A single amino acid substitution in MdLAZY1A dominantly impairs shoot gravitropism in Malus.

Plant architecture is 1 of the most important factors that determines crop yield potential and productivity. In apple (Malus domestica), genetic improvement of tree architecture has been challenging due to a long juvenile phase and growth as complex trees composed of a distinct scion and a rootstock. To better understand the genetic control of apple tree architecture, the dominant weeping growth phenotype was investigated. We report the identification of MdLAZY1A (MD13G1122400) as the genetic determinant underpinning the Weeping (W) locus that largely controls weeping growth in Malus. MdLAZY1A is 1 of the 4 paralogs in apple that are most closely related to AtLAZY1 involved in gravitropism in Arabidopsis (Arabidopsis thaliana). The weeping allele (MdLAZY1A-W) contains a single nucleotide mutation c.584T>C that leads to a leucine to proline (L195P) substitution within a predicted transmembrane domain that colocalizes with Region III, 1 of the 5 conserved regions in LAZY1-like proteins. Subcellular localization revealed that MdLAZY1A localizes to the plasma membrane and nucleus in plant cells. Overexpressing the weeping allele in apple cultivar Royal Gala (RG) with standard growth habit impaired its gravitropic response and altered the growth to weeping-like. Suppressing the standard allele (MdLAZY1A-S) by RNA interference (RNAi) in RG similarly changed the branch growth direction to downward. Overall, the L195P mutation in MdLAZY1A is genetically causal for weeping growth, underscoring not only the crucial roles of residue L195 and Region III in MdLAZY1A-mediated gravitropic response but also a potential DNA base editing target for tree architecture improvement in Malus and other crops.

Pituitary hyperplasia resulting in visual deficit.

Background: Pituitary hyperplasia is an infrequent cause of visual disturbance and few such cases have been reported in the literature. Case Description: We describe the case of a 16-year-old female who presented with a short history of progressive headache and visual blurring. Examination revealed markedly constricted visual fields. Imaging revealed an enlarged pituitary gland. Hormonal panel was normal. Following endoscopic endonasal transsphenoidal biopsy and decompression of the optic apparatus, an immediate improvement in vision was noted. Final histopathological examination revealed pituitary hyperplasia. Conclusion: In patients with pituitary hyperplasia, visual deficit, and no identifiable reversible causes, surgical decompression can be considered to preserve vision.

Amniotic Membrane Patching to Assist Closure of Recalcitrant Macular Holes.

BACKGROUND AND OBJECTIVE: This study reports a case series of patients with persistent macular holes (MHs) who underwent human amniotic membrane subretinal placement to achieve successful anatomic MH closure. PATIENTS AND METHODS: This was a retrospective case series of patients with persistently open full-thickness MHs who underwent human amniotic membrane placement. Patients were observed up to 6 months postoperatively. RESULTS: Ten patients were included. The mean preoperative best-corrected visual acuity was 1.6 logMAR (20/800). Postoperatively, mean best-corrected visual acuity improved to 1.3 logMAR (20/400) at 1 month and 1.1 logMAR (20/250) by the 3- and 6-month visits. In all cases, the MH appeared closed at the 1-week visit and remained closed at their last follow-up. Optical coherence tomography showed closure in all cases. No adverse events were reported. CONCLUSIONS: Human amniotic membrane sub-retinal placement may serve as a useful surgical technique to assist in the closure of recalcitrant macular holes. [Ophthalmic Surg Lasers Imaging Retina 2023;54:218-222.].

Malpractice Cases Arising From Telephone Based Telemedicine Triage in Ophthalmology.

PURPOSE: To determine the allegation, precipitating medical issue, and outcome of telephone triage focused malpractice litigation among ophthalmologists. METHODS: The WestLaw Edge database was reviewed using terms pertaining to ophthalmology and telemedicine. The search ranged from 4/7/30 to 1/25/22. RESULTS: Of the 510 lawsuits, 3.5% (18/510) met inclusion criteria. 94.5% (17/18) alleged delays in evaluation and/or treatment. 61.1% (11/18) alleged incorrect diagnoses, 38.9% (7/18) claimed improper discussion of risks or informed consent, and 5.6% (1/18) alleged delayed referrals. The precipitating medical issues included retinal detachment in 33.3% (6/18) of cases, post-procedure and post-trauma endophthalmitis in 33.3% (6/18) of cases, ocular trauma without endophthalmitis in 22.2% (4/18) of cases, and bilateral acute retinal necrosis and allergic reactions each accounting for 5.6% (1/18) of cases. CONCLUSION: Telephone triage creates potential malpractice litigation. Delay in in-person clinical evaluation and alleged failure to inform patients of possible irreversible vision loss may lead to potential malpractice litigation. We suggest offering the option of same day in person evaluation and informing the patient how delay may lead to irreversible vision loss.

Technical Performance of a 430-Gene Preventative Genomics Assay to Identify Multiple Variant Types Associated with Adult-Onset Monogenic Conditions, Susceptibility Loci, and Pharmacogenetic Insights.

DNA-based screening in individuals without known risk factors potentially identifies those who may benefit from genetic counseling, early medical interventions, and/or avoidance of late or missed diagnoses. While not currently in widespread usage, technological advances in genetic analysis overcome barriers to access by enabling less labor-intensive and more cost-efficient means to discover variants of clinical importance. This study describes the technical validation of a 430-gene next-generation sequencing based assay, GeneCompassTM, indicated for the screening of healthy individuals in the areas of actionable health risks, pharmaceutical drug response, and wellness traits. The test includes genes associated with Mendelian disorders and genetic susceptibility loci, encompassing 14 clinical areas and pharmacogenetic variants. The custom-designed target enrichment capture and bioinformatics pipelines interrogate multiple variant types, including single nucleotide variants, insertions/deletions (indels), copy number variants, and functional haplotypes (star alleles), including tandem alleles and structural variants. Validation was performed against reference DNA from three sources: 1000 Genomes Project (n = 3), Coriell biobank (n = 105), and previously molecularly characterized biological specimens: blood (n = 15) and saliva (n = 11). Analytical sensitivity and specificity for single nucleotide variants (SNVs) were 97.57% and 99.99%, respectively, and for indels were 74.57% and 97.34%, respectively. This study demonstrates the validity of an NGS assay for genetic screening and the broadening of access to preventative genomics.

Case report: BRAF-inhibitor therapy in BRAF-mutated primary CNS tumours including one case of BRAF-mutated Rosai-Dorfman disease.

BRAF V600E oncogene mutations have been reported in multiple central nervous system (CNS) tumor types, and emerging evidence supports the use of targeted therapy in BRAF-mutated gliomas. BRAF oncogene mutations have been recently identified in Rosai-Dorfman disease (RDD)-a rare non-Langerhans cell histiocytosis. This series describes three patients from two neurosurgical centers in Ireland with BRAF V600E-mutated CNS tumors. The study participants include a 19-year-old male patient with ganglioglioma with anaplastic features, a 21-year-old male patient with CNS involvement of RDD, and a 28-year-old female patient with ganglioglioma with anaplastic features. Two patients received radiation with concurrent temozolomide before BRAF-targeted therapy. This case series describes clinical and radiological responses to BRAF-targeted therapy in BRAF V600E-mutated gliomas across multiple tumor grades and is only the second published report of response to targeted therapy in BRAF-mutated RDD. The durability of disease control with BRAF-targeted therapy was generally superior to that achieved with chemoradiation; one patient has experienced ongoing disease control for 5 years. The reported case of treatment response in BRAF-mutated RDD supports the strategy of genotyping and utilization of targeted therapy in this rare disease. The optimal sequencing of BRAF-targeted therapy in BRAF-mutated gliomas/glioneuronal tumors remains unclear, and further prospective studies are required to guide the use of genome-matched therapy in this patient population.

Psychometrics of the observational scales of the Utrecht Scale for Evaluation of Rehabilitation (USER): Content and structural validity, internal consistency and reliability.

INTRODUCTION: Establish content and structural validity, internal consistency, inter-rater reliability, and measurement error of the physical and cognitive scales of the Utrecht Scale for Evaluation clinical Rehabilitation (USER) in geriatric rehabilitation. MATERIAL AND METHODS: First, an expert consensus-meeting (N=7) was organised for content validity wherein scale content validity index (CVI) was measured. Second, in a sample of geriatric rehabilitation patient structural validity (N=616) was assessed by confirmatory factor analyses for exploring unidimensionality. Cut-off criteria were: Root Mean Square Error of Approximation (RMSEA) ≤0.08; Comparative Fit Index (CFI) and Tucker Lewis Index (TLI) ≥0.95. Local independence (residual correlation<0.20) and monotonicity (Hi-coefficient ≥0.30 and Hs-coefficient ≥0.50) were also calculated. Cronbach alphas were calculated for internal consistency. Alpha's > 0.7 was considered adequate. Third, two nurses independently administered the USER to 37 patients. Intraclass-correlation coefficients (ICC) were calculated for inter-rater reliability (IRR), standard error of measurement (SEM) and Smallest Detectable Change (SDC). RESULTS: The CVI for physical functioning was moderate (0.73) and excellent for cognitive functioning (0.97). Structural validity physical scale was acceptable (CFI;0.95, TLI;0.93, RMSEA;0.07, ECV;0.78, OmegaH;0.87; Monotonicity;(Hi;0.52-0.75 and Hs;0.63)). Cognitive scale was good (CFI;0.98, TLI;0.96, RMSEA;0.05, ECV;0.66 and OmegaH;0.90. Monotonicity;(Hi;0.30 -0.70 and Hs;0.61)). Cronbach's alpha were high: physical scale;0.92 and cognitive scale;0.94. Reliability physical scale ICC;0.94, SEM;5 and SDC;14 and cognitive scale ICC;0.88, SEM;5 and SDC;13. CONCLUSION: The observational scales of the USER have shown sufficient content and structural validity, internal consistency, and interrater reliability for measuring physical and cognitive function in geriatric rehabilitation. TRIAL REGISTRATION: N/A.

The Diagnostic Yield of Electromyography at Detecting Abnormalities on Muscle Biopsy: A Single Center Experience.

Historically, electromyography (EMG) is utilized early in the diagnostic evaluation of neuromuscular disorders, but its importance may be diminishing with more sophisticated genetic, imaging and immunohistochemistry investigations now available. In the present study, the diagnostic yield of EMG at predicting pathological abnormalities confirmed by muscle biopsy was determined at our neuroscience center. A retrospective study of consecutive cases reviewed at neuromuscular multidisciplinary meetings between 2007 and 2016 identified patients who had EMG and muscle biopsy as part of their diagnostic evaluation. EMG and biopsy findings were categorized as myopathic, neurogenic or normal. The diagnostic accuracy was determined by calculating the concordance between EMG and pathological findings. Of the 175 cases included in the analysis, there was definite concordance between EMG and muscle biopsy findings in 134 cases (76.6%). Abnormal EMG produced sensitivity of 87% and specificity of 65% for abnormal muscle biopsy. Seventeen patients had a normal EMG and an abnormal muscle biopsy, of which 6 had histopathological findings consistent with mitochondrial myopathy, central core myopathy or glycogen storage disorder. Conflicting EMG and muscle biopsy findings were observed in 10 cases. Inclusion body myositis, chronic neuromuscular disorders and dual pathologies were associated with discordant findings. This study demonstrates that EMG has accurate predictive value in diagnosing neuromuscular disorders at our neuroscience center. EMG retains a vital role, particularly in initial diagnostic evaluations of neuromuscular disorders.

Combined autofluorescence and diffuse reflectance for brain tumour surgical guidance: initial ex vivo study results.

This ex vivo study was conducted to assess the potential of using a fibre optic probe system based on autofluorescence and diffuse reflectance for tissue differentiation in the brain. A total of 180 optical measurements were acquired from 28 brain specimens (five patients) with eight excitation and emission wavelengths spanning from 300 to 700 nm. Partial least square-linear discriminant analysis (PLS-LDA) was used for tissue discrimination. Leave-one-out cross validation (LOOCV) was then used to evaluate the performance of the classification model. Grey matter was differentiated from tumour tissue with sensitivity of 89.3% and specificity of 92.5%. The variable importance in projection (VIP) derived from the PLS regression was applied to wavelengths selection, and identified the biochemical sources of the detected signals. The initial results of the study were promising and point the way towards a cost-effective, miniaturized hand-held probe for real time and label-free surgical guidance.

Molecular screening of familial hypercholesterolemia in Icelanders.

Familial hypercholesterolemia (FH) is a monogenic disease characterized by a lifelong exposure to high LDL-C levels that can lead to early onset coronary heart disease (CHD). The main causes of FH identified to date include loss-of-function mutations in LDLR or APOB, or gain-of-function mutations in PCSK9. Early diagnosis and genetic testing of FH suspects is critical for improved prognosis of affected individuals as lipid lowering treatments are effective in preventing CHD related morbidity and mortality. In the present study, we carried out a comprehensive screening, using a next-generation sequencing (NGS) panel, for FH culprit mutations in two Icelandic studies representative of either FH families or the general population. We confirmed all previously known mutations in the FH families, and identified two subjects that had been misdiagnosed clinically at young age. We identified six new mutations in the Icelandic FH families and detected three pathogenic mutations in the general population-based study. The application of the NGS panel revealed substantial diagnostic yields in identifying pathogenic mutations, or 68.2% of those with definite clinical diagnosis of FH in the family material and 5.6-fold enrichment in the population-based genetic testing.

Immediate Release of Vitreomacular Traction After Pneumatic Vitreolysis Followed by the Drinking Bird Technique.

Purpose: To report a case of release of vitreomacular traction (VMT) in a patient with a full thickness macular hole (FTMH) immediately following pneumatic vitreolysis (PV) combined with head bobbing movements. Methods: A 71-year-old female with VMT and an FTMH presented with blurred vision for 2 months to the level of 20/400. At her 1-month follow-up visit, PV was performed using C3F8 gas and she was instructed to perform the drinking bird technique for ten minutes. Results: Optical coherence tomography performed ten minutes after PV with head bobbing showed VMT release and a smaller FTMH. Visual acuity improved to 20/150 immediately afterwards and to 20/80 two months later. Conclusions: Using the drinking bird technique for a continuous period of time immediately following PV may encourage rapid VMT release. PV may be a feasible option for patients with VMT and FTMH who do not want surgery.

Sinoatrial Arrest Caused by Ticagrelor after Angioplasty in a 62-Year-Old Woman with Acute Coronary Syndrome.

The platelet aggregation inhibitor ticagrelor, a P2Y12 receptor antagonist, is widely used after angioplasty in patients with acute coronary syndrome. Clinical trial data have shown that it is well tolerated by most patients. We present the case of a 62-year-old woman whose ticagrelor-related asymptomatic and persistent sinus pauses after angioplasty resolved when ticagrelor was replaced with prasugrel.

Avoidance of Catastrophic Structural Failure as an Evolutionary Constraint: Biomechanics of the Acorn Weevil Rostrum.

The acorn weevil (Curculio Linnaeus, 1758) rostrum (snout) exhibits remarkable flexibility and toughness derived from the microarchitecture of its exoskeleton. Modifications to the composite profile of the rostral cuticle that simultaneously enhance the flexibility and toughness of the distal portion of the snout are characterized. Using classical laminate plate theory, the effect of these modifications on the elastic behavior of the exoskeleton is estimated. It is shown that the tensile behavior of the rostrum across six Curculio species with high morphological variation correlates with changes in the relative layer thicknesses and orientation angles of layers in the exoskeleton. Accordingly, increased endocuticle thickness is strongly correlated with increased tensile strength. Rostrum stiffness is shown to be inversely correlated with work of fracture; thus allowing a highly curved rostrum to completely straighten without structural damage. Finally, exocuticle rich invaginations of the occipital sutures are identified both as a likely site of crack initiation in tensile failure and as a source of morphological constraint on the evolution of the rostrum in Curculio weevils. It is concluded that avoidance of catastrophic structural failure, as initiated in these sutures under tension, is the driving selective pressure in the evolution of the female Curculio rostrum.

Pain Control after Intravitreal Injection Using Topical Nepafenac 0.3% or Pressure Patching: A Randomized, Placebo-Controlled Trial.

PURPOSE: Pain after an intravitreal injection (IVI) can last up to 7 days and negatively impacts the patient's experience, potentially reducing treatment compliance. We prospectively evaluated topical nepafenac 0.3% suspension and patching for the reduction of pain after IVI. DESIGN: Randomized controlled trial. PARTICIPANTS: Sixty patients receiving an IVI of bevacizumab, aflibercept, or triamcinolone acetonide in 1 eye. METHODS: Participants were randomized equally to receive either a single drop of nepafenac 0.3%, a pressure patch for 2 hours, or a single drop of preservative-free artificial tears (control group). A single-blinded placebo-controlled design was used to mask the topical treatment used. Pain was assessed using the Numeric Pain Rating Scale that ranged from 0 to 10 (horizontal pain scale). Because pain scores were not normally distributed, statistical analysis was performed using a nonparametric randomization-based analysis of covariance. MAIN OUTCOME MEASURE: Pain scores. RESULTS: Fifty-six and 53 patients of the 60 patients enrolled completed the 6- and 24-hour follow-ups, respectively. Numeric Pain Rating Scale scores at 6 and 24 hours after IVI were lower in the nepafenac group (0.8±0.3 and 0.1±0.1, respectively; n = 18) and the patching group (1.3±0.4 and 0.4±0.2, respectively; n = 19) compared with the control group (2.5±0.6 and 0.9±0.4, respectively; n = 19). After controlling for age, gender, number of prior injections, and physician administering the injection, patients in the nepafenac group reported significantly lower pain scores than those in the control group at 6 hours (1.3±0.6 less; P = 0.047) and 24 hours (0.7±0.3 less; P = 0.047). Although the patching group reported lower pain scores than the control group, this was not statistically significant (6 hours, P = 0.24; 24 hours, P = 0.29). CONCLUSIONS: Nepafenac 0.3% was effective as a single drop in reducing pain at 6 and 24 hours after IVI compared with placebo. Limited patching was associated with lower pain scores than placebo, but the difference was not statistically significant. Additional studies are needed to determine the most effective method to maximize the patient's experience after an IVI without sacrificing outcomes.

Assessing Prognosis of Acute Coronary Syndrome in Recent Clinical Trials: A Systematic Review.

There is no recent comprehensive overview of contemporary clinical trials assessing short and long-term outcomes in patients with acute coronary syndrome (ACS). This paper reviews factors from recent clinical trials that influenced prognosis in patients with ACS. Cochrane and PubMed databases were screened systematically for clinical trials published in the English literature reporting on ACS prognosis. Two authors independently screened titles, abstracts, and full text. Studies meeting inclusion criteria evaluated the impact of modern practice on prognosis. In vitro and animal models studies, conference abstracts, imaging studies, and review articles were excluded. Disagreement in inclusion criteria was resolved by consensus. A large study of 8,859 patients showed no difference in all-cause mortality between 31 days and 2 years in patients with ST segment elevation myocardial infarction (STEMI) compared to those with non-ST segment elevation myocardial infarction (NSTEMI) or stable ischemic heart disease (SIHD). Other studies showed a significant increase in all-cause mortality in patients with STEMI within the first 30 days, with NSTEMI patients exhibiting a higher mortality rate compared to those with SIHD during the 2-year follow-up period. Our review found that women have a poorer short-term prognosis compared to men. Additionally, reports from patients receiving comprehensive and coordinated care showed longer survival rates. In view of the improved prognosis demonstrated for patients suffering from ACS, assessing prognosis in patients represents a formidable task in modern practice. Our review highlights the need for further evidence-based studies evaluating long-term outcomes on diagnostic and treatment strategies.

Causal inference accounts for heading perception in the presence of object motion.

The brain infers our spatial orientation and properties of the world from ambiguous and noisy sensory cues. Judging self-motion (heading) in the presence of independently moving objects poses a challenging inference problem because the image motion of an object could be attributed to movement of the object, self-motion, or some combination of the two. We test whether perception of heading and object motion follows predictions of a normative causal inference framework. In a dual-report task, subjects indicated whether an object appeared stationary or moving in the virtual world, while simultaneously judging their heading. Consistent with causal inference predictions, the proportion of object stationarity reports, as well as the accuracy and precision of heading judgments, depended on the speed of object motion. Critically, biases in perceived heading declined when the object was perceived to be moving in the world. Our findings suggest that the brain interprets object motion and self-motion using a causal inference framework.

Cortical Balance Between ON and OFF Visual Responses Is Modulated by the Spatial Properties of the Visual Stimulus.

The primary visual cortex of carnivores and primates is dominated by the OFF visual pathway and responds more strongly to dark than light stimuli. Here, we demonstrate that this cortical OFF dominance is modulated by the size and spatial frequency of the stimulus in awake primates and we uncover a main neuronal mechanism underlying this modulation. We show that large grating patterns with low spatial frequencies drive five times more OFF-dominated than ON-dominated neurons, but this pronounced cortical OFF dominance is strongly reduced when the grating size decreases and the spatial frequency increases, as when the stimulus moves away from the observer. We demonstrate that the reduction in cortical OFF dominance is not caused by a selective reduction of visual responses in OFF-dominated neurons but by a change in the ON/OFF response balance of neurons with diverse receptive field properties that can be ON or OFF dominated, simple, or complex. We conclude that cortical OFF dominance is continuously adjusted by a neuronal mechanism that modulates ON/OFF response balance in multiple cortical neurons when the spatial properties of the visual stimulus change with viewing distance and/or optical blur.

Navigated Retina Laser Therapy as a Novel Method for Laser Retinopexy of Retinal Tears.

BACKGROUND AND OBJECTIVE: To describe the use of a navigated laser system for the treatment of retinal tears. MATERIALS AND METHODS: A planned pattern laser retinopexy was performed using a navigated laser photocoagulator incorporating rapid panretinal photocoagulation technology with an individualized target overlay to produce a 3 × 3 square pattern surrounding a horseshoe tear. Institutional review board approval was not applicable for this case. RESULTS: Successful laser retinopexy 360° around the tear was achieved. CONCLUSION: In select cases, a navigated laser system may be utilized for the treatment of retinal tears. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e206-e209.].

Flavoprotein Fluorescence Correlation with Visual Acuity Response in Patients Receiving Anti-VEGF Injection for Diabetic Macular Edema.

Anti-VEGF treatment of diabetic macular edema (DME) complicating diabetic retinopathy (DR) has greatly improved structural and visual outcomes for patients with diabetes mellitus. However, up to 50% of patients are either nonresponsive or refractory to anti-VEGF treatment (no improvement in BCVA or central macular thickness (CMT)). It is believed that factors such as mitochondrial structural and functional damage, due to oxidative stress, are partially responsible for this lack of improvement. Flavoprotein fluorescence (FPF) has been shown to be a sensitive marker of mitochondrial function and has been found to correlate with the degree of diabetic retinopathy. FPF may also provide additional information regarding therapeutic response of patients receiving anti-VEGF treatment for DME. Eight patients with DR and DME with clinically significant DME (CSDME) who underwent anti-VEGF (bevacizumab) treatment were imaged before injection and at follow-up visit using FPF in addition to standard color fundus photography and OCT CMT. A strong correlation r = 0.98 (p = 0.000015) between the FPF decrease and the BCVA improvement was observed; BCVA improved as FPF values decreased. Notably, in the same patients, the correlation between OCT CMT decrease and BCVA improvement (r = 0.688) was not found to be significant (p = 0.13). These findings suggest that FPF can detect improvement in metabolic function preceding structural improvement and even with small changes in edema. Additionally, FPF may be supplementary to current diagnostic methods for earlier detection of therapeutic response to anti-VEGF treatment in patients with DME.