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IF YOU'VE SPENT ANY TIME ON planet Earth, you can't help but notice the hold science fiction has on kids' imaginations. Integrate science fiction into language arts, science, social studies, and math-- as we did-- and you're sure to bring some unearthly excitement to your classroom.

Development of viral vectors capable of transducing photoreceptors by less invasive methods than subretinal injection would provide a major advancement in retinal gene therapy. We sought to develop novel AAV vectors optimized for photoreceptor transduction following intravitreal delivery and to develop methodology for quantifying this transduction in vivo. Surface exposed tyrosine (Y) and threonine (T) residues on the capsids of AAV2, AAV5 and AAV8 were changed to phenylalanine (F) and valine (V), respectively. Transduction efficiencies of self-complimentary, capsid-mutant and unmodified AAV vectors containing the smCBA promoter and mCherry cDNA were initially scored in vitro using a cone photoreceptor cell line. Capsid mutants exhibiting the highest transduction efficiencies relative to unmodified vectors were then injected intravitreally into transgenic mice constitutively expressing a Rhodopsin-GFP fusion protein in rod photoreceptors (Rho-GFP mice). Photoreceptor transduction was quantified by fluorescent activated cell sorting (FACS) by counting cells positive for both GFP and mCherry. To explore the utility of the capsid mutants, standard, (non-self-complementary) AAV vectors containing the human rhodopsin kinase promoter (hGRK1) were made. Vectors were intravitreally injected in wildtype mice to assess whether efficient expression exclusive to photoreceptors was achievable. To restrict off-target expression in cells of the inner and middle retina, subsequent vectors incorporated multiple target sequences for miR181, an miRNA endogenously expressed in the inner and middle retina. Results showed that AAV2 containing four Y to F mutations combined with a single T to V mutation (quadY-F+T-V) transduced photoreceptors most efficiently. Robust photoreceptor expression was mediated by AAV2(quadY-F+T-V) -hGRK1-GFP. Observed off-target expression was reduced by incorporating target sequence for a miRNA highly expressed in inner/middle retina, miR181c. Thus we have identified a novel AAV vector capable of transducing photoreceptors following intravitreal delivery to mouse. Furthermore, we describe a robust methodology for quantifying photoreceptor transduction from intravitreally delivered AAV vectors.

ObjectivesWe aimed to determine (1) the proportion of women authors overall, in first (lead) and last (senior) author positions, (2) the proportion of women research participants and (3) the association between women in first and/or last author positions and the proportion of women research participants in original research articles and editorials/opinion pieces in four sport and exercise medicine/physiotherapy journals.MethodsThe journals evaluated were the British Journal of Sports Medicine, Journal of Orthopaedic and Sports Physical Therapy, Physical Therapy in Sport and International Journal of Sports Physical Therapy.We reviewed all original research articles and editorials/opinion pieces published in 2008, 2009, 2018 and 2019. For each, we aimed to determine the gender/sex of all authors (through gender pronouns, Google Scholar, ResearchGate, institutional profiles, personal websites, photographs and/or social media), and the gender/sex of study participants reported as ‘female’ or ‘male’ or ‘women’ or ‘men’ or ‘girls’ or ‘boys’.ResultsWe included 952 original studies and 219 editorials/opinion pieces. There were 5146 authors of original studies and 706 authors of editorials/opinion pieces. Compared with 2008/2009, the proportion of women as first and last authors was 3.6% (33.0% compared with 29.4%) and 4.8% (33.2% compared with 27.4%) higher respectively in 2018/2019. On average, the proportion of women participants in original studies remained largely unchanged over the 10-year period, only 10% of all participants were women in studies.ConclusionWomen are strikingly under-represented in first and last author positions, as are women participants in sports and exercise medicine/physiotherapy journals.

Colour centres in nanodiamonds are an important resource for applications in quantum sensing, biological imaging, and quantum optics. Here we report unprecedented narrow optical transitions for individual colour centres in nanodiamonds smaller than 200 nm. This demonstration has been achieved using the negatively charged silicon vacancy centre, which has recently received considerable attention due to its superb optical properties in bulk diamond. We have measured an ensemble of silicon-vacancy centres across numerous nanodiamonds to have an inhomogeneous distribution of 1.05 nm at 5 K. Individual spectral lines as narrower than 360 MHz were measured in photoluminescence excitation, and correcting for apparent spectral diffusion yielded an homogeneous linewidth of about 200 MHz which is close to the lifetime limit. These results indicate the high crystalline quality achieved in these nanodiamond samples, and advance the applicability of nanodiamond-hosted colour centres for quantum optics applications.

Purpose: The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are engaged in diagnosing and treating these patients. Methods: The Writing Group members were appointed by the Mitochondrial Medicine Society. The panel included members with expertise in several different areas. The panel members utilized a comprehensive review of the literature, surveys, and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Results: Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease. Conclusion: The Delphi process enabled the formation of consensus-based recommendations. We hope that these recommendations will help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease. Genet Med 17 9, 689–701.

ObjectiveInvestigate sex/gender differences in self-reported activity and knee-related outcomes after anterior cruciate ligament (ACL) injury.DesignSystematic review with meta-analysis.Data sourcesSeven databases were searched in December 2021.Eligibility criteriaObservational or interventional studies with self-reported activity (including return to sport) or knee-related outcomes after ACL injury.ResultsWe included 242 studies (n=123 687, 43% females/women/girls, mean age 26 years at surgery). One hundred and six studies contributed to 1 of 35 meta-analyses (n=59 552). After ACL injury/reconstruction, very low-certainty evidence suggests females/women/girls had inferior self-reported activity (ie, return to sport, Tegner Activity Score, Marx Activity Scale) compared with males/men/boys on most (88%, 7/8) meta-analyses. Females/women/girls had 23%–25% reduced odds of returning to sport within 1-year post-ACL injury/reconstruction (12 studies, OR 0.76 95% CI 0.63 to 0.92), 1–5 years (45 studies, OR 0.75 95% CI 0.69 to 0.82) and 5–10 years (9 studies, OR 0.77 95% CI 0.57 to 1.04). Age-stratified analysis (<19 years) suggests female athletes/girls had 32% reduced odds of returning to sport compared with male athletes/boys (OR 0.68, 95% CI 0.41 to 1.13, I2 0.0%). Very low-certainty evidence suggests females/women/girls experienced inferior knee-related outcomes (eg, function, quality of life) on many (70%, 19/27) meta-analyses: standardised mean difference ranging from −0.02 (Knee injury and Osteoarthritis Outcome Score, KOOS-activities of daily living, 9 studies, 95% CI −0.05 to 0.02) to −0.31 (KOOS-sport and recreation, 7 studies, 95% CI −0.36 to –0.26).ConclusionsVery low-certainty evidence suggests inferior self-reported activity and knee-related outcomes for females/women/girls compared with males/men/boys after an ACL injury. Future studies should explore factors and design targeted interventions to improve outcomes for females/women/girls.PROSPERO registration numberCRD42021205998.

PCR of upper respiratory specimens is the diagnostic standard for severe acute respiratory syndrome coronavirus 2 infection. However, saliva sampling is an easy alternative to nasal and throat swabbing. We found similar viral loads in saliva samples and in nasal and throat swab samples from 110 patients with coronavirus disease.

Missing data in clinical trials can have a major effect on the validity of the inferences that can be drawn from the trial. This article reviews methods for preventing missing data and, failing that, dealing with data that are missing. Background Missing data have seriously compromised inferences from clinical trials, yet the topic has received little attention in the clinical-trial community. 1 Existing regulatory guidances 2 – 4 on the design, conduct, and analysis of clinical trials have little specific advice on how to address the problem of missing data. A recent National Research Council (NRC) report 5 on the topic seeks to address this gap, and this article summarizes some of the main findings and recommendations of that report. The authors of this article served on the panel that prepared the report. Missing data have seriously compromised inferences from clinical trials. 1 For example, . . .

Host actin cytoskeleton is often targeted by pathogenic bacteria through the secretion of effectors. Legionella pneumophila virulence relies on the injection of the largest known arsenal of bacterial proteins, over 300 Dot/Icm type 4 secretion system effectors, into the host cytosol. Here, we define the functional interactions between VipA and LegK2, two effectors with antagonistic activities towards actin polymerization that have been proposed to interfere with the endosomal pathway. We confirmed the prominent role of LegK2 effector in Legionella infection, as the deletion of legK2 results in defects in the inhibition of actin polymerization at the Legionella-containing vacuole, as well as in endosomal escape of bacteria and subsequent intracellular replication. More importantly, we observed the restoration of the ΔlegK2 mutant defects, upon deletion of vipA gene, making LegK2/VipA a novel example of effector-effector suppression pair that targets the actin cytoskeleton and whose functional interaction impacts L. pneumophila virulence. We demonstrated that LegK2 and VipA do not modulate each other’s activity in a “metaeffector” relationship. Instead, the antagonistic activities of the LegK2/VipA effector pair would target different substrates, Arp2/3 for LegK2 and G-actin for VipA, to temporally control actin polymerization at the LCV and interfere with phagosome maturation and endosome recycling, thus contributing to the intracellular life cycle of the bacterium. Strikingly, the functional interaction between LegK2 and VipA is consolidated by an evolutionary history that has refined the best effector repertoire for the benefit of L. pneumophila virulence.

Background The impact of activity-related joint loading on cartilage is not clear. Abnormal loading is considered to be a mechanical driver of osteoarthritis (OA), yet moderate amounts of physical activity and rehabilitation exercise can have positive effects on articular cartilage. Our aim was to investigate the immediate effects of joint loading activities on knee and hip cartilage in healthy adults, as assessed using magnetic resonance imaging. We also investigated delayed effects of activities on healthy cartilage and the effects of activities on cartilage in adults with, or at risk of, OA. We explored the association of sex, age and loading duration with cartilage changes. Methods A systematic review of six databases identified studies assessing change in adult hip and knee cartilage using MRI within 48 h before and after application of a joint loading intervention/activity. Studies included adults with healthy cartilage or those with, or at risk of, OA. Joint loading activities included walking, hopping, cycling, weightbearing knee bends and simulated standing within the scanner. Risk of bias was assessed using the Newcastle–Ottawa Scale. Random-effects meta-analysis estimated the percentage change in compartment-specific cartilage thickness or volume and composition (T2 relaxation time) outcomes. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system evaluated certainty of evidence. Results Forty studies of 653 participants were included after screening 5159 retrieved studies. Knee cartilage thickness or volume decreased immediately following all loading activities investigating healthy adults; however, GRADE assessment indicated very low certainty evidence. Patellar cartilage thickness and volume reduced 5.0% (95% CI 3.5, 6.4, I 2  = 89.3%) after body weight knee bends, and tibial cartilage composition (T2 relaxation time) decreased 5.1% (95% CI 3.7, 6.5, I 2  = 0.0%) after simulated standing within the scanner. Hip cartilage data were insufficient for pooling. Secondary outcomes synthesised narratively suggest knee cartilage recovers within 30 min of walking and 90 min of 100 knee bends. We found contrasting effects of simulated standing and walking in adults with, or at risk of, OA. An increase of 10 knee bend repetitions was associated with 2% greater reduction in patellar thickness or volume. Conclusion There is very low certainty evidence that minimal knee cartilage thickness and volume and composition (T2 relaxation time) reductions (0–5%) occur after weightbearing knee bends, simulated standing, walking, hopping/jumping and cycling, and the impact of knee bends may be dose dependent. Our findings provide a framework of cartilage responses to loading in healthy adults which may have utility for clinicians when designing and prescribing rehabilitation programs and providing exercise advice.