Evolving SARS-CoV-2 severity among hospital and university affiliates in Spain and Greater Boston.

INTRODUCTION: The COVID-19 pandemic caused by the SARS-CoV-2 virus greatly affected healthcare workers and healthcare systems. It also challenged schools and universities worldwide negatively affecting in-person education. We conducted this study is to assess the evolution of SARs-CoV-2 virulence over the course of the pandemic. METHODS: A combined cohort of University students in Spain and HCWs from the two hospitals in Spain, and one healthcare system in the Greater Boston area was followed prospectively from March 8th, 2020, to January 31st, 2022 for diagnosis with COVID-19 by PCR testing and related sequelae. Follow-up time was divided into four periods according to distinct waves of infection during the pandemic. Severity of COVID-19 was measured by case-hospitalization rate. Descriptive statistics and multivariable-adjusted statistics using the Poisson mixed-effects regression model were applied. As a sensitivity analysis, information on SARS-CoV-2 RNA in wastewater and COVID-19 deaths through May 30, 2023 from the Boston area was collected. RESULTS: For the last two periods of the study (January 1st to December 15th, 2021 and December 16th, 2021 to January 31st, 2022) and relative to the first period (March 8th to May 31st, 2020), the incidence rate ratios (IRRs) of hospitalization were 0.08 (95% CI, 0.03-0.17) and 0.03 (95% CI, 0.01-0.15), respectively. In addition, a relative risk 0.012 CI95% (0.012-0.012) was observed when comparing COVID-19 mortality versus SARS-CoV-2 RNA copies/mL in Boston-area wastewater over the period (16th December 2021 to 30th May 2023) and relative to the first period. CONCLUSIONS: The severity of COVID-19 and immunity of our populations evolved over time, resulting in a decrease in case severity. We found the case-hospitalization rate decreased more than 90% in our cohort despite an increase in incidence.

Continued effectiveness of COVID-19 vaccination among urban healthcare workers during delta variant predominance.

BACKGROUND: Data on COVID-19 vaccine effectiveness (VE) among healthcare workers (HCWs) during periods of delta variant predominance are limited. METHODS: We followed a population of urban Massachusetts HCWs (45% non-White) subject to epidemiologic surveillance. We accounted for covariates such as demographics and community background infection incidence, as well as information bias regarding COVID-19 diagnosis and vaccination status. RESULTS: During the study period (December 16, 2020 to September 30, 2021), 4615 HCWs contributed to a total of 1,152,486 person-days at risk (excluding 309 HCWs with prior infection) and had a COVID-19 incidence rate of 5.2/10,000 (114 infections out of 219,842 person-days) for unvaccinated person-days and 0.6/10,000 (49 infections out of 830,084 person-days) for fully vaccinated person-days, resulting in an adjusted VE of 82.3% (95% CI 75.1-87.4%). For the secondary analysis limited to the period of delta variant predominance in Massachusetts (i.e., July 1 to September 30, 2021), we observed an adjusted VE of 76.5% (95% CI 40.9-90.6%). Independently, we found no re-infection among those with prior COVID-19, contributing to 74,557 re-infection-free person-days, adding to the evidence base for the robustness of naturally acquired immunity. CONCLUSIONS: We found a VE of 76.5% against the delta variant. Our work also provides further evidence of naturally acquired immunity.

Sociodemographic risk factors for coronavirus disease 2019 (COVID-19) infection among Massachusetts healthcare workers: A retrospective cohort study.

OBJECTIVE: To better understand coronavirus disease 2019 (COVID-19) transmission among healthcare workers (HCWs), we investigated occupational and nonoccupational risk factors associated with cumulative COVID-19 incidence among a Massachusetts HCW cohort. DESIGN, SETTING, AND PARTICIPANTS: The retrospective cohort study included adult HCWs in a single healthcare system from March 9 to June 3, 2020. METHODS: The SARS-CoV-2 nasopharyngeal RT-PCR results and demographics of the study participants were deidentified and extracted from an established occupational health, COVID-19 database at the healthcare system. HCWs from each particular job grouping had been categorized into frontline or nonfrontline workers. Incidence rate ratios (IRRs) and odds ratios (ORs) were used to compare subgroups after excluding HCWs involved in early infection clusters before universal masking began. A sensitivity analysis was performed comparing jobs with the greatest potential occupational risks with others. RESULTS: Of 5,177 HCWs, 152 (2.94%) were diagnosed with COVID-19. Affected HCWs resided in areas with higher community attack rates (median, 1,755.2 vs 1,412.4 cases per 100,000; P < .001; multivariate-adjusted IRR, 1.89; 95% CI, 1.03-3.44 comparing fifth to first quintile of community rates). After multivariate adjustment, African-American and Hispanic HCWs had higher incidence of COVID-19 than non-Hispanic white HCWs (IRR, 2.78; 95% CI, 1.78-4.33; and IRR, 2.41, 95% CI, 1.42-4.07, respectively). After adjusting for race and residential rates, frontline HCWs had a higher IRR (1.73, 95% CI, 1.16-2.54) than nonfrontline HCWs overall, but not within specific job categories nor when comparing the highest risk jobs to others. CONCLUSIONS: After universal masking was instituted, the strongest risk factors associated with HCW COVID-19 infection were residential community infection rate and race.

COVID-19 symptoms predictive of healthcare workers' SARS-CoV-2 PCR results.

BACKGROUND: Coronavirus 2019 disease (COVID-19) is caused by the virus SARS-CoV-2, transmissible both person-to-person and from contaminated surfaces. Early COVID-19 detection among healthcare workers (HCWs) is crucial for protecting patients and the healthcare workforce. Because of limited testing capacity, symptom-based screening may prioritize testing and increase diagnostic accuracy. METHODS AND FINDINGS: We performed a retrospective study of HCWs undergoing both COVID-19 telephonic symptom screening and nasopharyngeal SARS-CoV-2 assays during the period, March 9-April 15, 2020. HCWs with negative assays but progressive symptoms were re-tested for SARS-CoV-2. Among 592 HCWs tested, 83 (14%) had an initial positive SARS-CoV-2 assay. Fifty-nine of 61 HCWs (97%) who were asymptomatic or reported only sore throat/nasal congestion had negative SARS-CoV-2 assays (P = 0.006). HCWs reporting three or more symptoms had an increased multivariate-adjusted odds of having positive assays, 1.95 (95% CI: 1.10-3.64), which increased to 2.61 (95% CI: 1.50-4.45) for six or more symptoms. The multivariate-adjusted odds of a positive assay were also increased for HCWs reporting fever and a measured temperature ≥ 37.5°C (3.49 (95% CI: 1.95-6.21)), and those with myalgias (1.83 (95% CI: 1.04-3.23)). Anosmia/ageusia (i.e. loss of smell/loss of taste) was reported less frequently (16%) than other symptoms by HCWs with positive assays, but was associated with more than a seven-fold multivariate-adjusted odds of a positive test: OR = 7.21 (95% CI: 2.95-17.67). Of 509 HCWs with initial negative SARS-CoV-2 assays, nine had symptom progression and positive re-tests, yielding an estimated negative predictive value of 98.2% (95% CI: 96.8-99.0%) for the exclusion of clinically relevant COVID-19. CONCLUSIONS: Symptom and temperature reports are useful screening tools for predicting SARS-CoV-2 assay results in HCWs. Anosmia/ageusia, fever, and myalgia were the strongest independent predictors of positive assays. The absence of symptoms or symptoms limited to nasal congestion/sore throat were associated with negative assays.

Travel to Brazil: analysis of data from the Boston Area Travel Medicine Network (BATMN) and relevance to travelers attending world cup and olympics.

We describe travelers who were evaluated pre-travel to Brazil from March 2008 through July 2010 in the Boston area. Of 599 Brazil travelers, 71%, 58%, and 50% received vaccines for yellow fever (YF), typhoid, and hepatitis A, respectively. Fewer received influenza and hepatitis B vaccines (14%, 11%). A total of 60% traveled during Brazil's peak influenza season, and one fourth visited during peak dengue transmission. The 2014 World Cup and 2016 Olympics include events throughout Brazil. Travelers should seek pre-travel assessment including YF and malaria risk; travelers should be vaccinated against influenza, be up to date on other routine vaccines, and be prepared to protect themselves against mosquitoes.

Role of alpha 4 integrin (CD49d) in the pathogenesis of diabetic retinopathy.

PURPOSE: The pathophysiology of diabetic retinopathy is mediated by leukocyte adhesion to the vascular endothelium of the diabetic retina, which results in endothelial injury, blood-retina barrier breakdown, and capillary nonperfusion. Leukocyte adhesion is triggered by the interaction of vascular endothelium adhesion molecules, such as ICAM-1, with leukocyte integrins, such as CD18. Inhibition of ICAM-1/CD18 signaling suppresses but does not completely abolish the cardinal manifestations of diabetic retinopathy, suggesting a role for additional adhesion molecules. Integrin alpha 4 (CD49d), in complex with integrin beta1, forms very late antigen-4 (VLA-4), which interacts with vascular cell adhesion molecule-1. The authors have now studied the role of integrin alpha 4/CD49d in the pathogenesis of diabetic retinopathy. METHODS: Diabetes mellitus was induced in Long Evans rats with streptozotocin, and an anti-alpha 4 integrin/CD49d neutralizing antibody was injected 5 and 10 days later. Two weeks after streptozotocin administration, vascular leakage was quantified with the Evans Blue technique. Leukostasis was measured with a static adhesion assay ex vivo and the FITC-lectin perfusion method in vivo. Retinal VEGF and TNF-alpha levels and NF-kappaB activity were measured by ELISA. RESULTS: Blockade of alpha 4 integrin/CD49d attenuated the diabetes-induced upregulation of NF-kappaB activation, VEGF, and TNF-alpha protein levels and reduced significantly diabetes-induced leukocyte adhesion and vascular leakage. CONCLUSIONS: These data identify alpha 4 integrin/CD49d as a mediator of leukocyte adhesion and the resultant early signature abnormalities of diabetic retinopathy. Inhibition of this signaling pathway may hold promise for clinical activity in patients with diabetes.

Inhibition of Hsp90 attenuates inflammation in endotoxin-induced uveitis.

Heat shock protein (Hsp) 90 inhibitors, such as 17-allylamino-17-demethoxy-geldanamycin (17-AAG), constitute promising novel therapeutic agents. We investigated the anti-inflammatory activity of 17-AAG in endotoxin-induced uveitis (EIU) in rats. After the induction of EIU with a footpad injection of lipopolysaccharide (LPS), female Lewis rats received a single intraperitoneal. (i.p.) injection of 17-AAG or vehicle. Twenty-four hours later, the retinas were extracted and assayed for leukocyte adhesion; blood-retinal barrier breakdown; VEGF, TNF-alpha, IL-1beta, and CD14 protein levels; NF-kappaB and HIF-1alpha activity; hsp90 and 70 levels and expression and phosphorylation of the tight junction proteins ZO-1 and occludin. 17-AAG treatment significantly suppressed the LPS-induced increase in retinal leukocyte adhesion; vascular leakage; NF-kappaB, HIF-1alpha, p38, and PI-3K activity; and VEGF, TNF-alpha, and IL-1beta levels. 17-AAG also suppressed phosphorylation of ZO-1 and occludin by inhibiting their association with p38 and PI-3K. Although 17-AAG treatment did not reduce the LPS-induced increase in total CD14 levels in leukocytes, it significantly decreased membrane CD14 levels. These data suggest that Hsp90 inhibition suppresses several cardinal manifestations of endotoxin-induced uveitis in the rat. 17-AAG has demonstrated a favorable safety profile in clinical trials in cancer patients and represents a promising therapeutic agent for the treatment of inflammatory eye diseases.

Investigating the effect of ciliary body photodynamic therapy in a glaucoma mouse model.

PURPOSE: To investigate the morphologic and functional effects of verteporfin ciliary body photodynamic therapy (PDT) in a murine glaucoma model and normal mouse eyes. METHODS: A glaucomatous mouse strain, DBA/2J and a normal control mouse strain (C57BL/6) were used in the study. Verteporfin was injected intravenously at doses of 1.0 (DBA/2J) or 2.0 or 4.0 (C57BL/6) mg/kg. Transscleral irradiation of the ciliary body was performed with light at a wavelength of 689 nm delivered through an optical fiber, with irradiance of 1800 mW/cm2 and fluence of 100 J/cm2. Laser irradiation was applied for 360 degrees of the corneoscleral limbus in C57BL/6 normal mice and for 180 degrees in DBA/2J mice. Retreatment was performed in C57BL/6 normal mice that had been treated with 2.0 mg/kg of verteporfin at post-PDT day 7. One eye of each animal was treated, and the fellow eye served as the control. The morphologic effect of PDT on the ocular structures was assessed by light and electron microscopy. The IOP was measured using an applanation tonometer with a fiber-optic pressure sensor. Surviving retinal ganglion cells (RGCs) in DBA/2J mice eyes were retrogradely labeled with a neurotracer dye at 12 weeks after PDT. RESULTS: In all groups, almost all ciliary body blood vessels in the treated area were thrombosed 1 day after PDT. In DBA/2J mice, ciliary epithelium and stroma were severely damaged 1 day after PDT. The mean IOP in treated eyes was significantly reduced compared with that in the control eyes in all groups. The reduction of mean IOP in DBA/2J mouse eyes persisted for 7 weeks, although the mean IOP in normal mouse eyes treated with 2 or 4.0 mg/kg verteporfin returned to the level of the fellow control eyes by 7 and 17 days after treatment, respectively. The mean number of RGCs in the DBA/2J treated eyes was significantly higher than in control eyes. CONCLUSIONS: Ciliary body PDT resulted in morphologic changes in the ciliary body, significant reduction of IOP, and prevention of ganglion cell loss in a mouse glaucoma model. These results suggest that ciliary body PDT is a more selective cyclodestructive technique with potential clinical application in the treatment of glaucoma.

Insulin-like growth factor-I plays a pathogenetic role in diabetic retinopathy.

Diabetic retinopathy is a leading cause of blindness in the Western world. Aberrant intercellular adhesion molecule-1 expression and leukocyte adhesion have been implicated in its pathogenesis, raising the possibility of an underlying chronic inflammatory mechanism. In the current study, the role of insulin-like growth factor (IGF)-I in these processes was investigated. We found that systemic inhibition of IGF-I signaling with a receptor-neutralizing antibody, or with inhibitors of PI-3 kinase (PI-3K), c-Jun kinase (JNK), or Akt, suppressed retinal Akt, JNK, HIF-1alpha, nuclear factor (NF)-kappaB, and AP-1 activity, vascular endothelial growth factor (VEGF) expression, as well as intercellular adhesion molecule-1 levels, leukostasis, and blood-retinal barrier breakdown, in a relevant animal model. Intravitreous administration of IGF-I increased retinal Akt, JNK, HIF-1alpha, NF-kappaB, and AP-1 activity, and VEGF levels. IGF-I stimulated VEGF promoter activity in vitro, mainly via HIF-1alpha, and secondarily via NF-kappaB and AP-1. In conclusion, IGF-I participates in the pathophysiology of diabetic retinopathy by inducing retinal VEGF expression via PI-3K/Akt, HIF-1alpha, NF-kappaB, and secondarily, JNK/AP-1 activation. Taken together, these in vitro and in vivo signaling studies thus identify potential targets for pharmacological intervention to preserve vision in patients with diabetes.

Activin a in the regulation of corneal neovascularization and vascular endothelial growth factor expression.

Activin A, a dimeric glycoprotein that belongs to the transforming growth factor-beta superfamily, governs cellular differentiation in a wide variety of models and has been implicated in the regulation of angiogenesis. We examined the role of activin A and its downstream signaling pathway in a murine model of inflammatory corneal neovascularization induced by mechanical injury (debridement), and in vitro in corneal epithelial cells. Activin A expression increased steadily from day 2 until day 8 after mechanical debridement in vivo, paralleling vascular endothelial growth factor (VEGF) expression. Administration of recombinant activin A in mice increased the area of neovascularization, VEGF expression, and the kinase activities of p38 and p42/44 MAPKs after mechanical debridement. Systemic inhibition of activin A in vivo with a neutralizing antibody reduced the area of neovascularization, VEGF expression, and p38 and p42/44 MAPK activity, whereas administration of an isotype-matched control antibody had no effect. In vitro treatment with activin A increased VEGF secretion, as well as p38 and p42/44 MAPK activity in corneal epithelial cells, whereas concurrent administration of specific inhibitors of p38 or p42/44 MAPK abolished the stimulatory effect of activin A on VEGF production. We conclude that activin A stimulates inflammatory corneal angiogenesis by increasing VEGF levels through a p38 and p42/44 MAPK-dependent mechanism.