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Inherited retinal degenerations are blinding genetic disorders characterized by high genetic and phenotypic heterogeneity. In this retrospective study, we describe sixteen families with early-onset non-syndromic retinal degenerations in which affected probands carried rare bi-allelic variants in CFAP410, a ciliary gene previously associated with recessive Jeune syndrome. We detected twelve variants, eight of which were novel, including c.373+91A>G, which led to aberrant splicing. To our knowledge this is the first likely pathogenic deep-intronic variant identified in this gene. Analysis of all reported and novel CFAP410 variants revealed no clear correlation between the severity of the CFAP410-associated phenotypes and the identified causal variants. This is supported by the fact that the frequently encountered missense variant p.(Arg73Pro), often found in syndromic cases, was also associated with non-syndromic retinal degeneration. This study expands the current knowledge of CFAP410-associated ciliopathy by enriching its mutational landscape and supports its association with non-syndromic retinal degeneration.

Considering the evolving and unpredictable job market, adaptability is an important skill for young adults. Such adaptability implies that schools need to teach key social competences, like communication, collaboration, or problem-solving. In this area, a gender gap has consistently been found, showing that boys display social competences less than girls. A large-scale nationwide multilab longitudinal experiment--the ProFAN project--was conducted in France among more than 10,000 vocational high-school students. Its primary goal was to develop and test an intervention promoting a range of psychological and psychosocial variables in vocational high schools, including social competences. This 2-year long, three-wave field experiment compared the effects of a cooperative learning method--the jigsaw classroom, that entails positive goal and resource interdependence--to two control conditions: one that involves cooperation with resource independence, and the other that remains business-as-usual. This article focuses on the differential development of perceived social competences of adolescent boys and girls over time, comparing the three pedagogical methods. Results of longitudinal multilevel modeling replicate the gender gap in perceived social competences and show that this gap widens with time. However, and most importantly, the analyses revealed that such widening of the gender gap was greater in the two control conditions than in the jigsaw condition, in which the evolution of boys' and girls' perceptions of social competences remained similar over time. Contributions to the understanding of the development and teaching of social competences in education settings are discussed.

Genome analysis of individuals affected by retinitis pigmentosa (RP) identified two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]), in individuals of South Asian and African ancestry, respectively. Genotypes included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations. Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted. Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity. Nanopore sequencing confirmed the lower transcription of the TMEM216 c.-69G>T allele in blood-derived RNA from a heterozygous carrier, and reduced expression was further recapitulated by qPCR, using both leukocytes-derived RNA of c.-69G>T homozygotes and total RNA from genome-edited hTERT-RPE1 cells carrying homozygous TMEM216 c.-69G>A. In conclusion, these variants explain a significant proportion of unsolved cases, specifically in individuals of African ancestry, suggesting that reduced TMEM216 expression might lead to abnormal ciliogenesis and photoreceptor degeneration.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.

Formaldehyde (HCHO) is an important air pollutant with direct cancer risk and ozone-forming potential. HCHO sources are complex because HCHO is both directly emitted and produced from oxidation of most gas-phase reactive organic carbon. We update the secondary production of HCHO in the Community Regional Atmospheric Chemistry Multiphase Mechanism (CRACMM) in the Community Multiscale Air Quality (CMAQ) model. Production of HCHO from isoprene and monoterpenes is increased, correcting an underestimate in the current version. Simulated June–August surface HCHO during peak photochemical production (11:00–15:00 LT, local time) increased by 0.6 ppb (32 %) over the southeastern USA and by 0.2 ppb (13 %) over the contiguous USA. The increased HCHO compares more favorably with satellite-based observations from the TROPOspheric Monitoring Instrument (TROPOMI) and from aircraft-based observations. Evaluation against hourly surface observations indicates a missing nighttime sink that can be improved by increased nighttime deposition, which reduces June–August nocturnal (20:00–04:00 LT) surface HCHO by 1.1 ppb (36 %) over the southeastern USA and 0.5 ppb (29 %) over the contiguous USA. The ability of CRACMM to capture peak levels of HCHO at midday is improved, particularly at sites in the northeastern USA, while peak levels at sites in the southeastern USA are improved, although still lower than observed. Using established risk assessment methods, lifetime exposure of the population in the contiguous USA (∼ 320 million) to ambient HCHO levels predicted here may result in 6200 lifetime cancer cases, with 40 % from controllable anthropogenic emissions of nitrogen oxides and reactive organic compounds. Chemistry updates will be available in CRACMM version 2 (CRACMM2) in CMAQv5.5.

Abstract Inherited retinal degenerations are blinding genetic disorders characterized by high genetic and phenotypic heterogeneity. In this retrospective study, we describe sixteen families with early-onset non-syndromic retinal degenerations in which affected probands carried rare bi-allelic variants in CFAP410, a ciliary gene previously associated with recessive Jeune syndrome. We detected twelve variants, eight of which were novel, including c.373+91A>G, which led to aberrant splicing. To our knowledge this is the first likely pathogenic deep-intronic variant identified in this gene. Analysis of all reported and novel CFAP410 variants revealed no clear correlation between the severity of the CFAP410-associated phenotypes and the identified causal variants. This is supported by the fact that the frequently encountered missense variant p.(Arg73Pro), often found in syndromic cases, was also associated with non-syndromic retinal degeneration. This study expands the current knowledge of CFAP410-associated ciliopathy by enriching its mutational landscape and supports its association with non-syndromic retinal degeneration.

Abstract Asparaginase (ASP)-containing regimens for acute lymphoblastic leukemia (ALL) are associated with venous thromboembolism (VTE). We evaluated the prevalence, risk factors, role of prophylaxis and clinical impact of VTE among adolescents and young adult (AYA) patients (15–50 years) treated on Dana-Farber Cancer Institute (DFCI) ALL protocols. The 1- and 2-year cumulative incidence of VTE were 31.9% (95% CI: 27.0%, 36.9%) and 33.5% (95% CI: 28.5%, 38.5%) respectively, with most events occurring during ASP-based consolidation phase (68.6%). VTE was more frequent in patients with overweight/obese vs. normal BMI (39.2% vs. 29.0%, p = 0.048). In a 1-year landmark analysis, the 4-year overall survival was 91.5%, without difference between patients with vs. without VTE (93.8% vs. 90.0%, p = 0.93). Relapse and non-relapse mortality rates were also similar. Among patients treated at Dana-Farber/Harvard Cancer Center, cerebral sinus vein thrombosis occurred in 3.6% of patients (8.5% of VTE events) in comparison to pulmonary embolism (32.9%) and deep vein thromboses (58.6%, 24.4% line-associated). In a Cox regression model for VTE free-time, elevated BMI was associated with shorter VTE free-time (HR 1.94 [95% CI 1.13-3.35], p = 0.018), while low molecular weight heparin (LMWH) prophylaxis as time-varying covariate was not. In conclusion, we found that VTE was frequent in AYAs treated on DFCI ALL protocols but did not impact survival outcomes. Overweight/obese BMI increased risk for VTE.

Abstract Wide-pulse high-frequency neuromuscular electrical stimulation (WPHF NMES) can generate a progressive increase in tetanic force through reflexive recruitment of motor units, called extra force. This phenomenon has previously been observed on different muscle groups, but little is known on potential inter-muscle differences. We compared extra force and sustained electromyographic (EMG) activity induced by NMES between plantar flexors, knee extensors, elbow flexors and within muscle groups using pulse durations of 0.2, 1 and 2 ms and stimulation frequencies of 20, 50, 100 and 147 Hz. Extra force production and sustained EMG activity were higher for plantar flexors compared to elbow flexors at all tested parameters (except 0.2 ms for extra force). When compared to elbow flexors, extra force of the knee extensors was only higher at 100 Hz and with 1 ms while sustained EMG activity was higher at all frequencies with pulse durations of 0.2 and 2 ms. Peripheral nerve architecture as well as muscle typology and function could influence the occurrence and magnitude of centrally-mediated responses to NMES. The present findings suggest that the use of wide-pulse high-frequency NMES to promote reflexive recruitment seems to be more pertinent for lower limb muscles, plantar flexors in particular.

PURPOSE: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy. EXPERIMENTAL DESIGN: We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients. We identified a novel mutation in PDGFRA, p.D842N, and used an integrated structural modeling and molecular biology approach to characterize mutations at D842 to guide therapeutic targeting. We conducted a preclinical study of avapritinib in a mouse patient-derived xenograft (PDX) model of FIP1L1-PDGFRA and PDGFRA p.D842N leukemia. RESULTS: Two patients with T-ALL in the LEAP cohort (14%) had targetable genomic alterations affecting PDGFRA, a FIP1-like 1 protein/PDGFRA (FIP1L1-PDGFRA) fusion and a novel mutation in PDGFRA, p.D842N. The D842N mutation resulted in PDGFRA activation and sensitivity to tested PDGFRA inhibitors. In a T-ALL PDX model, avapritinib treatment led to decreased leukemia burden, significantly prolonged survival, and even cured a subset of mice. Avapritinib treatment was well tolerated and yielded clinical benefit in a patient with refractory T-ALL. CONCLUSIONS: Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making.

Abstract In 1957 Abbott and Ballantine described a highly toxic activity from a dinoflagellate isolated from the English Channel in 1949 by Mary Park. From a culture maintained at Plymouth Laboratory since 1950, we have been able to isolate two toxic molecules (abbotoxin and 59-E-Chloro-abbotoxin), determine the planar structures by analysis of HRMS and 1D and 2D NMR spectra, and found them to be karlotoxin (KmTx) congeners. Both toxins kill larval zebrafish with symptoms identical to those described by Abbot and Ballantine for gobies (Gobius virescens). Using surface plasma resonance the sterol binding specificity of karlotoxins is shown to require desmethyl sterols. Our results with black lipid membranes indicate that karlotoxin forms large-conductance channels in the lipid membrane, which are characterized by large ionic conductance, poor ionic selectivity, and a complex gating behavior that exhibits strong voltage dependence and multiple gating patterns. In addition, we show that KmTx 2 pore formation is a highly targeted mechanism involving sterol-specificity. This is the first report of the functional properties of the membrane pores formed by karlotoxins and is consistent with the initial observations of Abbott and Ballantine from 1957.

Measurements of carbon-14-containing carbon monoxide (14CO) in glacial ice are useful for studies of the past oxidative capacity of the atmosphere as well as for reconstructing the past cosmic ray flux. The 14CO abundance in glacial ice represents the combination of trapped atmospheric 14CO and in situ cosmogenic 14CO. The systematics of in situ cosmogenic 14CO production and retention in ice are not fully quantified, posing an obstacle to interpretation of ice core 14CO measurements. Here we provide the first comprehensive characterization of 14CO at an ice accumulation site (Summit, Greenland), including measurements in the ice grains of the firn matrix, firn air and bubbly ice below the firn zone. The results are interpreted with the aid of a firn gas transport model into which we implemented in situ cosmogenic 14C. We find that almost all (≈ 99.5 %) of in situ 14CO that is produced in the ice grains in firn is very rapidly (in <1 year) lost to the open porosity and from there mostly vented to the atmosphere. The timescale of this rapid loss is consistent with what is expected from gas diffusion through ice. The small fraction of in situ 14CO that initially stays in the ice grains continues to slowly leak out to the open porosity at a rate of ≈ 0.6 % yr−1. Below the firn zone we observe an increase in 14CO content with depth that is due to in situ 14CO production by deep-penetrating muons, confirming recent estimates of 14CO production rates in ice via the muon mechanisms and allowing for narrowing constraints on these production rates.

Using a case example from a mid-sized town in East Central Indiana, this article illustrates the development and implementation of a community-academic partnership (CAP), a novel approach to addressing substance misuse in local communities. A CAP can be defined as a formal, strategic partnership between the local community and university faculty, staff, and students that seeks to increase the community's harm-reduction, prevention, treatment, and recovery capacities and unify the effort to address addiction in the region. Details are provided on the key elements that compose a CAP; how this type of coalition can be developed and implemented without funding; the methods used to formulate the coalition's mission statement, organizational design, and strategic objectives; and the types of outcomes the coalition can expect to produce if implemented successfully.

ABSTRACT: Background: Pediatric spinal deformity surgery affects ultimate spinal height in the growing child. This effect on ultimate spinal height has also been shown to affect pulmonary development and ultimately pulmonary function. There has been an increasing trend toward growth-friendly spinal surgery in early onset scoliosis to minimize the negative consequences of early spinal fusion surgery. Such growth-friendly techniques include VEPTR, MCGR, and Shilla. Which technique allows for the most growth after initial implantation is still not clear. Methods: An extensive literature review on the topic of pediatric spinal growth was undertaken. Topics reviewed include: normal growth, growth after intervention by various methods, and the effect on pulmonary function. We have summarized the literature for the techniques identified and compared these with normal population data.. Results: The data for various surgical techniques were reviewed. These included VEPTR, standard growing rods, and MCGR. The measurement techniques for determining ultimate spinal growth varied based upon the technique for measurement and the timing of initial and final measurements. The results of attained spinal growth were not directly correlated to pulmonary function values. Conclusions: There is still no standardized ideal time or technique for assessing the best results in this area. We suggest that some of what is called growth from growth-friendly techniques is lengthening from the initial deformity correction. This nomenclature needs to be clarified. In addition, how and when to determine ultimate spinal growth from each surgical technique and by which radiographic technique needs to be standardized.

Described here is the construction of a low-cost, standalone underwater camera system designed for recording processes occurring on aquatic substrates. The Submerged Microscope for Observing Substrates (SuMOS) utilizes a Raspberry Pi Zero 2 W paired with a Raspberry Pi Camera Module v3 NoIR, with IR illumination for low-light situations. It features a waterproof housing inspired by the open-source PipeCam project, with enhancements for sealing and substrate mounting. The SuMOS system operates autonomously, capturing high-resolution images at fixed intervals under various lighting conditions. Tests in the Choptank River of Maryland demonstrated the system’s robustness in capturing patterns of amphipod activity under challenging optical conditions. This versatile tool offers a scalable solution for highly time-resolved, in situ studies of processes occurring at the interface of the aquatic/solid surface boundaries. The SuMOS provides significant advantages in cost, ease of deployment, and data collection.

Research-for-development (R4D) refers to research activities specifically designed to address critical social, environmental, and economic challenges and improve human well-being. It is essential to have well-designed indicators to monitor and evaluate progress, guide decision-making, and support learning and improvement. This paper reviews and compares two sets of indicators in use by a large international research consortium: i) ad hoc indicators developed by and for individual (non-pooled) projects, and ii) a standard set of indicators designed as part of a common results framework for a new portfolio of research initiatives. We assess both sets of indicators against the SMART (specific, measurable, achievable, relevant and time-bound) criteria, identify common errors in indicator formulation, compare the thematic coverage of the two sets of indicators, and derive lessons for improved indicator formulation. A large proportion of the non-pooled indicators fail to meet the SMART criteria. The indicators in the standard set are stronger, but with scope for improvement, especially in terms of relationship to the result of interest, specification of the indicator, measurability, standardization of outcome indicators, and impact indicators. We recommend having a balanced set of indicators of key outputs, outcomes, and impacts, based on clear and well-defined result statements.

PurposeThis study examined the physiological effects of 12 weeks of detraining and retraining in a highly trained master triathlete (age 53.8 years).MethodsVariables associated with swimming, cycling, and running performance, including V˙O2max, peak power output (PPO), gross cycling efficiency (CE), running maximal aerobic velocity (MAV), running economy (RE), muscle strength, and body composition were assessed before the last race of the season (baseline), after 12 weeks of detraining, and after 12 weeks of retraining.ResultsDetraining resulted in a 9.1% and 10.9% decrease in relative V˙O2max for cycling and running, respectively. PPO and MAV declined by 12.7% and 8.6%, respectively. After detraining, CE decreased by 6.2%, and RE was 22% higher than the baseline. The maximal strength capacity of the knee extensor muscles decreased by an average of 8.2%. Body fat percentage increased from 10.5% to 13.8%, while lean mass decreased by 2.2 kg. After retraining, almost all variables returned to baseline or even slightly increased, except RE and lean mass, which did not return to baseline.ConclusionAfter 12 weeks of detraining, a lifelong master triathlete can regain his cardiorespiratory fitness (i.e., V˙O2max) with 12 weeks of progressive and structured retraining, but his running economy and lean mass remain slightly depressed.

Abstract Because of its global abundance and reactivity with hydroxyl radicals (OH•), tropospheric carbon monoxide indirectly impacts the lifetimes of other OH•‐reactive gases, in particular methane and reactive hydrocarbons. The origin and chemistry of atmospheric CO have been studied using stable isotopes. Both 13CO and C18O undergo isotopic fractionation during its main chemical loss reaction, CO + OH•. The kinetic isotope effect (KIE) for 13CO is mass dependent, with a value of ∼5‰; 12CO reacts faster than 13CO with OH. Whereas C18O + OH• exhibits an inversely mass dependent KIE ∼−10‰. We hypothesize these KIEs result in a relative depletion of 13C18O, a CO clumped isotope. To test this, we collected CO from air samples on Long Island, NY, and discovered a −3 to −8‰ difference in the clumped isotope ratio, Δ31, relative to a random distribution of 13C and 18O in CO. A clear negative trend between [CO] and Δ31 is driven by two factors: (a) the atmospheric addition of CO from either a primary or secondary source with a Δ31 of ∼0‰ and (b) the continuing reaction of CO with OH•, leaving the remaining CO pool relatively depleted in 13C18O. This is analogous to the mechanism that determines CO Δ17O values. This study is among the first to show clumped isotope fractionation resulting from atmospheric chemistry and not thermal equilibration, which may inform the identification of clumped isotope KIEs in other atmospheric trace gases. These first Δ31 observations motivate future experimental and observational studies targeted at characterizing the clumped isotopes of CO sources, background CO, and experimentally fractionated CO.

Use of Emergency Departments (EDs) for psychiatric complaints has increased significantly in past decades. The onset of the COVID-19 pandemic saw large shifts in ED usage, with a relative increase in mental health complaints in EDs. This paper will investigate the difference in ED wait times for psychiatric and non-psychiatric complaints over this period. Utilized National Hospital Ambulatory Medical Care Survey (NHAMCS), from 2019 to 2021, for average wait times for psychiatric versus non-psychiatric complaints. Compared the average wait times for psychiatric complaints by region, triage status, and ICD-10 F code. There was no significant difference in the average wait times overall between these conditions (P = 0.57). People with schizophrenia or psychosis had a significantly higher wait time (P = 0.03) compared to mental health symptoms secondary to physiologic conditions. Northeastern American EDs also had prolonged wait times for psychiatric conditions (P < 0.01) Research into factors of prolonged wait times can advise quality improvements such as the implementation of evidence-based triage and workup tools, and directed psychiatric education.