International Classification of Retinopathy of Prematurity, Third Edition.

PURPOSE: The International Classification of Retinopathy of Prematurity is a consensus statement that creates a standard nomenclature for classification of retinopathy of prematurity (ROP). It was initially published in 1984, expanded in 1987, and revisited in 2005. This article presents a third revision, the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), which is now required because of challenges such as: (1) concerns about subjectivity in critical elements of disease classification; (2) innovations in ophthalmic imaging; (3) novel pharmacologic therapies (e.g., anti-vascular endothelial growth factor agents) with unique regression and reactivation features after treatment compared with ablative therapies; and (4) recognition that patterns of ROP in some regions of the world do not fit neatly into the current classification system. DESIGN: Review of evidence-based literature, along with expert consensus opinion. PARTICIPANTS: International ROP expert committee assembled in March 2019 representing 17 countries and comprising 14 pediatric ophthalmologists and 20 retinal specialists, as well as 12 women and 22 men. METHODS: The committee was initially divided into 3 subcommittees-acute phase, regression or reactivation, and imaging-each of which used iterative videoconferences and an online message board to identify key challenges and approaches. Subsequently, the entire committee used iterative videoconferences, 2 in-person multiday meetings, and an online message board to develop consensus on classification. MAIN OUTCOME MEASURES: Consensus statement. RESULTS: The ICROP3 retains current definitions such as zone (location of disease), stage (appearance of disease at the avascular-vascular junction), and circumferential extent of disease. Major updates in the ICROP3 include refined classification metrics (e.g., posterior zone II, notch, subcategorization of stage 5, and recognition that a continuous spectrum of vascular abnormality exists from normal to plus disease). Updates also include the definition of aggressive ROP to replace aggressive-posterior ROP because of increasing recognition that aggressive disease may occur in larger preterm infants and beyond the posterior retina, particularly in regions of the world with limited resources. ROP regression and reactivation are described in detail, with additional description of long-term sequelae. CONCLUSIONS: These principles may improve the quality and standardization of ROP care worldwide and may provide a foundation to improve research and clinical care.

Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial.

BACKGROUND: Despite increasing worldwide use of anti-vascular endothelial growth factor agents for treatment of retinopathy of prematurity (ROP), there are few data on their ocular efficacy, the appropriate drug and dose, the need for retreatment, and the possibility of long-term systemic effects. We evaluated the efficacy and safety of intravitreal ranibizumab compared with laser therapy in treatment of ROP. METHODS: This randomised, open-label, superiority multicentre, three-arm, parallel group trial was done in 87 neonatal and ophthalmic centres in 26 countries. We screened infants with birthweight less than 1500 g who met criteria for treatment for retinopathy, and randomised patients equally (1:1:1) to receive a single bilateral intravitreal dose of ranibizumab 0·2 mg or ranibizumab 0·1 mg, or laser therapy. Individuals were stratified by disease zone and geographical region using computer interactive response technology. The primary outcome was survival with no active retinopathy, no unfavourable structural outcomes, or need for a different treatment modality at or before 24 weeks (two-sided α=0·05 for superiority of ranibizumab 0·2 mg against laser therapy). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02375971. INTERPRETATION: Between Dec 31, 2015, and June 29, 2017, 225 participants (ranibizumab 0·2 mg n=74, ranibizumab 0·1 mg n=77, laser therapy n=74) were randomly assigned. Seven were withdrawn before treatment (n=1, n=1, n=5, respectively) and 17 did not complete follow-up to 24 weeks, including four deaths in each group. 214 infants were assessed for the primary outcome (n=70, n=76, n=68, respectively). Treatment success occurred in 56 (80%) of 70 infants receiving ranibizumab 0·2 mg compared with 57 (75%) of 76 infants receiving ranibizumab 0·1 mg and 45 (66%) of 68 infants after laser therapy. Using a hierarchical testing strategy, compared with laser therapy the odds ratio (OR) of treatment success following ranibizumab 0·2 mg was 2·19 (95% Cl 0·99-4·82, p=0·051), and following ranibizumab 0·1 mg was 1·57 (95% Cl 0·76-3·26); for ranibizumab 0·2 mg compared with 0·1 mg the OR was 1·35 (95% Cl 0·61-2·98). One infant had an unfavourable structural outcome following ranibizumab 0·2 mg, compared with five following ranibizumab 0·1 mg and seven after laser therapy. Death, serious and non-serious systemic adverse events, and ocular adverse events were evenly distributed between the three groups. FINDINGS: In the treatment of ROP, ranibizumab 0·2 mg might be superior to laser therapy, with fewer unfavourable ocular outcomes than laser therapy and with an acceptable 24-week safety profile. FUNDING: Novartis.

Speed and accuracy of saccades in patients with glaucoma evaluated using an eye tracking perimeter.

BACKGROUND: To examine the speed and accuracy of saccadic eye movements during a novel eye tracking threshold visual field assessment and determine whether eye movement parameters may improve ability to detect glaucoma. METHODS: A prospective study including both eyes of 31 patients with glaucoma and 23 controls. Standard automated perimetry (SAP) and eye tracking perimetry (saccadic vector optokinetic perimetry, SVOP) was performed. SVOP provided data on threshold sensitivity, saccade latency, and two measures of accuracy of saccades (direction bias and amplitude bias). The relationship between eye movement parameters and severity of glaucoma was examined and Receiver Operating Characteristic curves were used to assess ability to detect glaucoma. RESULTS: Patients with glaucoma had significantly slower saccades (602.9 ± 50.0 ms versus 578.3 ± 44.6 ms for controls, P = 0.009) and reduced saccade accuracy (direction bias = 7.4 ± 1.8 versus 6.5 ± 1.5 degrees, P = 0.006). There was a significant slowing of saccades and saccades became less accurate with worsening SAP sensitivity. Slower saccades were associated with increased odds of glaucoma; however, the AUC for saccade latency was only 0.635 compared to 0.914 for SVOP sensitivity. CONCLUSION: Patients with glaucoma had significant differences in eye movements compared to healthy subjects, with a relationship between slower and less accurate eye movements and worse glaucoma severity. However, in a multivariable model, eye movement parameters were not of additional benefit in differentiating eyes with glaucoma from healthy controls.

Outcomes of Two Trials of Oxygen-Saturation Targets in Preterm Infants.

BACKGROUND: The safest ranges of oxygen saturation in preterm infants have been the subject of debate. METHODS: In two trials, conducted in Australia and the United Kingdom, infants born before 28 weeks' gestation were randomly assigned to either a lower (85 to 89%) or a higher (91 to 95%) oxygen-saturation range. During enrollment, the oximeters were revised to correct a calibration-algorithm artifact. The primary outcome was death or disability at a corrected gestational age of 2 years; this outcome was evaluated among infants whose oxygen saturation was measured with any study oximeter in the Australian trial and those whose oxygen saturation was measured with a revised oximeter in the U.K. trial. RESULTS: After 1135 infants in Australia and 973 infants in the United Kingdom had been enrolled in the trial, an interim analysis showed increased mortality at a corrected gestational age of 36 weeks, and enrollment was stopped. Death or disability in the Australian trial (with all oximeters included) occurred in 247 of 549 infants (45.0%) in the lower-target group versus 217 of 545 infants (39.8%) in the higher-target group (adjusted relative risk, 1.12; 95% confidence interval [CI], 0.98 to 1.27; P=0.10); death or disability in the U.K. trial (with only revised oximeters included) occurred in 185 of 366 infants (50.5%) in the lower-target group versus 164 of 357 infants (45.9%) in the higher-target group (adjusted relative risk, 1.10; 95% CI, 0.97 to 1.24; P=0.15). In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P=0.02), and death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P=0.04). In the group in which revised oximeters were used, death or disability occurred in 287 of 580 infants (49.5%) in the lower-target group versus 248 of 563 infants (44.0%) in the higher-target group (relative risk, 1.12; 95% CI, 0.99 to 1.27; P=0.07), and death occurred in 144 of 587 infants (24.5%) versus 99 of 586 infants (16.9%) (relative risk, 1.45; 95% CI, 1.16 to 1.82; P=0.001). CONCLUSIONS: Use of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial but in significantly increased risks of this combined outcome and of death alone in post hoc combined analyses. (Funded by the Australian National Health and Medical Research Council and others; BOOST-II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry number, ACTRN12605000055606.).

Raised intracranial pressure and retinal haemorrhages in childhood encephalopathies.

AIM: To explore the relationship between raised intracranial pressure (RICP) and retinal haemorrhages in traumatic and non-traumatic childhood encephalopathies. METHOD: A prospective study of 112 children (35 females and 77 males, age range 0.01mo-17y 8.3mo; mean 5y 8.6mo, median 4y 5.6mo) included 57 accidental traumatic brain injuries (ATBIs), 21 inflicted traumatic brain injuries (ITBIs), and 34 non-traumatic encephalopathy cases. Measurements included intracranial pressure (ICP), cerebral perfusion pressure, pressure-time index of ICP, and number, zone, and layer of retinal haemorrhages on retinal imaging. RESULTS: Group I had measured elevated ICP (n=42), Group II had clinical and/or radiological signs of RICP (n=21), and Group III had normal ICP (n=49). In the combined Groups I and II, 38% had retinal haemorrhages. Multiple logistic regression confirmed that the presence of retinal haemorrhages was significantly related to the presence of RICP independent of age and aetiology; however, the occurrence and overall numbers were not significantly related to the specific ICP level. The numbers of intraretinal (nerve-fibre layer and dot blot) retinal haemorrhages were significantly greater in those with RICP. The ITBI population was significantly different from the other combined aetiological categories. INTERPRETATION: The study results indicate a complex RICP/retinal haemorrhage relationship. There was no evidence of existing retinal haemorrhages being exacerbated or new retinal haemorrhages developing during periods of confirmed RICP.

Oxygen saturation and outcomes in preterm infants.

BACKGROUND: The clinically appropriate range for oxygen saturation in preterm infants is unknown. Previous studies have shown that infants had reduced rates of retinopathy of prematurity when lower targets of oxygen saturation were used. METHODS: In three international randomized, controlled trials, we evaluated the effects of targeting an oxygen saturation of 85 to 89%, as compared with a range of 91 to 95%, on disability-free survival at 2 years in infants born before 28 weeks' gestation. Halfway through the trials, the oximeter-calibration algorithm was revised. Recruitment was stopped early when an interim analysis showed an increased rate of death at 36 weeks in the group with a lower oxygen saturation. We analyzed pooled data from patients and now report hospital-discharge outcomes. RESULTS: A total of 2448 infants were recruited. Among the 1187 infants whose treatment used the revised oximeter-calibration algorithm, the rate of death was significantly higher in the lower-target group than in the higher-target group (23.1% vs. 15.9%; relative risk in the lower-target group, 1.45; 95% confidence interval [CI], 1.15 to 1.84; P=0.002). There was heterogeneity for mortality between the original algorithm and the revised algorithm (P=0.006) but not for other outcomes. In all 2448 infants, those in the lower-target group for oxygen saturation had a reduced rate of retinopathy of prematurity (10.6% vs. 13.5%; relative risk, 0.79; 95% CI, 0.63 to 1.00; P=0.045) and an increased rate of necrotizing enterocolitis (10.4% vs. 8.0%; relative risk, 1.31; 95% CI, 1.02 to 1.68; P=0.04). There were no significant between-group differences in rates of other outcomes or adverse events. CONCLUSIONS: Targeting an oxygen saturation below 90% with the use of current oximeters in extremely preterm infants was associated with an increased risk of death. (Funded by the Australian National Health and Medical Research Council and others; BOOST II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry numbers, ACTRN12605000055606 and ACTRN12605000253606.).

Genome-wide association study identifies genetic risk underlying primary rhegmatogenous retinal detachment.

Rhegmatogenous retinal detachment (RRD) is an important cause of vision loss and can potentially lead to blindness. The underlying pathogenesis is complex and incompletely understood. We applied a two-stage genetic association discovery phase followed by a replication phase in a combined total of 2833 RRD cases and 7871 controls. The discovery phase involved a genome-wide association scan of 867 affected individuals and 1953 controls from Scotland, followed by genotyping and testing 4347 highest ranking or candidate single nucleotide polymorphisms (SNPs) in independent sets of cases (1000) and controls (2912) of Dutch and British origin. None of the SNPs selected reached a Bonferroni-corrected threshold for significance (P < 1.27 × 10(-7)). The strongest association, for rs12960119 (P = 1.58 × 10(-7)) located within an intron of the SS18 gene. Further testing was carried out in independent case-control series from London (846 cases) and Croatia (120 cases). The combined meta-analysis identified one association reaching genome-wide significance for rs267738 (OR = 1.29, P = 2.11 × 10(-8)), a missense coding SNP and eQTL for CERS2 encoding the protein ceramide synthase 2. Several of the top signals showing suggestive significance in the combined meta-analysis encompassed genes with a documented role in cell adhesion or migration, including SS18, TIAM1, TSTA3 and LDB2, which warrant further investigation. This first genetic association study of RRD supports a polygenic component underlying RRD risk since 27.4% of the underlying RRD liability could be explained by the collective additive effects of the genotyped SNP from the discovery genome-wide scan.

Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error.

Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study ('Cooperative Health Research in the Region of Augsburg'); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10(-9)) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins.

Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium.

To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.

Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): five-year outcomes of a randomised trial.

Background: Concerns remain over the long-term safety of vascular endothelial growth factor (VEGF) inhibitors to treat retinopathy of prematurity (ROP). RAINBOW is an open label randomised trial comparing intravitreal ranibizumab (in 0.2 mg and 0.1 mg doses) with laser therapy in very low birthweight infants (<1500 g) with ROP. Methods: Of 201 infants completing RAINBOW, 180 were enrolled in the RAINBOW Extension Study. At 5 years, children underwent ophthalmic, development and health assessments. The primary outcome was visual acuity in the better-seeing eye. The study is registered with ClinicalTrial.gov, NCT02640664. Findings: Between 16-6-2016 and 21-4-2022, 156 children (87%) were evaluated at 5 years. Of 32 children with no acuity test result, 25 had a preferential looking test, for 4 children investigators reported low vision for each eye, and in 3 further children no vision measurement was obtained. 124 children completed the acuity assessment, the least square mean (95% CI) letter score in the better seeing eye was similar in the three trial arms-66.8 (62.9-70.7) following ranibizumab 0.2 mg, 64.6 (60.6-68.5) following ranibizumab 0.1 mg and 62.1 (57.8-66.4) following laser therapy; differences in means: ranibizumab 0.2 mg v laser: 4.7 (95% CI: -1.1, 10.5); 0.1 mg v laser: 2.5 (-3.4, 8.3); 0.2 mg v 0.1 mg: 2.2 (-3.3, 7.8). High myopia (worse than -5 dioptres) in at least one eye occurred in 4/52 (8%) children following ranibizumab 0.2 mg, 8/55 (15%) following ranibizumab 0.1 mg and 11/45 (24%) following laser therapy (0.2 mg versus laser: odds ratio: 3.99 (1.16-13.72)). Ocular and systemic secondary outcomes and adverse events were distributed similarly in each trial arm. Interpretation: 5-year outcomes confirm the findings of the original RAINBOW trial and a planned interim analysis at 2 years, including a reduced frequency of high myopia following ranibizumab treatment. No effects of treatment on non-ocular outcomes were detected. Funding: Novartis Pharma AG.

The impact of heating, ventilation, and air conditioning design features on the transmission of viruses, including the 2019 novel coronavirus: A systematic review of filtration.

Historically, viruses have demonstrated airborne transmission. Emerging evidence suggests the novel coronavirus (SARS-CoV-2) that causes COVID-19 also spreads by airborne transmission. This is more likely in indoor environments, particularly with poor ventilation. In the context of airborne transmission, a vital mitigation strategy for the built environment is heating, ventilation, and air conditioning (HVAC) systems. HVAC features could modify virus transmission potential. A systematic review was conducted to identify and synthesize research examining the effectiveness of filters within HVAC systems in reducing virus transmission. A comprehensive search of OVID MEDLINE, Compendex, and Web of Science Core was conducted to January 2021. Two authors were involved in study selection, data extraction, and risk of bias assessments. Study characteristics and results were displayed in evidence tables and findings were synthesized narratively. Twenty-three relevant studies showed that: filtration was associated with decreased transmission; filters removed viruses from the air; increasing filter efficiency (efficiency of particle removal) was associated with decreased transmission, decreased infection risk, and increased viral filtration efficiency (efficiency of virus removal); increasing filter efficiency above MERV 13 was associated with limited benefit in further reduction of virus concentration and infection risk; and filters with the same efficiency rating from different companies showed variable performance. Adapting HVAC systems to mitigate virus transmission requires a multi-factorial approach and filtration is one factor offering demonstrated potential for decreased transmission. For filtration to be effective, proper installation is required. Of note, similarly rated filters from different companies may offer different virus reduction results. While increasing filtration efficiency (i.e., increasing MERV rating or moving from MERV to HEPA) is associated with virus mitigation, there are diminishing returns for filters rated MERV 13 or higher. Although costs increase with filtration efficiency, they are lower than the cost of ventilation options with the equivalent reduction in transmission. Systematic review registration: PROSPERO 2020 CRD42020193968.

New loci associated with central cornea thickness include COL5A1, AKAP13 and AVGR8.

Central corneal thickness (CCT) is a highly heritable trait, which has been proposed to influence disorders of the anterior segment of the eye. A genome-wide association study (GWAS) of CCT was performed in 2269 individuals from three Croatian and one Scottish population. In the discovery set (1445 individuals), two genome-wide significant associations were identified for single nucleotide polymorphisms rs12447690 (ß = 0.23 SD, P = 4.4 × 10(-9)) and rs1536482 (ß = 0.22 SD, P = 7.1 × 10(-8)) for which the closest candidate genes (although ≥90 kb away) were zinc finger 469 (ZNF469) on 16q24.2 and collagen 5 alpha 1 (COL5A1) on 9q34.2, respectively. Only the ZNF469 association was confirmed in our replication set (824 individuals, P = 8.0 × 10(-4)) but COL5A1 remained a suggestive association in the combined sample (ß = 0.16 SD, P = 1.1 × 10(-6)). Following a larger meta-analysis including recently published CCT GWAS summary data, COL5A1 was genome-wide significant (ß = 0.13 SD, P = 5.1 × 10(-8)), together with two additional novel loci. The second new locus (defined by rs1034200) was 5 kb from the AVGR8 gene, encoding a putative transcription factor with typical ZNF and KRAB domains, in chromosomal region 13q12.11 (ß = 0.14 SD, P = 3.5 × 10(-9)). The third new locus (rs6496932), on 15q25.3 (ß = 0.13, P = 1.4 × 10(-8)), was within a wide linkage disequilibrium block extending into the 5' end of the AKAP13 gene, encoding a scaffold protein concerned with signal transduction from the cell surface. These associations offer mechanistic insights into the regulation of CCT and offer new candidate genes for susceptibility to common disorders in which CCT has been implicated, including primary open-angle glaucoma and keratoconus.

Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium.

Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10(-12) for SNP rs634990 in Caucasians, and 9.65 × 10(-4) for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10(-23) for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10(-2) for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.

The impact of heating, ventilation, and air conditioning design features on the transmission of viruses, including the 2019 novel coronavirus: A systematic review of ultraviolet radiation.

Respiratory viruses are capable of transmitting via an aerosol route. Emerging evidence suggests that SARS-CoV-2 which causes COVID-19 can be spread through airborne transmission, particularly in indoor environments with poor ventilation. Heating, ventilation, and air conditioning (HVAC) systems can play a role in mitigating airborne virus transmission. Ultraviolet germicidal irradiation (UVGI), a feature that can be incorporated into HVAC systems, can be used to impede the ability of viruses to replicate and infect a host. We conducted a systematic review of the scientific literature examining the effectiveness of HVAC design features in reducing virus transmission-here we report results for ultraviolet (UV) radiation. We followed international standards for conducting systematic reviews and developed an a priori protocol. We conducted a comprehensive search to January 2021 of published and grey literature using Ovid MEDLINE, Compendex, and Web of Science Core. Two reviewers were involved in study selection, data extraction, and risk of bias assessments. We presented study characteristics and results in evidence tables, and synthesized results across studies narratively. We identified 32 relevant studies published between 1936 and 2020. Research demonstrates that: viruses and bacteriophages are inactivated by UV radiation; increasing UV dose is associated with decreasing survival fraction of viruses and bacteriophages; increasing relative humidity is associated with decreasing susceptibility to UV radiation; UV dose and corresponding survival fraction are affected by airflow pattern, air changes per hour, and UV device location; and UV radiation is associated with decreased transmission in both animal and human studies. While UV radiation has been shown to be effective in inactivating viruses and reducing disease transmission, practical implementation of UVGI in HVAC systems needs to consider airflow patterns, air changes per hour, and UV device location. The majority of the scientific literature is comprised of experimental, laboratory-based studies. Further, a variety of viruses have been examined; however, there are few studies of coronaviruses and none to date of SARS-CoV-2. Future field studies of UVGI systems could address an existing research gap and provide important information on system performance in real-world situations, particularly in the context of the current COVID-19 pandemic. This comprehensive synthesis of the scientific evidence examining the impact of UV radiation on virus transmission can be used to guide implementation of systems to mitigate airborne spread and identify priorities for future research. Trial registration PROSPERO 2020 CRD42020193968.

The Impact of Heating, Ventilation, and Air-Conditioning Design Features on the Transmission of Viruses, Including SARS-CoV-2: Overview of Reviews.

BACKGROUND: The COVID-19 or SARS-CoV-2 outbreak was declared a pandemic by the World Health Organization in March 2020. Almost 2 years later (early February 2022), the World Health Organization reported over 383 million cases of the disease caused by the virus, with over 5.6 million deaths worldwide. Debate regarding the routes of transmission was substantial early in the pandemic; however, airborne transmission emerged as an important consideration. Infectious airborne agents can spread within the built environment through heating, ventilation, and air-conditioning (HVAC) systems. Multiple features of HVAC systems can influence transmission (eg, ventilation, filtration, UV radiation, and humidity). Understanding how HVAC features influence airborne transmission is critical to mitigate the spread of infectious agents. OBJECTIVE: Given the airborne transmission of SARS-CoV-2, an overview of reviews was conducted to understand what is already known from the scientific literature about how virus transmission may be affected by HVAC design features in the built environment. METHODS: Ovid MEDLINE and Compendex were searched from inception to January 2021. Two reviewers independently screened the titles, abstracts, and full text of potentially relevant reviews, using a priori inclusion criteria: systematic reviews examining the effects of HVAC design features on virus transmission. Two reviewers independently assessed the methodological quality using AMSTAR2. RESULTS: Searching identified 361 citations, of which 45 (12.5%) were potentially relevant and 7 (2%) were included. Reviews were published between 2007 and 2021 and included 47 virus studies. Two earlier reviews (2007 and 2016) of 21 studies found sufficient evidence that mechanical ventilation (airflow patterns and ventilation rates) plays a role in airborne transmission; however, both found insufficient evidence to quantify the minimum mechanical ventilation requirements. One review (2017) of 9 studies examining humidity and indoor air quality found that influenza virus survival was lowest between 40% and 80% relative humidity; the authors noted that ventilation rates were a confounding variable. Two reviews (2021) examined mitigation strategies for coronavirus transmission, finding that transmission decreased with increasing temperature and relative humidity. One review (2020) identified 14 studies examining coronavirus transmission in air-conditioning systems, finding that HVAC systems played a role in virus spread during previous coronavirus outbreaks. One review (2020) examined virus transmission interventions in public ground transportation, finding ventilation and filtration to be effective. CONCLUSIONS: Seven reviews synthesizing 47 studies demonstrated a role for HVAC in mitigating airborne virus transmission. Ventilation, humidity, temperature, and filtration can play a role in the viability and transmission of viruses, including coronaviruses. Recommendations for minimum standards were not possible owing to few studies investigating a given HVAC parameter. This overview examining HVAC design features and their effects on the airborne transmission of viruses serves as a starting point for future systematic reviews and identifying priorities for primary research.

The impact of heating, ventilation and air conditioning (HVAC) design features on the transmission of viruses, including the 2019 novel coronavirus (COVID-19): A systematic review of humidity.

The aerosol route has been a pathway for transmission of many viruses. Similarly, recent evidence has determined aerosol transmission for SARS-CoV-2 to be significant. Consequently, public health officials and professionals have sought data regarding the role of Heating, Ventilation, and Air Conditioning (HVAC) features as a means to mitigate transmission of viruses, particularly coronaviruses. Using international standards, a systematic review was conducted to comprehensively identify and synthesize research examining the effect of humidity on transmission of coronaviruses and influenza. The results from 24 relevant studies showed that: increasing from mid (40-60%) to high (>60%) relative humidity (RH) for SARS-CoV-2 was associated with decreased virus survival; although SARS-CoV-2 results appear consistent, coronaviruses do not all behave the same; increasing from low (<40%) to mid RH for influenza was associated with decreased persistence, infectivity, viability, and survival, however effects of increased humidity from mid to high for influenza were not consistent; and medium, temperature, and exposure time were associated with inconsistency in results for both coronaviruses and influenza. Adapting humidity to mitigate virus transmission is complex. When controlling humidity as an HVAC feature, practitioners should take into account virus type and temperature. Future research should also consider the impact of exposure time, temperature, and medium when designing experiments, while also working towards more standardized testing procedures. Clinical trial registration: PROSPERO 2020 CRD42020193968.

The impact of heating, ventilation, and air conditioning design features on the transmission of viruses, including the 2019 novel coronavirus: A systematic review of ventilation and coronavirus.

Aerosol transmission has been a pathway for the spread of many viruses. Similarly, emerging evidence has determined aerosol transmission for Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) and the resulting COVID-19 pandemic to be significant. As such, data regarding the effect of Heating, Ventilation, and Air Conditioning (HVAC) features to control and mitigate virus transmission is essential. A systematic review was conducted to identify and comprehensively synthesize research examining the effectiveness of ventilation for mitigating transmission of coronaviruses. A comprehensive search was conducted in Ovid MEDLINE, Compendex, Web of Science Core to January 2021. Study selection, data extraction, and risk of bias assessments were performed by two authors. Evidence tables were developed and results were described narratively. Results from 32 relevant studies showed that: increased ventilation rate was associated with decreased transmission, transmission probability/risk, infection probability/risk, droplet persistence, virus concentration, and increased virus removal and virus particle removal efficiency; increased ventilation rate decreased risk at longer exposure times; some ventilation was better than no ventilation; airflow patterns affected transmission; ventilation feature (e.g., supply/exhaust, fans) placement influenced particle distribution. Few studies provided specific quantitative ventilation parameters suggesting a significant gap in current research. Adapting HVAC ventilation systems to mitigate virus transmission is not a one-solution-fits-all approach. Changing ventilation rate or using mixing ventilation is not always the only way to mitigate and control viruses. Practitioners need to consider occupancy, ventilation feature (supply/exhaust and fans) placement, and exposure time in conjunction with both ventilation rates and airflow patterns. Some recommendations based on quantitative data were made for specific scenarios (e.g., using air change rate of 9 h-1 for a hospital ward). Other recommendations included using or increasing ventilation, introducing fresh air, using maximum supply rates, avoiding poorly ventilated spaces, assessing fan placement and potentially increasing ventilation locations, and employing ventilation testing and air balancing checks. Trial registration: PROSPERO 2020 CRD42020193968.

Time Course of Retinopathy of Prematurity Regression and Reactivation After Treatment with Ranibizumab or Laser in the RAINBOW Trial.

PURPOSE: To study the time course of retinopathy of prematurity (ROP) regression and reactivation after treatment with intravitreal ranibizumab or laser in the ranibizumab compared with laser therapy for the treatment of infants born prematurely with ROP trial. DESIGN: Post hoc analysis of a randomized, clinical trial. SUBJECTS: A total of 225 infants (448 eyes) were randomized to ranibizumab 0.2 mg (n = 74, 148 eyes), ranibizumab 0.1 mg (n = 77, 152 eyes), and laser (n = 74, 148 eyes). METHODS: Features of disease regression were measured using time-to-event analysis per eye, corrected for within-subject association. Analyses of disease reactivation and additional treatments were descriptive. MAIN OUTCOME MEASURES: Median time to regression of plus disease, stage 3 ROP, aggressive posterior (AP)-ROP to 24-week follow-up and disease reactivation and first additional treatment to 2-year follow-up. RESULTS: The median times to regression after ranibizumab 0.2 mg vs. laser were as follows: plus disease, 4 vs. 16 days (P < 0.001); stage 3 ROP, 8 vs. 16 days (P = 0.004); and AP-ROP, 7.3 vs. 22 days (P = 0.03). Results for ranibizumab 0.1 mg were similar to those for 0.2 mg, with a median of 4, 9, and 8 days, respectively. Additional treatments were given in 34 (25%) of 138 eyes after laser and 40 (27%) of 146 and 42 (28%) of 152 eyes after 0.2 mg and 0.1 mg ranibizumab, respectively. Incomplete disease regression requiring additional treatment occurred in 30 (22%) of 138 eyes after laser after a median interval of 15 days compared with 11 (8%) of 146 and 9 (6%) of 152 after 0.2 mg and 0.1 mg ranibizumab after a median interval of 21 and 13 days, respectively. Retinopathy of prematurity reactivation requiring additional treatment occurred in 3 (2%) of 138 eyes after laser after a median interval of 43 days compared with 22 (15%) of 146 and 26 (17%) of 152 after 0.2 and 0.1 mg ranibizumab after a median interval of 53.5 (maximum, 105) and 54.5 days (maximum, 128), respectively. CONCLUSIONS: Intravitreal 0.2 or 0.1 mg ranibizumab induced a faster regression of plus disease, stage 3 ROP, and AP-ROP than laser did. Ranibizumab was associated with fewer additional treatments for incomplete disease regression but more for disease reactivation.