Understanding overall shoulder function and health: the value of specific quantitative vs. qualitative shoulder range of motion on patient-reported outcome measures.

HYPOTHESIS AND BACKGROUND: It is known that, though widely used, shoulder range of motion (ROM) measurements are not standardized and have a high rate of intra- and interobserver differences. Particularly, the inconsistency in quantitative and qualitative measurements and their relationship to patient-reported outcome measures (PROMs) make shoulder health difficult to determine. METHODS: This was a prospective study of 147 patients who presented with a chief complaint of shoulder pain to the orthopedic sports medicine and shoulder clinic of a single fellowship-trained surgeon. Measured by 1 examiner, quantitative ROM measurements were taken with a goniometer and qualitative ROM measured by the anatomic level that the patient could reach. The following PROMs were used as well: American Shoulder and Elbow Surgeons shoulder score, Single Assessment Numeric Evaluation, Shoulder Pain and Disability Index, Oxford Shoulder Score, Disabilities of the Arm, Shoulder, and Hand questionnaire, 12-Item Short Form Health Survey, and Patient-Reported Outcomes Measurement Information System pain interference short form 6a (PROMIS 6a). Statistical analysis was performed with SPSS using the Pearson correlation and 2-sample t test. The Benjamini-Hochberg correction was used to determine the P value at which statistical significance was reached to correct for multiple comparisons. RESULTS: Qualitative internal rotation (IR) (the hand behind back reach test) and qualitative forward flexion (FF) correlated with all goniometer angle measurements and PROMs (both shoulder and general health scores). These qualitative measures proved to be an appropriate proxy for IR and FF goniometer measurements. Qualitative external rotation (ER) was not a good substitute for quantitative ER measurement. Quantitative ER correlated with all PROMs. As ROM increased when measured by quantitative ER, qualitative IR, and qualitative FF, shoulder and general health PROMs incrementally increased as well. DISCUSSION/CONCLUSIONS: Qualitative IR measurement, the hand-behind-back reach test, is an adequate substitution for IR goniometer angle as well as a strong representation of global shoulder ROM, shoulder health, and general health while factoring in patient age. Qualitative FF measurement is also an appropriate proxy for quantitative FF and represents global shoulder and general health without factoring in age. Quantitative ER, via goniometer angle, is a better assessment of the shoulder than qualitative ER and is a representation of overall shoulder and general health. We recommend the use of quantitative ER, qualitative IR, and qualitative FF measurements to best understand a patient's overall shoulder health and its impact on their overall health.

Affinity-optimizing enhancer variants disrupt development.

Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease1-3. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb4. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly4-6. However, how this enhancer encodes tissue-specific activity, and the mechanisms by which SNVs alter the number of digits, are poorly understood. Here we show that the ETS sites within the ZRS are low affinity, and identify a functional ETS site, ETS-A, with extremely low affinity. Two human SNVs and a synthetic variant optimize the binding affinity of ETS-A subtly from 15% to around 25% relative to the strongest ETS binding sequence, and cause polydactyly with the same penetrance and severity. A greater increase in affinity results in phenotypes that are more penetrant and more severe. Affinity-optimizing SNVs in other ETS sites in the ZRS, as well as in ETS, interferon regulatory factor (IRF), HOX and activator protein 1 (AP-1) sites within a wide variety of enhancers, cause gain-of-function gene expression. The prevalence of binding sites with suboptimal affinity in enhancers creates a vulnerability in genomes whereby SNVs that optimize affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs in genomes could provide a mechanistic approach to identify causal variants that underlie enhanceropathies.

Single-nucleotide variants within heart enhancers increase binding affinity and disrupt heart development.

Transcriptional enhancers direct precise gene expression patterns during development and harbor the majority of variants associated with phenotypic diversity, evolutionary adaptations, and disease. Pinpointing which enhancer variants contribute to changes in gene expression and phenotypes is a major challenge. Here, we find that suboptimal or low-affinity binding sites are necessary for precise gene expression during heart development. Single-nucleotide variants (SNVs) can optimize the affinity of ETS binding sites, causing gain-of-function (GOF) gene expression, cell migration defects, and phenotypes as severe as extra beating hearts in the marine chordate Ciona robusta. In human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, a SNV within a human GATA4 enhancer increases ETS binding affinity and causes GOF enhancer activity. The prevalence of suboptimal-affinity sites within enhancers creates a vulnerability whereby affinity-optimizing SNVs can lead to GOF gene expression, changes in cellular identity, and organismal-level phenotypes that could contribute to the evolution of novel traits or diseases.

Peer evaluation of teaching programs within pharmacy education: A review of the literature.

BACKGROUND: Student evaluations of teaching are one method to evaluate faculty teaching, but alone may have bias. Peer evaluation of teaching represents an important approach in assessing and providing feedback to faculty, however, numerous strategies exist for implementation. This review was conducted to identify existing peer evaluation of teaching programs and to describe their development, implementation, and outcomes. METHODS: A literature search was conducted through January 2023 using the following search terms alone or in combination: peer evaluation, peer evaluation of teaching, peer review of teaching, pharmacy, pharmacy education, teaching evaluation, peer assessment. Articles were included that described and evaluated the development and/or specific outcomes of individual peer evaluation of teaching programs in the didactic setting within pharmacy education. RESULTS: Eight articles were identified for review; six described peer evaluation of teaching in individual programs and two described components of the same program. Classroom observation was the core component of all programs and some but not all programs included pre- and/or post-observation meetings. Outcomes of programs included perception of participants via survey in seven studies with generally positive perceptions noted. Time burden was the most common concern noted for the implementation of the peer evaluation programs. IMPLICATIONS: Limited literature exists describing peer evaluation of teaching programs and outcomes within in pharmacy education. Peer evaluation processes are individualized and vary across institutions. Opportunities exist to develop time-efficient programs to further assess the outcomes of peer evaluation of teaching and compare with student evaluations or other tools to evaluate education quality.

Diverse logics and grammar encode notochord enhancers.

The notochord is a defining feature of all chordates. The transcription factors Zic and ETS regulate enhancer activity within the notochord. We conduct high-throughput screens of genomic elements within developing Ciona embryos to understand how Zic and ETS sites encode notochord activity. Our screen discovers an enhancer located near Lama, a gene critical for notochord development. Reversing the orientation of an ETS site within this enhancer abolishes expression, indicating that enhancer grammar is critical for notochord activity. Similarly organized clusters of Zic and ETS sites occur within mouse and human Lama1 introns. Within a Brachyury (Bra) enhancer, FoxA and Bra, in combination with Zic and ETS binding sites, are necessary and sufficient for notochord expression. This binding site logic also occurs within other Ciona and vertebrate Bra enhancers. Collectively, this study uncovers the importance of grammar within notochord enhancers and discovers signatures of enhancer logic and grammar conserved across chordates.

Assessment of long-range transboundary aerosols in Seoul, South Korea from Geostationary Ocean Color Imager (GOCI) and ground-based observations.

To better understand air quality issues in South Korea, it is essential to identify the main contributors of air pollution and to quantify the effects of transboundary transport. In this study, geostationary satellite measurements were used to assess the effects of aerosol transport on air quality in South Korea. This study proposes a method to define the long-range transport (LRT) of aerosols into the Korean Peninsula using remote sensing obervations and back-trajectories and estimates the LRT effects on air quality in Seoul using in-situ particulate matter (PM) measurements. Aerosol optical depths (AODs) are obtained from the Geostationary Ocean Color Imager (GOCI), and the back-trajectories are from the National Ocean and Atmospheric Administration (NOAA) HYbrid Single Particle Lagrangian Integrated Trajectory (HYSPLIT) model. For LRT events, satellite observations showed high AOD plumes over the Yellow Sea, a pathway between Eastern China and South Korea, and the movements of aerosol plumes transported to South Korea were also detected. PM2.5 concentrations, PM10 concentrations, and AOD during LRT increased by 52%, 49%, and 81%, respectively, relative to their average values for 2015-2018. To quantitatively characterize the LRT of aerosols, the effects of LRT on PM2.5 concentrations were estimated for each PM concentration category. The contribution of LRT to PM2.5 concentrations was estimated to be 33% during 2015-2018. When high concentrations of PM2.5 were observed in Seoul, they were likely to be associated with LRT events.

Anticancer Efficacy of Oral Docetaxel Nanoformulation for Metronomic Chemotherapy in Metastatic Lung Cancer.

Metronomic chemotherapy, giving low doses of chemotherapeutics (e.g., docetaxel) on a frequent schedule over a long time, may improve outcomes and reduce side effects for cancer patients. Oral medications are vital for applying metronomic chemotherapy. However, low solubility, low absorption, low drug availability in the targeted tissue, and side effects limit the development of oral chemotherapeutics. Many chemotherapeutics are intravenously delivered. In this work, we developed a new docetaxel granule that produces docetaxel-loaded in situ self-assembled nanoparticle (180 nm) upon contact with water. The process of manufacturing docetaxel granules is scalable in industrial settings. The lung selectivity of docetaxel granule was observed in animals. The mechanistic studies demonstrated the nanoparticle bound with red blood cells, which selectively delivers docetaxel to the lungs. Finally, docetaxel granule (5 mg/kg twice per week) can profoundly inhibit the tumor growth of lung-metastatic cancer xenograft model over 24 days. The material-based lungselective oral nanoformulation provides an opportunity for conventionally intravenous chemotherapy drugs to be easily applied in oral administration for metronomic chemotherapy for cancer patients with lung cancers.

Molecular structure and thermodynamic predictions to create highly sensitive microRNA biosensors.

Many studies have established microRNAs (miRNAs) as post-transcriptional regulators in a variety of intracellular molecular processes. Abnormal changes in miRNA have been associated with several diseases. However, these changes are sometimes subtle and occur at nanomolar levels or lower. Several biosensing hurdles for in situ cellular/tissue analysis of miRNA limit detection of small amounts of miRNA. Of these limitations the most challenging are selectivity and sensor degradation creating high background signals and false signals. Recently we developed a reporter+probe biosensor for let-7a that showed potential to mitigate false signal from sensor degradation. Here we designed reporter+probe biosensors for miR-26a-2-3p and miR-27a-5p to better understand the effect of thermodynamics and molecular structures of the biosensor constituents on the analytical performance. Signal changes from interactions between Cy3 and Cy5 on the reporters were used to understand structural aspects of the reporter designs. Theoretical thermodynamic values, single stranded conformations, hetero- and homodimerization structures, and equilibrium concentrations of the reporters and probes were used to interpret the experimental observations. Studies of the sensitivity and selectivity revealed 5-9 nM detection limits in the presence and absence of interfering off-analyte miRNAs. These studies will aid in determining how to rationally design reporter+probe biosensors to overcome hurdles associated with highly sensitive miRNA biosensing.