Transcranial magnetic stimulation maps the neurophysiology of chronic noncancer pain: A scoping review.

BACKGROUND: Chronic noncancer pain is a global public health challenge. It is imperative to identify biological markers ("biomarkers") to understand the mechanisms underlying chronic pain and to monitor pain over time and after interventions. Transcranial magnetic stimulation (TMS) is a promising method for this purpose. OBJECTIVES: To examine differences in TMS-based outcomes between persons with chronic pain and healthy controls (HCs) and/or before versus after pain-modulating interventions and relationships between pain measures and TMS outcomes; To summarize the neurophysiological mechanisms underlying chronic pain as identified by TMS. METHODS: We searched the PubMed database for literature from January 1, 1985, to June 9, 2020, with the keywords "pain" and "transcranial magnetic stimulation." Eligible items included original studies of adult human participants with pain lasting for ≥ 6 months. We completed a narrative synthesis of the study findings stratified by chronic pain etiology (primary pain, neuropathic pain, and secondary musculoskeletal pain). RESULTS: The search yielded 1265 records. The final 12 articles included 244 patients with chronic pain (192 females, aged 35-65 years) and 169 HCs (89 females, aged 28-59 years). Abnormalities in TMS outcomes that reflect GABAergic and glutamatergic activities were associated with many of the disorders studied and were distinct for each pain etiology. Chronic primary pain is characterized by reduced intracortical inhibition and corticospinal excitability, chronic neuropathic pain shows evidence of increased excitation and disinhibition, and chronic secondary musculoskeletal pain involves low corticospinal excitability. DISCUSSION: TMS could be a useful tool for delineating the neurophysiological underpinnings of chronic pain syndromes.

Utilising fluorescent reporters to probe the mode of action of norbornen-7-one CO releasing molecules.

The synthesis of the fluorescent organic carbon monoxide releasing molecules oCOm-57, oCOm-58, and oCOm-66 are reported. These oCOms are water soluble and exhibit a "turn-on" fluorescent behaviour when CO is released under physiological conditions. oCOm-66 also contains an additional nitro-naphthalimide moiety that functions as a fluorescent reporter. Delivery of CO released from these oCOms to the mitochondria of AC-16 cardiomyocytes was confirmed using confocal microscopy in conjuction with MitoTracker Red. While the neutral, PEGylated oCOm-57 was found to remain in the extracellular environment releasing CO to diffuse into the cellular compartments, the positively charged oCOm-58 and -66 are targeted to the mitochondria where they release CO. Notably, the use of the fluorescent oCOms in live cellular imaging, allows the intracellular CO delivery and oCOm localisation to be characterised. This cellular confocal study also shows that, subtoxic concentrations of CO released from these molecules preserved mitochondrial energetics as indicated by the membrane potential dependent MitoTracker Red.

A mixed methods study of provider factors in buprenorphine treatment retention.

BACKGROUND: Low retention is a persistent challenge in the delivery of buprenorphine treatment for opioid use disorder (OUD). The goal of this study was to identify provider factors that could drive differences in treatment retention while accounting for the contribution of patient characteristics to retention. METHODS: We developed a novel a mixed-methods approach to explore provider factors that could drive retention while accounting for patient characteristics. We used Medicaid claims data from North Carolina in the United States to identify patient characteristics associated with higher retention. We then identified providers who achieved high and low retention rates. We matched high- and low-retention providers on their patients' characteristics. This matching created high- and low-retention provider groups whose patients had similar characteristics. We then interviewed providers while blinded to which belonged in the high- and low-retention groups on aspects of their practice that could affect retention rates, such as treatment criteria, treatment cost, and services offered. RESULTS: Less than half of patients achieved 180-day treatment retention with large differences by race and ethnicity. We did not find evidence that providers who achieved higher retention consistently did so by providing more comprehensive services or selecting for more stable patients. Rather, our findings suggest use of "high-threshold" clinical approaches, such as requiring participation in psychosocial services or strictly limiting dosages, explain differences in retention rates between providers whose patients have similar characteristics. All low-retention providers interviewed used a high-threshold practice compared to half of high-retention providers interviewed. Requiring patients to participate in psychosocial services, which were often paid out-of-pocket, appeared to be especially important in limiting retention. CONCLUSION: Providers who adopt low-threshold approaches to treatment may achiever higher retention rates than those who adopt high-threshold approaches. Addressing cost barriers and systemic racism are likely also necessary for improving buprenorphine treatment retention.

Insights from system dynamics applications in addiction research: A scoping review.

BACKGROUND AND AIMS: Substance misuse and use disorders are dynamic and complex problems, situated within systems of interacting social, environmental, and neurobiological factors. System dynamics (SD) methods broaden, test, and improve understanding of complex systems and can help inform effective action. We sought to systematically review the use of SD tools in addiction-related research. METHODS: Following PRISMA guidelines, we searched several databases from 1958 to 2019. We included studies focused on addiction-related screening and diagnosis, treatment, and return to use, as well as studies focused on earlier stages that may begin a path to addiction (e.g., experimentation, misuse onset). RESULTS: We extracted information from 59 articles with a median publication year of 2014. In addition to using SD to understand the underlying complexity driving addiction-related trends, other commonly cited reasons for use of SD included assessing impacts of potential actions (n = 35), predicting future trends (n = 28), and supporting strategic planning processes (n = 22). Most studies included simulation models (n = 43); however, some presented insights from qualitative SD diagrams (n = 9) and concept models (n = 6). The majority of studies focused on stages leading to potential addiction: initiation/ experimentation (n = 42) and misuse onset (n = 38). One-third (n = 20) engaged persons with lived experience or other stakeholders during the modeling process. CONCLUSIONS: Addiction-related SD research has increased over the last few decades with applications varying in several ways, from model purpose and types of data used to stakeholder involvement. Future applications should consider the benefits of stakeholder engagement throughout the modeling process and expanding models to include concomitant substance use.

Characterising residual malaria transmission in forested areas with low coverage of core vector control in central Viet Nam.

BACKGROUND: Despite great success in significantly reducing the malaria burden in Viet Nam over recent years, the ongoing presence of malaria vectors and Plasmodium infection in remote forest areas and among marginalised groups presents a challenge to reaching elimination and a threat to re-emergence of transmission. Often transmission persists in a population despite high reported coverage of long-lasting insecticidal nets (LLINs), the mainstay control method for malaria. To investigate what factors may contribute to this, a mixed-methods study was conducted in Son Thai commune, a community in south-central Viet Nam that has ongoing malaria cases despite universal LLIN coverage. A cross-sectional behavioural and net-coverage survey was conducted along with observations of net use and entomological collections in the village, farm huts and forest sites used by members of the community. RESULTS: Most community members owned a farm hut plot and 71.9% of adults aged 18+ years sometimes slept overnight in the farm hut, while one-third slept overnight in the forest. Ownership and use of nets in the village households was high but in the farm huts and forest was much lower; only 44.4% reported regularly using a bednet in the farm and 12.1% in the forest. No primary anopheline species were captured in the village, but Anopheles dirus (s.l.) (n = 271) and An. maculatus (s.l.) (n = 14) were captured as far as 4.5 km away in farm huts and forest. A high proportion of biting was conducted in the early evening before people were under nets. Entomological inoculation rates (EIR) of An. dirus (s.l.) were 17.8 and 25.3 infectious bites per person per year in the outdoor farm hut sites and forest, respectively, for Plasmodium falciparum and 25.3 in the forest sites for P. vivax. CONCLUSIONS: Despite high net coverage in the village, gaps in coverage and access appear in the farm huts and forest where risk of anopheline biting and parasite transmission is much greater. Since subsistence farming and forest activities are integral to these communities, new personal protection methods need to be explored for use in these areas that can ideally engage with the community, be durable, portable and require minimal behavioural change.

The combined effect of high-intensity intermittent training and vitamin D supplementation on glycemic control in overweight and obese adults.

High-intensity intermittent training (HIIT) has been shown to reduce the risk of chronic conditions including the development of type 2 diabetes mellitus (T2DM). Independently, a low vitamin D status has also been linked to the prevalence of T2DM. The aim of this study was to investigate if there was a synergistic metabolic effect of HIIT and vitamin D supplementation on glycemic control. A total of 20 male and female participants (age, 34 ± 9 year; BMI, 31.4 ± 2.8 kg·m-2 ) completed 6 weeks HIIT, and were randomized to ingest 100 µg·day-1 of vitamin D3 or placebo. Response to an oral glucose tolerance test (OGTT) was determined at baseline and at 72 h postintervention. Glucose tolerance was improved as a result of the HIIT intervention, shown through a reduction in glucose and insulin concentrations during the OGTT, accompanied by a decrease in glucose (829 ± 110 to 786 ± 139 mmol·h-1 ·L-1 ; P = 0.043) and insulin (8101 ± 4755-7024 ± 4489 mU·h-1 ·L-1 ; P = 0.049) area under the curve (AUC). Supplementation increased 25-hydroxyvitamin D3 concentration by 120% to a sufficiency status (P < 0.001). However, the consumption of vitamin D3 seemed to attenuate the glucose response during an OGTT. Triglyceride content was lowered following the intervention (P = 0.025). There was no effect of the intervention on insulin sensitivity (IS) indices: ISIMatsuda and HOMA-IR. Our findings demonstrate that HIIT improves glucose tolerance in nondiabetic overweight and obese adults; however vitamin D3 supplementation did not proffer any additional positive effects on the measured indices of metabolic health.

Evidence-based Pediatric Orthopaedics: How Safe is "Safe"?

BACKGROUND: The aim of minimizing the risks of complications and adverse events is at the center of surgical practice.This study aimed to assess the evidence on which pediatric orthopaedic surgical procedures are described as "safe." In particular, the objective was to ascertain the proportion of studies describing a procedure as "safe," which achieved a 95% upper limit confidence interval of risk of 5% or less for major adverse events. METHOD: A primary search of Journal of Paediatric Orthopaedics 2009 to 2014 for the single term "safe" returned 71 papers appropriate for analysis. Of these, 60 positively identified at least 1 intervention as "safe." These papers were analyzed and the number of interventions and the number of complications recorded. Data sets (n=67) were created and the 95% upper confidence interval calculated for the probability of a complication. RESULTS: Only 16 data sets (ex 67) provided evidence that the probability of a major complication was under 5%. CONCLUSIONS: This work suggests there is widespread failure of understanding of how low sample sizes or can lead to an unjustifiable claim that procedures are "safe." LEVEL OF EVIDENCE: Unclassifiable.

A small shared epitope-mimetic compound potently accelerates osteoclast-mediated bone damage in autoimmune arthritis.

We have recently proposed that the shared epitope (SE) may contribute to rheumatoid arthritis pathogenesis by acting as a ligand that activates proarthritogenic signal transduction events. To examine this hypothesis, in this study we characterized a novel small SE-mimetic compound, c(HS4-4), containing the SE primary sequence motif QKRAA, which was synthesized using a backbone cyclization method. The SE-mimetic c(HS4-4) compound interacted strongly with the SE receptor calreticulin, potently activated NO and reactive oxygen species production, and markedly facilitated osteoclast differentiation and function in vitro. The pro-osteoclastogenic potency of c(HS4-4) was 100,000- to 1,000,000-fold higher than the potency of a recently described linear SE peptidic ligand. When administered in vivo at nanogram doses, c(HS4-4) enhanced Th17 expansion, and in mice with collagen-induced arthritis it facilitated disease onset, increased disease incidence and severity, enhanced osteoclast abundance in synovial tissues and osteoclastogenic propensities of bone marrow-derived cells, and augmented bone destruction. In conclusion, c(HS4-4), a highly potent small SE-mimetic compound enhances bone damage and disease severity in inflammatory arthritis. These findings support the hypothesis that the SE acts as a signal transduction ligand that activates a CRT-mediated proarthritogenic pathway.

A perspective on the future public health: an integrative and ecological framework.

Modernity has brought health and social benefits to many societies, not least through the insights of science and technology. Yet, modernity has also been associated with a number of cultural characteristics, such as materialism, individualism, consumerism and an addiction to continuing economic growth, that seem potentially harmful to health and well-being and inimical to social equity. There is an emerging body of evidence that suggests that, in the affluent world, some of our most intractable contemporary health problems are, in fact, the product of modernity. This suggests that the tools of modernity (its science and its technology) are ill suited to finding solutions. This poses a problem for public health, as this discipline is itself a product of modernity and thus appears ill equipped to deal with the conditions and challenges of a rapidly changing and unstable world, one where the very sustainability of human society is now in question. This paper argues that a new paradigm for the future public health is needed. It presents an integrative, ecological framework as a starting point from which public health might grasp the opportunities for change inherent in the 'modern' threats we face. It suggests a number of features that will need to underpin such a paradigm shift in thinking and practice. However, as this paper is written from the perspective of an affluent, developed society (albeit from a perspective that is explicitly critical of the goals, trends and values that seem to characterise such societies), other voices from other places need to be heard. We hope that others will want to engage with our arguments and suggestions, whether to challenge and refute these, or to further their development.

A perspective on the future public health practitioner.

In the centuries following the Enlightenment, scientific and technological developments gave 'modern people' an unprecedented ability to understand, predict and control the natural world. This has brought health and social benefits unimaginable to our ancestors and sets us apart from all previous generations. Yet there is a wide-ranging body of evidence that suggests that modernity is now in decline, largely because its methods and mindset are increasingly recognized as unsustainable. Problems are manifest in the emergence of new public health epidemics such as obesity and addictive behaviours, the loss of well-being and increase in anxiety and depression in affluent society, and the persistence of ever-widening health and social inequalities at national and global levels. Still larger problems now confront us, such as climate change, peak oil and the loss of biodiversity, all of which are linked to the 'modern' way of life. We are potentially faced with the collapse of certain aspects of modern society: we are certainly faced with the prospect of inevitable change. While the broad public health community has an important role to play in developing workable solutions to such daunting problems, we argue that some profound changes will be needed in order for us to cope successfully. No blueprints for dealing with change exist, which means that we will need to learn our way into the future. In this paper we take a perspective on the role and nature of the future practitioner in public health and health promotion. We argue that future practitioners will need to develop new ways of thinking, being and doing; new perspectives and new forms of understanding the world. We believe our discipline - and people generally - to be capable of such development, as insights from multiple sources tell us that human nature is malleable, not fixed. We use this analysis to trace, as examples, the imagined lives of five women living in different eras over the course of history in a Western society, and the emergence of different mindsets or worldviews, as the social, economic and cultural context changes. Post-modern analysts might insist that we have no basis for making value judgements between such different worldviews. In this paper, however, we argue that future practitioners should be empathetic to different views and willing to move beyond them, as necessary. We will need to learn and develop in ways that are compatible with our intrinsic needs as human beings and the needs of our ecosystem. We conclude by suggesting just some of the supportive processes of change needed in mapping out a more sustainable future for the public health community.

Talking openly: using '6D cards' to facilitate holistic, patient-led communication.

OBJECTIVE: The study investigates the effectiveness and acceptability of a communication tool (the '6D Cards') in facilitating holistic, patient-led communication in medical consultations. DESIGN: A between-subjects design was employed, whereby patients were randomly allocated to either use the '6D Cards' to initiate conversation or engage in the usual discussion processes. SETTING: The study was carried out in an outpatient gynaecology clinic at a National Health Service (NHS) public hospital in a small town. PARTICIPANTS: Seventy-one patients were given the '6D Cards' and 69 control patients had a normal consultation. All participants were females aged 18 years or older. Participants were consenting patients visiting the clinic during the 3-month data collection period and included both first time and known patients. INTERVENTION: The Cards contain 40 issues across 6 dimensions ('6D') of health and were designed in consultation with clinical staff. The aim of the '6D Cards' is to give patients the option of discussing broader aspects of their presenting problem. MAIN OUTCOME MEASURES: The primary outcome measures were the number and types of issues raised by all patients, with and without the use of the cards and a short acceptability questionnaire, which was completed by all patients following their consultations. RESULTS: /st> Patients using the cards raised significantly more issues than the control patients. Furthermore, patients raised overall no concerns about the acceptability of the cards. CONCLUSIONS: The '6D Cards' could be a useful communication tool to enable patients to raise general concerns and issues during their consultations.

Learning our way into the future public health: a proposition.

This article attempts to bridge the gap between the values and skills that currently inform public health and those that we need to confront the future. We draw on a set of radical arguments. Firstly, the ability of modern people to understand, predict and control the natural world has brought many benefits but evidence is accumulating that the methods and mindsets of modernity are subject to diminishing returns and adverse effects. This is manifest in the rise of new epidemics: obesity, addiction-related harm, loss of well-being, rising rates of depression and anxiety and widening inequalities. Secondly, there is little evidence that people are embracing new forms of thinking or practice, despite other threats which have the potential for massive effects on many lives, such as climate change and peak oil. Thirdly, if the problems we face may indicate that 'modernity' is in decline because unsustainable, then profound change is necessary if we are to avoid collapse. This analysis suggests that public health needs a new approach. We set out propositions and models that could help us learn our way into the future.

Status, taste and distinction in consumer culture: acknowledging the symbolic dimensions of inequality.

The relationship between social position and health has been the focus of extensive public health debate. In the UK and elsewhere, most researchers have focused on physical aspects of health, using indicators such as mortality and morbidity to draw a picture of profound and widening social inequalities. This paper draws attention to the (neglected) influence of contemporary culture on wellbeing, arguing that the social meanings created within consumer culture possess symbolic force that can add to wider inequalities. The possession of greater material and cultural resources by people of higher social status enables them to label their preferred forms of consumption and lifestyle as desirable and legitimate, thus conveying messages about superior taste and social distinction. Symbolic rather than material forms of inequality are implicated here, with consequences for the psychological wellbeing of disadvantaged people. This paper argues that analyses of inequality need broadening to include such considerations. However, there are implications for efforts to address health inequalities because this analysis suggests that if some forms of social inequality are removed, elements within society would be motivated to invent new forms to replace them. Therefore, this article suggests processes whereby people can develop the self-awareness needed to resist the glossy illusions of the good life represented by modern consumer capitalism.