Saliva diagnostics for oral diseases

Oral diseases, or stomatognathic diseases, denote the diseases of the mouth (“stoma”) and jaw (“gnath”). Dental caries and periodontal diseases have been traditionally considered as the most important global oral health burdens. It is important to note that in oral diagnostics, the greatest challenges are determining the clinical utility of potential biomarkers for screening (in asymptomatic people), predicting the early onset of disease (prognostic tests), and evaluating the disease activity and the efficacy of therapy through innovative diagnostic tests. An oral diagnostic test, in principle, should provide valuable information for differential diagnosis, localization of disease, and severity of infection. This information can then be incorporated by the physician when planning treatments and will provide means for assessing the effectiveness of therapy.

Functional and psychosocial outcomes 1 year after mild stroke

Background Mild stroke survivors are generally discharged from acute care within a few days of the stroke event, often without rehabilitation follow-up. We aimed to examine the recovery trajectory for male patients and their wife-caregivers during the 12 months postdischarge. Methods A descriptive study was undertaken to examine functional outcomes, quality of life (QOL), depression, caregiver strain, and marital function in a prospective cohort of male survivors of mild stroke and their wife-caregivers during the 12 months postdischarge. Data from each point in time were summarized and repeated measures analyses undertaken. Logistic regression was used to determine which baseline demographic and biopsychosocial variables influenced or predicted marital functioning 1 year postdischarge. Results A total of 38 male patients (mean age 63.4 years) and their wife-caregivers (mean age 58.5 years) were examined. The median discharge National Institutes of Health Stroke Scale score was 1.5, modified Rankin Scale score was 1.0, Barthel Index was 100.0, and Stroke Impact Scale-16v2 score was 78.5. The patients' modified Rankin Scale (function) and QOL scores improved significantly over time (F (2) = 4.583, P = .017; and F (6) = 5.632, P < .001, respectively). However, the wife-caregiver QOL scores did not change. Multivariate analysis revealed overall worsening of depression for both the patient and wife-caregivers (F (6, 32) = 3.087, P = .017) and marital function (F (6, 32) = 3.961, P = .004), although the wife-caregivers' perceptions of caregiver strain improved (F (6, 32) = 3.923, P = .007). None of the measured variables were associated with marital functioning 1 year postdischarge. Conclusions Despite improvement in patients' functional status, other patient and wife-caregiver psychosocial outcomes during the 12 months postdischarge may be negatively affected. Thus, attention needs to focus on recovery beyond functional outcomes.

Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia

This paper describes algorithms that can identify patterns of brain structure and function associated with Alzheimer's disease, schizophrenia, normal aging, and abnormal brain development based on imaging data collected in large human populations. Extraordinary information can be discovered with these techniques: dynamic brain maps reveal how the brain grows in childhood, how it changes in disease, and how it responds to medication. Genetic brain maps can reveal genetic influences on brain structure, shedding light on the nature-nurture debate, and the mechanisms underlying inherited neurobehavioral disorders. Recently, we created time-lapse movies of brain structure for a variety of diseases. These identify complex, shifting patterns of brain structural deficits, revealing where, and at what rate, the path of brain deterioration in illness deviates from normal. Statistical criteria can then identify situations in which these changes are abnormally accelerated, or when medication or other interventions slow them. In this paper, we focus on describing our approaches to map structural changes in the cortex. These methods have already been used to reveal the profile of brain anomalies in studies of dementia, epilepsy, depression, childhood- and adult-onset schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, fetal alcohol syndrome, Tourette syndrome, Williams syndrome, and in methamphetamine abusers. Specifically, we describe an image analysis pipeline known as cortical pattern matching that helps compare and pool cortical data over time and across subjects. Statistics are then defined to identify brain structural differences between groups, including localized alterations in cortical thickness, gray matter density (GMD), and asymmetries in cortical organization. Subtle features, not seen in individual brain scans, often emerge when population-based brain data are averaged in this way. Illustrative examples are presented to show the profound effects of development and various diseases on the human cortex. Dynamically spreading waves of gray matter loss are tracked in dementia and schizophrenia, and these sequences are related to normally occurring changes in healthy subjects of various ages.

If you don’t know, you can’t help: A practical guide for alcohol and other drug screening in psychological services

Alcohol is implicated in over 60 diseases and injuries and accounted for 6.2 per cent of all male deaths globally in 2004 (WHO, 2011). Alcohol and other drug (AOD) abuse causes significant individual, family and social harms at all age levels and across all socioeconomic groups. These may result from intoxication (e.g., overdose, vulnerability to physical injury/trauma or death, consequences of impulsive behaviour, aggression and driving under the influence) and longer-term consequences (e.g., alcohol or drug-related brain injury, cardiovascular and liver diseases, blood borne viruses e.g., Chikritzhs et al., 2003, Roxburgh et al., 2013). Mental health problems may be triggered or exacerbated, and family breakdown, poor self-esteem, legal issues and lack of community engagement may also be evident. Despite the prevalence of substance use disorders and evident consequences for the individual, family and wider community, it would seem that health professionals, including psychologists, are reluctant to ask about substance use.

Miami heat: Patent law, informed consent and benefit-sharing

This article considers whether the granting of patents in respect of biomedical genetic research should be conditional upon the informed consent of research participants. It focuses upon several case studies. In Moore v the Regents of the University Of California, a patient sued his physician for breach of fiduciary duty and lack of informed consent, because the doctor had obtained a patent on the patient's cell line, without the patient's authorisation. In Greenberg v Miami Children's Hospital, the research participants, the Greenbergs, the National Tay Sachs and Allied Diseases Association, and Dor Yeshorim brought a legal action against the geneticist Reubon Matalon and the Miami Children's Hospital over a patent obtained on a gene related to the Canavan disease and accompany genetic diagnostic test. PXE International entered into a joint venture with Charles Boyd and the University of Hawaii, and obtained a patent together for ‘methods for diagnosing Pseudoxanthoma elasticum’. In light of such case studies, it is contended that there is a need to reform patent law, so as to recognise the bioethical principles of informed consent and benefit-sharing. The 2005 UNESCO Declaration on Bioethics and Human Rights provides a model for future case law and policy-making.

Is there evidence to support the use of the angle of peak torque as a marker of hamstring injury and re-injury risk?

Hamstring strain injuries are the predominant injury in many sports, costing athletes and clubs a significant financial and performance burden. Therefore the ability to identify and intervene with individuals who are considered at a high risk of injury is important. One measure which has grown in popularity as an outcome variable following hamstring intervention/prevention studies and rehabilitation is the angle of peak knee flexor torque. This current opinion article will firstly introduce the measure and the processes behind it. Secondly, this article will summarise how the angle of peak knee flexor torque has been suggested to measure hamstring strain injury risk. Finally various limitations will be presented and outlined as to how they may influence the measure. These include the lack of muscle specificity, the common concentric contraction mode of assessment, reliability of the measure, various neural contributions (such as rate of force development and neuromuscular inhibition) as well as the lack of prospective data showing any predictive value in the measure.

Bayesian refinement of association signals for 14 loci in 3 common diseases

To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies. © 2012 Nature America, Inc. All rights reserved.

Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: Results of a randomised placebo-controlled trial (ABILITY-1)

Purpose: To evaluate the efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis (nr-axSpA). Methods: Patients fulfilled Assessment of Spondyloarthritis international Society (ASAS) criteria for axial spondyloarthritis, had a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥ 4, total back pain score of ≥ 4 (10 cm visual analogue scale) and inadequate response, intolerance or contraindication to non-steroidal anti-inflammatory drugs (NSAIDs); patients fulfilling modified New York criteria for ankylosing spondylitis were excluded. Patients were randomised to adalimumab (N=91) or placebo (N=94). The primary endpoint was the percentage of patients achieving ASAS40 at week 12. Efficacy assessments included BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS). MRI was performed at baseline and week 12 and scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) index. Results: Significantly more patients in the adalimumab group achieved ASAS40 at week 12 compared with patients in the placebo group (36% vs 15%, p<0.001). Significant clinical improvements based on other ASAS responses, ASDAS and BASDAI were also detected at week 12 with adalimumab treatment, as were improvements in quality of life measures. Inflammation in the spine and sacroiliac joints on MRI significantly decreased after 12 weeks of adalimumab treatment. Shorter disease duration, younger age, elevated baseline C-reactive protein or higher SPARCC MRI sacroiliac joint scores were associated with better week 12 responses to adalimumab. The safety profile was consistent with what is known for adalimumab in ankylosing spondylitis and other diseases. Conclusions: In patients with nr-axSpA, adalimumab treatment resulted in effective control of disease activity, decreased inflammation and improved quality of life compared with placebo. Results from ABILITY-1 suggest that adalimumab has a positive benefit-risk profile in active nr-axSpA patients with inadequate response to NSAIDs.

Temperature variation between neighboring days and mortality: a distributed lag non-linear analysis

Objectives To investigate whether a sudden temperature change between neighboring days has significant impact on mortality. Methods A Poisson generalized linear regression model combined with a distributed lag non-linear models was used to estimate the association of temperature change between neighboring days with mortality in a subtropical Chinese city during 2008–2012. Temperature change was calculated as the current day’s temperature minus the previous day’s temperature. Results A significant effect of temperature change between neighboring days on mortality was observed. Temperature increase was significantly associated with elevated mortality from non-accidental and cardiovascular diseases, while temperature decrease had a protective effect on non-accidental mortality and cardiovascular mortality. Males and people aged 65 years or older appeared to be more vulnerable to the impact of temperature change. Conclusions Temperature increase between neighboring days has a significant adverse impact on mortality. Further health mitigation strategies as a response to climate change should take into account temperature variation between neighboring days.

Evaluation of the relationship between Chlamydia pecorum sequence types and disease using a species-specific multi-locus sequence typing scheme (MLST)

Chlamydia pecorum is globally associated with several ovine diseases including keratoconjunctivitis and polyarthritis. The exact relationship between the variety of C. pecorum strains reported and the diseases described in sheep remains unclear, challenging efforts to accurately diagnose and manage infected flocks. In the present study, we applied C. pecorum multi-locus sequence typing (MLST) to C. pecorum positive samples collected from sympatric flocks of Australian sheep presenting with conjunctivitis, conjunctivitis with polyarthritis, or polyarthritis only and with no clinical disease (NCD) in order to elucidate the exact relationships between the infecting strains and the range of diseases. Using Bayesian phylogenetic and cluster analyses on 62 C. pecorum positive ocular, vaginal and rectal swab samples from sheep presenting with a range of diseases and in a comparison to C. pecorum sequence types (STs) from other hosts, one ST (ST 23) was recognised as a globally distributed strain associated with ovine and bovine diseases such as polyarthritis and encephalomyelitis. A second ST (ST 69) presently only described in Australian animals, was detected in association with ovine as well as koala chlamydial infections. The majority of vaginal and rectal C. pecorum STs from animals with NCD and/or anatomical sites with no clinical signs of disease in diseased animals, clustered together in a separate group, by both analyses. Furthermore, 8/13 detected STs were novel. This study provides a platform for strain selection for further research into the pathogenic potential of C. pecorum in animals and highlights targets for potential strain-specific diagnostic test development.

Lost in space: The place of the architectural milieu in the aetiology and treatment of schizophrenia

Purpose – Psychological and epidemiological literature suggests that the built environment plays both causal and therapeutic roles in schizophrenia, but what are the implications for designers? The purpose of this paper is to focus on the role the built environment plays in psycho‐environmental dynamics, in order that negative effects can be avoided and beneficial effects emphasised in architectural design. Design/methodology/approach – The approach taken is a translational exploration of the dynamics between the built environment and psychotic illness, using primary research from disciplines as diverse as epidemiology, neurology and psychology. Findings – The built environment is conceived as being both an agonist and as an antagonist for the underlying processes that present as psychosis. The built environment is implicated through several means, through the opportunities it provides. These may be physical, narrative, emotional, hedonic or personal. Some opportunities may be negative, and others positive. The built environment is also an important source of unexpected aesthetic stimulation, yet in psychotic illnesses, aesthetic sensibilities characteristically suffer from deterioration. Research limitations/implications – The findings presented are based on research that is largely translated from very different fields of enquiry. Whilst findings are cogent and logical, much of the support is correlational rather than empirical. Social implications – The WHO claims that schizophrenia destroys 24 million lives worldwide, with an exponential effect on human and financial capital. Because evidence implicates the built environment, architectural and urban designers may have a role to play in reducing the human costs wrought by the illness. Originality/value – Never before has architecture been so explicitly implicated as a cause of mental illness. This paper was presented to the Symposium of Mental Health Facility Design, and is essential reading for anyone involved in designing for improved mental health.

Identification of seven loci affecting mean telomere length and their association with disease

Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 x 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.

Loci affecting gamma-glutamyl transferase in adults and adolescents show age x SNP interaction and cardiometabolic disease associations

Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 x 10(-8); rs944002 in C14orf73 on chromosome 14, P = 4.7 x 10(-13); rs340005 in RORA on chromosome 15, P = 2.4 x 10(-8)), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P(HET) = 5.6 x 10(-12) at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.

Turing and the Trans-Pacific Partnership: Intellectual Property, Public Health, and Access to Essential Medicines

A recent controversy in the United States over drug pricing by Turing Pharmaceuticals AG has raised larger issues in respect of intellectual property, access to medicines, and the Trans-Pacific Partnership (TPP). In August 2015, Turing Pharmaceuticals AG – a private biopharmaceutical company with offices in New York, the United States, and Zug, Switzerland - acquired the exclusive marketing rights to Daraprim in the United States from Impax Laboratories Incorporated. Martin Shkreli, Turing’s Founder and Chief Executive Officer, maintained: “The acquisition of Daraprim and our toxoplasmosis research program are significant steps along Turing’s path of bringing novel medications to patients with serious disorders, some of whom often go undiagnosed and untreated.” He emphasised: “We intend to invest in the development of new drug candidates that we hope will yield an even better clinical profile, and also plan to launch an educational effort to help raise awareness and improve diagnosis for patients with toxoplasmosis.” In September 2015, there was much public controversy over the decision of Martin Shkreli to raise the price of a 62 year old drug, Daraprim, from $US13.50 to $US750 a pill. The drug is particularly useful in respect to the treatment and prevention of malaria, and in the treatment of infections in individuals with HIV/AIDS. Daraprim is listed on the World Health Organization’s (WHO) List of Essential Medicines. In the face of much criticism, Martin Shkreli has said that he will reduce the price of Daraprim. He observed: “We've agreed to lower the price on Daraprim to a point that is more affordable and is able to allow the company to make a profit, but a very small profit.” He maintained: “We think these changes will be welcomed.” However, he has been vague and ambiguous about the nature of the commitment. Notably, the lobby group, Pharmaceutical Research and Manufacturers of America (PhARMA), disassociated itself from the claims of Turing Pharmaceuticals. The group said: “PhRMA members have a long history of drug discovery and innovation that has led to increased longevity and improved lives for millions of patients.” The group noted: “Turing Pharmaceutical is not a member of PhRMA and we do not embrace either their recent actions or the conduct of their CEO.” The biotechnology peak body Biotechnology Industry Organization also sought to distance itself from Turing Pharmaceuticals. A hot topic: United States political debate about access to affordable medicines This controversy over Daraprim is unusual – given the age of drug concerned. Daraprim is not subject to patent protection. Nonetheless, there remains a monopoly in respect of the marketplace. Drug pricing is not an isolated problem. There have been many concerns about drug pricing – particularly in respect of essential medicines for HIV/AIDS, tuberculosis, and malaria. This recent controversy is part of a larger debate about access to affordable medicines. The dispute raises larger issues about healthcare, consumer rights, competition policy, and trade. The Daraprim controversy has provided impetus for law reform in the US. US Presidential Candidate Hillary Clinton commented: “Price gouging like this in this specialty drug market is outrageous.” In response to her comments, the Nasdaq Biotechnology Index fell sharply. Hillary Clinton has announced a prescription drug reform plan to protect consumers and promote innovation – while putting an end to profiteering. On her campaign site, she has emphasised that “affordable healthcare is a basic human right.” Her rival progressive candidate, Bernie Sanders, was also concerned about the price hike. He wrote a letter to Martin Shkreli, complaining about the price increase for the drug Daraprim. Sanders said: “The enormous, overnight price increase for Daraprim is just the latest in a long list of skyrocketing price increases for certain critical medications.” He has pushed for reforms to intellectual property to make medicines affordable. The TPP and intellectual property The Daraprim controversy and political debate raises further issues about the design of the TPP. The dispute highlights the dangers of extending the rights of pharmaceutical drug companies under intellectual property, investor-state dispute settlement, and drug administration. Recently, the civil society group Knowledge Ecology International published a leaked draft of the Intellectual Property Chapter of the TPP. Knowledge Ecology International Director, James Love, was concerned the text revealed that the US “continues to be the most aggressive supporter of expanded intellectual property rights for drug companies.” He was concerned that “the proposals contained in the TPP will harm consumers and in some cases block innovation.” James Love feared: “In countless ways, the Obama Administration has sought to expand and extend drug monopolies and raise drug prices.” He maintained: “The astonishing collection of proposals pandering to big drug companies make more difficult the task of ensuring access to drugs for the treatment of cancer and other diseases and conditions.” Love called for a different approach to intellectual property and trade: “Rather than focusing on more intellectual property rights for drug companies, and a death-inducing spiral of higher prices and access barriers, the trade agreement could seek new norms to expand the funding of medical research and development (R&D) as a public good, an area where the US has an admirable track record, such as the public funding of research at the National Institutes of Health (NIH) and other federal agencies.” In addition, there has been much concern about the Investment Chapter of the TPP. The investor-state dispute settlement regime would enable foreign investors to challenge government policy making, which affected their investments. In the context of healthcare, there is a worry that pharmaceutical drug companies will deploy their investor rights to challenge public health measures – such as, for instance, initiatives to curb drug pricing and profiteering. Such concerns are not merely theoretical. Eli Lilly has brought an investor action against the Canadian Government over the rejection of its drug patents under the investor-state dispute settlement regime of the North American Free Trade Agreement (NAFTA). The Health Annex to the TPP also raises worries that pharmaceutical drug companies will able to object to regulatory procedures in respect of healthcare. It is disappointing that the TPP – in the leaks that we have seen – has only limited recognition of the importance of access to essential medicines. There is a need to ensure that there are proper safeguards to provide access to essential medicines – particularly in respect of HIV/AIDs, malaria, and tuberculosis. Moreover, there must be protection against drug profiteering and price gouging in any trade agreement. There should be strong measures against the abuse of intellectual property rights. The dispute over Turing Pharmaceuticals AG and Daraprim is an important cautionary warning in respect of some of the dangers present in the secret negotiations in respect of the TPP. There is a need to preserve consumer rights, competition policy, and public health in trade negotiations over an agreement covering the Pacific Rim.

Clinical relevance of MTHFR, eNOS, ACE, and ApoE gene polymorphisms and serum vitamin profile among Malay patients with ischemic stroke

Background The purpose of this study was threefold. First, it was to determine the relationship between serum vitamin profiles and ischemic stroke. The second purpose was to investigate the association of methylenetetrahydrofolate reductase (MTHFR), endothelial nitric oxide synthase (eNOS), angiotensin converting enzyme (ACE), and apolipoprotein-E (ApoE) gene polymorphisms with ischemic stroke and further correlate with serum vitamin profiles among ischemic stroke patients. The third purpose of the study was to highlight the interaction of MTHFR and eNOS haplotypes with serum vitamin profiles and ischemic stroke risks. Methods Polymorphisms of these genes were analyzed in age-, sex-, and ethnicity-matched case–controls (n = 594); serum vitamin profiles were determined using immunoassays. Results The MTHFR 677C>T, 1298A>C, eNOS intron 4a/b, and ApoE polymorphisms were significantly associated with the increased risk of ischemic stroke. Elevated serum homocysteine and vitamin B12 levels were associated with MTHFR 677C>T and eNOS intron 4a/b polymorphisms. The ApoE and eNOS −786T>C polymorphisms were associated with increased serum vitamin B12 levels. However, none of the polymorphisms influenced serum folate levels except for the MTHFR 1298A>C. Different patterns of MTHFR and eNOS haplotypes tend to affect serum vitamin profiles to different degrees, which contribute to either different susceptibility risk or protective effect on ischemic stroke. Overall, increased levels of serum homocysteine and vitamin B12 levels were associated with higher risk of ischemic stroke in the investigated population. Conclusions The present study suggests that the genotypes and haplotypes of MTHFR 677C>T and eNOS intron 4a/b polymorphisms are potential serum biomarkers in the pathophysiological processes of ischemic stroke, by modulating homocysteine and vitamin B12 levels.