A 12-Month Randomized Clinical Trial of 38% SDF vs. Restorative Treatment.

PURPOSE: The aim of this 2-arm, parallel-group, 12-mo randomized clinical trial was to compare the effectiveness of semiannual application of 38% silver diamine fluoride (SDF) versus restorative treatment (RT) to manage cavitated caries lesions in primary teeth in a diverse population of children in Michigan. METHODS: Children aged 2 to 10 y with at least 1 soft cavitated lesion (International Caries Detection and Assessment System 5 or 6) with no pain or signs/symptoms of irreversible pulpitis were recruited and randomly assigned to 2 intervention groups. One random lesion per child received 38% SDF (twice, at a 6-mo interval) or RT. All interventions and assessments were done by calibrated dentists. Primary outcome measures were clinical failure rates: minor (e.g., reversible pulpitis, active/soft lesion or progression, restoration loss or need for replacement/repair, secondary caries) and major (e.g., irreversible pulpitis, abscess, extraction). Parent, child, and provider acceptability was also assessed. RESULTS: Ninety-eight children were enrolled and randomized, with a mean (SD) age of 4.8 y (1.8); 46% were female and their mean dmft + DMFT was 6.3 (3.9). Sixty-nine children were assessed at 12 mo (sample was within the planned 30% attrition rate). There were significantly more teeth with minor failures (SDF = 65%, RT = 23%, P ≤ 0.001) and major failures (SDF = 13%, RT = 3%, P ≤ 0.001) in the SDF group than the RT group; 74% of SDF-treated lesions were hard at 12 mo vs. 57% at 6 mo. Providers stated that SDF was easier, faster, and more preferable than RT (P ≤ 0.001). No significant differences were found in parental satisfaction and acceptability. At 12 mo, children in the RT arm felt significantly (P < 0.05) happier with their tooth appearance and stated that their visit to the dentist hurt less. CONCLUSION: At 12 mo, SDF-treated lesions had significantly more minor and major failures than RT, suggesting that SDF-treated teeth need to be closely monitored in a population at high caries risk (ClinicalTrials.gov NCT02601833). KNOWLEDGE OF TRANSFER STATEMENT: The results of this study can be used by clinicians when deciding whether to restore or apply silver diamine fluoride to cavitated lesions in primary teeth. Information on treatment outcomes and parent, child, and provider acceptability can help guide appropriate treatment decisions and need for monitoring.

Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.

BACKGROUND: The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes. PATIENTS AND METHODS: A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results. RESULTS: In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort. CONCLUSIONS: In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01607957 (RECOURSE). JAPAN PHARMACEUTICAL INFORMATION CENTER NUMBER: JapicCTI-090880 (J003).

Diagnosis of rotavirus infection in a vaccinated population: Is a less sensitive immunochromatographic method more suitable for detecting wild-type rotavirus than real-time RT-PCR?

BACKGROUND: Diagnosis of wild-type rotavirus disease may be complicated by the detection of vaccine-derived virus which can be detected in stool samples following immunisation. We evaluate an immunochromatographic assay and real-time RT-PCR to determine which is more suitable for the detection of wild-type rotavirus. OBJECTIVES: To compare the Ct values of wild-type rotavirus and Rotarix determined by real-time RT-PCR. To establish the Ct value corresponding to the limit of detection of the immunochromatographic Combi-Strip method (Coris, BioConcept). STUDY DESIGN: Retrospective review of real-time RT-PCR Ct values was performed on 100 samples tested by a pan-rotavirus assay (n = 50 wild-type, n = 50 Rotarix). Secondly the limit of detection of the Combi-Strip assay was determined by testing; wild-type rotavirus (n = 33, Ct range 6.85-34.26) samples, Rotarix (n = 9, Ct range 20.86-34.26) samples and rotavirus negative (n = 21) samples. RESULTS: The median Ct of 50 wild-type rotavirus was Ct 12.43; range 6.11-32.66 compared with the median of 50 Rotarix, Ct 29.09; range 18.91-35.28, p=<0.0001. The limit of detection of the Combi-Strip method was approximately Ct 18. The 21 rotavirus negative samples were negative by real-time RT-PCR and Combi-Strip. CONCLUSIONS: We found the Ct value was significantly lower, and therefore the viral load higher, for wild-type rotavirus compared to detectable Rotarix. The Combi-Strip assay detects most wild-type infections; however, it lacks sensitivity to detect low-level wild-type rotavirus and, beneficially, is unlikely to detect Rotarix. It is not a more suitable method than real-time RT-PCR when a definitive rotavirus result is required.

Parp3 promotes long-range end joining in murine cells.

Chromosomal rearrangements, including translocations, are early and essential events in the formation of many tumors. Previous studies that defined the genetic requirements for rearrangement formation have identified differences between murine and human cells, most notably in the role of classic and alternative nonhomologous end-joining (NHEJ) factors. We reported that poly(ADP)ribose polymerase 3 (PARP3) promotes chromosomal rearrangements induced by endonucleases in multiple human cell types. We show here that in contrast to classic (c-NHEJ) factors, Parp3 also promotes rearrangements in murine cells, including translocations in murine embryonic stem cells (mESCs), class-switch recombination in primary B cells, and inversions in tail fibroblasts that generate Eml4-Alk fusions. In mESCs, Parp3-deficient cells had shorter deletion lengths at translocation junctions. This was corroborated using next-generation sequencing of Eml4-Alk junctions in tail fibroblasts and is consistent with a role for Parp3 in promoting the processing of DNA double-strand breaks. We confirmed a previous report that Parp1 also promotes rearrangement formation. In contrast with Parp3, rearrangement junctions in the absence of Parp1 had longer deletion lengths, suggesting that Parp1 may suppress double-strand break processing. Together, these data indicate that Parp3 and Parp1 promote rearrangements with distinct phenotypes.

Corrigendum: PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA.

This corrects the article DOI: 10.1038/ncomms15110.

PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA.

Chromosomal rearrangements are essential events in the pathogenesis of both malignant and nonmalignant disorders, yet the factors affecting their formation are incompletely understood. Here we develop a zinc-finger nuclease translocation reporter and screen for factors that modulate rearrangements in human cells. We identify UBC9 and RAD50 as suppressors and 53BP1, DDB1 and poly(ADP)ribose polymerase 3 (PARP3) as promoters of chromosomal rearrangements across human cell types. We focus on PARP3 as it is dispensable for murine viability and has druggable catalytic activity. We find that PARP3 regulates G quadruplex (G4) DNA in response to DNA damage, which suppresses repair by nonhomologous end-joining and homologous recombination. Chemical stabilization of G4 DNA in PARP3-/- cells leads to widespread DNA double-strand breaks and synthetic lethality. We propose a model in which PARP3 suppresses G4 DNA and facilitates DNA repair by multiple pathways.

The global mechanical properties and multi-scale failure mechanics of heterogeneous human stratum corneum.

UNLABELLED: The outermost layer of skin, or stratum corneum, regulates water loss and protects underlying living tissue from environmental pathogens and insults. With cracking, chapping or the formation of exudative lesions, this functionality is lost. While stratum corneum exhibits well defined global mechanical properties, macroscopic mechanical testing techniques used to measure them ignore the structural heterogeneity of the tissue and cannot provide any mechanistic insight into tissue fracture. As such, a mechanistic understanding of failure in this soft tissue is lacking. This insight is critical to predicting fracture risk associated with age or disease. In this study, we first quantify previously unreported global mechanical properties of isolated stratum corneum including the Poisson's ratio and mechanical toughness. African American breast stratum corneum is used for all assessments. We show these parameters are highly dependent on the ambient humidity to which samples are equilibrated. A multi-scale investigation assessing the influence of structural heterogeneities on the microscale nucleation and propagation of cracks is then performed. At the mesoscale, spatially resolved equivalent strain fields within uniaxially stretched stratum corneum samples exhibit a striking heterogeneity, with localized peaks correlating closely with crack nucleation sites. Subsequent crack propagation pathways follow inherent topographical features in the tissue and lengthen with increased tissue hydration. At the microscale, intact corneocytes and polygonal shaped voids at crack interfaces highlight that cracks propagate in superficial cell layers primarily along intercellular junctions. Cellular fracture does occur however, but is uncommon. STATEMENT OF SIGNIFICANCE: Human stratum corneum protects the body against harmful environmental pathogens and insults. Upon mechanical failure, this barrier function is lost. Previous studies characterizing the mechanics of stratum corneum have used macroscopic testing equipment designed for homogenous materials. Such measurements ignore the tissue's rich topography and heterogeneous structure, and cannot describe the underlying mechanistic process of tissue failure. For the first time, we establish a mechanistic insight into the failure mechanics of soft heterogeneous tissues by investigating how cracks nucleate and propagate in stratum corneum. We further quantify previously unreported values of the tissue's Poisson's ratio and toughness, and their dramatic variation with ambient humidity. To date, skin models examining drug delivery, wound healing, and ageing continue to estimate these parameters.

Changes in developmental body weight as a function of toluene exposure: A meta-analysis of animal studies.

Inhalant abuse is a globally prevalent health issue with particular concerns about substance-abusing pregnant women. In both animal models and clinical case reports of toluene exposure, the primary physiological outcome measure of prenatal inhalant exposure is low birth weight (BW). However, the effect of prenatal toluene exposure on animal BW varies widely in the literature. To clarify this effect and investigate possible design moderators of pup BW, a systematic review and meta-analytic techniques were applied to the existing peer-reviewed animal literature of prenatal and postnatal exposure models to the inhaled solvent toluene. Of 288 studies screened, 24 studies satisfied the inclusion criteria. Evaluation of these studies indicated that toluene exposure was negatively associated with pup BW (d = -0.39), with external inhaled concentration, route of administration, day of weighing, and toluene exposure magnitude moderating this association. Investigators doing animal studies should be cognizant of these factors before investigating the reproductive and developmental outcomes associated with prenatal and postnatal toluene exposure.

Asymmetric photonic resonances in GaN slab waveguide for mid infrared selective filters.

We demonstrate a spectrally selective reflector that exploits asymmetric photonic resonances of a 1D photonic crystal. The proposed spectrally selective reflector has a very simple structure - essentially just a single high-index slab of GaN, properly perforated, and supported by a transparent sapphire substrate. With the proper 1D array design, nearly 100% reflection is achieved with a narrow spectral width between 10 cm⁻¹ - 18 cm⁻¹, while the background reflection remains low across the entire mid-IR range. The reflection peak can be tuned over a large wavelength span based on physical parameters. Resonant transmission dips in the experimentally measured spectra corroborate the device theory and simulation, exhibiting the narrowband low-background mid-IR reflection as predicted.

Pertussis in young infants: clinical presentation, course and prevention.

Pertussis is a highly contagious disease caused by the Gram negative aerobic coccobacillus, Bordetella pertussis. It may present with severe symptoms and complications in infants and can pose a diagnostic challenge. This is a vaccine preventable illness covered by the Irish Childhood Immunisation Schedule. In 2011, a retrospective review was conducted of the records of infants, under six months, with a confirmed diagnosis of pertussis, presenting to Temple Street Children's University Hospital (TSCUH). A summery of notifications of pertussis nationally, from 2001 to 2012, was also examined as part of the study. This found that the rate of reported cases of pertussis has been increasing in Ireland. This national increase corresponds with a rising number of cases identified at TSCUH. Patients commonly presented severely ill with cyanosis and apnoea, on a background of prolonged cough. We found that pertussis was diagnosed rapidly in most cases however in all cases there was a delay to commencement of appropriate macrolide therapy.

Cardiac toxicity of the echinocandins: chance or cause and effect association?

WHAT IS KNOWN AND OBJECTIVE: Fungal infections pose a constant risk to critically ill and immunosuppressed patients. The echinocandin antifungals give practitioners an arsenal of agents with apparently lower toxicity relative to older agents. The objective of this commentary is to review the cardiac toxicity of the echinocandin antifungals in the light of recent evidence and published case reports. COMMENT: Three case reports detail cardiac decompensation following the initiation of anidulafungin and caspofungin and corroborate ex vivo laboratory results, in which rat hearts exposed to anidulafungin and caspofungin had significantly decreased cardiac contractility. Our hypothesized mechanism of toxicity of anidulafungin and caspofungin is mitochondrial toxicity. WHAT IS NEW AND CONCLUSION: The clinical corroboration of the ex vivo work presented above highly suggests that the cardiac toxicity seen with some of the echinocandin antifungals is a cause and effect pattern, not a chance finding.

Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Africa: a report from the Global Opioid Policy Initiative (GOPI).

With nearly 1.1 billion inhabitants living in more than 50 countries, Africa is the world's poorest and most socioeconomically underdeveloped continent. Despite some advances for individual states, many African countries have very low opioid consumption and, overall, the continent has the lowest consumption per capita of any in the world. This article presents the findings of the first systematic study of the availability and accessibility of opioids for the management of cancer pain across the continent. Data are reported on the availability and accessibility of opioids for the management of cancer pain in 25 of 52 countries, with 744 million of the region's 1127 million people (66%) covered by the survey. Many countries had severely restricted formularies of opioids and only 15 of 25 had morphine available in oral IR, CR and injectable formulations. Even when opioids are on formulary they are often unavailable, and access is significantly impaired by widespread over-regulation that is pervasive across the region.

Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Asia: a report from the Global Opioid Policy Initiative (GOPI).

Asia is a heterogeneous region with substantial variability in economic, social and palliative care development. While the global consumption of opioids has increased, the consumption in most Asian countries has not increased at the same rate. This is the first comprehensive study of opioid availability and accessibility for cancer patients in Asia. Data are reported on the availability and accessibility of opioids for the management of cancer pain in 20 of 28 countries. The countries in the report represent 2515 million of the region's 2612 million people (96%). With the exception of Japan and South Korea, opioid availability continues to be low throughout most of Asia. Formulary deficiencies are severe in several countries, in particular Bangladesh, Myanmar, Afghanistan, Kazakhstan and Laos. Even when opioids are on formulary, they are often unavailable, particularly in the same countries. Access is significantly impaired by widespread over-regulation that continues to be pervasive across the region.

Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in India: a report from the Global Opioid Policy Initiative (GOPI).

India is the world's largest democracy with control of opioids divided between the national and state governments. While the global consumption of opioids has increased, the consumption has not increased at the same rate. This is the first comprehensive study of opioid availability and accessibility for cancer patients in India. Data are reported on the availability and accessibility of opioids for the management of cancer pain in 24 of the states that make up India and the Administrative area around Delhi. About 1061 million of the nation's 1189 million people (89%) are covered by this survey. Without exception, opioid availability continues to be low throughout all of India. Even when opioids are on formulary, they are often unavailable. Access is significantly impaired by widespread over-regulation that continues to be pervasive across the nation.

Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Latin America and the Caribbean: a report from the Global Opioid Policy Initiative (GOPI).

The nations of the Caribbean, Central America and South America form a heterogeneous region with substantial variability in economic, social and palliative care development. Palliative care provision is at varied stages of development throughout the region. The consumption of opioids in Latin America and the Caribbean is variable with moderate levels of consumption by international standards (1-10 mg morphine equivalents/capita/year) observed in Argentine, Brazil, Chile, Colombia, Cuba, Mexico, Costa Rica, Uruguay and most of the Caribbean but relatively low levels of consumption in other countries particularly Guatemala, Honduras and Bolivia. Data for Latin American and Caribbean is reported on the availability and accessibility of opioids for the management of cancer pain in 24 of the 33 countries surveyed. The results of this survey are relevant to 560 million of the region's 595 million people (94%). Opioid availability continues to be low throughout most of Latin America and the Caribbean. While formularies in this region generally include all recommended morphine formulations, access is significantly impaired by widespread over-regulation that continues to be pervasive across the region.

Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in the Middle East: a report from the Global Opioid Policy Initiative (GOPI).

The Middle East is a heterogeneous region with substantial variability in social development, wealth and palliative care development. The region has few democracies, strong but diverse religious affiliations, and many of the region's counties are involved in political upheavals or regional conflicts. While the global consumption of opioids has increased throughout the last 30 years, there has been little increase in opioid consumption in the Middle East. This is the first comprehensive study of opioid availability and accessibility of opioids in the Middle East. Data are reported on the availability and accessibility of opioids for the management of cancer pain in 16 of 24 countries. The data are relevant to 329 million of the region's 403 million people (82%). The survey found that with the exception of Israel, opioid availability continues to be low throughout most of the Middle East. Formulary deficiencies are severe in several countries in particular Afghanistan, Iraq, Lebanon, Libya, Palestine and Tunisia. Even when opioids are on formulary, they are often unavailable, particularly in these same countries. Access is also significantly impaired by widespread over-regulation that is pervasive across the region.

Next steps in access and availability of opioids for the treatment of cancer pain: reaching the tipping point?

The reports of the Global Opioid Policy Initiative (GOPI) project to evaluate the availability and accessibility of opioids for the management of cancer pain in Africa, Asia, Latin America and the Caribbean, and the Middle East, together with the previous 2010 European Society for Medical Oncology (ESMO)/European Association for Palliative Care (EAPC) report from Europe, have provided critical data in demonstrating the deficiencies in many countries throughout the world. Formulary deficiencies and over-regulation are pandemic and must be addressed. This process is challenging and will require concerted and sustained efforts by clinical leaders and advocacy groups partnering with international and regional organizations and, of course, with national governments and their competent authorities. There is a growing international expertise and infrastructure to coordinate advocacy and strategic planning based on the World Health Organization (WHO) Model of Education, Policy Reform and Medication Availability.

The Global Opioid Policy Initiative (GOPI) project to evaluate the availability and accessibility of opioids for the management of cancer pain in Africa, Asia, Latin America and the Caribbean, and the Middle East: introduction and methodology.

Opioid analgesics are critical to the effective relief of cancer pain. Effective treatment is predicated on sound assessments, individually tailored analgesic therapy, and the availability and accessibility of the required medications. In some countries, pain relief is hampered by the lack of availability or barriers to the accessibility of opioid analgesics. As the follow-up to a successful project to evaluate the availability and accessibility of opioids and regulatory barriers in Europe, the European Society for Medical Oncology (ESMO) and the European Association for Palliative Care (EAPC) undertook to expand their research to those parts of the world where data were lacking regarding these aspects of care, in particular Africa, Asia, the Middle East, Latin America and the Caribbean, and the states of India. This project has been undertaken in collaboration with the Union for International Cancer Control (UICC), the Pain and Policy Studies Group (PPSG) of the University of Wisconsin, and the World Health Organization (WHO), together with a consortium of 17 international oncology and palliative care societies. This article describes the study methodology.

Imaging features of bowel toxicities in the setting of molecular targeted therapies in cancer patients.

Molecular targeted therapies are becoming ubiquitous in cancer treatment. These drugs may cause gastrointestinal toxicities including perforation, pneumatosis, enteritis, colitis and fistula formation. Knowledge of these complications and their management enables early radiological identification and appropriate intervention, reducing patient morbidity and mortality.

Decreasing trends in overweight and obesity among an Australian population of preschool children.

BACKGROUND: After several decades of increasing prevalence, recent evidence suggests a levelling of obesity rates in some groups, although little is known about trends in children under 5 years of age. AIM: To investigate the prevalence, trends and sociodemographic correlates of overweight and obesity in Australian preschool children between 1999 and 2007. METHODS: Child anthropometric and demographic data were extracted from records of routine maternal and child health consultations for children aged 2 and 3.5 years in the Australian state of Victoria. Data were analysed for prevalence of overweight and obesity (according to International Obesity Task Force definitions), trends in prevalence from 1999 to 2007 and sociodemographic correlates of prevalence and trends. RESULTS: Complete data were available for 129,266 2-year-old children and 96,164 3.5-year-old children from 41 local government areas across Victoria. Combined prevalence of overweight and obesity decreased significantly between 1999 and 2007 in 3.5-year-old children (by 3.1% points from 18.5 to 15.4%) and in 2-year-old children (1.1% point decrease from 13.5 to 12.4%). There was no accompanying increase in rates of underweight. Decreases were more pronounced in areas of lower socioeconomic status (SES). Prevalence of both overweight and obesity was consistently higher across time in the older group of children, in the lowest quartile of SES and among girls. CONCLUSIONS: Prevalence of overweight and obesity in preschool children in Victoria has decreased significantly between 1999 and 2007, whereas socioeconomic disparities have narrowed. Further research is needed to understand the reasons for the decreasing prevalence, and to better evaluate existing and emerging health promotion initiatives. Such evidence will be important to build on the findings of this study and to transfer lessons learnt to other population groups.