Editorial - Writing Together: Practitioners, Academics and Policy Makers

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Educational Leaders Can Lead the Way for Increased Academic Achievement for Students on the Autism Spectrum

The problem that drove this study was the increasing number of students with autism entering the school system, and the barriers often encountered for both academic and social inclusion for students on the autism spectrum. Autism Spectrum Disorder, as defined by diagnostic criteria, includes deficits in social-relational communication; social-communication deficits can lead to educational impacts and limit opportunities upon transitioning from the public-school system. The purpose of this study was to examine the barriers to inclusion, from the perspectives of key stakeholders to include Local Education Agency (LEA) representatives, general and special education teachers, school counselors, school psychologists, speech-language pathologists and other educators who may be involved with Individualized Educational Plans (IEP). A phenomenological, qualitative study with a critical paradigm was conducted to discuss and examine individual experiences and perspectives concerning barriers encountered to inclusion as well as suggestions for better practices through and reported successes. The findings suggest several barriers to inclusion from each perspective and that collaboration of the IEP team is key to the development and implementation of successful IEPS that include both academic and social inclusion goals. Inclusive climates begin with a vision and mission of inclusion academically and socially from educational leadership

Mechanical regulation of cardiac development

Mechanical forces are essential contributors to and unavoidable components of cardiac formation, both inducing and orchestrating local and global molecular and cellular changes. Experimental animal studies have contributed substantially to understanding the mechanobiology of heart development. More recent integration of high-resolution imaging modalities with computational modeling has greatly improved our quantitative understanding of hemodynamic flow in heart development. Merging these latest experimental technologies with molecular and genetic signaling analysis will accelerate our understanding of the relationships integrating mechanical and biological signaling for proper cardiac formation. These advances will likely be essential for clinically translatable guidance for targeted interventions to rescue malforming hearts and/or reconfigure malformed circulations for optimal performance. This review summarizes our current understanding on the levels of mechanical signaling in the heart and their roles in orchestrating cardiac development

In vivo strains in the femur of river cooter turtles (Pseudemys concinna) during terrestrial locomotion: tests of force-platform models of loading mechanics

Previous analyses of ground reaction force (GRF) and kinematic data from river cooter turtles (Pseudemys concinna) during terrestrial walking led to three primary conclusions about the mechanics of limb bone loading in this lineage: (1) the femur was loaded in a combination of axial compression, bending and torsion, similar to previously studied non-avian reptiles, (2) femoral shear stresses were high despite the possession of a reduced tail in turtles that does not drag on the ground and (3) stress-based calculations of femoral safety factors indicated high values in bending and torsion, similar to other reptiles and suggesting that substantial `overbuilding\u27 of limb bones could be an ancestral feature of tetrapods. Because force-platform analyses produce indirect estimates of bone loading, we sought to validate these conclusions by surgically implanting strain gauges on turtle femora to directly measure in vivo strains during terrestrial walking. Strain analyses verified axial compression and bending as well as high torsion in turtle femora, with peak axial strains comparable to those of other non-avian reptiles at similar walking speeds but higher peak shear strains approaching 2000 μϵ. Planar strain analyses showed patterns of neutral axis (NA) of femoral bending orientations and shifting generally consistent with our previous force-platform analyses of bone stresses, tending to place the anterior and dorsal aspects of the femur in tension and verifying an unexpected pattern from our force studies that differs from patterns in other non-avian reptiles. Calculated femoral safety factors were 3.8 in torsion and ranged from 4.4 to 6.9 in bending. Although these safety factors in bending were lower than values derived from our stress-based calculations, they are similar to strain-based safety factors calculated for other non-avian reptiles in terrestrial locomotion and are still high compared with safety factors calculated for limb bones of birds and mammals. These findings are consistent with conclusions drawn from our previous models of limb bone stresses in turtles and suggest that not only are turtle limb bones `overbuilt\u27 in terms of resisting the loads that they experience during locomotion but also, across tetrapod lineages, elevated torsion and high limb bone safety factors may be primitive features of limb bone design

Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans

The highly conserved, ubiquitous molecular chaperone Hsp90 is a key regulator of cellular proteostasis and environmental stress responses. In human pathogenic fungi, which kill more than 1.6 million patients each year worldwide, Hsp90 governs cellular morphogenesis, drug resistance, and virulence. Yet, our understanding of the regulatory mechanisms governing fungal Hsp90 function remains sparse. Post-translational modifications are powerful components of nature’s toolbox to regulate protein abundance and function. Phosphorylation in particular is critical in many cellular signaling pathways and errant phosphorylation can have dire consequences for the cell. In the case of Hsp90, phosphorylation affects its stability and governs its interactions with co-chaperones and clients. Thereby modulating the cell’s ability to cope with environmental stress. Candida albicans, one of the leading human fungal pathogens, causes ~750,000 life-threatening invasive infections world-wide with unacceptably high mortality rates. Yet, it remains unknown if and how Hsp90 phosphorylation affects C. albicans virulence traits. Here, we show that phosphorylation of Hsp90 is critical for expression of virulence traits. We combined proteomics, molecular evolution analyses and structural modelling with molecular biology to characterize the role of Hsp90 phosphorylation in this non-model pathogen. We demonstrated that phosphorylation negatively affects key virulence traits, such as the thermal stress response, morphogenesis, and drug susceptibility. Our results provide the first record of a specific Hsp90 phosphorylation site acting as modulator of fungal virulence. Post-translational modifications of Hsp90 could prove valuable in future exploitations as antifungal drug targets

Community seroprevalence survey for yaws and trachoma in the Western Division of Fiji.

BACKGROUND: Both yaws and trachoma are endemic in several countries in the Pacific. In co-endemic countries there may be potential synergies between both control programmes. METHODS: We undertook a cluster randomised trachoma and yaws seroprevalence survey of children in the Western Division of Fiji. Children were examined for skin lesions consistent with active yaws. A dried blood spot was collected which was tested using the Treponema pallidum particle agglutination (TPPA) test and an ELISA to detect antibodies against Pgp3. RESULTS: A total of 607 children from 305 households across 23 villages were recruited into the survey. On skin examination, no child had clinical evidence of yaws, and the TPPA assay was negative in all children (0%, 95% CI 0.0-0.6). The seroprevalence of Pgp3 antibodies was 20.9% (95% CI 17.8-24.6%). DISCUSSION: In this study there was neither clinical nor serological evidence that transmission of yaws was ongoing. The Pgp3 seroprevalence pattern was consistent with either low level transmission of ocular Chlamydia trachomatis or exposure to C. trachomatis in the birth canal which is consistent with a survey conducted in the same region in 2013. These data suggest neither yaws nor ocular chlamydia infection are a significant public health problem in the Western Division of Fiji

Dealing with missing standard deviation and mean values in meta-analysis of continuous outcomes: a systematic review

Background: Rigorous, informative meta-analyses rely on availability of appropriate summary statistics or individual participant data. For continuous outcomes, especially those with naturally skewed distributions, summary information on the mean or variability often goes unreported. While full reporting of original trial data is the ideal, we sought to identify methods for handling unreported mean or variability summary statistics in meta-analysis. Methods: We undertook two systematic literature reviews to identify methodological approaches used to deal with missing mean or variability summary statistics. Five electronic databases were searched, in addition to the Cochrane Colloquium abstract books and the Cochrane Statistics Methods Group mailing list archive. We also conducted cited reference searching and emailed topic experts to identify recent methodological developments. Details recorded included the description of the method, the information required to implement the method, any underlying assumptions and whether the method could be readily applied in standard statistical software. We provided a summary description of the methods identified, illustrating selected methods in example meta-analysis scenarios. Results: For missing standard deviations (SDs), following screening of 503 articles, fifteen methods were identified in addition to those reported in a previous review. These included Bayesian hierarchical modelling at the meta-analysis level; summary statistic level imputation based on observed SD values from other trials in the meta-analysis; a practical approximation based on the range; and algebraic estimation of the SD based on other summary statistics. Following screening of 1124 articles for methods estimating the mean, one approximate Bayesian computation approach and three papers based on alternative summary statistics were identified. Illustrative meta-analyses showed that when replacing a missing SD the approximation using the range minimised loss of precision and generally performed better than omitting trials. When estimating missing means, a formula using the median, lower quartile and upper quartile performed best in preserving the precision of the meta-analysis findings, although in some scenarios, omitting trials gave superior results. Conclusions: Methods based on summary statistics (minimum, maximum, lower quartile, upper quartile, median) reported in the literature facilitate more comprehensive inclusion of randomised controlled trials with missing mean or variability summary statistics within meta-analyses

Infiltration efficiency and subsurface water processes of a sustainable drainage system and consequences to flood management

With increased intensity rainfall events globally and urban expansion decreasing permeable surfaces, there is an increasing problem of urban flooding. This study aims to better understand rainfall infiltration into a Sustainable Drainage System (SuDS) permeable pavement, compared with an adjacent Green Area of made ground, in relationship to groundwater levels below both areas. Both areas were instrumented with soil water content and matric potential sensors and four shallow boreholes were instrumented with groundwater level sensors. Surface infiltration rates were measured using a double‐ring infiltrometer. Results showed that average infiltration rates of the SuDS (1,925 mm/hr) were significantly higher than the Green Area (56 mm/hr). The SuDS was well designed to transfer rainfall rapidly to the aquifer below, where groundwater levels rapidly rose within 1 hr of a 1 in 30 year event (32.8 mm/hr). In comparison, soil compaction of the made ground Green Area decreased infiltration rates, but still enabled the majority of rainfall events to infiltrate. The aquifer below the Green Area responded more slowly, as lower matrix potentials facilitated water retention in the soil profile, slowing water draining to the aquifer. This work reiterates the importance of ensuring a 1 m separation depth between the base of the SuDS infiltration zone and aquifer depth

Prevalence of signs of trachoma, ocular Chlamydia trachomatis infection and antibodies to Pgp3 in residents of Kiritimati Island, Kiribati.

OBJECTIVE: In some Pacific Island countries, such as Solomon Islands and Fiji, active trachoma is common, but ocular Chlamydia trachomatis (Ct) infection and trachomatous trichiasis (TT) are rare. On Tarawa, the most populous Kiribati island, both the active trachoma sign "trachomatous inflammation-follicular" (TF) and TT are present at prevalences warranting intervention. We sought to estimate prevalences of TF, TT, ocular Ct infection, and anti-Ct antibodies on Kiritimati Island, Kiribati, to assess local relationships between these parameters, and to help determine the need for interventions against trachoma on Kiribati islands other than Tarawa. METHODS: As part of the Global Trachoma Mapping Project (GTMP), on Kiritimati, we examined 406 children aged 1-9 years for active trachoma. We collected conjunctival swabs (for droplet digital PCR against Ct plasmid targets) from 1-9-year-olds with active trachoma, and a systematic selection of 1-9-year-olds without active trachoma. We collected dried blood spots (for anti-Pgp3 ELISA) from all 1-9-year-old children. We also examined 416 adults aged ≥15 years for TT. Prevalence of TF and TT was adjusted for age (TF) or age and gender (TT) in five-year age bands. RESULTS: The age-adjusted prevalence of TF in 1-9-year-olds was 28% (95% confidence interval [CI]: 24-35). The age- and gender-adjusted prevalence of TT in those aged ≥15 years was 0.2% (95% CI: 0.1-0.3%). Twenty-six (13.5%) of 193 swabs from children without active trachoma, and 58 (49.2%) of 118 swabs from children with active trachoma were positive for Ct DNA. Two hundred and ten (53%) of 397 children had anti-Pgp3 antibodies. Both infection (p<0.0001) and seropositivity (p<0.0001) were strongly associated with active trachoma. In 1-9-year-olds, the prevalence of anti-Pgp3 antibodies rose steeply with age. CONCLUSION: Trachoma presents a public health problem on Kiritimati, where the high prevalence of ocular Ct infection and rapid increase in seropositivity with age suggest intense Ct transmission amongst young children. Interventions are required here to prevent future blindness

A Pan-Canadian Validation Study for the Detection of EGFR T790M Mutation Using Circulating Tumor DNA From Peripheral Blood

Introduction: Genotyping circulating tumor DNA (ctDNA) is a promising noninvasive clinical tool to identify the EGFR T790M resistance mutation in patients with advanced NSCLC with resistance to EGFR inhibitors. To facilitate standardization and clinical adoption of ctDNA testing across Canada, we developed a 2-phase multicenter study to standardize T790M mutation detection using plasma ctDNA testing. Methods: In phase 1, commercial reference standards were distributed to participating clinical laboratories, to use their existing platforms for mutation detection. Baseline performance characteristics were established using known and blinded engineered plasma samples spiked with predetermined concentrations of T790M, L858R, and exon 19 deletion variants. In phase II, peripheral blood collected from local patients with known EGFR activating mutations and progressing on treatment were assayed for the presence of EGFR variants and concordance with a clinically validated test at the reference laboratory. Results: All laboratories in phase 1 detected the variants at 0.5 % and 5.0 % allele frequencies, with no false positives. In phase 2, the concordance with the reference laboratory for detection of both the primary and resistance mutation was high, with next-generation sequencing and droplet digital polymerase chain reaction exhibiting the best overall concordance. Data also suggested that the ability to detect mutations at clinically relevant limits of detection is generally not platform-specific, but rather impacted by laboratory-specific practices. Conclusions: Discrepancies among sending laboratories using the same assay suggest that laboratory-specific practices may impact performance. In addition, a negative or inconclusive ctDNA test should be followed by tumor testing when possible