Megadactyly with syndactyly of the right toes, a rare case report.

INTRODUCTION AND IMPORTANCE: Megadactyly of the foot is uncommon non hereditary congenital anomalies of the extremities and poses a dilemma on treatment however multiple treatment modalities were developed but is not uniform to all patients with megadactyly. The goal of the surgical treatment is to achieve painless and function of the foot. CASE PRESENTATION: We report a 14 years old male presented with complaints of progressive enlargement 2nd, 3rd, 4th and 5th toes of the right foot since birth, associated with inability to wear shoes. One month prior to admission he experienced gradual onset painful forefoot and toes that was increasing in severity with time associated with inability to walk normally. He is the first born in a family of four children and his other siblings are healthy with no anomalies. On clinical evaluation, he was health with stable vitals, with enlarged 2nd, 3rd, 4th and 5th toes of the right foot with no tenderness with intact neurovascular status. On clinical and radiological evaluation he was diagnosed with congenital megadactyly of the right foot, a multidisciplinary team including orthopedic surgeons and prosthetics team agreed to do trans-metatarsal, then partial foot prosthesis fabrication. He underwent trans-metatarsal amputation of the affected foot and tissue sample was taken for histopathology. The histological findings revealed bone enlargement with increased proliferation of subcutaneous adipose tissues with increased fibrous septae together with thinning of the epidermis, features suggestive of lipomatosis. The wound site healed very well after 14 days stitches were removed and the child was scheduled for follow-up after six weeks, 12 weeks and 6 month post-surgery. On the last visit he was free from pain on his right forefoot and toes, able to wear fabricated partial foot prosthesis and shoes normally, walk with no incapacitation. DISCUSSION: Our case report is unique due to the involvement of the multiple toes of the right foot with syndactyly at third and fourth toes and its management is challenging because there is no uniformity in its surgical treatment, in our case trans-metatarsal amputation was done and the patient progressed well after six months of follow up. CONCLUSION: Foot megadactyly is uncommon congenital malformation, most common on the right foot. Regardless of the dilemma on treatment, the trans-metatarsal amputation and a fabricated prosthesis to our patient fulfilled the goals of painless right foot and able to wear shoes and walk normally with no impairment.

Timeline to dysphagia resolution after endoscopic intervention of an interarytenoid defect based on Video Fluoroscopic Swallow Study dysphagia severity.

INTRODUCTION: We previously reported that endoscopic repair of a Type 1 Laryngeal Cleft (LC1) or Deep Interarytenoid Groove (DIG) improves swallowing function postoperatively. However, caregivers often ask about the timeline to resolution of the need for thickening. This study re-examines this cohort to answer this important caregiver-centered question. METHODS: We reassessed a 3-year retrospective, single-center dataset of children with dysphagia found to have a LC-1 or DIG on endoscopic exam. The primary outcome was rate of complete resolution of dysphagia at 2, 6, and 12 months after endoscopic intervention. A sub-group analysis was made based on severity of dysphagia prior to intervention and by type of endoscopic repair. RESULTS: Thirty-nine patients with mean age 1.35 years that had a LC-1 or DIG met criteria for inclusion. Rate of complete dysphagia resolution increased over time. Those with mild dysphagia (flow-reducing nipple and/or IDDSI consistency 1 or 2) had brisker resolution than those with moderate dysphagia (IDDSI consistency 3 or 4) at 2 months (67% vs 5%, p < 0.01) and at 6 months (80% vs 18%, p < 0.01) after endoscopic repair. There was no difference in dysphagia resolution between patients grouped by type of endoscopic repair. CONCLUSION: Addressing an interarytenoid defect in patients will not result in immediate, complete dysphagia resolution in most patients. However, patients that only require a flow-reducing nipple and/or thickening to an IDDSI consistency 1 or 2 have brisker resolution of the need for thickening than those that require an IDSSI consistency 3 or 4 prior to intervention. These results inform pre-operative discussions of the timeline to resolution based upon severity of dysphagia and help manage caregiver expectations.

Towards precision medicine for anxiety disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs.

Anxiety disorders are increasingly prevalent, affect people's ability to do things, and decrease quality of life. Due to lack of objective tests, they are underdiagnosed and sub-optimally treated, resulting in adverse life events and/or addictions. We endeavored to discover blood biomarkers for anxiety, using a four-step approach. First, we used a longitudinal within-subject design in individuals with psychiatric disorders to discover blood gene expression changes between self-reported low anxiety and high anxiety states. Second, we prioritized the list of candidate biomarkers with a Convergent Functional Genomics approach using other evidence in the field. Third, we validated our top biomarkers from discovery and prioritization in an independent cohort of psychiatric subjects with clinically severe anxiety. Fourth, we tested these candidate biomarkers for clinical utility, i.e. ability to predict anxiety severity state, and future clinical worsening (hospitalizations with anxiety as a contributory cause), in another independent cohort of psychiatric subjects. We showed increased accuracy of individual biomarkers with a personalized approach, by gender and diagnosis, particularly in women. The biomarkers with the best overall evidence were GAD1, NTRK3, ADRA2A, FZD10, GRK4, and SLC6A4. Finally, we identified which of our biomarkers are targets of existing drugs (such as a valproate, omega-3 fatty acids, fluoxetine, lithium, sertraline, benzodiazepines, and ketamine), and thus can be used to match patients to medications and measure response to treatment. We also used our biomarker gene expression signature to identify drugs that could be repurposed for treating anxiety, such as estradiol, pirenperone, loperamide, and disopyramide. Given the detrimental impact of untreated anxiety, the current lack of objective measures to guide treatment, and the addiction potential of existing benzodiazepines-based anxiety medications, there is a urgent need for more precise and personalized approaches like the one we developed.

Longitudinal Exposure-Response Modeling of Multiple Indicators of Alzheimer's Disease Progression.

BACKGROUND: Progression in Alzheimer's disease manifests as changes in multiple biomarker, cognitive, and functional endpoints. Disease progression modeling can be used to integrate these multiple measures into a synthesized metric of where a patient lies within the disease spectrum, allowing for a more dynamic measure over the range of the disease. OBJECTIVES: This study aimed to combine modeling techniques from psychometric research (e.g., item response theory) and pharmacometrics (e.g., hierarchical models) to describe the multivariate longitudinal disease progression for patients with mild-to-moderate Alzheimer's disease. Additionally, we aimed to extend the subsequent model to make it suitable for clinical trial simulation, with the inclusion of covariates, to explain variability in latent progression (i.e., disease progression) and to aid in the assessment of enrichment strategies. DESIGN: Multiple longitudinal endpoints in the Alzheimer's Disease Neuroimaging Initiative database were modeled. This model was validated internally using visual predictive checks, and externally by comparing data from the placebo arms of two Phase 2 crenezumab studies, ABBY (NCT01343966) and BLAZE (NCT01397578). SETTING: The Alzheimer's Disease Neuroimaging Initiative began in 2004: the initial 5-year study (ADNI-1) was extended by 2 years in 2009 by a Grand Opportunities grant (ADNI-GO), and in 2011 and 2016 by further competitive renewals of the ADNI-1 grant (ADNI-2 and ADNI-3, respectively). This work studies natural progression data from patients with confirmed Alzheimer's disease. The Phase 2 ABBY and BLAZE trials evaluated the safety and efficacy of crenezumab in patients with mild-to-moderate Alzheimer's disease. PARTICIPANTS: From the Alzheimer's Disease Neuroimaging Initiative database, 305 subjects who had a baseline diagnosis of mild-to-moderate Alzheimer's disease were included in modeling. From the ABBY and BLAZE studies, 158 patients were included from the studies' placebo arms. MEASUREMENTS: Longitudinal cognitive and functional assessments modeled included the Clinical Dementia Rating (both as Sum of Boxes and individual item scores), the Mini-Mental State Examination, the Alzheimer's Disease Assessment Scale - Cognitive Subscale, the Functional Activities Questionnaire, the Montreal Cognitive Assessment, and the Rey Auditory Verbal Learning Test. Also included were the imaging variable fluorodeoxyglucose-positron emission tomography and the following magnetic resonance imaging volumetrics: entorhinal, fusiform, hippocampal, intra-cranial, mid-temporal, ventricular, and whole brain. RESULTS: Applying item response theory approaches in this longitudinal setting showed clinical assessments informing a common disease scale in the following order (from early disease to late disease): Rey Auditory Verbal Learning Test, Functional Activities Questionnaire, Montreal Cognitive Assessment, Alzheimer's Disease Assessment Scale - Cognitive Subscale 12, Clinical Dementia Rating - Sum of Boxes, and Mini-Mental State Examination. The Clinical Dementia Rating communication and home-and-hobbies items were most informative at earlier disease stages, while memory, orientation, and personal care informed the disease status at later stages. A clinical trial simulation model was developed and accurately described within-sample longitudinal distribution of endpoints. Simplifying the model to use only baseline age, MMSE, and APOEε4 status as predictors, out-of-sample mean progression of ADAS-Cog and CDR Sum of Boxes in the ABBY and BLAZE placebo arms was accurately described; however, the variability in these endpoints was underpredicted and suggests possibility for further model refinement when extrapolating from the ADNI sample to trial data. Clinical trial simulations were performed to exemplify use of the model to investigate hypothetical disease modification effects on the multivariate, longitudinal progression on the Alzheimer's Disease Assessment Scale - Cognitive Subscale and the Clinical Dementia Rating - Sum of Boxes. CONCLUSIONS: The latent variable structure of item response theory can be extended to capture a variety of scales that are common assessments and indicators of disease status in mild-to-moderate Alzheimer's disease. These models are not intended to support causal inferences, but they do successfully characterize the observed correlation between endpoints over time and result in concise numerical indices of disease status that reflect the totality of evidence from considering the endpoints jointly. As such, the models have utility for a variety of tasks in clinical trial design, including simulation of hypothetical drug effects, interpolation of missing data, and assessment of in-sample information.

The pinene scaffold: its occurrence, chemistry, synthetic utility, and pharmacological importance.

Plant-based secondary metabolites have been a major source of drug discovery and inspiration for new generations of drugs. Plants offer a wide variety of compound classes, including alkaloids, terpenes, flavonoids, and glycosides, with different molecular architectures (fused bridgehead, bi- and polycyclic, spirocyclic, polycyclic, and acyclic). The diversity, abundance, and accessibility of plant metabolites make plants an attractive source of human and animal medicine. Even though the pinene scaffold is abundant in nature and has historical use in traditional medicine, pinene and pinene-derived compounds have not been comprehensively studied for medicinal applications. This review provides insight into the utility of the pinene scaffold as a crucial building block of important natural and synthetic products and as a chiral reagent in the asymmetric synthesis of important compounds.

Insights into Diagnostic Radiography students' perception of clinical stressors.

INTRODUCTION: Clinical placements are integral components of Diagnostic Radiography (DR) university training programs, providing students with necessary and unique learning experiences. Educators' understanding of the student experience on placement is growing, and it is important for educators to be attentive to students' reactions to their learning environments and to situations identified to reduce wellbeing. This study aimed to explore DR students' perceptions of challenges experienced during clinical placements and their use of coping strategies. METHODS: Final year DR Students at the University of Sydney, were invited to participate in an online focus group. Three focus groups were conducted with a total of 13 participants. Participants were asked to narrate situations experienced while on clinical placement that reduced their emotional wellbeing, and coping strategies considered to support emotional wellbeing. An inductive thematic analysis of focus group transcripts was undertaken to identify the main discussion themes. RESULTS: Three themes were identified regarding situations considered to reduce emotional wellbeing: adapting to the 'reality' of the clinical environment, forming effective relationships, and balancing student role expectations and responsibilities of patient care. Three themes were identified about coping strategies for emotionally challenging situations: support from clinical and academic staff, peer support and personal strategies, and growing knowledge and confidence over time. CONCLUSION: Students' emotional wellbeing during experiential learning experiences is an underappreciated factor in their transformations into competent diagnostic radiographers. Academic training programs are therefore encouraged to be sensitive to the wellbeing of their trainees, and to take deliberate steps to equip students with the skills to navigate emotions and to normalise emotional responses that may be experienced in the clinical setting. IMPLICATIONS FOR PRACTICE: Students' experience of challenges in the clinical environment is largely influenced by students' abilities to deal with negative experiences, hence students' concerns require implementation of focused interventions prior to first clinical placement.

Suicide, self-harm and thoughts of suicide or self-harm in infectious disease epidemics: a systematic review and meta-analysis.

AIMS: Suicide accounts for 2.2% of all years of life lost worldwide. We aimed to establish whether infectious epidemics are associated with any changes in the incidence of suicide or the period prevalence of self-harm, or thoughts of suicide or self-harm, with a secondary objective of establishing the frequency of these outcomes. METHODS: In this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO and AMED were searched from inception to 9 September 2020. Studies of infectious epidemics reporting outcomes of (a) death by suicide, (b) self-harm or (c) thoughts of suicide or self-harm were identified. A random-effects model meta-analysis for the period prevalence of thoughts of suicide or self-harm was conducted. RESULTS: In total, 1354 studies were screened with 57 meeting eligibility criteria, of which 7 described death by suicide, 9 by self-harm, and 45 thoughts of suicide or self-harm. The observation period ranged from 1910 to 2020 and included epidemics of Spanish Flu, severe acute respiratory syndrome, human monkeypox, Ebola virus disease and coronavirus disease 2019 (COVID-19). Regarding death by suicide, data with a clear longitudinal comparison group were available for only two epidemics: SARS in Hong Kong, finding an increase in suicides among the elderly, and COVID-19 in Japan, finding no change in suicides among children and adolescents. In terms of self-harm, five studies examined emergency department attendances in epidemic and non-epidemic periods, of which four found no difference and one showed a reduction during the epidemic. In studies of thoughts of suicide or self-harm, one large survey showed a substantial increase in period prevalence compared to non-epidemic periods, but smaller studies showed no difference. As a secondary objective, a meta-analysis of thoughts of suicide and self-harm found that the pooled prevalence was 8.0% overall (95% confidence interval (CI) 5.2-12.0%; 14 820 of 99 238 cases in 24 studies) over a time period of between seven days and six months. The quality assessment found 42 studies were of high quality, nine of moderate quality and six of high quality. CONCLUSIONS: There is little robust evidence on the association of infectious epidemics with suicide, self-harm and thoughts of suicide or self-harm. There was an increase in suicides among the elderly in Hong Kong during SARS and no change in suicides among young people in Japan during COVID-19, but it is unclear how far these findings may be generalised. The development of up-to-date self-harm and suicide statistics to monitor the effect of the current pandemic is an urgent priority.

Nopol-Based Quinoline Derivatives as Antiplasmodial Agents.

Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new antimalarial therapeutics that complement parasite control strategies to combat malaria, especially in the tropics. In this work, nopol-based quinoline derivatives were investigated for their inhibitory activity against Plasmodium falciparum, one of the parasites that cause malaria. The nopyl-quinolin-8-yl amides (2-4) were moderately active against the asexual blood stage of chloroquine-sensitive strain Pf3D7 but inactive against chloroquine-resistant strains PfK1 and PfNF54. The nopyl-quinolin-4-yl amides and nopyl-quinolin-4-yl-acetates analogs were generally less active on all three strains. Interesting, the presence of a chloro substituent at C7 of the quinoline ring of amide 8 resulted in sub-micromolar EC50 in the PfK1 strain. However, 8 was more than two orders of magnitude less active against Pf3D7 and PfNF54. Overall, the nopyl-quinolin-8-yl amides appear to share similar antimalarial profile (asexual blood-stage) with previously reported 8-aminoquinolines like primaquine. Future work will focus on investigating the moderately active and selective nopyl-quinolin-8-yl amides on the gametocyte or liver stages of Plasmodium falciparum and Plasmodium vivax.

The Stirling Protocol - Putting the environment at the heart of prosperity and social inclusion.

While the global coronavirus crisis impacts society and the economy in a myriad of ways, it provides, what is likely to be, a once in a lifetime opportunity for us to rethink our response to climate change. According to the 2020 Global Risk Register, extreme weather and climate action failure are the two most likely and impactful risks to the global economy, which now more than ever needs to be avoided. Addressing the major challenges that we face from climate change can often appear to conflict with economic priorities. Add to this the fact that environmental mitigation steps can inadvertently exclude sections of the population and the enormity and complexity of climate change responses can result in paralysis. In contrast, the Stirling Protocol provides the framework for rapid, effective action and comprises three pillars: Environment, Economy & Inclusion. By addressing and balancing these three pillars, the simple protocol can be adopted throughout organisations putting the environment at the heart of sustainable prosperity and inclusion and provide a benchmark for positive action.

Concurrent advanced HIV disease and viral load suppression in a high-burden setting: Findings from the 2015-6 ZIMPHIA survey.

BACKGROUND: As Zimbabwe approaches epidemic control of HIV, programs now prioritize viral load over CD4 monitoring, making it difficult to identify persons living with HIV (PLHIV) suffering from advanced disease (AD). We present an analysis of cross-sectional ZIMPHIA data, highlighting PLHIV with AD and concurrent viral load suppression (VLS). METHODS: ZIMPHIA collected blood specimens for HIV testing from 22,501 consenting adults (ages 15 years and older); 3,466 PLHIV had CD4 and VL results. Household HIV testing used the national serial algorithm, and those testing positive then received point-of-care CD4 enumeration with subsequent VL testing. We used logistic regression analysis to explore factors associated with concurrent AD and VLS (<1000 copies/mL). All analyses were weighted to account for complex survey design. RESULTS: Of the 3,466 PLHIV in the survey with CD4 and VL results, 17% were found to have AD (CD4<200cells/mm3). Of all AD patients, 30% had VLS. Concurrent AD and VLS was associated with male sex (aOR 2.45 95%CI 1.61-3.72), older age (35-49 years [aOR 2.46 95%CI 1.03-5.91] and 50+ years [aOR 4.82 95%CI 2.02-11.46] vs 15-24 years), and ART duration (<6 months [aOR 0.46 95%CI 0.29-0.76] and 6-24 months [aOR 2.07 95%CI 1.35-3.17] vs more than 2 years). The relationship between sex and AD is driven by age with significant associations among men aged 25-34, (aOR 3.37 95%CI 1.35-8.41), 35-49 (aOR 5.13 95%CI 2.16-12.18), and 50+ (aOR 12.56 95%CI 4.82-32.72) versus men aged 15-24. CONCLUSIONS: The percentage of PLHIV with AD and VLS illustrates the conundrum of decreased support for CD4 monitoring, as these patients may not receive appropriate clinical services for advanced HIV disease. In high-prevalence settings such as Zimbabwe, CD4 monitoring support warrants further consideration to differentiate care appropriately for the most vulnerable PLHIV. Males may need to be prioritized, given their over-representation in this sub-population.

Introduction of a care bundle effectively and sustainably reduces patient-reported surgical site infection in patients undergoing colorectal surgery.

BACKGROUND: Surgical site infection (SSI) is one of the most common healthcare-associated infections and is particularly prevalent following colorectal surgery. It is associated with an increase in patient morbidity and healthcare costs. SSI is difficult to monitor as it frequently presents after discharge from hospital, especially if enhanced recovery programmes are in place. AIM: To develop an effective method for measuring patient-reported 30-day SSI in patients undergoing colorectal resection. To implement a new care bundle capable of delivering a sustainable reduction in SSI. METHODS: The Public Health England SSI surveillance questionnaire was used. Several data collection methods were tested including postal and telephone-based systems. A new SSI bundle was introduced in our centre incorporating four evidence-based interventions: 2% chlorhexidine skin preparation; repeat-dose antibiotics after 4 h; dual-ring wound protectors; and triclosan-coated sutures for wound closure. System changes were introduced to ensure that the change was sustainable. FINDINGS: The most reliable method of measuring patient-reported SSI was found to be postal questionnaire with telephone calls made to non-responders. Response rates to the SSI surveillance questionnaire were consistently >75%. Introduction of the new care bundle produced a significant reduction in SSI from 20% to 10% (P ≤ 0.0001) which has been sustained for six years. CONCLUSION: This is a reliable method for measuring 30-day patient-reported SSI rates. The introduction of this new care bundle has halved the rate of SSI from 20% to 10%.

Differential CpG DNA methylation in peripheral naïve CD4+ T-cells in early rheumatoid arthritis patients.

BACKGROUND: The genetic risk associated with rheumatoid arthritis (RA) includes genes regulating DNA methylation, one of the hallmarks of epigenetic re-programing, as well as many T-cell genes, with a strong MHC association, pointing to immunogenetic mechanisms as disease triggers leading to chronicity. The aim of our study was to explore DNA methylation in early, drug-naïve RA patients, towards a better understanding of early events in pathogenesis. RESULT: Monocytes, naïve and memory CD4+ T-cells were sorted from 6 healthy controls and 10 RA patients. DNA methylation was assessed using a genome-wide Illumina 450K CpG promoter array. Differential methylation was confirmed using bisulfite sequencing for a specific gene promoter, ELISA for several cytokines and flow cytometry for cell surface markers. Differentially methylated (DM) CpGs were observed in 1047 genes in naïve CD4+ T-cells, 913 in memory cells and was minimal in monocytes with only 177 genes. Naive CD4+ T-cells were further investigated as presenting differential methylation in the promoter of > 500 genes associated with several disease-relevant pathways, including many cytokines and their receptors. We confirmed hypomethylation of a region of the TNF-alpha gene in early RA and differential expression of 3 cytokines (IL21, IL34 and RANKL). Using a bioinformatics package (DMRcate) and an in-house analysis based on differences in ß values, we established lists of DM genes between health and RA. Publicly available gene expression data were interrogated to confirm differential expression of over 70 DM genes. The lists of DM genes were further investigated based on a functional relationship database analysis, which pointed to an IL6/JAK1/STAT3 node, related to TNF-signalling and engagement in Th17 cell differentiation amongst many pathways. Five DM genes for cell surface markers (CD4, IL6R, IL2RA/CD25, CD62L, CXCR4) were investigated towards identifying subpopulations of CD4+ T-cells undergoing these modifications and pointed to a subset of naïve T-cells, with high levels of CD4, IL2R, and CXCR4, but reduction and loss of IL6R and CD62L, respectively. CONCLUSION: Our data provided novel conceptual advances in the understanding of early RA pathogenesis, with implications for early treatment and prevention.

Towards precision medicine for stress disorders: diagnostic biomarkers and targeted drugs.

The biological fingerprint of environmental adversity may be key to understanding health and disease, as it encompasses the damage induced as well as the compensatory reactions of the organism. Metabolic and hormonal changes may be an informative but incomplete window into the underlying biology. We endeavored to identify objective blood gene expression biomarkers for psychological stress, a subjective sensation with biological roots. To quantify the stress perception at a particular moment in time, we used a simple visual analog scale for life stress in psychiatric patients, a high-risk group. Then, using a stepwise discovery, prioritization, validation, and testing in independent cohort design, we were successful in identifying gene expression biomarkers that were predictive of high-stress states and of future psychiatric hospitalizations related to stress, more so when personalized by gender and diagnosis. One of the top biomarkers that survived discovery, prioritization, validation, and testing was FKBP5, a well-known gene involved in stress response, which serves as a de facto reassuring positive control. We also compared our biomarker findings with telomere length (TL), another well-established biological marker of psychological stress and show that newly identified predictive biomarkers such as NUB1, APOL3, MAD1L1, or NKTR are comparable or better state or trait predictors of stress than TL or FKBP5. Over half of the top predictive biomarkers for stress also had prior evidence of involvement in suicide, and the majority of them had evidence in other psychiatric disorders, providing a molecular underpinning for the effects of stress in those disorders. Some of the biomarkers are targets of existing drugs, of potential utility in patient stratification, and pharmacogenomics approaches. Based on our studies and analyses, the biomarkers with the best overall convergent functional evidence (CFE) for involvement in stress were FKBP5, DDX6, B2M, LAIR1, RTN4, and NUB1. Moreover, the biomarker gene expression signatures yielded leads for possible new drug candidates and natural compounds upon bioinformatics drug repurposing analyses, such as calcium folinate and betulin. Our work may lead to improved diagnosis and treatment for stress disorders such as PTSD, that result in decreased quality of life and adverse outcomes, including addictions, violence, and suicide.

Low-cost reflective Hilger-Chance refractometer used to determine Sellmeier coefficients of bulk polydimethylsiloxane.

Refractometry is important for characterizing the optical performance of materials. The refractive index can quickly be assessed using critical angle or thin-film techniques. However, these methods only assess the material surface. Measurement of bulk refractive index is performed by measuring the refracted angle of a transmitted beam but requires precision sample geometry. The method presented here avoids costly sample preparation by measuring the sample geometry and refracted angle simultaneously, using reflections from the front and back surfaces of a wedge of material. The method is demonstrated for polydimethylsiloxane prepared under a range of curing conditions, and no significant dependence was observed. Spectral dependence is characterized, and Sellmeier coefficients are reported.

Archaeological assessment reveals Earth's early transformation through land use.

Environmentally transformative human use of land accelerated with the emergence of agriculture, but the extent, trajectory, and implications of these early changes are not well understood. An empirical global assessment of land use from 10,000 years before the present (yr B.P.) to 1850 CE reveals a planet largely transformed by hunter-gatherers, farmers, and pastoralists by 3000 years ago, considerably earlier than the dates in the land-use reconstructions commonly used by Earth scientists. Synthesis of knowledge contributed by more than 250 archaeologists highlighted gaps in archaeological expertise and data quality, which peaked for 2000 yr B.P. and in traditionally studied and wealthier regions. Archaeological reconstruction of global land-use history illuminates the deep roots of Earth's transformation and challenges the emerging Anthropocene paradigm that large-scale anthropogenic global environmental change is mostly a recent phenomenon.

Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs.

We endeavored to identify objective blood biomarkers for pain, a subjective sensation with a biological basis, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We studied psychiatric patients, a high risk group for co-morbid pain disorders and increased perception of pain. For discovery, we used a powerful within-subject longitudinal design. We were successful in identifying blood gene expression biomarkers that were predictive of pain state, and of future emergency department (ED) visits for pain, more so when personalized by gender and diagnosis. MFAP3, which had no prior evidence in the literature for involvement in pain, had the most robust empirical evidence from our discovery and validation steps, and was a strong predictor for pain in the independent cohorts, particularly in females and males with PTSD. Other biomarkers with best overall convergent functional evidence for involvement in pain were GNG7, CNTN1, LY9, CCDC144B, and GBP1. Some of the individual biomarkers identified are targets of existing drugs. Moreover, the biomarker gene expression signatures were used for bioinformatic drug repurposing analyses, yielding leads for possible new drug candidates such as SC-560 (an NSAID), and amoxapine (an antidepressant), as well as natural compounds such as pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), and apigenin (a plant flavonoid). Our work may help mitigate the diagnostic and treatment dilemmas that have contributed to the current opioid epidemic.

Salivary characteristics and dental caries experience in remote Indigenous children in Australia: a cross-sectional study.

BACKGROUND: While associations between salivary characteristics and dental caries have been well studied, we are not aware of this being assessed in a remote Indigenous child population, where lifestyles may be different from urban children. Our aim was to assess associations between caries experience and putative biomarkers in saliva, accounting for oral hygiene and dietary habits. METHODS: Children attending schools in an Indigenous community in remote north Queensland, Australia were invited to an oral examination by qualified and calibrated examiners. Salivary flow rate, pH, buffering capacity and loads of mutans streptococci (MS), lactobacilli (LB) and yeasts were determined. Also, data on tooth brushing frequency and soft drinks consumption were obtained via a questionnaire. Caries experience was recorded by the International Caries Detection and Assessment System (ICDAS-II), and quantified as decayed, missing and filled surfaces. Relationships between the salivary variables and the cumulative caries experience (dmfs+DMFS) in the deciduous and permanent dentitions were examined by multivariate analyses to control the effect of confounders. RESULTS: The mean cumulative decayed (DS + ds), missing (MS + ms) and filled (FS + fs) surfaces were 3.64 (SD: 4.97), 1.08 (4.38) and 0.79 (1.84) respectively. Higher salivary MS and LB counts, low tooth brushing frequency and daily soft drink consumption were significantly related to greater caries experience. Caries experience was about twice in those with ≥10^5 CFU/ml saliva counts of MS (mean = 6.33, SD: 8.40 vs 3.11, 5.77) and LB (7.03, 7.49 vs 4.41, 8.00). In the fully-adjusted multivariate model, caries experience in those with higher counts of MS and LB were 51 and 52% more than those with lower counts. CONCLUSIONS: As with studies in other populations, childhood salivary counts of MS and LB were significantly associated with greater caries experience in this remote Indigenous community. To address the serious burden of oral disease, we are researching ways to promote a healthy oral environment by encouraging good dietary habits, and emphasising the importance of daily tooth brushing with a fluoridated toothpaste. Our ongoing longitudinal studies will indicate the success of measures employed to reduce the counts of bacteria closely associated with cariogenesis and their impact on caries increment. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ANZCTR ), No: ACTRN12615000693527; date of registration: 3rd July 2015.

Analysis of soluble or titanium dioxide derived titanium levels in human whole blood: consensus from an inter-laboratory comparison.

Exposure to titanium (Ti), via the ingestion of pigment grade Ti dioxide (TiO2), is commonplace for westernised populations. It may also occur as a consequence of metal ion leaching in subjects bearing Ti-containing implants. Accurate exposure analysis requires fit-for-purpose analytical methodology, especially for true measures of baseline levels. Inductively coupled plasma (ICP) techniques are, mainly, now used for bio-analysis of Ti. Since whole blood reference materials, certified for natural low levels of Ti, are not currently available, we undertook an inter-laboratory comparison of pooled human blood from fasted volunteers ±low level (+∼2.5 µg L-1) or high level (+10-20 µg L-1) spikes of soluble Ti or TiO2 particles. Seven established laboratories were enrolled to analyse the samples using ICP based techniques, which included at least one of ICP optical emission spectrometry (ICP-OES), high resolution ICP mass spectrometry (HR-ICP-MS), triple quadrupole ICP-MS (ICP-MS/MS) or single quadrupole ICP-MS (SQ-ICP-MS). Five laboratories diluted the blood for analysis whilst two performed acid digestion. Overall, we showed that the laboratories could, mostly, quantitatively detect modest levels of spiked Ti in blood. Markedly varying levels of Ti, however, were reported for the same baseline pooled sample (0.4-24.6 µg L-1) and, in this study, specificity was poor for SQ-ICP-MS. Digestion of samples caused sample contamination compromising limits of detection and accuracy, whilst simple dilution had no such problem, and remained linear in response for spikes with ionic and TiO2 particles. We conclude that measuring baseline levels of Ti in whole blood is challenging but should be readily achievable down to 0.5-1.5 µg L-1, if sample preparation avoids contamination and instrument techniques are used that negate polyatomic or isobaric interferences from the sample matrix. We also remind those relying upon Ti bio-analytical data for their experimental outcomes that (a) spiking and recovery experiments provide information only on linearity of detection but not at all on accuracy as this will not detect constant positive errors and that (b) biological standard materials for Ti generally contain high levels of the analyte and tend to mask baseline analytical errors. Caution may be required in interpreting the findings of some published Ti/TiO2 bio-exposure studies.

Adaptation of the adult Functional Mobility Assessment (FMA) into a FMA-Family Centred (FMA-FC) paediatric version.

AIM: The aims of this study were to adapt an adult wheeled mobility outcome measure, the Functional Mobility Assessment, for use with children (FMA-Family Centred) and establish the new measure's content validity, test-retest reliability, and internal consistency. BACKGROUND: Although several tools exist to measure a child's ability to operate and move a wheeled mobility device, none focus on the ability of the wheeled mobility device to support children and their families as they perform daily activities. METHODS: After adapting the FMA items with examples relevant to children aged 3-21, parent/caregiver and therapist stakeholder groups recommended adaptations relevant for families with children who cannot respond for themselves. RESULTS: Six of the initial FMA items were retained with child-appropriate examples, and 4 new items were developed. CONCLUSION: The content validity of the FMA-Family Centred was strongly supported, and internal consistency and test-retest reliability met accepted psychometric standards.

Longitudinal study on the occurrence in pigs of colistin-resistant Escherichia coli carrying mcr-1 following the cessation of use of colistin.

AIMS: In 2015, colistin-resistant Escherichia coli and Salmonella with the mcr-1 gene were isolated from a pig farm in Great Britain. Pigs were subsequently monitored over a ~20-month period for the occurrence of mcr-1-mediated colistin resistance and the risk of mcr-1 E. coli entering the food chain was assessed. METHODS AND RESULTS: Pig faeces and slurry were cultured for colistin-resistant E. coli and Salmonella, tested for the mcr-1 gene by PCR and selected isolates were further analysed. Seventy-eight per cent of faecal samples (n = 275) from pigs yielded mcr-1 E. coli after selective culture, but in positive samples only 0·2-1·3% of the total E. coli carried mcr-1. Twenty months after the initial sampling, faecal samples (n = 59) were negative for E. coli carrying mcr-1. CONCLUSIONS: The risk to public health from porcine E. coli carrying mcr-1 was assessed as very low. Twenty months after cessation of colistin use, E. coli carrying mcr-1 was not detected in pig faeces on a farm where it was previously present. SIGNIFICANCE AND IMPACT OF THE STUDY: The results suggest that cessation of colistin use may help over time to reduce or possibly eliminate mcr-1 E. coli on pig farms where it occurs.