Placebo Effect and Its Determinants in Ocular Hypotensive Therapy: Meta-analysis and Multiple Meta-regression Analysis.

TOPIC: The placebo effect and its potential determinants in ocular hypotensive therapy. CLINICAL RELEVANCE: The placebo effect has been studied and documented within a wide clinical context. It remains unclear whether placebo is effective in glaucoma treatment or, if so, which factors are determinative of effect size (ES). METHODS: Randomized controlled trials (RCTs) of topical ocular hypotensive therapy for patients with open-angle glaucoma or ocular hypertension, conducted through June 2, 2022, were included. First, a perceived placebo effect was measured as the overall intraocular pressure (IOP) change from the baseline. It was evaluated in terms of the ES (mean difference between the baseline and the end point) and then was compared with the ES, as obtained from the untreated control participant to obtain a true placebo effect. The primary outcome was ES based on 4 weeks of treatment. Meta-analysis-based statistical pooling was performed where appropriate, and 95% confidence intervals (CIs) were used for comparison. Potential placebo effect determinants were scrutinized using a multiple meta-regression model (PROSPERO identifier, CRD42022348098). RESULTS: A total of 40 RCTs (7829 eyes) with 33 placebo groups (2055 eyes) along with 7 untreated groups (1184 eyes) were included. Among placebo-controlled trials, placebo was determined to be effective in lowering IOP (ES, -1.30 mmHg; 95% CI, -1.75 to -0.84 mmHg). Using NMA, the ES for placebo was -2.27 mmHg (95% CI, -3.52 to -1.01 mmHg) greater than ES for untreated control participants.. According to the multiple meta-regression model, the active treatment ES was a significant factor to predict the amount of placebo effect. Placebo additionally lowered IOP by -0.45 mmHg per -1 mmHg of active treatment effect. Add-on study design and larger sample size also were associated with greater amount of placebo effect. No publication bias was evident in either a funnel plot or the Begg and Mazumdar adjusted rank correlation test results (P = 0.24). DISCUSSION: This meta-analysis indicated that placebo is effective in lowering IOP and is superior to the effect observed for the untreated control participants. However, caution is required in interpreting the results because of the small number of untreated controlled trials and potential bias from the lack of direct comparison between the placebo and untreated arms. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The Effect of Vertical Versus Horizontal Vaginal Cuff Closure on Vaginal Length After Laparoscopic Hysterectomy.

STUDY OBJECTIVE: To determine whether vertical versus horizontal closure of the vaginal cuff during laparoscopic hysterectomy has an effect on postoperative vaginal length and pelvic organ prolapse. DESIGN: A prospective randomized controlled trial. Subjects were randomly assigned to vertical or horizontal vaginal cuff closure at the time of total laparoscopic hysterectomy. Pelvic organ prolapse quantization (POP-Q) tests were performed before surgery, 2 to 4 weeks after surgery, and 3 to 4 months after surgery (Canadian Task Force classification I). SETTING: An academic university-affiliated community hospital. PATIENTS: Patients undergoing laparoscopic or robotic-assisted laparoscopic total hysterectomy for benign or malignant disease, excluding those undergoing radical hysterectomy or concomitant pelvic floor procedure. INTERVENTIONS: Subjects were randomized into the vertical or horizontal vaginal cuff closure group. Total hysterectomy was completed with traditional laparoscopic techniques or with robotic assistance. A colpotomy ring was used in each subject. Vaginal cuff closure was performed with barbed suture in a running fashion according to the group assignment. MEASUREMENTS AND MAIN RESULTS: A total of 43 subjects were enrolled and randomized. One patient was excluded because the vaginal cuff was closed vaginally, 1 cancelled surgery, and 1 was completed without a uterine manipulator. The mean change in vaginal length was -0.89 cm (standard deviation [SD] = 1.03) in the horizontal group and -0.86 cm (SD = 1.19) in the vertical group (p = .57). POP-Q evaluation revealed no differences between groups and an overall trend toward improved POP-Q measurements. The average duration of vaginal cuff closure did not differ (p = .45), and there were no intraoperative complications related to vaginal cuff closure. CONCLUSION: Horizontal and vertical laparoscopic closure of the vaginal cuff after laparoscopic hysterectomy results in similar changes in vaginal length and other POP-Q scores.

Relationship between disc margin to fovea distance and central visual field defect in normal tension glaucoma.

BACKGROUND: To investigate the relationship between ocular geometric factors, including temporal disc margin to fovea distance (DFD) measured by optic disc stereophotography (ODP) and central visual field (VF) defect, in normal-tension glaucoma (NTG) patients. METHODS: This retrospective, single-center, cross-sectional study included 88 eyes of 88 NTG patients with mild VF defects (MD > -6.0 dB). NTG patients were divided into two groups according to VF tests: central VF-invading and central VF-sparing groups. Optic nerve head (ONH) parameters including disc dimensions, peripapillary atrophy (PPA), and DFD were obtained by ODP, and retinal nerve fiber layer (RNFL) thickness was measured by Stratus optical coherence tomography (OCT). RESULTS: In the invading group, DFD was shorter (3.642 ± 0.401 mm) than in the sparing group (3.877 ± 0.278 mm; p = 0.002). The sparing group had more vertically oval ONH (p = 0.023) and wider temporal PPA width (p = 0.031). The RNFL thickness in the invading group was thinner in the temporal and inferior quadrants, but thicker in the superior quadrant than that of the sparing group. In a multiple linear regression analysis, DFD was the only geometric factor associated with degree of central VF involvement (p = 0.002). DFD was positively correlated with temporal RNFL thickness in the sparing group (r = 0.484, p < 0.001) but not in the invading group (r = -0.080, p = 0.631). CONCLUSIONS: Eyes with a shorter DFD should be monitored carefully because central VF involvement appears to be related to shorter DFD in NTG patients with mild VF defects.

Comparison of event-based methods using optical coherence tomography and automated perimetry to detect the progression of glaucoma in patients with open-angle glaucoma.

BACKGROUND/AIMS: To compare event-based methods for estimating the incidence of glaucoma progression using optical coherence tomography (OCT) and automated perimetry and to assess agreement between structural and functional tests for detecting glaucoma progression. METHODS: Functional progression of glaucoma was estimated by guided progression analysis (GPA) using a Humphrey field analyzer (HFA), and structural progression was assessed by OCT and defined as the decrease in retinal nerve fiber layer thickness based on test-retest variability data of previous reports on clock-hour and quadrant maps. The level of agreement between structural and functional progression was evaluated using kappa statistics. RESULTS: Fifty eyes of 50 patients with open-angle glaucoma were enrolled in this retrospective study. The incidence of visual field progression estimated by GPA was 18%. The occurrence of structural progression assessed by OCT ranged from 18 to 68%. The more stringent OCT progression criterion using a quadrant map showed the best agreement with HFA GPA (ĸ = 0.423) and detected perimetric progression with high specificity, while the less stringent OCT criterion considering any clock hour showed the lowest agreement with functional progression (ĸ = 0.098). CONCLUSION: OCT progression criteria based on test-retest variability showed moderate agreement with perimetric progression, and more stringent criteria showed better agreement with functional progression than less stringent ones.

The problem of 'thick in status, thin in content' in Beauchamp and Childress' principlism.

For many, Thomas Beauchamp and James Childress have elaborated moral reasoning by using the four principles whereby all substantive problems of medical ethics (and of ethics more generally) can be properly analysed and cogent philosophical solutions for the problems can be found. It seems that their 'principlism' gets updated, with better features being added during the course of the six editions of Principles of Biomedical Ethics. Nonetheless, Beauchamp and Childress seem to have been losing their way when it comes to the common-morality justification, which is the epistemological (and perhaps metaphysical) backbone of their method, and this is shown more vividly in their most recent (2009) edition of Principles of Biomedical Ethics. The author points out what he calls the problem of 'thick in status, thin in content' in principlism. The problem exists because principlism cannot adequately explain how the prescriptive sense of common morality it supports is consistent with the existence of what Beauchamp and Childress call the 'legitimate moral diversity in the world'. Because of this problem, first, the practical end that principlism allegedly accomplishes (ie, providing practical moral guidelines in a relatively 'thick' content, based on common morality) is frustrated, and, second, principlism makes itself the method of common morality de jure and of moral pluralism de facto.

Synthesis and biological characterisation of novel N-alkyl-deoxynojirimycin alpha-glucosidase inhibitors.

The N-alkylated deoxynojirimycin compound, N-(6'-(4''-azido-2''-nitrophenylamino)hexyl)-1-deoxynojirimycin (6) was synthesised as a potential photoaffinity probe for endoplasmic reticulum (ER) alpha-glucosidases I and II. Surprisingly this compound was a highly potent inhibitor of alpha-glucosidase I (IC(50), 17 nM) in an in vitro assay and proved equally effective at inhibiting cellular ER glucosidases, as determined by a free oligosaccharide (FOS) analysis. A modest library of compounds was synthesised to obtain structure-activity information by variation of the N-alkyl chain length and modifications to the azido-nitrophenyl group. All of these compounds failed to improve on the efficacy of compound 6, but most showed greater enzyme inhibitory potency than N-butyl-deoxynojirimycin (NB-DNJ), a pharmacological agent that has been evaluated for the treatment of several viruses for which infectivity is dependent on host cell glycosylation.

A Novel Application of Electroactive Polyimide Doped with Gold Nanoparticles: As a Chemiresistor Sensor for Hydrogen Sulfide Gas.

This research paper presents a new application of electroactive polyimide doped with gold nanoparticles (PI/AuNPs) as a chemiresistor sensor for detecting hydrogen sulfide gas. The synthesis of PI/AuNPs was done in a simple 3-step process of polymerization using the as prepared amine-capped aniline trimer (ACAT), followed by imidization, and doping. Spectral analyses via FTIR, LC-MS and 1H-NMR confirmed the formation of amine-capped aniline trimer with a MW of 288 g mol-1. Comparison of ACAT, BSAA, and PI FTIR spectra showed successful polymerization of the last, while XRD validated the incorporation of metal nanoparticles onto the polymer matrix, showing characteristic diffraction peaks corresponding to gold. Furthermore, TEM, and FE-SEM revealed the presence of well-dispersed Au nanoparticles with an average diameter of about 60 nm. The electroactive PI/AuNPs-based sensor showed a sensitivity of 0.29% ppm-1 H2S at a linear concentration range of 50 to 300 ppm H2S (r = 0.9777). The theoretical limit of detection was found at 0.142 ppm or 142 ppb H2S gas. The sensor provided a stable response reading at an average response time of 43 ± 5 s, which was easily recovered after an average time of 99 ± 5 s. The sensor response was highly repeatable and reversible, with RSD values of 8.88%, and 8.60%, respectively. Compared with the performance of the conventional conducting polyaniline also doped with gold nanoparticles (PANI/AuNPs), the fabricated electroactive PI/AuNPs exhibited improved sensing performance making it a potential candidate in monitoring H2S in the environment and for work-related safety.

Phonemic awareness skill of speech-language pathologists and other educators.

PURPOSE: Educators rely on sufficient knowledge and skill to provide effective phonemic awareness instruction, an important component of early literacy instruction, particularly for children who experience difficulty learning to read. The purpose of this study was to evaluate and compare the phonemic awareness skill of several groups of educators, including speech-language pathologists (SLPs; n = 160), kindergarten teachers (n = 109), first-grade teachers (n = 112), reading teachers (n = 100), and special education teachers (n = 60). METHOD: Participants completed a paper-pencil measure of phonemic awareness skill that included 3 tasks. The measure was designed to assess sophisticated explicit phonemic awareness skill within a print context, representing an advanced skill level that has been deemed critical to teaching. RESULTS: SLPs demonstrated superior performance on the measure of phonemic awareness skill when compared to other educators (d = 1.54). The performance of reading and special education teachers was comparable to that of kindergarten and first-grade teachers. Orthographic knowledge had an adverse impact on the performance of all groups. However, SLPs were far more proficient than other educators at segmenting words that had a complex relationship between speech and print (e.g., box, use). CLINICAL IMPLICATIONS: SLPs have relative expertise in phonemic awareness, yet their performance may not be proficient. Three recommendations are discussed: (a) Increase the phonemic awareness skill of all educators, (b) revise instructional materials to enhance educators' efforts to provide accurate and effective phonemic awareness instruction, and (c) include SLPs as members of the team responsible for phonemic awareness instruction and intervention.

Why Naming Disease Differs From Naming Illness.

Addressing the question of how medicine should engage with people who consider their clinical disease condition to be importantly constitutive of their identity, this article focuses on one group-advocates for the fat acceptance (FA) or body positivity movement in American society. Drawing on philosophical analysis, I try to show that FA and physician communities represent different traditions within the larger culture and that whether obesity should be considered a disease is a culture battle. I argue that diseases (medical) and illnesses (cultural) are 2 different designations of clinical symptoms and that both disease and illness designations can change over time or be uncertain.

Clinical and sociodemographic characteristics associated with disease severity in juvenile recurrent respiratory papillomatosis: A study of 104 patients in a tertiary care pediatric hospital.

BACKGROUND: Juvenile recurrent respiratory papillomatosis (JRRP) is generally aggressive and with a high recurrence rate. Currently, there is no definite curative treatment for JRRP. Therefore, a greater understanding of the aspects that influence the severity and prognosis of the disease is required. OBJECTIVE: The aim of this study was to establish the clinical and socioeconomic characteristics of pediatric patients with JRRP and its relationship with the severity of the disease in a tertiary care pediatric hospital. RESULTS: A strong relationship was observed between the severity of the disease and the age at the time of diagnosis, and having a tracheostomy. A moderate association was found between the severity of the disease and the age at the time of the study, the area of origin and the recurrence rate. None of the socioeconomic statuses had a correlation with the severity of the JRRP. CONCLUSIONS: JRRP is associated with multiple surgeries due to the recurrence and aggressiveness of the disease. The socioeconomic status does not seem to influence the severity of the disease, whereas younger patients and users of tracheostomy should receive a more strict follow-up given the increased risk of severe disease.

Agreement of New Automated Matched Alternation Flicker using Undilated Fundus Photography for the Detection of Glaucomatous Structural Change.

PURPOSE: To determine the agreement among glaucoma experts and general ophthalmologists regarding detection of glaucomatous structural changes using a new automated matched alternation flicker (AMAF) method with fundus photographs (FPs) of undilated eyes. METHODS: Sixty-six pairs of FPs of normal tension glaucoma patients were collected. FPs were taken at intervals of more than 12 months. Alternating flicker images were created using a new AMAF application. In a blinded manner, two glaucoma experts and two general ophthalmologists compared the presence of glaucomatous structural changes using either the AMAF method or the side-by-side comparison method. The interobserver and intraobserver agreements were compared using the Bland and Altman plot analysis. RESULTS: The glaucoma experts detected more glaucoma progression using the AMAF method (average, 50.7%) compared with the side-by-side method (average, 32.5%). General ophthalmologists detected more glaucomatous progression with the AMAF method (average, 40.9%) than with the side-by-side method (average, 25.0%). The AMAF method showed fair to substantial interreader agreement (k = 0.511-0.724) and fair to perfect intrareader agreement (k = 0.631-0.943). Interreader and intrareader agreements using the AMAF method were better for the glaucoma experts compared with the general ophthalmologists. CONCLUSIONS: The AMAF method showed more changes in FPs than the classical side-by-side comparison method. Regarding inter- and intrareader agreements, agreement for the glaucoma experts was best using the AMAF method, but for the general ophthalmologists agreement was best using the side-by-side comparison method.

Burst-shot infrared digital photography to determine scotopic pupil diameter.

PURPOSE: To evaluate the usefulness of infrared digital photography for determining scotopic pupil size by comparing infrared digital photography with a Colvard pupillometer (Oasis Medical). SETTING: Department of Ophthalmology, Ajou University School of Medicine, Suwon, Korea. METHODS: Scotopic pupil size in 50 eyes of 25 healthy individuals was measured with a Colvard pupillometer and a digital camera (DSC-F828) using infrared burst shots after 5 minutes of dark adaptation. Measurements were performed by 2 independent examiners (E1 and E2). The digital photograph images were read using the ruler function of Adobe Photoshop 7.0 by 2 independent readers (R1 and R2). Agreement and repeatability were analyzed using the comparison method described by Bland and Altman. RESULTS: The mean scotopic pupil diameter measured using the Colvard pupillometer was 6.69 mm +/- 0.78 (SD) (E1) and 6.70 +/- 0.71 mm (E2). The mean scotopic pupil diameter measured from the digital photograph images was 6.67 +/- 0.75 mm (E1) and 6.66 +/- 0.78 mm (E2). The mean difference between E1 and E2 with both devices was small; however, the result with the infrared digital camera was marginally smaller than with the Colvard pupillometer. The limits of agreement were -0.01 +/- 0.70 mm with the Colvard pupillometer and 0.01 +/- 0.20 mm with the digital photograph image. The digital photograph image showed better agreement. The coefficient of interrater repeatability was smaller for the digital photograph image (0.39) than for the Colvard pupillometer (0.70). CONCLUSIONS: Scotopic pupil measurement using an infrared digital camera with a burst shot had good agreement with the Colvard pupillometer and better repeatability. The infrared digital camera is less expensive, and pupil unrest can be overcome by taking serial images.

Effects of Central Corneal Stromal Thickness and Epithelial Thickness on Intraocular Pressure Using Goldmann Applanation and Non-Contact Tonometers.

PURPOSE: To investigate whether corneal thickness parameters measured by optical coherence tomography (OCT), such as central corneal thickness (CCT), central corneal stromal thickness (CCST), and central corneal epithelial thickness (CCET), influence the intraocular pressure (IOP) difference measured by Goldmann applanation tonometry (GAT) and non-contact tonometry (NCT). METHODS: In total, 50 eyes from 50 subjects without glaucomatous defects were included in this retrospective, cross-sectional study. We measured IOP using GAT and NCT and calculated the difference between the two methods. CCT was measured by a Cirrus HD-OCT device using anterior segment imaging. The basement membrane of the epithelium, which was seen as a high-reflection line in the OCT image, was taken as a reference line to measure CCST and CCET. RESULTS: The mean IOP measured by GAT and NCT was 16.7 ± 3.0 and 18.1 ± 3.8 mmHg, respectively. The mean IOP difference was 1.5 ± 1.7 mmHg, and the IOP measured by NCT was 8.4% ± 11.3% higher than that measured by GAT. The CCET and CCST were 57.9 ± 5.6 and 501.7 ± 33.8 µm, respectively. CCT showed a positive correlation with both GAT IOP (r = 0.648, P < 0.001) and NCT IOP (r = 0.676, P < 0.001). Although CCST showed a significant correlation with GAT IOP and NCT IOP, CCET did not. The difference between GAT IOP and NCT IOP increased with CCT (r = 0.333, P = 0.018), and CCET was positively correlated with the IOP difference between GAT and NCT (r = 0.435, P = 0.002). CONCLUSIONS: IOP increased with greater CCT, and CCST seemed to have a more important role than CCET. CCET also increased with greater CCT, and this may be a possible explanation for the increasing difference in IOP between GAT and NCT with increasing CCT.

Comparison of disc analysis algorithms provided by cirrus OCT and stereo optic-disc photography in normal and open angle glaucoma patients.

PURPOSE: To compare optic nerve head (ONH) parameters obtained by semi-automated disc analysis of stereo optic-disc photography (ODP) with those by spectral domain optical coherence tomography (SD-OCT) regarding their reproducibility, agreement and relationship with the retinal nerve fiber layer (RNFL) thickness. PATIENTS AND METHODS: In this cross-sectional retrospective study, 91 eyes (50 normal and 41 with open angle glaucoma) from 47 patients were examined. ONH parameters were obtained by ODP and SD-OCT. Agreement and reproducibility were assessed by intra-class correlation coefficients (ICCs). Inter-device agreement and precision were also evaluated. The structural factors related to the ONH measurements by both instruments and the disparity between the measurements were evaluated by the generalized estimating equation model. RESULTS: ODP showed good intra-reader and inter-reader reproducibility, comparable to that of SD-OCT (ICC: >0.970). Disc area (DA) (ICC: 0.950) showed better inter-device agreement than rim area (RA) (ICC: 0.859). RNFL thickness was correlated with RA, but not with DA, for both devices. SD-OCT RA showed significant correlation with RNFL thickness in both the normal and glaucoma groups, whereas ODP RA correlated with RNFL only in the glaucoma group. The measurement disparity between the devices was influenced by the DA in both groups. The inter-device difference in RA was not correlated with RA, but instead with the RNFL thickness in the glaucoma group. CONCLUSION: ONH parameters obtained by semi-automated algorithms of ODP showed excellent reproducibility and good agreement with those measured by SD-OCT. SD-OCT RA was a better indicator of RNFL thickness, compared with ODP RA for both normal patients and glaucoma patients; however, the inter-device disparity of the RA was less in glaucoma patients who had a thinner RNFL.

Relationship between ocular pulse amplitude and glaucomatous central visual field defect in normal-tension glaucoma.

PURPOSE: To investigate the relationship between central visual field (VF) defects and ocular pulse amplitude (OPA) in early normal-tension glaucoma (NTG). PATIENTS AND METHODS: This retrospective study included 100 eyes of 100 subjects: 54 NTG patients whose mean deviations were better than -7.00 dB and 46 normal subjects. OPA was measured by dynamic contour tonometry. NTG patients were divided into 2 subgroups according to VF tests: the central VF-invading and the central VF-sparing groups. Ocular parameters including OPA, intraocular pressure (IOP), and indices of VF tests were analyzed in glaucoma patients and normal subjects. RESULTS: There was no difference in the OPA between the NTG and normal groups. However, IOP and OPA of the central VF-invading group (14.4 ± 2.87 and 2.9 ± 0.78 mm Hg) were higher than those of the central VF-sparing group (12.7 ± 2.52 and 2.0 ± 0.80 mm Hg; P = 0.025 and P < 0.001, respectively). OPA, but not IOP, showed a positive correlation with the VF test indices that represented central field defects (r = 0.494, P < 0.001). CONCLUSIONS: Increased OPA was related to more centrally located VF defects in NTG patients with mild VF defects.

Induction of apoptosis by the severe acute respiratory syndrome coronavirus 7a protein is dependent on its interaction with the Bcl-XL protein.

The severe acute respiratory syndrome coronavirus (SARS-CoV) 7a protein, which is not expressed by other known coronaviruses, can induce apoptosis in various cell lines. In this study, we show that the overexpression of Bcl-XL, a prosurvival member of the Bcl-2 family, blocks 7a-induced apoptosis, suggesting that the mechanism for apoptosis induction by 7a is at the level of or upstream from the Bcl-2 family. Coimmunoprecipitation experiments showed that 7a interacts with Bcl-XL and other prosurvival proteins (Bcl-2, Bcl-w, Mcl-1, and A1) but not with the proapoptotic proteins (Bax, Bak, Bad, and Bid). A good correlation between the abilities of 7a deletion mutants to induce apoptosis and to interact with Bcl-XL was observed, suggesting that 7a triggers apoptosis by interfering directly with the prosurvival function of Bcl-XL. Interestingly, amino acids 224 and 225 within the C-terminal transmembrane domain of Bcl-XL are essential for the interaction with the 7a protein, although the BH3 domain of Bcl-XL also contributes to this interaction. In addition, fractionation experiments showed that 7a colocalized with Bcl-XL at the endoplasmic reticulum as well as the mitochondria, suggesting that they may form complexes in different membranous compartments.