-induced infertility, may now be risk factors for degenerative disease. Moderation of the dose of nicotinamide could prevent some common diseases and personalised doses at times of stress or, depending on genetic background or age, may treat some other conditions.

Meat and nicotinamide acquisition was a defining force during the 2-million-year evolution of the big brains necessary for, anatomically modern, Homo sapiens to survive. Our next move was down the food chain during the Mesolithic ‘broad spectrum’, then horticultural, followed by the Neolithic agricultural revolutions and progressively lower average ‘doses’ of nicotinamide. We speculate that a fertility crisis and population bottleneck around 40 000 years ago, at the time of the Last Glacial Maximum, was overcome by Homo (but not the Neanderthals) by concerted dietary change plus profertility genes and intense sexual selection culminating in behaviourally modern Homo sapiens. Increased reliance on the ‘de novo’ synthesis of nicotinamide from tryptophan conditioned the immune system to welcome symbionts, such as TB (that excrete nicotinamide), and to increase tolerance of the foetus and thereby fertility. The trade-offs during the warmer Holocene were physical and mental stunting and more infectious diseases and population booms and busts. Higher nicotinamide exposure could be responsible for recent demographic and epidemiological transitions to lower fertility and higher longevity, but with more degenerative and auto-immune disease.

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Purpose In neovascular age-related macular degeneration (AMD) blood vessels grow from the choroid under the retina causing macular damage and scarring. Anti-VEGF drugs such as, ranibizumab or aflibercept are administered by intravitreal injection to treat AMD related neovascularisation, We present a novel cell-penetrating peptide construct (CPPC) topical delivery system to deliver Ranibizumab to the retina using drops. Methods Peptides were produced using standard solid-phase peptide synthesis. They were analysed using mass spectrometry and purified using high-pressure liquid chromatography and used at a purity of >95%. CPPC were built around the drugs by vortexing for 10 seconds and incubating at room temperature. Drug delivery experiments were carried out ex-vivo in freshly enucleated porcine eyes. In vivo experiments were carried out in C57 mice. Mice had a three 100 μm laser burns to the choroid to model neo-vascularisation in AMD. They then received a single intravitreal injection of an anti-VEGF agent or CPPC/Ranibizumab applied topically to the conjunctival sac twice daily for the duration of the experiment. Choroidal neovascularisation was measured by immunohistochemistry. Results Ex vivo delivery to enucleated porcine eyes demonstrated that a single 60 μL drop could deliver 1.7 ± 0.4 μg/mL of ranibizumab to the vitreous cavity. Confocal images of immunohistochemistry on retinal wholemounts showed ranibizumab within the retina. In vivo experiments demonstrated both intravitreal injection and CPPC bound Ranibizumab reduced neovascularisation equally, compared to controls Conclusions CPPC can be used topically to deliver therapeutic levels of Ranibizumab to the posterior segment.

PURPOSE:\ud\udTo investigate whether Decorin, a matrikine that regulates extracellular matrix (ECM) deposition, can reverse established trabecular meshwork (TM) fibrosis, lower IOP, and reduce progressive retinal ganglion cell (RGC) death in a novel rodent model of TM fibrosis.\udMETHODS:\ud\udAdult rats had intracameral (IC) injections of human recombinant (hr) TGF-β over 30 days (30 d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17 d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30 d to evaluate resultant visual pathway dysfunction. In some animals TGF-β injections were stopped at 17 d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21 d and 30 d. Intraocular pressure was measured biweekly and eyes were processed for immunohistochemical analysis of ECM deposition to assess TM fibrosis and levels of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) to assess fibrolysis. The effect of hrDecorin treatment on RGC survival was also assessed.\udRESULTS:\ud\udTransforming growth factor-β injections caused sustained increases in ECM deposition in the TM and raised IOP by 17 d, responses that were associated with 42% RGC loss and a significant decrease in VEP amplitude measured at 30 d. Decorin treatment from 17 d reduced TGF-β-induced TM fibrosis, increased levels of MMP2 and MMP9 and lowered TIMP2 levels, and lowered IOP, preventing progressive RGC loss.\udCONCLUSIONS:\ud\udHuman recombinant Decorin reversed established TM fibrosis and lowered IOP, thereby rescuing RGC from progressive death. These data provide evidence for the candidacy of hrDecorin as a treatment for open-angle glaucoma.

Objective This study aims to investigate the role of microRNAs in early and late assessments of concussed athletes. Our hypothesis is that expression of certain microRNAs is altered following concussion, and these microRNAs have the potential to become novel biomarkers for early detection and monitoring of concussion. Design Prospective observational case control study. Setting University research centre, single centre. Participants 15 concussed athletes divided into 2 groups: Group A (n=9, assessed within a week post-concussion, median 4 days) and B (n=6, assessed over 2 weeks, median 31 days); and 8 age-matched healthy volunteers. Inclusion criteria: male/female elite athletes in contact sports (aged 18-40) who suffered concussion(s) in the games, and being symptomatic with normal neuro-radiological findings at enrolment. Outcome measures Levels of microRNAs (miR-21, miR-335, miR-425-5p, and miR-502) were measured in blood samples obtained from all participants. Main results miR425-5p was significantly down-regulated in Group A compared with Group B and healthy volunteers (grouping effect p=0.014; post hoc tests p=0.009 and 0.028, respectively). The level of miR425-5p correlated with the interval between assessment and concussion (r2=0.88, p Conclusions miR-425-5p is down-regulated in the early phase following sport concussion, and reaches normal levels in the late period, suggesting that it may be a unique microRNA signature for concussion. This makes miR-435-5p a promising candidate biomarker for early evaluation of concussion and monitoring of its recovery. Further longitudinal studies are on-going to establish the time course of miR-425-5p normalisation after concussion. Competing interests None.

Objective Changes in cerebral N-acetylaspartate and choline (NAA/Cho) or creatine (NAA/Cr) following a mild traumatic brain injury (mTBI) in sport have been measured by 1H (Proton) magnetic resonance spectroscopy (1H-MRS). We intend to investigate the effect that presenting symptomatology has on these parameters. Design Observational cohort study. Setting UK Premiership and Championship Rugby. Participants Athletes aged 18-40 years. Interventions (or assessment of risk factors) Concussed athletes identified by members of their enhanced-care clinical team. Imaging undertaken on a Philips Achieva 3.0 T MR scanner (32 channel SENSE coil). A PRESS sequence (et 37 ms, rt 2000 ms) generated spectra in a 20 mm MRS cubic voxel in right-sided superior frontal white matter. Symptoms were assessed using the IMPACT and SCAT-3 concussion assessment tools. Recruits were divided into either ‘symptomatic’ or ‘non-symptomatic’ at presentation based on a minimum severity score from either of these assessments. Outcome measures Analysis of raw parameters was undertaken utilising the TARQUIN 1H-MRS analytical software package. A Mann-Whitney-U test was performed to compare results between the symptomatic and non-symptomatic groups. Main results 33 concussed professional athletes were recruited. Of these a total of 7 Symptomatic (6 male, mean age 24yrs, scoring a total symptom severity score of Conclusions Within this population of concussed professional athletes early 1H-MRS did not differentiate between athletes presenting with modest/no symptoms and those presenting with significant symptoms. Competing interests None.

INTRODUCTION: Current treatments for Glioblastoma (GBM) are inadequate and immunotherapeutics may provide better outcomes for patients. Human recombinant Decorin is a glycoprotein that modulates inflammation & GBM growth by inhibiting Transforming Growth Factor, Vascular Endothelial Growth Factor and Epidermal Growth Factor Receptor. As Decorin is found in human tissue rich in fibrillar collagen (e.g. skin, heart, bone lung & liver) it is a potentially safe drug to be trialled in humans. METHOD: The local immune and microglial response to intracerebral injections of Decorin was investigated. Rats (n = 6 for each group) received either an injection of PBS (control) or 5¼l 5mg/ml Decorin and were sacrificed at 30min, 3 & 24 hrs or after continuous infusion of either PBS (control) or Decorin for 7 days. CSF samples were taken and analysed by ELISA and Luminex for presence of Decorin and change in inflammatory markers. Immunohistochemistry was also performed to investigate the effects of Decorin on microglia using OX42. RESULTS: There was no inflammatory reaction or cavity formation in brain. Decorin supressed the microglial response after direct injections into the brain compared to PBS control. At 30 mins, low levels of decorin were detected (with ELISA) in CSF and serum but none was detected at 3hrs and 24hrs after injection. CONCLUSION: Decorin showed no dose limiting toxicity, whilst maintaining its immunomodulatory effects in brain. These findings show a safe pharmacokinetic and toxicological profile.

In this perspective, we discuss the use of an anti-fibrotic agent Decorin to treat established fibrosis associated with glaucoma originally published by Hill et al. (2015). Glaucoma describes a group of progressive optic neuropathies that have the potential to cause irreversible blindness, for which it is recognized that a main risk factor is raised intraocular pressure (IOP). Currently, there is no precise explanation of why high IOP causes retinal ganglion cell (RGC) death. Factors contributing to IOP-related RGC death include compromised retrograde axonal transport of target derived neurotrophic factors, leading to activation of apoptosis and mitochondrial dysfunction after the biomechanical and ischemic insult of optic nerve head compression. In open-angle glaucoma (OAG), increases in IOP occur when aqueous humour (AqH) outflow through the trabecular meshwork (TM) is reduced, usually as a result of progressive abnormalities in TM cellularity and extracellular matrix (ECM) levels culminating in TM fibrosis (Prendes et al., 2013). These cellular and ECM changes (which includes upregulation of collagen IV, laminin, and fibronectin) in the TM, together with altered TM cell contractility, result in TM dysfunction and ultimately loss of the tightly controlled AqH outflow. Currently, treatments for glaucoma are symptomatic and focus on the use of drugs formulated as eye drops to lower IOP either by reducing AqH production or increasing AqH outflow through non-TM pathways. Alternatively, surgical insertion of shunts through the TM can drain AqH directly to the exterior of the eye, although these often become blocked. For some patients it seems that primary open-angle glaucoma is a fibroproliferative condition and no current treatment addresses the TM fibrosis that is the predominant underlying causes of TM dysregulation. The mechanisms that lead to TM dysfunction in OAG are multifactorial and may relate to dysregulated ocular inflammation since pathologically high levels of the pro-inflammatory cytokine transforming growth factor β (TGF-β) within the AqH and TM have been implicated. For example, some OAG patients have elevated levels of TGF-β1 and/or TGF-β2 in their AqH compared to age-matched patients with other forms of glaucoma (e.g., primary angle closure glaucoma and uveitis-associated secondary glaucoma) and with cataracts (Prendes et al., 2013). Other studies have shown that it is the TGF-β2 isoform that is significantly elevated in eyes with primary OAG compared with non-glaucomatous eyes, and have shown elevated TGF-β1 and TGF-β3 isoforms in pseudoexfoliative glaucoma and in primary angle closure glaucoma (Prendes et al., 2013). TGF-β1 and TGF-β2 are known potent fibrogenic factors and, at pathologically high levels in the eye, can induce the overexpression of ECM proteins that lead to TM dysfunctions (Prendes et al., 2013). TGF-βs also prevent the breakdown of ECM by inhibiting matrix metalloproteinases (MMP) (Ahmed et al. 2014), creating a pro-fibrotic microenvironment within the TM. TGF-β is directly implicated in the pathogenesis of ocular hypertension since: (1) infusion of TGF-β2 for 14 days in an anterior eye segment perfusion culture model significantly increased IOP (Battacharya et al., 2009); (2) adenoviral gene delivery of human TGF-β2 into the anterior segment to the rodent eye reduced AqH outflow and increased IOP (Shepard et al., 2010); and (3) TGF-β1 gene delivery by adenovirus to the anterior segment of the rat eye increased IOP (Robertson et al., 2010). Thus, treatment of the TM in OAG with a TGF-β antagonist may help to ablate TM fibrogenesis, thereby perturbing the progression of OAG pathology. The matrikine Decorin is a small leucine-rich proteoglycan that regulates cell proliferation, survival and differentiation by antagonizing a panel of growth factors and/or their receptors, including TGF-β, epidermal growth factor, vascular endothelial growth factor, hepatocyte growth factor and insulin-like growth factor-1. Decorin also ‘decorates’ collagen, interfering with collagen fibrillogenesis and stabilizing collagen fibres. In addition, Decorin enhances matrix metalloproteinases (MMP) activity by increasing levels of tissue plasminogen activator (tPA), thus enabling plasmin-dependent activation of MMP by cleavage of plasminogen to plasmin, and reducing levels of PAI-1 and tissue inhibitors of MMPs, further facilitating MMP activation. The fibrolytic actions of Decorin have been harnessed to attenuate the progression of tissue damage in other fibroproliferative pathologies, including juvenile communicating hydrocephalus (Botfield et al., 2013) and spinal cord injury (Ahmed et al., 2014), making Decorin an ideal candidate for treating TM fibrosis and progressive RGC loss in glaucoma. Modelling raised IOP in OAG using intracameral (IC) injections of TGF-β: In the study by Hill et al. (2015), we used immunohistochemistry to visualize fibrosis and count RGCs, tonometry to measure IOP and visual evoked potentials (VEP) to measure function of the visual pathway, and found that repeated (twice a week) intracameral injections of TGF-β in adult rats promoted TM fibrosis, elevated IOP and led to RGC death and retinal dysfunction. Consistent with other fibrotic models of raised IOP, our rodent model generated a sustained and significant increase in IOP by 14 days compared with PBS controls. The baseline level of IOP (before any treatment) in our study was similar to that observed previously in rats (Robertson et al. 2010). However, overexpression of TGF-β by gene transfer (Robertson et al. 2010) led to greater levels of IOP (20 mmHg) compared to IOP levels (14 mmHg) achieved in our study, differences that maybe explained by the constant production of TGF-β through gene transcription compared with our discontinuous bolus regime of biweekly IC injections. One feature of our method was that TGF-β treatment for 17 days led to TM fibrosis and elevated IOP that persisted for at least 30 days despite withdrawal of TGF-β from this time point. To confirm that there was no natural resolution of the TM fibrosis and raised IOP (due to continued ECM turnover in the TM) after the cessation of TGF-β treatment we used a control group in which intracameral injection of TGF-β injections for 17 days was followed by intracameral injection of PBS from 21–30 days with no resolution of IOP. Thus, in this in vivo model of TGF-β-induced TM fibrosis, IOP was increased by 17 days and sustained through to 30 days, resulting in 42% RGC death and associated functional VEP deficits, consequences that were similar to those seen in other experimental models of raised IOP (Belforte et al., 2010). Of note, in the study of Hill et al. (2015) it was important to identify and account for any inflammatory reactions induced by the intracameral injections that may have perpetuated TM fibrosis. This was addressed by counting the number of ED1+ macrophages situated within the proximity of the TM. The results showed that intracameral TGF-β and PBS did increase the number of macrophages in the angle compared with numbers in the intact control eyes. These results suggest that, since there were similar macrophage numbers in the PBS and TGF-β-treated groups, the induced differences between the two treatments were not a consequence of post-surgical inflammation. Evaluating the utility of human recombinant Decorin hrDecorin for the treatment of OAG: Once the model was successfully established, hrDecorin was injected intracamerally after TM fibrosis was established to ascertain if the induced TM fibrosis and increased IOP could be resolved. hrDecorin significantly reduced the laminin and fibronectin levels within the fibrosed TM, an effect that was correlated with raised levels of MMP and their TIMP inhibitors. Thus, hrDecorin reversed the TM microenvironment back to MMP/TIMP ratios favourable for tissue remodelling, causing the dissolution of established ECM protein deposits in and around the TM, an anti-scarring response reminiscent of that seen to Decorin in models of spinal cord injury (Ahmed et al., 2013), hydrocephalus (Botfield et al., 2013) and conjunctival scarring for post-filtration surgery (Grisanti et al., 2005). The study of Hill et al. (2015) in the OAG model also showed that the anti-scarring Decorin treatment lowered IOP when compared with controls in vivo, with associated enhancement of RGC survival. Primary retinal cultures containing RGC demonstrated that the neuroprotective effects of Decorin were indirectly related to the resolution of TM fibrosis and lowering of IOP rather than by direct actions on neurons. However, other studies have shown contradictory results on other cell types. For example, Seidler et al. (2006) reported an anti-apoptotic effect of Decorin on cultured fibroblasts by prevention of DNA fragmentation. By contrast, studies using cancer cells have convincingly demonstrated the ability of Decorin to induce cell death through apoptosis (Goldoni et al., 2008). Therefore, we suggest that the actions of Decorin are dependent on the cell type and their environment. Conclusion: Our observations show that intracameral hrDecorin reverses established TM fibrosis and normalizes IOP, indirectly protecting RGC from progressive IOP-related death. Further confirmatory studies will be required to understand the exact mechanism of Decorin's fibrolytic actions within the TM but we believe that hrDecorin is an ideal candidate therapy to develop into a treatment for patients with OAG associated with TM fibrosis. LJH was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), No. BB/F017553/1.

Hunting for meat was a critical step in all animal and human evolution. A key brain-trophic element in meat is vitamin B3/nicotinamide. The supply of meat and nicotinamide steadily increased from the Cambrian origin of animal predators ratcheting ever larger brains. This culminated in the 3-million-year evolution of Homo sapiens and our overall demographic success. We view human evolution, recent history, and agricultural and demographic transitions in the light of meat and nicotinamide intake. A biochemical and immunological switch is highlighted that affects fertility in the ‘de novo’ tryptophan-to-kynurenine-nicotinamide ‘immune tolerance’ pathway. Longevity relates to nicotinamide adenine dinucleotide consumer pathways. High meat intake correlates with moderate fertility, high intelligence, good health, and longevity with consequent population stability, whereas low meat/high cereal intake (short of starvation) correlates with high fertility, disease, and population booms and busts. Too high a meat intake and fertility falls below replacement levels. Reducing variances in meat consumption might help stabilise population growth and improve human capital.

Meat and vitamin B3 – nicotinamide – intake was high during hunter-gatherer times. Intake then fell and variances increased during and after the Neolithic agricultural revolution. Health, height, and IQ deteriorated. Low dietary doses are buffered by ‘welcoming’ gut symbionts and tuberculosis that can supply nicotinamide, but this co-evolved homeostatic metagenomic strategy risks dysbioses and impaired resistance to pathogens. Vitamin B3 deficiency may now be common among the poor billions on a low-meat diet. Disease transitions to non-communicable inflammatory disorders (but longer lives) may be driven by positive ‘meat transitions’. High doses of nicotinamide lead to reduced regulatory T cells and immune intolerance. Loss of no longer needed symbiotic ‘old friends’ compounds immunological over-reactivity to cause allergic and auto-immune diseases. Inhibition of nicotinamide adenine dinucleotide consumers and loss of methyl groups or production of toxins may cause cancers, metabolic toxicity, or neurodegeneration. An optimal dosage of vitamin B3 could lead to better health, but such a preventive approach needs more equitable meat distribution. Some people may require personalised doses depending on genetic make-up or, temporarily, when under stress.

Assessment of risk and uncertainty is crucial for natural hazard risk management, facilitating risk communication and informing strategies to successfully mitigate our society's vulnerability to natural disasters. Written by some of the world's leading experts, this book provides a state-of-the-art overview of risk and uncertainty assessment in natural hazards. It presents the core statistical concepts using clearly defined terminology applicable across all types of natural hazards and addresses the full range of sources of uncertainty, the role of expert judgement and the practice of uncertainty elicitation. The core of the book provides detailed coverage of all the main hazard types and concluding chapters address the wider societal context of risk management. This is an invaluable compendium for academic researchers and professionals working in the fields of natural hazards science, risk assessment and management and environmental science and will be of interest to anyone involved in natural hazards policy.