Change in lacrimal gland volume and aqueous tear production following treatment with teprotumumab.

BACKGROUND: Dry eye syndrome occurs in up to 85% of patients with thyroid eye disease (TED). Lacrimal gland enlargement correlates with subjective tearing and a reduction in quality of life in patients with TED. METHODS: In this prospective longitudinal study, patients presenting for the treatment of TED were considered for eligible. Primary outcomes included a change in the volume of the lacrimal gland and the production of tears following treatment with teprotumumab. The volume of lacrimal glands and proptosis was calculated using 3D volumetric analysis. Tear production was measured by Schirmer's test and associated symptoms were assessed using the VLSQ-8. The orbit with the most proptosis was designated the study orbit and the contralateral orbit was designated the fellow orbit. RESULTS: Twenty patients were included. Mean (SD) age was 61 (18) and mean duration of TED prior to therapy was 48 months (47). Lacrimal gland volume in the study orbit decreased from 768 mm3 (288) to 486 mm3 (173) (p < 0.01) following therapy. For the fellow orbit, volume reduced from 637 mm3 (261) to 379 mm3 (147) (p < 0.01). Schirmer's test reading (STR) in the study orbit increased from 14.5 mm (8.2) to 23 mm (10) (p < 0.01) (59%) following treatment. In the fellow orbit, STR increased from 12.7 mm (7) to 21 mm (9) post therapy (69%) (p < 0.01). There was a significant improvement on all parts of the VLSQ-8. CONCLUSION: Teprotumumab significantly reduces TED related expansion of the lacrimal gland, increases tear production, and improves dry eye symptoms.

Changes to Eye Whiteness and Eyelid/Brow Position With Topical Oxymetazoline in Aesthetic Patients.

BACKGROUND: Oxymetazoline hydrochloride 0.1% ophthalmic solution has recently been approved in the United States for the treatment of ptosis. OBJECTIVES: The aim of this study was to assess the upper and lower eyelid position as well as the brow position and the color of the sclera following the ophthalmic administration of oxymetazoline hydrochloride 0.1%. METHODS: In this prospective cohort study, consecutive patients presenting with ptosis received topical oxymetazoline 0.1%. The primary outcome was measurement of the upper eyelid height (margin-to-reflex distance 1 [MRD1]) and lower eyelid height (MRD2) relative to the center of pupil, along with assessment of brow height, measured on photographs at baseline and 2 hours after instillation of oxymetazoline. The secondary outcome was the assessment of the color of the sclera (eye whiteness) before and after treatment with a novel color space algorithm. RESULTS: Twenty-nine patients participated in the study. The mean [SD] MRD1 at baseline was 2.3 [0.6] mm. At 2 hours following oxymetazoline treatment, the mean MRD1 significantly increased to 4.2 [0.9] mm (P < 0.01). The mean MRD2 also significantly increased from 5.3 [0.9] mm to 5.7 [1.0] mm (P < 0.01). Brow position did not change with treatment (P = 0.4). Following treatment, the eye sclera became significantly whiter, with a mean ΔEab (color change) of 9.7 [3.9], with 57 out of 58 eyes experiencing a significant change in color. A change of ΔEab ≥2 is considered visually perceptible to the human eye. CONCLUSIONS: Within 2 hours of use, oxymetazoline significantly improves the size of the palpebral aperture (MRD1 + MRD2) and also makes the eye appear significantly whiter.

Teprotumumab for the treatment of chronic thyroid eye disease.

BACKGROUND: Teprotumumab, a novel IGF-1R antibody was recently shown to significantly reduce the signs of active Thyroid eye disease (TED). The current study reviews its efficacy in chronic TED. METHODS: In this retrospective review, consecutive patients with chronic stable TED (>2 years), who had received ≥3 infusions of teprotumumab were included. All patients had measurements of proptosis, and calculation of the CAS and diplopia scores before and after therapy. Five-point strabismus scores were also calculated. Patients who had imaging within 4 months prior to therapy and 6 weeks post therapy underwent orbital 3D volumetric analysis. RESULTS: Thirty-one patients met the inclusion criteria. The mean (SD) duration of TED was 81 months (56) and the mean (SD) number of infusions received by each patient was 7 (2). Mean (SD) reduction in proptosis for each study orbit was 3.5 mm (0.4) and 3 mm (0.3) for the fellow orbit. The CAS response was 90% for the study orbit and 87% for the fellow orbit. Of the 15 patients who had diplopia at baseline, 67% had a clinically significant response, while 47% had complete resolution following treatment. Following teprotumumab, mean (SD) reduction of muscle tissue was 2011 mm3 (1847) in the study orbit and 1620 mm3 (1759) in the fellow orbit. The mean (SD) reduction of fat volume was 2101 mm3 (1681) in the study orbit and 1370 mm3 (1181) in the fellow orbit. CONCLUSION: Teprotumumab significantly reduces proptosis, inflammation, diplopia, strabismus and orbital soft tissue volume in patients with chronic TED.

Facial and Eyelid Changes in Thyroid Eye Disease Are Reversed by Teprotumumab.

Thyroid eye disease (TED) causes orbital soft-tissue expansion. Recent studies have suggested that brow and temple changes may also occur. Teprotumumab, a monoclonal antibody to the insulin-like growth factor 1 receptor reduces soft-tissue swelling in TED. In this study, we quantified the changes to pan facial soft-tissue volumes and eyelid position, following treatment with teprotumumab. METHODS: In this prospective study, consecutive patients who were treated with teprotumumab were appraised for study eligibility. All patients had 3D facial imaging using the Vectra H2. Soft-tissue volume changes in the upper face, periorbita, temples, midface, and lower face were quantified before and after teprotumumab therapy. Furthermore, the marginal reflex distance (MRD)1, MRD2, and intercanthal distance were also measured pretreatment and posttreatment. RESULTS: Twenty-three patients were included in the study. The mean duration of TED was 29 months (38). Following teprotumumab therapy, the mean (SD) decrease in volume for each region was 0.75 mL (0.84) in the upper face, 1.8 mL (1.3) in the periorbital region, 0.17 mL (0.5) in the temples, 1.62 mL (3.16) in the midface, and 2.67 mL (4.6) in the lower face. The mean (SD) decrease in the volume of the full face was 8.9 mL (8.7). There was also a significant reduction in MRD1, MRD2, and the intercanthal space following treatment. There was no relationship between previous steroid use and total body weight reduction and changes in facial volume. CONCLUSION: TED may cause significant tissue expansion across the entire face and this may be reduced following teprotumumab therapy.

Early outcomes of primary total hip arthroplasty with use of a smartphone-based care platform: a prospective randomized controlled trial.

AIMS: The purpose of this study is to evaluate early outcomes with the use of a smartphone-based exercise and educational care management system after total hip arthroplasty (THA) and demonstrate decreased use of in-person physiotherapy (PT). METHODS: A multicentre, prospective randomized controlled trial was conducted to evaluate a smartphone-based care platform for primary THA. Patients randomized to the control group (198) received the institution's standard of care. Those randomized to the treatment group (167) were provided with a smartwatch and smartphone application. PT use, THA complications, readmissions, emergency department/urgent care visits, and physician office visits were evaluated. Outcome scores include the Hip disability and Osteoarthritis Outcome Score (HOOS, JR), health-related quality-of-life EuroQol five-dimension five-level score (EQ-5D-5L), single leg stance (SLS) test, and the Timed Up and Go (TUG) test. RESULTS: The control group was significantly younger by a mean 3.0 years (SD 9.8 for control, 10.4 for treatment group; p = 0.007), but there were no significant differences between groups in BMI, sex, or preoperative diagnosis. Postoperative PT use was significantly lower in the treatment group (34%) than in the control group (55.4%; p = 0.001). There were no statistically significant differences in complications, readmissions, or outpatient visits. The 90-day outcomes showed no significant differences in mean hip flexion between controls (101° (SD 10.8)) and treatment (100° (SD 11.3); p = 0.507) groups. The HOOS, JR scores were not significantly different between control group (73 points (SD 13.8)) and treatment group (73.6 points (SD 13); p = 0.660). Mean 30-day SLS time was 22.9 seconds (SD 19.8) in the control group and 20.7 seconds (SD 19.5) in the treatment group (p = 0.342). Mean TUG time was 11.8 seconds (SD 5.1) for the control group and 11.9 (SD 5) seconds for the treatment group (p = 0.859). CONCLUSION: The use of the smartphone care management system demonstrated similar early outcomes to those achieved using traditional care models, along with a significant decrease in PT use. Noninferiority was demonstrated with regard to complications, readmissions, and ED and urgent care visits. This technology allows patients to rehabilitate on a more flexible schedule and avoid unnecessary healthcare visits, as well as potentially reducing overall healthcare costs. Cite this article: Bone Joint J 2021;103-B(7 Supple B):91-97.

EBCOG position statement - Simulation-based training for obstetrics and gynaecology during the COVID-19 pandemic.

The specialty of Obstetrics and Gynaecology has been on the forefront of introducing simulation in post graduate education for the past two decades. Simulation training is known to enhance psychomotor skills and is considered an important step in the transition from classroom learning to clinical practice. Training on simulators allows trainees to acquire basic skills before getting involved in day to day care in real life situations. Clinical circumstances around the COVID 19 pandemic have highlighted the key importance of simulation training in delivering post graduate curriculum.

Floral evolution and phylogeny of the Dialioideae, a diverse subfamily of tropical legumes.

PREMISE OF THE STUDY: The Dialioideae is an early diverging clade of caesalpinioid legumes containing approximately 85 species in 17 genera. Dialioideae floral morphology is highly variable and may provide clues to caesalpinioid evolution, but a well-resolved phylogeny is needed. Here, we have carried out a comprehensive morphological study of 78 Dialioideae and four outgroup species. METHODS: For all available Dialioideae DNA samples, the plastid rpS16 and trnL introns were sequenced. A combined phylogenetic analysis using the parsimony criterion was completed on a reduced taxon set for which both molecular and morphological data were available. Highly supported clades from the strict consensus tree of this analysis were then used to constrain the nodes of a second analysis on an expanded taxon set with missing molecular data for some taxa. KEY RESULTS: Several new, highly supported relationships have been discovered at the species and genus levels. The loss of the antepetalous stamen whorl was found to be a synapomorphy for most of the clade. CONCLUSIONS: A high degree of organ loss is common in the Dialioideae and often results in a bilaterally symmetrical flower. The absence of consistent morphological features in the Dialioideae, coupled with the small size of each florally diagnosed genus, suggests a lack of canalization in the floral evolution in early diverging legume lineages.

Directional genomic hybridization for chromosomal inversion discovery and detection.

Chromosomal rearrangements are a source of structural variation within the genome that figure prominently in human disease, where the importance of translocations and deletions is well recognized. In principle, inversions-reversals in the orientation of DNA sequences within a chromosome-should have similar detrimental potential. However, the study of inversions has been hampered by traditional approaches used for their detection, which are not particularly robust. Even with significant advances in whole genome approaches, changes in the absolute orientation of DNA remain difficult to detect routinely. Consequently, our understanding of inversions is still surprisingly limited, as is our appreciation for their frequency and involvement in human disease. Here, we introduce the directional genomic hybridization methodology of chromatid painting-a whole new way of looking at structural features of the genome-that can be employed with high resolution on a cell-by-cell basis, and demonstrate its basic capabilities for genome-wide discovery and targeted detection of inversions. Bioinformatics enabled development of sequence- and strand-specific directional probe sets, which when coupled with single-stranded hybridization, greatly improved the resolution and ease of inversion detection. We highlight examples of the far-ranging applicability of this cytogenomics-based approach, which include confirmation of the alignment of the human genome database and evidence that individuals themselves share similar sequence directionality, as well as use in comparative and evolutionary studies for any species whose genome has been sequenced. In addition to applications related to basic mechanistic studies, the information obtainable with strand-specific hybridization strategies may ultimately enable novel gene discovery, thereby benefitting the diagnosis and treatment of a variety of human disease states and disorders including cancer, autism, and idiopathic infertility.

Allelic differences within and among sister spores of the arbuscular mycorrhizal fungus Glomus etunicatum suggest segregation at sporulation.

Arbuscular mycorrhizal fungi (AMF) are root-inhabiting fungi that form mutualistic symbioses with their host plants. AMF are made up of coenocytic networks of hyphae through which nuclei and organelles can freely migrate. In this study, we investigated the possibility of a genetic bottleneck and segregation of allelic variation at sporulation for a low-copy Polymerase1-like gene, PLS. Specifically, our objectives were (1) to estimate what allelic diversity is passed on to a single spore (2) to determine whether this diversity is less than the total amount of variation found in all spores (3) to investigate whether there is any differential segregation of allelic variation. We inoculated three tomato plants with a single spore of Glomus etunicatum each and after six months sampled between two and three daughter spores per tomato plant. Pyrosequencing PLS amplicons in eight spores revealed high levels of allelic diversity; between 43 and 152 alleles per spore. We corroborated the spore pyrosequencing results with Sanger- and pyrosequenced allele distributions from the original parent isolate. Both sequencing methods retrieved the most abundant alleles from the offspring spore allele distributions. Our results indicate that individual spores contain only a subset of the total allelic variation from the pooled spores and parent isolate. Patterns of allele diversity between spores suggest the possibility for segregation of PLS alleles among spores. We conclude that a genetic bottleneck could potentially occur during sporulation in AMF, with resulting differences in genetic variation among sister spores. We suggest that the effects of this bottleneck may be countered by anastomosis (hyphal fusion) between related hyphae.

Cell-cell communication and signalling pathways within the ovule: from its inception to fertilization.

Cell-cell communication pervades every aspect of the life of a plant. It is particularly crucial for the development of the gametes and their subtle interaction leading to double fertilization. The ovule is composed of a funiculus, one or two integuments, and a gametophyte surrounded by nucellus tissue. Proper ovule and embryo sac development are critical to reproductive success. To allow fertilization, the correct relative positioning and differentiation of the embryo sac cells are essential. Integument development is also intimately linked with the normal development of the female gametophyte; the sporophyte and gametophyte are not fully independent tissues. Inside the gametophyte, numerous signs of cell-cell communication take place throughout development, including cell fate patterning, fertilization and the early stages of embryogenesis. This review highlights the current evidence of cell-cell communication and signalling elements based on structural and physiological observations as well as the description and characterization of mutants in structurally specific genes. By combining data from different species, models of cell-cell interactions have been built, particularly for the establishment of the germline, for the progression through megagametogenesis and for double fertilization.

Olfactory deficit detected by fMRI in early Alzheimer's disease.

Alzheimer's disease (AD) is accompanied by smell dysfunction, as measured by psychophysical tests. Currently, it is unknown whether AD-related alterations in central olfactory system neural activity, as measured by functional magnetic resonance imaging (fMRI), are detectable beyond those observed in healthy elderly. Moreover, it is not known whether such changes are correlated with indices of odor perception and dementia. To investigate these issues, 12 early stage AD patients and 13 nondemented controls underwent fMRI while being exposed to each of three concentrations of lavender oil odorant. All participants were administered the University of Pennsylvania Smell Identification Test (UPSIT), the Mini-Mental State Examination (MMSE), the Mattis Dementia Rating Scale-2 (DRS-2), and the Clinical Dementia Rating Scale (CDR). The blood oxygen level-dependent (BOLD) signal at primary olfactory cortex (POC) was weaker in AD than in HC subjects. At the lowest odorant concentration, the BOLD signals within POC, hippocampus, and insula were significantly correlated with UPSIT, MMSE, DRS-2, and CDR scores. The BOLD signal intensity and activation volume within the POC increased significantly as a function of odorant concentration in the AD group, but not in the control group. These findings demonstrate that olfactory fMRI is sensitive to the AD-related olfactory and cognitive functional decline.

Microsatellite characterization of subspecies and their hybrids in Culex pipiens complex (Diptera: Culicidae) mosquitoes along a north-south transect in the central United States.

Mosquitoes in the Culex pipiens complex, Cx. p. pipiens L. and Cx. p. quinquefasciatus Say are morphologically similar and important vectors of West Nile and St. Louis Encephalitis viruses in the United States. The subspecies differ with respect to overwintering strategies, with Cx. p. pipiens entering diapause in response to winter conditions and Cx. p. quinquefasciatus lacking this ability, yet they hybridize when found in sympatry. Specimens (n = 646) were collected using gravid traps set along a transect from New Orleans, LA, to Chicago, IL. Microsatellite markers were used to: genetically characterize subspecies and hybrids, determine the degree and extent of hybridization to better define the hybrid zone, and examine the efficacy of hybrid detection between microsatellites and a single-gene assay based on the acetylcholinesterase.2 gene (HotAce.2). The results support the presence of two distinct genetic entities, with abroad, stable hybrid zone in between. Admixture analyses classified >40% of individuals as hybrids. Allelic richness was markedly different at the northern and southern ends of the transect, and there was a significant isolation by distance effect. The hybrid zone seems to be wider and extends further to the south than previous work indicated, and as a result, we propose new boundaries compared with those indicated by a previous study. Microsatellites detected more hybrids than the HotAce.2 assay, although the latter assay remains useful as a screening tool. We suggest that the parental subspecies and the hybrid zone are maintained by heterosis combined with selection for diapause at northern latitudes.

Developmental shifts in fMRI activations during visuospatial relational reasoning.

To investigate maturational plasticity of fluid cognition systems, functional brain imaging was undertaken in healthy 8-19 year old participants while completing visuospatial relational reasoning problems similar to Raven's matrices and current elementary grade math textbooks. Analyses revealed that visuospatial relational reasoning across this developmental age range recruited activations in the superior parietal cortices most prominently, the dorsolateral prefrontal, occipital-temporal, and premotor/supplementary cortices, the basal ganglia, and insula. There were comparable activity volumes in left and right hemispheres for nearly all of these regions. Regression analyses indicated increasing activity predominantly in the superior parietal lobes with developmental age. In contrast, multiple anterior neural systems showed significantly less activity with age, including dorsolateral and ventrolateral prefrontal, paracentral, and insula cortices bilaterally, basal ganglia, and particularly large clusters in the midline anterior cingulate/medial frontal cortex, left middle cingulate/supplementary motor cortex, left insula-putamen, and left caudate. Findings suggest that neuromaturational changes associated with visuospatial relational reasoning shift from a more widespread fronto-cingulate-striatal pattern in childhood to predominant parieto-frontal activation pattern in late adolescence.

Emotional perception deficits in amyotrophic lateral sclerosis.

OBJECTIVE: Cognitive deficits associated with frontal lobe dysfunction can occur in amyotrophic lateral sclerosis (ALS), particularly in individuals with bulbar ALS who can also suffer pathologic emotional lability. Because frontal pathophysiology can alter emotional perception, we examined whether emotional perception deficits occur in ALS, and whether they are related to depressive or dementia symptoms. METHODS: Bulbar ALS participants (n=13) and age-matched healthy normal controls (n=12) completed standardized tests of facial emotional and prosodic recognition, the Geriatric Depression Scale, and the Mini-Mental State Examination. Participants identified the basic emotion (happy, sad, angry, afraid, surprised, disgusted) that matched 39 facial expressions and 28 taped, semantically neutral, intoned sentences. RESULTS: ALS patients performed significantly worse than controls on facial recognition but not on prosodic recognition. Eight of 13 patients (62%) scored below the 95% confidence interval of controls in recognizing facial emotions, and 3 of these patients (23% overall) also scored lower in prosody recognition. Among the 8 patients with emotional perceptual impairment, one-half did not have depressive, or memory or cognitive symptoms on screening, whereas the remainder showed dementia symptoms alone or together with depressive symptoms. CONCLUSIONS: Emotional recognition deficits occur in bulbar ALS, particularly with emotional facial expressions, and can arise independent of depressive and dementia symptoms or comorbid with depression and dementia. These findings expand the scope of cognitive dysfunction detected in ALS, and bolsters the view of ALS as a multisystem disorder involving cognitive and also motor deficits.