Ab Interno Canaloplasty and Trabeculotomy Outcomes for Mild, Moderate, and Advanced Open-Angle Glaucoma: A ROMEO Analysis

Jaime E Dickerson Jr,1,2 Alison E Harvey,1 Reay H Brown1,3 1Sight Sciences, Inc., Menlo Park, CA, USA; 2North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USA; 3Atlanta Ophthalmology Associates, Atlanta, GA, USACorrespondence: Jaime E Dickerson Jr, Email [email protected]: To determine if there was an association between severity of glaucoma and intraocular pressure (IOP) and medication (med) outcomes for patients in the ROMEO (Retrospective, Observational, Multicenter Evaluation of OMNI) study.Setting: Eleven ophthalmology practices in 8 US states.Design: Post-hoc analysis of all eyes enrolled and treated with ab interno canaloplasty and trabeculotomy in the retrospective, multicenter ROMEO study.Methods: Eyes were grouped according to visual field mean deviation (MD): mild (MD better than − 6 dB), moderate (MD between − 6 and − 12 dB), advanced (− 12 dB or worse). IOP and med outcomes at 12 months were compared across groups. Least squares regression was used to assess the relationship of MD with month 12 IOP. Outcomes for 1st and last MD deciles were compared as a sensitivity analysis.Results: One hundred and twenty-seven eyes were available for analysis including 79 mild, 42 moderate, 6 advanced. Most eyes had a reduction in IOP at Month 12 (70%) with most at 18 mmHg or less. Percentage IOP reduction was similar across the groups (mild 16.9%, moderate 18.6%, advanced 18.0%) with mean month 12 IOP between 14 and 16 mmHg. Medications were also reduced in all three groups; − 0.8 (mild, P < 0.001), − 0.55 (moderate, P < 0.05), and − 1.0 (advanced, P = 0.139, ns). Regression analysis revealed no relationship between month 12 IOP and MD. Med reductions were observed for all groups with a reduction of 1 or more medications seen in (%, 95% CI) 69%, 59– 79 (mild), 50%, 35– 65 (moderate), and 60%, 21– 99 (advanced). Secondary interventions tended to have greater incidence with worse MD likely reflecting lower desired IOP targets.Conclusion: Analysis of data from the ROMEO study suggests that similar meaningful IOP and med reductions can be expected across the range of disease severity studied.Keywords: MIGS, canaloplasty, primary open-angle glaucoma, trabeculotomy, OMN

Establishing the precise evolutionary history of a gene improves prediction of disease-causing missense mutations

PURPOSE: Predicting the phenotypic effects of mutations has become an important application in clinical genetic diagnostics. Computational tools evaluate the behavior of the variant over evolutionary time and assume that variations seen during the course of evolution are probably benign in humans. However, current tools do not take into account orthologous/paralogous relationships. Paralogs have dramatically different roles in Mendelian diseases. For example, whereas inactivating mutations in the NPC1 gene cause the neurodegenerative disorder Niemann-Pick C, inactivating mutations in its paralog NPC1L1 are not disease-causing and, moreover, are implicated in protection from coronary heart disease. METHODS: We identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism’s fitness. RESULTS: Removing the paralogs and distant homologs improved the overall performance of categorizing disease-causing and benign amino acid substitutions. CONCLUSION: The results show that a thorough evolutionary analysis followed by identification of orthologs improves the accuracy in predicting disease-causing missense mutations. We anticipate that this approach will be used as a reference in the interpretation of variants in other genetic diseases as well. Genet Med 18 10, 1029–1036

Intake of dietary soy isoflavones in relation to perimenstrual symptoms of Korean women living in the USA

This study was conducted to identify the potential relationship between the dietary intake level of soy isoflavones and perimenstrual symptomatology. The research design was a cross-sectional study. The sample was made up of 84 Korean women living in the USA, aged 28–40 years. The Moos Menstrual Distress Questionnaire (MDQ) and the Food Frequency Questionnaire were used as measurement tools. The soy isoflavone intake was significantly correlated with MDQ scores in the menstrual phase. In conclusion, the beneficial effect of dietary soy isoflavones on certain menstrual symptoms was established, suggesting that soy isoflavones could be one of the dietary factors related to the complexity of premenstrual syndrome (PMS). The positive effect of soy isoflavones on PMS warrants further study.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72547/1/j.1442-2018.2006.00270.x.pd

Histoplasma capsulatum Encodes a Dipeptidyl Peptidase Active against the Mammalian Immunoregulatory Peptide, Substance P

The pathogenic fungus Histoplasma capsulatum secretes dipeptidyl peptidase (Dpp) IV enzyme activity and has two putative DPPIV homologs (HcDPPIVA and HcDPPIVB). We previously showed that HcDPPIVB is the gene responsible for the majority of secreted DppIV activity in H. capsulatum culture supernatant, while we could not detect any functional contribution from HcDPPIVA. In order to determine whether HcDPPIVA encodes a functional DppIV enzyme, we expressed HcDPPIVA in Pichia pastoris and purified the recombinant protein. The recombinant enzyme cleaved synthetic DppIV substrates and had similar biochemical properties to other described DppIV enzymes, with temperature and pH optima of 42°C and 8, respectively. Recombinant HcDppIVA cleaved the host immunoregulatory peptide substance P, indicating the enzyme has the potential to affect the immune response during infection. Expression of HcDPPIVA under heterologous regulatory sequences in H. capsulatum resulted in increased secreted DppIV activity, indicating that the encoded protein can be expressed and secreted by its native organism. However, HcDPPIVA was not required for virulence in a murine model of histoplasmosis. This work reports a fungal enzyme that can function to cleave the immunomodulatory host peptide substance P

The genetic basis of DOORS syndrome: an exome-sequencing study.

Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals

Hydrostatic and osmotic pressure study of the RNA hydration

The tertiary structure of nucleic acids results from an equilibrium between electrostatic interactions of phosphates, stacking interactions of bases, hydrogen bonds between polar atoms and water molecules. Water interactions with ribonucleic acid play a key role in its structure formation, stabilization and dynamics. We used high hydrostatic pressure and osmotic pressure to analyze changes in RNA hydration. We analyzed the lead catalyzed hydrolysis of tRNAPhe from S. cerevisiae as well as hydrolytic activity of leadzyme. Pb(II) induced hydrolysis of the single phosphodiester bond in tRNAPhe is accompanied by release of 98 water molecules, while other molecule, leadzyme releases 86

Associations between HIV and Human Pathways Revealed by Protein-Protein Interactions and Correlated Gene Expression Profiles

BACKGROUND: AIDS is one of the most devastating diseases in human history. Decades of studies have revealed host factors required for HIV infection, indicating that HIV exploits host processes for its own purposes. HIV infection leads to AIDS as well as various comorbidities. The associations between HIV and human pathways and diseases may reveal non-obvious relationships between HIV and non-HIV-defining diseases. PRINCIPAL FINDINGS: Human biological pathways were evaluated and statistically compared against the presence of HIV host factor related genes. All of the obtained scores comparing HIV targeted genes and biological pathways were ranked. Different rank results based on overlapping genes, recovered virus-host interactions, co-expressed genes, and common interactions in human protein-protein interaction networks were obtained. Correlations between rankings suggested that these measures yielded diverse rankings. Rank combination of these ranks led to a final ranking of HIV-associated pathways, which revealed that HIV is associated with immune cell-related pathways and several cancer-related pathways. The proposed method is also applicable to the evaluation of associations between other pathogens and human pathways and diseases. CONCLUSIONS: Our results suggest that HIV infection shares common molecular mechanisms with certain signaling pathways and cancers. Interference in apoptosis pathways and the long-term suppression of immune system functions by HIV infection might contribute to tumorigenesis. Relationships between HIV infection and human pathways of disease may aid in the identification of common drug targets for viral infections and other diseases

Treatment Outcome in Patients Receiving Assertive Community Treatment

In an observational study of severely mentally ill patients treated in assertive community treatment (ACT) teams, we investigated how treatment outcome was associated with demographic factors, clinical factors, and motivation for treatment. To determine psychosocial outcome, patients were routinely assessed using the Health of the Nation Outcome Scales (HoNOS). Trends over time were analyzed using a mixed model with repeated measures. The HoNOS total score was modeled as a function of treatment duration and patient-dependent covariates. Data comprised 637 assessments of 139 patients; mean duration of follow-up was 27.4 months (SD = 5.4). Substance abuse, higher age, problems with motivation, and lower educational level were associated with higher HoNOS total scores (i.e., worse outcome). To improve treatment outcome, we recommend better implementation of ACT, and also the implementation of additional programs targeting subgroups which seem to benefit less from ACT

Deficits in Implicit Attention to Social Signals in Schizophrenia and High Risk Groups: Behavioural Evidence from a New Illusion

Background An increasing body of evidence suggests that the apparent social impairments observed in schizophrenia may arise from deficits in social cognitive processing capacities. The ability to process basic social cues, such as gaze direction and biological motion, effortlessly and implicitly is thought to be a prerequisite for establishing successful social interactions and for construing a sense of "social intuition." However, studies that address the ability to effortlessly process basic social cues in schizophrenia are lacking. Because social cognitive processing deficits may be part of the genetic vulnerability for schizophrenia, we also investigated two groups that have been shown to be at increased risk of developing schizophrenia-spectrum pathology: first-degree relatives of schizophrenia patients and men with Klinefelter syndrome (47,XXY). Results We compared 28 patients with schizophrenia, 29 siblings of patients with schizophrenia, and 29 individuals with Klinefelter syndrome with 46 matched healthy control subjects on a new paradigm. This paradigm measures one's susceptibility for a bias in distance estimation between two agents that is induced by the implicit processing of gaze direction and biological motion conveyed by these agents. Compared to control subjects, patients with schizophrenia, as well as siblings of patients and Klinefelter men, showed a lack of influence of social cues on their distance judgments. Conclusions We suggest that the insensitivity for social cues is a cognitive aspect of schizophrenia that may be seen as an endophenotype as it appears to be present both in relatives who are at increased genetic risk and in a genetic disorder at risk for schizophrenia-spectrum psychopathology. These social cue-processing deficits could contribute, in part, to the difficulties in higher order social cognitive tasks and, hence, to decreased social competence that has been observed in these groups