Rosacea Core Domain Set for Clinical Trials and Practice: A Consensus Statement.

Importance: Inconsistent reporting of outcomes in clinical trials of rosacea is impeding and likely preventing accurate data pooling and meta-analyses. There is a need for standardization of outcomes assessed during intervention trials of rosacea. Objective: To develop a rosacea core outcome set (COS) based on key domains that are globally relevant and applicable to all demographic groups to be used as a minimum list of outcomes for reporting by rosacea clinical trials, and when appropriate, in clinical practice. Evidence Review: A systematic literature review of rosacea clinical trials was conducted. Discrete outcomes were extracted and augmented through discussions and focus groups with key stakeholders. The initial list of 192 outcomes was refined to identify 50 unique outcomes that were rated through the Delphi process Round 1 by 88 panelists (63 physicians from 17 countries and 25 patients with rosacea in the US) on 9-point Likert scale. Based on feedback, an additional 11 outcomes were added in Round 2. Outcomes deemed to be critical for inclusion (rated 7-9 by ≥70% of both groups) were discussed in consensus meetings. The outcomes deemed to be most important for inclusion by at least 85% of the participants were incorporated into the final core domain set. Findings: The Delphi process and consensus-building meetings identified a final core set of 8 domains for rosacea clinical trials: ocular signs and symptoms; skin signs of disease; skin symptoms; overall severity; patient satisfaction; quality of life; degree of improvement; and presence and severity of treatment-related adverse events. Recommendations were also made for application in the clinical setting. Conclusions and Relevance: This core domain set for rosacea research is now available; its adoption by researchers may improve the usefulness of future trials of rosacea therapies by enabling meta-analyses and other comparisons across studies. This core domain set may also be useful in clinical practice.

Can paediatric surgical registrars safely perform supervised hypospadias surgery?

INTRODUCTION: Hypospadias repair is regarded as a technically demanding, complex procedure, with variable outcomes. Therefore, it tends to be performed by consultants, with limited trainee involvement. We aimed to study the clinical outcomes of supervised registrars performing proximal and distal hypospadias repairs, compared to their consultant mentors. METHODS: We undertook a retrospective review of all primary hypospadias repairs performed between April 2013-April 2022 at our tertiary paediatric urology centre. Redo repairs and patients lost to follow-up were excluded. Pre-operative anatomy, theatre time, grade of primary surgeon (registrar (trainees and non-training middle grades) or consultant), operative technique, follow-up duration, complications, and reoperation rates were recorded. The procedures were assessed in two groups according to the primary operator: registrar or consultant. The Zwisch scale is used to describe level of consultant support. Registrars as primary operators received "passive help" or "supervision" (Zwisch levels 3/4). Consultants as primary operators provided registrars with "show-and-tell" or "active help" (Zwisch levels 1/2). RESULTS: 270 procedures performed on 228 patients met the inclusion criteria. 109 were performed by registrars and 161 by consultants. In both groups, median age was two years (p = 0.23). Median theatre time was similar (registrars 2.8 h vs. consultants 2.7 h, p = 0.88), as was median follow-up (registrars 25months, vs. consultants 21months, p = 0.99). Operations performed by registrars were 76% distal and 24% proximal; and by consultants were 62% distal and 38% proximal. The overall urethroplasty complication rate was similar, at 24% for registrars and 23% for consultants (p = 0.89). The summary table shows the distribution of different complications. Re-operation rate was 16% in both groups (p = 0.99). Complications were further assessed according to operation type (TIP vs. two-stage repair). DISCUSSION: Contrary to popular belief amongst hypospadiologists, we found complication rates were similar for registrar and consultant surgeons. We question that involvement of registrars increases complications. The literature demonstrates safety of trainee performance of limited steps of the procedure. However our institution permits registrars to perform up to the whole hypospadias repair under direct supervision, with no predefined limit to their involvement. CONCLUSION: Paediatric surgical registrars can be safely supervised to have substantial involvement in proximal and distal hypospadias repair, without compromising the duration or outcomes of surgery. We hope that allowing more registrar involvement can lead to faster acquisition of surgical skills, whilst remaining under the safety of senior supervision. Increasing opportunities for those with an aptitude for hypospadias repair can equip them with skills and confidence for entering fellowship training.

Viral infections and pathogenesis of glaucoma: a comprehensive review.

Glaucoma is a leading cause of irreversible blindness worldwide, caused by the gradual degeneration of retinal ganglion cells and their axons. While glaucoma is primarily considered a genetic and age-related disease, some inflammatory conditions, such as uveitis and viral-induced anterior segment inflammation, cause secondary or uveitic glaucoma. Viruses are predominant ocular pathogens and can impose both acute and chronic pathological insults to the human eye. Many viruses, including herpes simplex virus, varicella-zoster virus, cytomegalovirus, rubella virus, dengue virus, chikungunya virus, Ebola virus, and, more recently, Zika virus (ZIKV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), have been associated with sequela of either primary or secondary glaucoma. Epidemiological and clinical studies suggest the association between these viruses and subsequent glaucoma development. Despite this, the ocular manifestation and sequela of viral infections are not well understood. In fact, the association of viruses with glaucoma is considered relatively uncommon in part due to underreporting and/or lack of long-term follow-up studies. In recent years, literature on the pathological spectrum of emerging viral infections, such as ZIKV and SARS-CoV-2, has strengthened this proposition and renewed research activity in this area. Clinical studies from endemic regions as well as laboratory and preclinical investigations demonstrate a strong link between an infectious trigger and development of glaucomatous pathology. In this article, we review the current understanding of the field with a particular focus on viruses and their association with the pathogenesis of glaucoma.

Trifarotene Reduces Risk for Atrophic Acne Scars: Results from A Phase 4 Controlled Study.

BACKGROUND: Atrophic acne scarring often accompanies acne vulgaris. The efficacy of topical retinoids for treatment of acne is well documented; however, evidence for use in atrophic acne scars is limited. METHODS: In this randomized, split-face, double-blind study, subjects (age: 17-34 years, N = 121) with moderate-to-severe facial acne, with acne scars present, were treated with either trifarotene 50 µg/g or vehicle once daily for 24 weeks. Efficacy was assessed by absolute and percent change from baseline in atrophic acne scar counts, Scar Global assessment (SGA), and IGA success rates as well as acne lesion counts. RESULTS: At week 24, a statistically significantly greater reduction in the mean absolute change from baseline in the total atrophic scar count was noted in the trifarotene- vs vehicle-treated area (- 5.9 vs - 2.7; p < 0.0001) with differences between sides noted as early as week 2 (- 1.5 vs - 0.7; p = 0.0072). The SGA success rate was higher in the trifarotene side at week 12 (14.9% vs 5.0%, P < 0.05) and improved through week 24 (31.3% vs 8.1%, P < 0.001). Similarly, at week 24, the IGA success rate was higher with trifarotene (63.6% vs 31.3%, P < 0.0001) along with reductions in total (70% vs 45%) and inflammatory (76% vs 48%) lesion counts. The incidence of treatment-emergent adverse events was 5.8% (trifarotene) and 2.5% (vehicle); most common (> 1%) was skin tightness (1.7% vs 0.8%), and all events were mild to moderate in severity. CONCLUSIONS: Trifarotene was effective and well tolerated in treating moderate-to-severe facial acne and reducing atrophic acne scars, with reduction of total atrophic scar count as early as week 2. TRIAL REGISTRATION: Clinicaltrials.gov NCT04856904.

Digital health competencies for the next generation of physicians.

As health care continues to change and evolve in a digital society, there is an escalating need for physicians who are skilled and enabled to deliver care using digital health technologies, while remaining able to successfully broker the triadic relationship among patients, computers and themselves. The focus needs to remain firmly on how technology can be leveraged and used to support good medical practice and quality health care, particularly around resolution of longstanding challenges in health care delivery, including equitable access in rural and remote areas, closing the gap on health outcomes and experiences for First Nations peoples and better support in aged care and those living with chronic disease and disability. We propose a set of requisite digital health competencies and recommend that the acquisition and evaluation of these competencies become embedded in physician training curricula and continuing professional development programmes.

Mule deer fawn recruitment dynamics in an energy disturbed landscape.

Wildlife population dynamics are modulated by abiotic and biotic factors, typically climate, resource availability, density-dependent effects, and predator-prey interactions. Understanding whether and how human-caused disturbances shape these ecological processes is helpful for the conservation and management of wildlife and their habitats within increasingly human-dominated landscapes. However, many jurisdictions lack either long-term longitudinal data on wildlife populations or measures of the interplay between human-mediated disturbance, climate, and predator density. Here, we use a 50-year time series (1962-2012) on mule deer (Odocoileus hemionus) demographics, seasonal weather, predator density, and oil and gas development patterns from the North Dakota Badlands, USA, to investigate long-term effects of landscape-level disturbance on mule deer fawn fall recruitment, which has declined precipitously over the last number of decades. Mule deer fawn fall recruitment in this study represents the number of fawns per female (fawn:female ratio) that survive through the summer to October. We used this fawn recruitment index to evaluate the composite effects of interannual extreme weather conditions, energy development, and predator density. We found that density-dependent effects and harsh seasonal weather were the main drivers of fawn fall recruitment in the North Dakota Badlands. These effects were further shaped by the interaction between harsh seasonal weather and predator density (i.e., lower fawn fall recruitment when harsh weather was combined with higher predator density). Additionally, we found that fawn fall recruitment was modulated by interactions between seasonal weather and energy development (i.e., lower fawn fall recruitment when harsh weather was combined with higher density of active oil and gas wells). Interestingly, we found that the combined effect of predator density and energy development was not interactive but rather additive. Our analysis demonstrates how energy development may modulate fluctuations in mule deer fawn fall recruitment concurrent with biotic (density-dependency, habitat, predation, woody vegetation encroachment) and abiotic (harsh seasonal weather) drivers. Density-dependent patterns emerge, presumably due to limited quality habitat, being the primary factor influencing fall fawn recruitment in mule deer. Secondarily, stochastic weather events periodically cause dramatic declines in recruitment. And finally, the additive effects of human disturbance and predation can induce fluctuations in fawn fall recruitment. Here we make the case for using long-term datasets for setting long-term wildlife management goals that decision makers and the public can understand and support.

Spherical Aberration of Cataractous Eyes and Its Relationship With Age, Ocular Biometry, and Various IOL Platforms.

PURPOSE: To determine the median spherical aberration (SA) of the cataractous population, how it relates to biometry, and the theoretical effect of different intraocular lens (IOL) platforms. METHODS: A retrospective chart review of patients undergoing cataract surgery evaluation with a high quality Pentacam (Oculus Optikgeräte GmbH) were included. Age, gender, Q-value, mean total SA, higher order aberration root mean square wavefront error, and equivalent keratometry were collected from the Holladay report and axial length and anterior chamber depth (ACD) from the IOLMaster 700 (Carl Zeiss Meditec AG). RESULTS: Data from 1,725 eyes of 999 patients were collected. SA had a median of 0.37 µm (95% confidence interval: 0.36 to 0.38. Age (r = .136, P < .001), Q-factor (r = .743, P < .001), and higher order aberration root mean square wavefront error (r = .307, P < .001) were positively correlated with SA. Average equivalent keratometry (r = -.310, P < .001) was negatively correlated with SA. Axial length (r = -0.037, P = .120) and ACD (r = .004, P = .856) had no association with SA. Up to 1,499 (86.9%) theoretically had SA moved closer to zero with IOLs that had negative SA. Up to 102 (5.9%) had SA theoretically worsened. CONCLUSIONS: SA is not normally distributed, suggesting that there may be no "average" SA that IOLs should aim to correct. Patients might benefit from tailoring IOL choice to individual SA. Without access to SA data, eyes with steeper average keratometry or younger patients may have less SA, which could influence IOL choice. [J Refract Surg. 2023;39(2):89-94.].

Australian children living with rare diseases: health service use and barriers to accessing care.

BACKGROUND: Children with rare diseases experience challenges at home and school and frequently require multi-disciplinary healthcare. We aimed to determine health service utilization by Australian children with rare diseases and barriers to accessing healthcare. METHODS: Parents completed an online survey on health professional and emergency department (ED) presentations, hospitalization, and barriers to accessing services. Potential barriers to service access included residential location (city, regional, remote) and child health-related functioning, determined using a validated, parent-completed measure-of-function tool. RESULTS: Parents of 462 children with over 240 rare diseases completed the survey. Compared with the general population, these children were more likely to be hospitalized [odds ratio (OR) = 17.25, 95% confidence interval (CI) = 15.50-19.20] and present to the ED (OR = 4.15, 95% CI = 3.68-4.68) or a family physician (OR = 4.14, 95% CI = 3.72-4.60). Child functional impairment was nil/mild (31%), moderate (48%) or severe (22%). Compared to children with nil/mild impairment, those with severe impairment were more likely to be hospitalized (OR = 13.39, 95% CI = 7.65-23.44) and present to the ED (OR = 11.16, 95% CI = 6.46-19.27). Most children (75%) lived in major cities, but children from regional (OR = 2.78, 95% CI = 1.72-4.55) and remote areas (OR = 9.09, 95% CI = 3.03-25.00) experienced significantly more barriers to healthcare access than children from major cities. Barriers included distance to travel, out-of-pocket costs, and lack of specialist medical and other health services. CONCLUSIONS: Children with rare diseases, especially those with severe functional impairment have an enormous impact on health services, and better integrated multidisciplinary services with patient-centered care are needed. Access must be improved for children living in rural and remote settings.

Risk Factors for Nephrotoxicity in Methicillin-Resistant Staphylococcus aureus Bacteraemia: A Post Hoc Analysis of the CAMERA2 Trial.

BACKGROUND: Clinical risk factors for nephrotoxicity in Staphylococcus aureus bacteraemia remain largely undetermined, despite its common occurrence and clinical significance. In an international, multicentre, prospective clinical trial (CAMERA2), which compared standard therapy (vancomycin monotherapy) to combination therapy (adding an anti-staphylococcal beta-lactam) for methicillin-resistant S. aureus bacteraemia, significantly more people in the combination therapy arm experienced acute kidney injury compared with those in the monotherapy arm (23% vs 6%). OBJECTIVE: The aim of this post hoc analysis was to explore in greater depth the risk factors for acute kidney injury from the CAMERA2 trial. METHODS: Among participants of the CAMERA2 trial, demographic-related, infection-related and treatment-related risk factors were assessed for their relationship with acute kidney injury by univariable and multivariable logistic regression. Acute kidney injury was defined by a modified-KDIGO (Kidney Disease: Improving Global Outcomes) criteria (not including urinary output). RESULTS: Of the 266 participants included, age (p = 0.04), randomisation to combination therapy (p = 0.002), vancomycin area under the concentration-time curve (p = 0.03) and receipt of (flu)cloxacillin as the companion beta-lactam (p < 0.001) were significantly associated with acute kidney injury. On a multivariable analysis, concurrent use of (flu)cloxacillin increased the risk of acute kidney injury over four times compared with the use of cefazolin or no beta-lactam. The association of vancomycin area under the concentration-time curve with acute kidney injury also persisted in the multivariable model. CONCLUSIONS: For participants receiving vancomycin for S. aureus bacteraemia, use of (flu)cloxacillin and increased vancomycin area under the concentration-time curve were risk factors for acute kidney injury. These represent potentially modifiable risk factors for nephrotoxicity and highlight the importance of avoiding the use of concurrent nephrotoxins.

What Can State Medical Boards Do to Effectively Address Serious Ethical Violations?

State Medical Boards (SMBs) can take severe disciplinary actions (e.g., license revocation or suspension) against physicians who commit egregious wrongdoing in order to protect the public. However, there is noteworthy variability in the extent to which SMBs impose severe disciplinary action. In this manuscript, we present and synthesize a subset of 11 recommendations based on findings from our team's larger consensus-building project that identified a list of 56 policies and legal provisions SMBs can use to better protect patients from egregious wrongdoing by physicians.

A Randomized, Controlled Trial of Trifarotene Plus Doxycycline for Severe Acne Vulgaris.

Objective: We evaluated the efficacy and safety of trifarotene plus oral doxycycline in acne. Methods: This was a randomized (2:1 ratio) 12-week, double-blind study of once-daily trifarotene cream 50µg/g plus enteric-coated doxycycline 120mg (T+D) versus trifarotene vehicle and doxycycline placebo (V+P). Patients were aged 12 years or older with severe facial acne (≥20 inflammatory lesions, 30 to 120 non-inflammatory lesions, and ≤4 nodules). Efficacy outcomes included change from baseline in lesion counts and success (score of 0/1 with ≥2 grade improvement) on investigator global assessment (IGA). Safety was assessed by adverse events and local tolerability. Results: The study enrolled 133 subjects in the T+D group and 69 subjects in the V+P group. The population was balanced, with an approximately even ratio of adolescent (12-17 years) and adult (≥18 years) subjects. The absolute change in lesion counts from baseline were: -69.1 T+D versus -48.1 V+P for total lesions, -29.4 T+D versus -19.5 V+P for inflammatory lesions, and -39.5 T+D versus -28.2 for non-inflammatory lesions (P<0.0001 for all). Success was achieved by 31.7 percent of subjects in the T+D group versus 15.8 percent in the V+P group (P=0.0107). The safety and tolerability profiles were comparable between the T+D and V+P arms. Conclusion: T+D was demonstrated to be safe and efficacious as a treatment option for patients with severe acne.

State-wide genomic epidemiology investigations of COVID-19 in healthcare workers in 2020 Victoria, Australia: Qualitative thematic analysis to provide insights for future pandemic preparedness.

Background: COVID-19 has affected many healthcare workers (HCWs) globally. We performed state-wide SARS-CoV-2 genomic epidemiological investigations to identify HCW transmission dynamics and provide recommendations to optimise healthcare system preparedness for future outbreaks. Methods: Genome sequencing was attempted on all COVID-19 cases in Victoria, Australia. We combined genomic and epidemiologic data to investigate the source of HCW infections across multiple healthcare facilities (HCFs) in the state. Phylogenetic analysis and fine-scale hierarchical clustering were performed for the entire dataset including community and healthcare cases. Facilities provided standardised epidemiological data and putative transmission links. Findings: Between March-October 2020, approximately 1,240 HCW COVID-19 infection cases were identified; 765 are included here, requested for hospital investigations. Genomic sequencing was successful for 612 (80%) cases. Thirty-six investigations were undertaken across 12 HCFs. Genomic analysis revealed that multiple introductions of COVID-19 into facilities (31/36) were more common than single introductions (5/36). Major contributors to HCW acquisitions included mobility of staff and patients between wards and facilities, and characteristics and behaviours of patients that generated numerous secondary infections. Key limitations at the HCF level were identified. Interpretation: Genomic epidemiological analyses enhanced understanding of HCW infections, revealing unsuspected clusters and transmission networks. Combined analysis of all HCWs and patients in a HCF should be conducted, supported by high rates of sequencing coverage for all cases in the population. Established systems for integrated genomic epidemiological investigations in healthcare settings will improve HCW safety in future pandemics. Funding: The Victorian Government, the National Health and Medical Research Council Australia, and the Medical Research Future Fund.

Comparison of Locally Sourced Pericardium and Other Conventional Patch Graft Materials in a Glaucoma Drainage Device Surgery.

PURPOSE: Our study aimed to compare the outcomes and costs of various patch graft materials used in the setting of glaucoma drainage device (GDD) surgeries: conventional Tutoplast® pericardium (TP), locally-obtained Lifenet® pericardium (LP), and tissue-banked corneal (CP) and scleral (SP) patches. DESIGN: Retrospective observational study. SUBJECTS: One hundred and ninety-five eyes of 185 patients who underwent glaucoma device surgery with patch grafts were included. MATERIALS AND METHODS: Patient records were reviewed for demographics and surgical data including age at the time of GDD surgery, race, sex, eye, history of diabetes or immunologic disease, glaucoma diagnosis, length of follow-up, pre- and postoperative intraocular pressure (IOP), type and location of GDD, patch type, and tube-related complications. MAIN OUTCOME MEASURES: The primary outcome measures were rates of patch graft-related complications including conjunctival dehiscence with and without tube exposure. Secondary outcome measures were IOP control achieved and cost of patch graft materials. RESULTS: Mean follow-up for all eyes was 17.1 months. Overall, conjunctival dehiscence without tube exposure occurred in four eyes (2.1%); tube exposure was seen in six eyes (3.1%). The mean time to exposure was 3.3 months (range 1-8 months). The rate of tube exposure was 2.3% of eyes with TP grafts, 10.7% of eyes with CP grafts, 2.8% of eyes with SP grafts, and 0% of eyes with LP grafts. There was no significant difference in rates of tube exposure rates by graft material (p = 0.26). Multivariate logistic regression analysis with adjustment for patch type, age, sex, implant type, and location revealed no significant risk factors for tube exposure. Univariate logistic regression was then performed on the same risk factors as well as diabetes, prior and concurrent ocular surgery, and showed no significance. CONCLUSION: Our preliminary, short-term results show that locally sourced patch graft material can be a cost-effective alternative to traditionally used patch grafts without an increase in tube exposure rates. To further determine the efficacy of the different patch graft materials, longer-term comparative prospective trials are needed. Longer prospective studies are needed to compare the long-term safety and rate of tube exposures in these locally obtained patch graft materials. HOW TO CITE THIS ARTICLE: Aggarwal S, Kremer C, Engelhard S, et al. Comparison of Locally Sourced Pericardium and Other Conventional Patch Graft Materials in a Glaucoma Drainage Device Surgery. J Curr Glaucoma Pract 2021;15(1):14-18.

Cell contact guidance via sensing anisotropy of network mechanical resistance.

Despite the ubiquitous importance of cell contact guidance, the signal-inducing contact guidance of mammalian cells in an aligned fibril network has defied elucidation. This is due to multiple interdependent signals that an aligned fibril network presents to cells, including, at least, anisotropy of adhesion, porosity, and mechanical resistance. By forming aligned fibrin gels with the same alignment strength, but cross-linked to different extents, the anisotropic mechanical resistance hypothesis of contact guidance was tested for human dermal fibroblasts. The cross-linking was shown to increase the mechanical resistance anisotropy, without detectable change in network microstructure and without change in cell adhesion to the cross-linked fibrin gel. This methodology thus isolated anisotropic mechanical resistance as a variable for fixed anisotropy of adhesion and porosity. The mechanical resistance anisotropy |Y*| -1 - |X*| -1 increased over fourfold in terms of the Fourier magnitudes of microbead displacement |X*| and |Y*| at the drive frequency with respect to alignment direction Y obtained by optical forces in active microrheology. Cells were found to exhibit stronger contact guidance in the cross-linked gels possessing greater mechanical resistance anisotropy: the cell anisotropy index based on the tensor of cell orientation, which has a range 0 to 1, increased by 18% with the fourfold increase in mechanical resistance anisotropy. We also show that modulation of adhesion via function-blocking antibodies can modulate the guidance response, suggesting a concomitant role of cell adhesion. These results indicate that fibroblasts can exhibit contact guidance in aligned fibril networks by sensing anisotropy of network mechanical resistance.