Oceanic forcing of penultimate deglacial and last interglacial sea-level rise.

Sea-level histories during the two most recent deglacial-interglacial intervals show substantial differences1-3 despite both periods undergoing similar changes in global mean temperature4,5 and forcing from greenhouse gases6. Although the last interglaciation (LIG) experienced stronger boreal summer insolation forcing than the present interglaciation7, understanding why LIG global mean sea level may have been six to nine metres higher than today has proven particularly challenging2. Extensive areas of polar ice sheets were grounded below sea level during both glacial and interglacial periods, with grounding lines and fringing ice shelves extending onto continental shelves8. This suggests that oceanic forcing by subsurface warming may also have contributed to ice-sheet loss9-12 analogous to ongoing changes in the Antarctic13,14 and Greenland15 ice sheets. Such forcing would have been especially effective during glacial periods, when the Atlantic Meridional Overturning Circulation (AMOC) experienced large variations on millennial timescales16, with a reduction of the AMOC causing subsurface warming throughout much of the Atlantic basin9,12,17. Here we show that greater subsurface warming induced by the longer period of reduced AMOC during the penultimate deglaciation can explain the more-rapid sea-level rise compared with the last deglaciation. This greater forcing also contributed to excess loss from the Greenland and Antarctic ice sheets during the LIG, causing global mean sea level to rise at least four metres above modern levels. When accounting for the combined influences of penultimate and LIG deglaciation on glacial isostatic adjustment, this excess loss of polar ice during the LIG can explain much of the relative sea level recorded by fossil coral reefs and speleothems at intermediate- and far-field sites.

Topical Chlorhexidine 0.2% versus Topical Natamycin 5% for the Treatment of Fungal Keratitis in Nepal: A Randomized Controlled Noninferiority Trial.

PURPOSE: To investigate if topical chlorhexidine 0.2%, which is low cost and easy to formulate, is noninferior to topical natamycin 5% for the treatment of filamentous fungal keratitis. DESIGN: Randomized controlled, single-masked, noninferiority clinical trial. PARTICIPANTS: Adults attending a tertiary-level ophthalmic hospital in Nepal with filamentous fungal infection confirmed on smear or confocal microscopy. METHODS: Participants were randomly allocated to receive topical chlorhexidine 0.2% or topical natamycin 5%. Primary analysis (intention-to-treat) was by linear regression, using baseline logarithm of the minimum angle of resolution (logMAR) best spectacle-corrected visual acuity (BSCVA) and treatment arm as prespecified covariates. Mixed fungal-bacterial infections were excluded from the primary analysis but included in secondary analyses and secondary safety-related outcomes. The noninferiority margin was 0.15 logMAR. This trial was registered with ISRCTN, number ISRCTN14332621. MAIN OUTCOME MEASURES: The primary outcome measure was BSCVA at 3 months. Secondary outcome measures included perforation or therapeutic penetrating keratoplasty by 90 days. RESULTS: Between June 3, 2019, and November 9, 2020, 354 eligible participants were enrolled and randomly assigned: 178 to chlorhexidine and 176 to natamycin. Primary outcome data were available for 153 and 151 of the chlorhexidine and natamycin groups, respectively. Of these, mixed bacterial-fungal infections were found in 20 cases (12/153 chlorhexidine, 8/151 natamycin) and excluded from the primary analysis. Therefore, 284 patients were assessed for the primary outcome (141 chlorhexidine, 143 natamycin). We did not find evidence to suggest chlorhexidine was noninferior to natamycin and in fact found strong evidence to suggest that natamycin-treated participants had significantly better 3-month BSCVA than chlorhexidine-treated participants, after adjusting for baseline BSCVA (regression coefficient, -0.30; 95% confidence interval [CI], -0.42 to -0.18; P < 0.001). There were more perforations and emergency corneal grafts in the chlorhexidine arm (24/175, 13.7%) than in the natamycin arm (10/173, 5.8%; P = 0.018, mixed infections included), whereas natamycin-treated cases were less likely to perforate or require an emergency corneal graft, after adjusting for baseline ulcer depth (odds ratio, 0.34; 95% CI, 0.15-0.79; P = 0.013). CONCLUSIONS: Treatment with natamycin is associated with significantly better visual acuity, with fewer adverse events, compared with treatment with chlorhexidine. Natamycin remains the preferred first-line monotherapy treatment for filamentous fungal keratitis.

In vivo confocal microscopy and trachomatous conjunctival scarring: Predictors for clinical progression.

IMPORTANCE: In vivo confocal microscopy (IVCM) provides high-resolution images of the ocular surface and has been validated in trachomatous conjunctival scarring. BACKGROUND: This study used IVCM to identify parameters associated with clinical scarring progression. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 800 participants in Northern Tanzania with trachomatous scarring. METHODS: Participants underwent clinical examination, photography and IVCM at baseline and 24-months. Clinical progression of scarring was defined by comparing baseline and 24-month photographs. Masked grading of IVCM images was used to identify scarring at both time points. Multivariable logistic regression was used to assess factors associated with clinical progression. MAIN OUTCOME MEASURES: Risk factors associated with clinical scarring progression. RESULTS: Clinical and IVCM assessment of 800 participants were performed at baseline, with 617 (77.1%) seen at 24-months. Of these, 438 of 617 (71.0%) had gradable IVCM images at both time points and 342 of 438 (78.1%) of these could be graded as showing definite clinical progression or no progression on image comparison. Clinical progression was found to occur in 79 of 342 (23.1%). After adjusting for age and sex, clinical scarring progression was strongly associated with a high IVCM connective tissue organization score at both baseline (odds ratio [OR] = 1.84 for each increase in scarring category; P = .002) and 24-months (OR = 1.60; P = .02). Dendritiform cells present at 24-months were strongly associated with clinical scarring progression after adjustment (OR = 2.62; P = .03). CONCLUSIONS AND RELEVANCE: Quantitative IVCM parameters, including connective tissue organization score and the presence of dendritiform cells, are associated with disease progression and may be useful markers in trachoma and other conjunctival fibrotic diseases.

Telephone follow-up for cataract surgery: feasibility and patient satisfaction study.

Purpose - The purpose of this paper is to investigate the feasibility of telephone follow-up (TFU) after uncomplicated cataract surgery in low-risk patients and patient satisfaction with this alternative clinical pathway. Design/methodology/approach - Prospective, non-randomised cohort study. A ten-point subjective ophthalmic assessment questionnaire and a six-point patient satisfaction questionnaire were administered to patients following routine cataract surgery at two to three weeks post-procedure. All patients were offered a further clinic review if required. Exclusion criteria comprised ophthalmic co-morbidities, hearing/language impairment and high risk of post-operative complications. Patient notes were retrospectively reviewed over the study period to ensure no additional emergency attendances took place. Findings - Over three months, 50 eyes of 50 patients (mean age: 80; age range 60-91; 66 per cent second eye surgery) underwent uncomplicated phacoemulsification surgery received a TFU at 12-24 days (mean: 16 days) post-operatively. Subjective visual acuity was graded as good by 92 per cent of patients; 72 per cent patients reported no pain and 20 per cent reported mild occasional grittiness. Patient satisfaction was graded 8.9 out of 10; 81.6 per cent defined TFU as convenient and 75.5 per cent of patients preferred TFU to routine outpatient review. No additional visits were required. Research limitations/implications - Non-randomised with no control group; small sample size. One patient was unable to be contacted. Practical implications - Post-operative TFU can be suitably targeted to low-risk patients following uncomplicated cataract surgery. This study demonstrated a high patient satisfaction. A larger, randomised study is in progress to assess this further. Originality/value - This is the first study reporting TFU results and patient satisfaction to the usual alternative two-week outpatient review.

A Heat Emergency: Urban Heat Exposure and Access to Refuge in Richmond, VA.

The urban heat island effect exacerbates independent climate change-induced shifts toward longer, stronger, and more frequent heat extremes. Environmental inequity, driven by a history of racially motivated urban planning policies, has led particular demographics to bear the worst impacts of urban heat exposure and thus also climate change. These impacts cause adverse health outcomes in the form of heat emergencies. Through a novel demographic and spatial analysis of heat-related illness Emergency Medical Services data from Richmond, Virginia, this study investigates the relationships between heat health emergencies and intra-urban heat islands quantified through three heat exposure metrics. We also evaluate the accessibility of built refuge from urban heat in the form of public transit infrastructure, libraries, and government cooling centers in relation to these emergencies. We found that heat emergencies are inequitably distributed among racial, age, and socioeconomic groups in Richmond, particularly among residents identified as Male, Black or African American, 50+ years old, and experiencing mental health, intoxication, and/or homelessness. We found significant associations between the location of these heat emergencies and urban heat islands as estimated from remotely-sensed surface and community science-derived air temperature metrics, but not a co-estimated heat index. We also found that available refuge facilities are insufficiently located to protect individuals with reduced mobility across areas with the highest number of heat-related health emergencies. Community involvement in the mitigation and management of extreme heat threats, especially for those disproportionately impacted, is necessary to decrease the number of summertime heat illnesses.

Improving polymerase chain reaction diagnostic rates for herpes simplex keratitis: results of a pilot study.

Background: Laboratory confirmation is crucial for diagnosis and management of herpes simplex virus (HSV) keratitis. However, the sensitivity of polymerase chain reaction (PCR) in keratitis is low (25%) compared with that of mucocutaneous disease (75%). We developed an educational intervention aimed at improving the diagnostic yield of PCR. Methods: The medical records of keratitis cases seen at the emergency department of a London tertiary ophthalmic referral hospital over two distinct periods, before and after an educational program on swab technique, were reviewed retrospectively. Results: A total of 252 HSV cases were included. Increases in the laboratory-confirmed diagnosis of HSV-1 were observed, in both first presentations (11.1%-57.7%) and recurrent cases (20%-57.6%). The rate of positive HSV-1 PCR in eyes with an epithelial defect increased from 19% pre-intervention to 62% post intervention. Notably, 3% were positive for varicella zoster virus DNA, and there was a single case of Acanthamoeba keratitis. Conclusion: Our results suggest that, with proper swabbing technique, PCR may be more sensitive than previously reported.

Incidence of Acanthamoeba Keratitis in the United Kingdom in 2015: A Prospective National Survey.

PURPOSE: The aims of this study were to quantify the incidence of Acanthamoeba keratitis (AK) in the United Kingdom and investigate risk factors and management parameters. METHODS: This was a prospective population-based study from January to December 2015 through the British Ophthalmic Surveillance Unit. Data were collected on demographics, clinical features, and management. Incidence rates were calculated from estimates of population and contact lens (CL) user numbers. Statistical analysis compared annualized incidences per million and altered risk ratios for AK with the England and Wales 24 months 1997/1998 to 1998/1999 study. RESULTS: The study identified 124 AK cases, an overall incidence of 2.35 per million. CL wearers accounted for 108 of 124 cases (87%), in whom the AK incidence was 26.94 per million. Herpes keratitis was initially misdiagnosed in 25 of 124 cases (20.2%). The highest incidence of AK was among planned replacement soft CL (PRSCL) wearers (50.65 per million), 7-fold greater than for daily disposable CL (DDSCL) users (7.24 per million). There was a significant increase in AK incidence ( P < 0.001) compared with both 1997/1998 [risk ratio 1.92, 95% confidence interval (CI) 1.38-2.66] and 1998/1999 (risk ratio 2.13, 95% CI 1.52-2.98) together with a higher incidence per million CL users of 26.94 versus 21.14 (1997/1998) and 17.53 (1998/1999). CONCLUSIONS: This study provides the first published data on the nationwide incidence of AK in the United Kingdom. The findings confirm an increasing incidence of AK, particularly among contact lens wearers since 1997/1998 to 1998/1999. PRSCLs were identified as a significant risk factor compared with DDSCLs. Misdiagnosis and treatment delays remain an ongoing problem for patients with AK.

Local Ugandan Production of Stable 0.2% Chlorhexidine Eye Drops.

Purpose: The purpose of this study was to develop a protocol to prepare buffered chlorhexidine (CHX) eye drops (0.2% w/v) in the United Kingdom that can be reproduced at a production facility in Uganda. Buffered CHX eye drops can prevent CHX degradation and improve ocular tolerability during the treatment of fungal keratitis. Methods: Buffered CHX eye drops in amber glass containers were prepared using sodium acetate buffer at pH 5.90 to 6.75. Two commercial CHX solutions and CHX in water were used as controls. Eye drops were stored at 40°C (70% humidity, 21 months) in the United Kingdom and at ambient temperature in Uganda (30 months). High-performance liquid chromatography was used to determine CHX stability over time, and pH was monitored. Sterility was achieved using an autoclave (121°C, 15 minutes) and water bath (100°C, 30 minutes). Results: The pH of acetate-buffered CHX eye drops did not change over 21 months at 40°C or at ambient temperature (30 months), whereas the pH of the unbuffered aqueous CHX displayed significant fluctuations, with an increase in acidity. The CHX concentration remained the same in both buffered and unbuffered eye-drop solutions. Eye drops sterilization was successful using an autoclave and a water bath. Conclusions: Stable, sterile, buffered CHX eye drops (pH 6.75) were successfully prepared first in the United Kingdom and then reproducibly in Uganda. This eye drops can be prepared in a hospital or pharmacy setting with limited resources, thus providing a cost-effective treatment for fungal keratitis. Translational Relevance: A protocol has been developed to prepare buffered CHX eye drops in low- and middle-income countries to treat fungal keratitis.

Assessing Virginia cooling centers as a heat mitigation strategy.

In the United States, heat kills more people on average than any other weather-related hazard, thus the mitigation of heat-related impacts remains a significant issue within emergency management and public health communities. Research indicates the use of community cooling centers as an effective way to reduce vulnerability and adverse heat impacts. Using the Commonwealth of Virginia as a study location, this research evaluates the placement of cooling centers and assesses emergency managers' understanding of heat-related issues. Surveying local emergency managers and aggregating media reports, a total of 256 cooling centers were identified across 39 localities. Vulnerable populations differed in their proximity to the identified cooling centers. While over 65 percent of Virginians live within a 15-minute drive of a cooling center, this favors wealthier community members; less than 7 percent of Virginia's population below poverty lives within this same 15-minute driveshed. Spatial variability exists with many communities not opening any cooling centers. Within city and county hazard plans, the inclusion of comprehensive heat-related hazard information remains low. The research suggests further cooperation across government and nongovernment agencies is needed to improve the resilience to heat-health concerns across Virginia.

Comparison of culture, confocal microscopy and PCR in routine hospital use for microbial keratitis diagnosis.

AIMS: To evaluate the sensitivity and specificity of polymerase chain reaction (PCR), in vivo confocal microscopy (IVCM) and culture for microbial keratitis (MK) diagnosis. METHODS: Retrospective review of PCR, IVCM and culture results for MK diagnosis at Moorfields Eye Hospital between August 2013 and December 2014. RESULTS: PCR results were available for 259 MK patients with concurrent culture for 203/259 and IVCM for 149/259. Sensitivities and specificities with 95% confidence intervals [95% CI] were calculated for Acanthamoeba keratitis (AK) and fungal keratitis (FK), by comparison with culture, for both IVCM and PCR. For AK, FK and bacterial keratitis (BK) sensitivities were calculated, for each diagnostic method, by comparison with a composite reference standard (a positive result for one or more of culture, PCR or IVCM having a specificity of 100% by definition). For the latter, sensitivities with [95% CI] were: for AK, IVCM 77.1% [62.7-88.0%], PCR 63.3% [48.3-76.6%], culture 35.6 [21.9-51.2]; for FK, IVCM 81.8% [48.2-97.7%], PCR 30.8% [9.09-61.4%], culture 41.7% [15.2-72.3%]; for BK, PCR 25.0% [14.7-37.9%], culture 95.6% [87.6-99.1%]. CONCLUSION: IVCM was the most sensitive technique for AK and FK diagnosis but culture remains our gold standard for BK. These findings reflect results to be expected from service providers to UK ophthalmology units and demonstrates the need at our centre for ongoing diagnostic result audit leading to the potential to improve PCR diagnosis. Both FK and AK are now common in the UK; ophthalmology units need to have all these techniques available to optimise their MK management.

Management of Filamentous Fungal Keratitis: A Pragmatic Approach.

Filamentous fungal infections of the cornea known as filamentous fungal keratitis (FK) are challenging to treat. Topical natamycin 5% is usually first-line treatment following the results of several landmark clinical trials. However, even when treated intensively, infections may progress to corneal perforation. Current topical antifungals are not always effective and are often unavailable. Alternatives topical therapies to natamycin include voriconazole, chlorhexidine, amphotericin B and econazole. Surgical therapy, typically in the form of therapeutic penetrating keratoplasty, may be required for severe cases or following corneal perforation. Alternative treatment strategies such as intrastromal or intracameral injections of antifungals may be used. However, there is often no clear treatment strategy and the evidence to guide therapy is often lacking. This review describes the different treatment options and their evidence and provides a pragmatic approach to the management of fungal keratitis, particularly for clinicians working in tropical, low-resource settings where fungal keratitis is most prevalent.

The watery eye quality of life (WEQOL) questionnaire: a patient-reported outcome measure for surgically amenable epiphora.

OBJECTIVE OR PURPOSE: To develop and test a patient-reported outcome measure for assessing health-related quality of life (HRQOL) in surgically amenable epiphora. DESIGN: Questionnaire development and validation study. PARTICIPANTS: 201 patients with a cause of epiphora amenable to surgical intervention, recruited across three independent centres. METHODS, INTERVENTION OR TESTING: The watery eye quality of life (WEQOL) questionnaire was developed and refined according to defined psychometric standards. Both surgical and non-surgical participants completed WEQOL at baseline and follow-up (>3 months), along with the Lacrimal Symptom Questionnaire (Lac-Q), RAND Short Form Health Survey (SF-36) and Glasgow Benefit Inventory (GBI). Convergent validity of WEQOL was evaluated according to correlation (R > 0.40) with each of these additional tests. Responsiveness of WEQOL to intervention was evaluated according to patient-reported success. Test-retest reliability was assessed by the Bland-Altman method and intraclass correlation (ICC) in a subset of 64 participants at baseline. MAIN OUTCOME MEASURES: WEQOL construct validity, responsiveness and test-retest reliability. RESULTS: WEQOL was moderately correlated (R > 0.4) with the Lac-Q and several subscales of the SF-36 (physical role limitation, social, emotional role limitation and emotional well-being). A stronger correlation was found between the change in WEQOL at follow-up and GBI (R = 0.61). An appropriate graded response was found with a significant change in WEQOL score being observed in patients reporting successful (-28%, p < 0.0001) and partially successful surgery (-6%, p = 0.04), but not in those reporting unsuccessful surgery (+2%, p = 0.9). High test-retest reliability was observed (ICC = 0.93). CONCLUSIONS: The WEQOL questionnaire has been developed systematically according to modern psychometric standards and has been designed to evaluate the quality of life in patients with epiphora that is of a surgically amenable cause. In this study, it has demonstrated appropriate test-retest reliability, responsiveness and construct validity.

Microbial Keratitis in Nepal: Predicting the Microbial Aetiology from Clinical Features.

Fungal corneal infection (keratitis) is a common clinical problem in South Asia. However, it is often challenging to distinguish this from other aetiologies, such as bacteria or acanthamoeba. In this prospective study, we investigated clinical and epidemiological features that can predict the microbial aetiology of microbial keratitis in Nepal. We recruited patients presenting with keratitis to a tertiary eye hospital in lowland eastern Nepal between June 2019 and November 2020. A structured assessment, including demographics, history, and clinical signs, was carried out. The aetiology was investigated with in vivo confocal microscopy and corneal scrape for microscopy and culture. A predictor score was developed using odds ratios calculated to predict aetiology from features. A fungal cause was identified in 482/642 (75.1%) of cases, which increased to 532/642 (82.9%) when including mixed infections. Unusually, dematiaceous fungi accounted for half of the culture-positive cases (50.6%). Serrated infiltrate margins, patent nasolacrimal duct, raised corneal slough, and organic trauma were independently associated with fungal keratitis (p < 0.01). These four features were combined in a predictor score. The probability of fungal keratitis was 30.1% if one feature was present, increasing to 96.3% if all four were present. Whilst microbiological diagnosis is the "gold standard" to determine the aetiology of an infection, certain clinical signs can help direct the clinician to find a presumptive infectious cause, allowing appropriate treatment to be started without delay. Additionally, this study identified dematiaceous fungi, specifically Curvularia spp., as the main causative agent for fungal keratitis in this region. This novel finding warrants further research to understand potential implications and any trends over time.

Diagnosis of Fungal Keratitis in Low-Income Countries: Evaluation of Smear Microscopy, Culture, and In Vivo Confocal Microscopy in Nepal.

Clinically diagnosing fungal keratitis (FK) is challenging; diagnosis can be assisted by investigations including in vivo confocal microscopy (IVCM), smear microscopy, and culture. The aim of this study was to estimate the sensitivity in detecting fungal keratitis (FK) using IVCM, smear microscopy, and culture in a setting with a high prevalence of FK. In this cross-sectional study nested within a prospective cohort study, consecutive microbial keratitis (MK) patients attending a tertiary-referral eye hospital in south-eastern Nepal between June 2019 and November 2020 were recruited. IVCM and corneal scrapes for smear microscopy and culture were performed using a standardised protocol. Smear microscopy was performed using potassium hydroxide (KOH), Gram stain, and calcofluor white. The primary outcomes were sensitivities with 95% confidence intervals [95% CI] for IVCM, smear microscopy and culture, and for each different microscopy stain independently, to detect FK compared to a composite referent. We enrolled 642 patients with MK; 468/642 (72.9%) were filamentous FK, 32/642 (5.0%) were bacterial keratitis and 64/642 (10.0%) were mixed bacterial-filamentous FK, with one yeast infection (0.16%). No organism was identified in 77/642 (12.0%). Smear microscopy had the highest sensitivity (90.7% [87.9-93.1%]), followed by IVCM (89.8% [86.9-92.3%]) and culture (75.7% [71.8-79.3%]). Of the three smear microscopy stains, KOH had the highest sensitivity (85.3% [81.9-88.4%]), followed by Gram stain (83.2% [79.7-86.4%]) and calcofluor white (79.1% [75.4-82.5%]). Smear microscopy and IVCM were the most sensitive tools for identifying FK in our cohort. In low-resource settings we recommend clinicians perform corneal scrapes for microscopy using KOH and Gram staining. Culture remains an important tool to diagnose bacterial infection, identify causative fungi and enable antimicrobial susceptibility testing.

Delay in accessing definitive care for patients with microbial keratitis in Nepal.

Background: The aim of this study was to describe the health-seeking journey for patients with microbial keratitis (MK) in Nepal and identify factors associated with delay. Methods: Prospective cohort study where MK patients attending a large, tertiary-referral eye hospital in south-eastern Nepal between June 2019 and November 2020 were recruited. We collected demographic details, clinical history, and examination findings. Care-seeking journey details were captured including places attended, number of journeys, time from symptom onset, and costs. We compared "direct" with "indirect" presenters, analyzing for predictors of delay. Results: We enrolled 643 patients with MK. The majority (96%) self-referred. "Direct" attenders accounted for only 23.6% (152/643) of patients, the majority of "indirect" patients initially presented to a pharmacy (255/491). Over half (328/643) of all cases presented after at least 7 days. The total cost of care increased with increasing numbers of facilities visited (p < 0.001). Those living furthest away were least likely to present directly (p < 0.001). Factors independently associated with delayed presentation included distance >50 km from the eye hospital [aOR 5.760 (95% CI 1.829-18.14, p = 0.003)], previous antifungal use [aOR 4.706 (95% CI 3.139-5.360)], and two or more previous journeys [aOR 1.442 (95% CI 1.111-3.255)]. Conclusions: Most patients visited at least one facility prior to our institution, with time to presentation and costs increasing with the number of prior journeys. Distance to the eye hospital is a significant barrier to prompt, direct presentation. Based on these findings, improving access to eye care services, strengthening referral networks and encouraging early appropriate treatment are recommended to reduce delay, ultimately improving clinical outcomes.