Online Information About the Effectiveness of Shoulder Surgery Is Not Based on the Best Available Evidence: A Content Analysis.

OBJECTIVE: To summarize the proportion of consumer webpages on subacromial decompression and rotator cuff repair surgery that make an accurate portrayal of the evidence for these operations (primary outcome), mention the benefits and harms of surgery, outline alternatives to surgery, and make various surgical recommendations. DESIGN: Content analysis. SETTING: Online consumer information about subacromial decompression and rotator cuff repair surgery. Webpages were identified through (1) Google searches using terms synonymous with "shoulder pain" and "shoulder surgery" and searching "orthopedic surgeon" linked to each Australian capital city and (2) websites of relevant professional associations (eg, Australian Orthopaedic Association). Two reviewers independently identified webpages and extracted data. PARTICIPANTS: Not applicable. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Whether the webpage made an accurate portrayal of the evidence for subacromial decompression or rotator cuff repair surgery (primary outcome), mentioned benefits and harms of surgery, outlined alternatives to surgery, and made various surgical recommendations (eg, delay surgery). Outcome data were summarized using counts and percentages. RESULTS: A total of 155 webpages were analyzed (n=89 on subacromial decompression, n=90 on rotator cuff repair, n=24 on both). Only 18% (n=16) and 4% (n=4) of webpages made an accurate portrayal of the evidence for subacromial decompression and rotator cuff repair surgery, respectively. For subacromial decompression and rotator cuff repair, respectively, 85% (n=76) and 80% (n=72) of webpages mentioned benefits, 38% (n=34) and 47% (n=42) mentioned harms, 94% (n=84) and 92% (n=83) provided alternatives to surgery, and 63% (n=56) and 62% (n=56) recommended delayed surgery (the most common recommendation). CONCLUSIONS: Most online information about subacromial decompression and rotator cuff repair surgery does not accurately portray the best available evidence for surgery and may be inadequate to inform patient decision making.

Contact Transscleral Cyclodiode Laser Treatment for Refractory Glaucoma After Penetrating Keratoplasty: Retrospective Long-term Outcomes.

PRéCIS:: This is a retrospective study with long-term follow-up using transscleral cyclodiode laser photocoagulation (TCP) with low complication rate and good graft survival and intraocular pressure (IOP) control. Selective 180-degree TCP may offer a good IOP control with reduced complication rates. PURPOSE: To study the long-term safety and efficacy of contact TCP in eyes with refractory glaucoma after penetrating keratoplasty (PKP). PATIENTS AND METHODS: All consecutive patients who were treated with TCP for refractory glaucoma following PKP between March 1996 and February 2017 in a tertiary corneal transplantation service in the United Kingdom. Only patients with a follow-up of 5 years were included. Eligible patients were identified through the corneal transplantation service database. Medical records and database data were retrospectively analyzed and compared at 5 years from baseline. RESULTS: In total, 28 eyes of 28 patients presented with a mean IOP of 30.4 mm Hg (SD, 7.5) at baseline despite maximally tolerated topical and systemic antiglaucoma medications. IOP was reduced significantly to 12.8 mm Hg (SD, 3.6) (P<0.0001) at 5 years with 100% of patients with a successfully controlled IOP (defined as ≤21 mm Hg). All patients had a clear graft at the beginning of the study period and at 5 years 60.7% (n=17) still presented clear grafts. The average number of topical glaucoma medication was reduced from 2.8 (SD, 0.8) to 1.7 (SD, 1.2) (P=0.019) at 5 years. Visual acuity remained stable in 67.9% of patients at 5-year endpoint. No complications (ie, hypotony or phthisis bulbi) were reported during the study period and the corneal graft failure rate remained low at 5 years (39.3%). CONCLUSIONS: Cyclodiode laser treatment with initial selective 180-degree protocol seems to be an efficient therapeutic option in the management of patients with refractory glaucoma post-PKP when compared with other surgical alternatives. A selective 180-degree protocol seems to potentially reduce the rate of complications. Further randomized controlled studies are needed to compare outcomes with modified treatment's protocols and glaucoma drainage device.

The Orotomide Olorofim Is Efficacious in an Experimental Model of Central Nervous System Coccidioidomycosis.

Olorofim (formerly F901318) is an advanced analog of the orotomide class that inhibits fungal pyrimidine biosynthesis. We evaluated the in vitro and in vivo activities of olorofim against Coccidioides species. In vitro activity was assessed against 59 clinical Coccidioides isolates. Central nervous system infections were established in mice via intracranial inoculation with Coccidioides immitis arthroconidia. Oral therapy began 48 h postinoculation and consisted of vehicle control, olorofim daily doses of 20 mg/kg (6.67 mg/kg three times daily or 10 mg/kg twice daily) or 40 mg/kg (13.3 mg/kg three times daily or 20 mg/kg twice daily), or fluconazole (25 mg/kg twice daily). Treatment continued for 7 and 14 days in the fungal burden and survival arms, respectively. Fungal burdens were assessed by CFU counts in brains. Olorofim demonstrated potent in vitro activity (MIC range, ≤0.008 to 0.06 µg/ml). Survival was significantly enhanced in mice treated with olorofim. Reductions in brain tissue fungal burdens were also observed on day 9 in the olorofim-treated groups. Improvements in survival and reductions in fungal burdens also occurred with fluconazole. More frequent dosing of olorofim was associated with enhanced survival and greater reductions in fungal burdens. In the group treated with 13.3 mg/kg olorofim three times daily, fungal burdens remained low on day 30 (15 days after treatment was stopped), with undetectable levels in 7 of 10 mice. In contrast, fungal burdens rebounded in all other groups after therapy stopped. Olorofim was highly active in vitro and in vivo against Coccidioides These results demonstrate that olorofim may have a role in the treatment of coccidioidomycosis.

In vitro activity of the novel antifungal compound F901318 against Australian Scedosporium and Lomentospora fungi.

We determined the in vitro activity of the novel orotomide antifungal, F901318, against 30 Lomentospora prolificans, 20 Scedosporium apiospermum, 7 S. aurantiacum, and 3 S. boydii, isolates in comparison with standard antifungals. Against L. prolificans, F901318 was the most potent compound (MIC90 0.25 µg/ml); the geometric mean MIC (0.26 µg/ml) was significantly lower (23-80-fold) than those of itraconazole, voriconazole, posaconazole, and isavuconazole (all P < .001), and amphotericin B (P < .05). F901318 also had good activity against S. apiospermum, S. aurantiacum, and S. boydii, comparable to that of voriconazole and posaconazole but was more active than isavuconazole for all three species.

Pharmacodynamics of the Orotomides against Aspergillus fumigatus: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease.

F901318 is an antifungal agent with a novel mechanism of action and potent activity against Aspergillus spp. An understanding of the pharmacodynamics (PD) of F901318 is required for selection of effective regimens for study in phase II and III clinical trials. Neutropenic murine and rabbit models of invasive pulmonary aspergillosis were used. The primary PD endpoint was serum galactomannan. The relationships between drug exposure and the impacts of dose fractionation on galactomannan, survival, and histopathology were determined. The results were benchmarked against a clinically relevant exposure of posaconazole. In the murine model, administration of a total daily dose of 24 mg/kg of body weight produced consistently better responses with increasingly fractionated regimens. The ratio of the minimum total plasma concentration/MIC (Cmin/MIC) was the PD index that best linked drug exposure with observed effect. An average Cmin (mg/liter) and Cmin/MIC of 0.3 and 9.1, respectively, resulted in antifungal effects equivalent to the effect of posaconazole at the upper boundary of its expected human exposures. This pattern was confirmed in a rabbit model, where Cmin and Cmin/MIC targets of 0.1 and 3.3, respectively, produced effects previously reported for expected human exposures of isavuconazole. These targets were independent of triazole susceptibility. The pattern of maximal effect evident with these drug exposure targets was also apparent when survival and histopathological clearance were used as study endpoints. F901318 exhibits time-dependent antifungal activity. The PD targets can now be used to select regimens for phase II and III clinical trials.IMPORTANCE Invasive fungal infections are common and often lethal. There are relatively few antifungal agents licensed for clinical use. Antifungal drug toxicity and the emergence of drug resistance make the treatment of these infections very challenging. F901318 is the first in a new class of antifungal agents called the orotomides. This class has a novel mechanism of action that involves the inhibition of the fungal enzyme dihydroorotate dehydrogenase. F901318 is being developed for clinical use. A deep understanding of the relationship between dosages, drug concentrations in the body, and the antifungal effect is fundamental to the identification of the regimens to administer to patients with invasive fungal infections. This study provides the necessary information to ensure that the right dose of F901318 is used the first time. Such an approach considerably reduces the risks in drug development programs and ensures that patients with few therapeutic options can receive potentially life-saving antifungal therapy at the earliest opportunity.

Dihydroorotate dehydrogenase inhibitor F901318 has potent in vitro activity against Scedosporium species and Lomentospora prolificans.

Background: Scedosporium species and Lomentospora prolificans are increasing causes of invasive infections in immunocompromised hosts and many isolates are resistant to available antifungals. Our objective was to assess the in vitro potency of F901318, a member of the orotomide class of antifungals, against Scedosporium species and L. prolificans . Methods: The in vitro potency of F901318 was evaluated against 66 Scedosporium and 7 L. prolificans clinical isolates using the CLSI M38-A2 reference standard. Scedosporium species included Scedosporium apiospermum ( n = 43), Scedosporium aurantiacum ( n = 6), Scedosporium dehoogii ( n = 2) and Scedosporium boydii ( n = 15). Positive comparators included amphotericin B, caspofungin, posaconazole and voriconazole. Results: Against S. apiospermum and S. boydii F901318 geometric mean MICs/MECs (0.079 and 0.046 mg/L, respectively) were significantly lower than those observed with amphotericin (3.404 and 5.595 mg/L), posaconazole (1.937 and 1.823 mg/L), voriconazole (0.784 and 0.630 mg/L) and caspofungin (5.703 and 7.639 mg/L) ( P < 0.001). Against S. aurantiacum and S. dehoogii the F901318 MIC range (0.12-0.5 mg/L) was also lower than those for the other antifungals (0.5 to >8 mg/L). F901318 also maintained activity against L. prolificans isolates (range 0.12-0.25 mg/L) in contrast to other antifungals, of which none demonstrated in vitro activity. Conclusions: F901318 demonstrated potent in vitro activity against Scedosporium species and L. prolificans . This activity was maintained against isolates that had significantly reduced susceptibility to the other antifungals. Further studies are warranted to evaluate the in vivo efficacy of F901318 against Scedosporium species and L. prolificans .

Evolutionary Stability of Minimal Mutation Rates in an Evo-epidemiological Model.

We consider the evolution of mutation rate in a seasonally forced, deterministic, compartmental epidemiological model with a transmission-virulence trade-off. We model virulence as a quantitative genetic trait in a haploid population and mutation as continuous diffusion in the trait space. There is a mutation rate threshold above which the pathogen cannot invade a wholly susceptible population. The evolutionarily stable (ESS) mutation rate is the one which drives the lowest average density, over the course of one forcing period, of susceptible individuals at steady state. In contrast with earlier eco-evolutionary models in which higher mutation rates allow for better evolutionary tracking of a dynamic environment, numerical calculations suggest that in our model the minimum average susceptible population, and hence the ESS, is achieved by a pathogen strain with zero mutation. We discuss how this result arises within our model and how the model might be modified to obtain a nonzero optimum.

Efficacy of transscleral diode laser cyclophotocoagulation in patients with good visual acuity.

PURPOSE: To study the effect on central vision of transscleral diode laser cyclophotocoagulation (TSDLC) for the reduction of intraocular pressure (IOP) in patients with visual acuity (VA) better than 6/18. METHODS: Retrospective chart review was conducted of patients undergoing cyclophotocoagulation between 2000 and 2008. Patients who underwent TSDLC with VA of 6/18 or better and at least 24 months follow-up were included. Primary outcome was decrease of 2 or more lines at 24 months. Secondary outcome was IOP control with or without treatment. RESULTS: A total of 46 eyes of 44 patients were included with VA ranging from 6/18 to 6/5 (median VA 6/12). Mean IOP was 24 mm Hg (range 12-35). A mean of 1.3 treatments were given per eye, with 12 eyes (26%) requiring retreatment. At 24 months, the median VA was 6/18 (range light perception-6/5). Eighteen eyes (39.1%) retained the same VA, 35 eyes (76.1%) retained VA of 6/18 or better, in 7 eyes (19.4%) VA was <6/60. Loss of ≥2 lines was recorded in 11 eyes (23.9%), and loss of 1 line in 13 eyes (28.3%). Mean IOP at 24 months was 17.2 mm Hg (range 12-28). Thirty-nine (84.8%) patients had IOP ≤21 mm Hg. CONCLUSIONS: This study suggests a role of TSDLC as an effective, safe, and rapid method of treatment in patients with good vision over a 24-month period. The loss of VA in some patients is similar to previously reported studies in patients having cyclodiode, trabeculectomy, or tube surgery.

The accuracy of continued clinical use of goldmann applanation tonometers with known calibration errors.

OBJECTIVES: With normal clinical use, Goldmann applanation tonometers frequently develop calibration errors. Only the manufacturer can perform recalibration. This study aimed to assess whether intraocular pressure (IOP) measured by Goldmann applanation tonometers with known small calibration errors could be adjusted to reflect true IOP to allow continued clinical use. DESIGN: Evaluation of diagnostic test. PARTICIPANTS: Patients under regular review who had undergone previous applanation tonometry. METHODS: Patients with a range of IOPs underwent IOP measurement using a gold standard 0-error tonometer and tonometers with known calibration errors in a randomized blind fashion. The calibration errors of the tonometers ranged 0 to +5 mmHg. MAIN OUTCOME MEASURES: Intraocular pressure. RESULTS: For the first part of the study, 125 eyes of 125 patients with a mean IOP of 18.5 mmHg (range, 8-43 mmHg) were tested. Mean IOP measured by the tonometer with an error of +1 mmHg was +1.0 (95% confidence interval [CI], 0.3-1.7 mmHg; P = 0.0076, compared with gold standard 0-error), with the +2 mmHg error was +1.2 (95% CI, 0.8-1.7 mmHg; P<0.0001), with the +3 mmHg error was +1.6 (95% CI, 1.2-1.9 mmHg; P<0.0001), with the +4 mmHg error was +3.6 (95% CI, 2.9-4.2 mmHg; P<0.0001), and with the +5 mmHg error was +3.3 (95% CI, 2.9-3.8 mmHg; P<0.0001). In the second part of the study, IOP measured by each of the tonometers with +2 mmHg error was +0.6 mmHg (95% CI, 0.1-1.1 mmHg; P = 0.0241), +1.5 mmHg (95% CI, 1.0-2.0 mmHg; P<0.0001), and +1.5 mmHg (95% CI, 1.9-2.1 mmHg; P<0.0001). CONCLUSIONS: There is a relationship between calibration error and clinical error in IOP measured, but it is not a one-to-one relationship. The error overestimates IOP and is consistent over a clinical range of IOPs. In certain circumstances where resources are limited, it may be clinically acceptable to use tonometers with calibration errors of less than +3 mmHg, because they do not overestimate IOP by more than 2 mmHg. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Deafness alters auditory nerve fibre responses to cochlear implant stimulation.

Here we characterized the relationship between duration of sensorineural hearing loss and the response of the auditory nerve to electrical stimulus rate. Electrophysiological recordings were made from undeafened guinea pigs and those ototoxically deafened for either 5 weeks or 6 months. Auditory neuron survival decreased significantly with the duration of deafness. Extracellular recordings were made from auditory nerve fibres responding to biphasic, charge-balanced current pulses delivered at rates of 20 and 200 pulses/s via a monopolar scala tympani stimulating electrode. The response to 20 pulses/s electrical stimulation of the deafened cochlea exhibited a decrease in spike latency, unaltered temporal jitter and unaltered dynamic range (of nerve firing rate against stimulus current), and a reduction in threshold after 6 months of deafness. The response to a 200-pulse/s stimulus was similar except that the dynamic range was greater than with 20 pulses/s and was also greater in deafened animals than in undeafened animals. Deafness and pulse rate are related; in deaf animals spike recovery appears to be complete between successive stimulus pulses at a low rate (20 pulses/s), but incomplete between pulses at a moderate pulse rate (200 pulses/s). These results suggest that changes in the function of individual auditory nerve fibres after deafness may affect clinical responses during high-rate stimulation such as that used in contemporary speech processing strategies, but not during lower rate stimulation such as that used to record evoked potentials.

Scleral perforation after trans-scleral cyclodiode laser for intraocular pressure reduction.

Herein a case is reported of a full-thickness scleral burn in the left eye of a 61-year-old man, following contact trans-scleral cyclodiode laser treatment for traumatic aphakic glaucoma, unresponsive to maximal medical treatment. The defect was successfully repaired by scleral suturing under local anaesthetic.

Short-term effects of focal argon laser treatment in diabetic maculopathy as demonstrated by optical coherence tomography.

PURPOSE: To assess the short-term effects of argon laser on retinal thickening as demonstrated by optical coherence tomography (OCT). METHODS: A prospectively collected consecutive series of patients undergoing routine focal argon laser treatment for sight-threatening diabetic maculopathy had bilateral OCT performed before laser treatment and 1 hour, 24 hours, and 2 weeks after treatment. The main outcome measure was change in retinal thickness in the region of laser treatment. RESULTS: Forty-six eyes were analyzed. There was a small increase in retinal thickness in the treated area 1 hour after laser treatment, with a mean change from before laser treatment of +2.6 microm (95% confidence interval [CI], +0.2 to + 5.0). However, there was a larger change 24 hours after treatment of +39.0 microm (95% CI, +31.6 to + 46.4) and a significant decrease 2 weeks after treatment of -14.6 microm (95% CI, -21.6 to -7.7) from before laser treatment values. CONCLUSION: Focal argon laser treatment remains the first-line treatment for sight-threatening diabetic maculopathy. This study shows that in the short-term, areas of retinal thickening worsen before settling in response to argon laser treatment as demonstrated by OCT.

Frequency of goldmann applanation tonometer calibration error checks.

PURPOSE: To investigate how quickly Goldmann applanation tonometers used in clinical practice develop calibration errors, and to determine the frequency of checks required to detect these errors. MATERIALS AND METHODS: Prospective check of the calibration error of all Haag-Streit Goldmann applanation tonometers in the department at month zero, month one, and month four. The tonometers were checked according to the Haag-Streit method using a standard calibration check weight bar by two independent observers. Calibration errors were classed as +/-0.5 to 2.5 mm Hg, +/-3 to 4 mm Hg, or >+/-4 mm Hg. Tonometers with a calibration error greater than +/-2.5 mm Hg were returned to the manufacturer for re-calibration. RESULTS: At month zero 2 of 34 (5.9%), at month one 3 of 29 (10.3%), and at month four 0 of 33 (0.0%) tonometers fell within the manufacturer's recommended calibration range of +/-0.5 mm Hg. A total of 14 of 34 (41.2%) tonometers at month zero, 10 of 29 (34.5%) tonometers at month one, and 17 of 33 (51.5%) tonometers at month four were identified to have calibration errors greater than +/-2.5 mm Hg. CONCLUSIONS: Goldmann applanation tonometers are not as accurate as the manufacturer's recommended calibration error tolerance of +/-0.5 mm Hg would suggest. Calibration error of less than +/-2.5 mm Hg is clinically acceptable. Calibration error checks should be carried out once monthly and tonometers with calibration error greater than +/-2.5 mm Hg returned to the manufacturer for re-calibration. Additional checks should be made if tonometers suffer specific damage. Ideally individual ophthalmologists should check calibration before each session.

A polymorphism at codon 31 of gene p21 is not associated with primary open angle glaucoma in Caucasians.

BACKGROUND: Primary open angle glaucoma (POAG) is considered to be a neurodegenerative optic neuropathy, in which cell death occurs by apoptosis. p21, is an important protective component of the apoptotic pathway, regulating cellular arrest in the presence of DNA damage. An unstable or altered p21 protein could modify the cellular response to genomic injury and abolish the effect of p21. A previous study on a Chinese cohort suggested that the p21 codon 31 polymorphism may alter the state of apoptosis in glaucomatous optic neuropathy, failing to protect the ganglion cells. The aim of this study was to test the hypothesis that a p21 codon 31 polymorphism is associated with POAG on a Caucasian cohort. METHODS: 140 POAG patients and a control group of 73 healthy individuals were included in the study. All the subjects were of Caucasian origin. Genomic DNA was amplified by polymerase chain reaction, followed by enzymatic restriction fragment length polymorphism technique (PCR-RFLP). Patients and controls were genotyped for a single nucleotide polymorphism (C/A transversion) in the third base of codon 31 of p21, which leads to a serine (Ser)/arginine (Arg) substitution. RESULTS: The distribution of the genotypes in the POAG patients showed 128 (91.4%) Ser homozygotes, 10 (7.1%) Ser/Arg heterozygotes and 2 (1.5%) Arg homozygotes. In the control cohort, there were 61 (83.6%) Ser homozygotes and 12 (16.4%) Ser/Arg heterozygotes. No Arg homozygotes were present amongst the control group. Both the allelic and genotypic frequencies of the Ser or Arg residues at codon 31 were not significantly different between POAG patients and controls (Fisher's exact test, P = 0.20 for alleles and P = 0.0561 for genotypes). CONCLUSION: This study suggests that the p21 codon 31 polymorphism does not contribute to the risk of POAG in the Caucasian population.

Apolipoprotein E promoter polymorphisms do not have a major influence on the risk of developing primary open angle glaucoma.

PURPOSE: Primary open angle glaucoma (POAG) is a major cause of late onset visual failure of unknown etiology. Recent genetic association studies have implicated the apolipoprotein E (APOE) gene in the pathophysiology of primary open angle glaucoma, but there have been conflicting findings. METHODS: To resolve this issue we studied 140 cases and 73 controls that were carefully phenotyped, and used a logistic regression model to simultaneously analyze the effect of apolipoprotein E genotype and functional polymorphisms in the apolipoprotein E gene promoter while controlling for potentially confounding variables. RESULTS: We found no evidence of an association between the apolipoprotein E promoter region polymorphisms and primary open angle glaucoma. CONCLUSIONS: Apolipoprotein E promoter polymorphisms are unlikely to have a major impact on the pathophysiology of primary open angle glaucoma.

The role of apolipoprotein E gene polymorphisms in primary open-angle glaucoma.

OBJECTIVE: To test the hypothesis that genetic polymorphisms of the apolipoprotein E (APOE) gene are associated with primary open-angle glaucoma (POAG), based on the association between neurodegenerative diseases and the APOE genotype. METHODS: Genomic DNA was examined from an unrelated cohort of 137 POAG patients and 75 control subjects from the ophthalmology department of the Royal Victoria Infirmary. The APOE allele frequency (epsilon2, epsilon3, and epsilon4 alleles) was studied by polymerase chain reaction amplification of the related locus (19q13.2), enzymatic digestion of the products, gel electrophoresis, and imaging under UV illumination. For statistical analysis, we used a logistic regression model that included intraocular pressure as a continuous variable to study the possible correlation between POAG and APOE allele frequency. RESULTS: Logistic regression analysis showed no statistically significant association between the frequency of the APOE allele and POAG for the population studied, irrespective of the IOP (epsilon2 odds ratio, 0.82; 95% confidence interval, 0.12-5.79 [P =.84]; epsilon3 odds ratio, 0.39; 95% confidence interval, 0.10-1.49 [P =.17]; and epsilon4 odds ratio, 3.84; 95% confidence interval, 0.80-18.49 [P =.09]). CONCLUSION: In our cohort, the APOE genotype does not constitute a risk factor for developing POAG, even in patients with normal-tension glaucoma.Clinical Relevance Apolipoprotein E polymorphisms do not appear to be contributory to POAG.