In this autofiction novella, a young Chinese and Korean-American girl goes to college with a strong protestant Christian background. Hoping to take more ownership of her faith, she joins Genesis Church, a hip Asian-American church in Los Angeles during her freshman year. She quickly makes friends, finding the community and sense of belonging that she’s always searched for and enters her first relationship with a Chinese-American student involved in the college ministry’s leadership. As this seemingly perfect Christian relationship progresses, her religious boyfriend pressures her sexually, while also blaming her for not preventing this “sin.” After painful experiences a therapist later defines as rapes, she finally leaves her boyfriend. The novella opens after she’s left the relationship; she goes to the church’s pastor and his wife, but their support is flimsy and non-committal. She seeks comfort from her family as well, but her parents are judgmental about her lapsed virginity. Her roommate, a non-believer, becomes her main source of support. The novella follows her recovery and her attempts to integrate the ideas she inherited from her upbringing about virginity, femininity, and Christianity, with the person she’s now becoming.

Purpose

Epidemic and seasonal infectious conjunctivitis outbreaks can impact education, workforce, and economy adversely. Yet conjunctivitis typically is not a reportable disease, potentially delaying mitigating intervention. Our study objective was to determine if conjunctivitis epidemics could be identified using Google Trends search data.

Design

Search data for conjunctivitis-related and control search terms from 5 years and countries worldwide were obtained. Country and term were masked. Temporal scan statistics were applied to identify candidate epidemics. Candidates then were assessed for geotemporal concordance with an a priori defined collection of known reported conjunctivitis outbreaks, as a measure of sensitivity.

Participants

Populations by country that searched Google's search engine using our study terms.

Main outcome measures

Percent of known conjunctivitis outbreaks also found in the same country and period by our candidate epidemics, identified from conjunctivitis-related searches.

Results

We identified 135 candidate conjunctivitis epidemic periods from 77 countries. Compared with our a priori defined collection of known reported outbreaks, candidate conjunctivitis epidemics identified 18 of 26 (69% sensitivity) of the reported country-wide or island nationwide outbreaks, or both; 9 of 20 (45% sensitivity) of the reported region or district-wide outbreaks, or both; but far fewer nosocomial and reported smaller outbreaks. Similar overall and individual sensitivity, as well as specificity, were found on a country-level basis. We also found that 83% of our candidate epidemics had start dates before (of those, 20% were more than 12 weeks before) their concurrent reported outbreak's report issuance date. Permutation tests provided evidence that on average, conjunctivitis candidate epidemics occurred geotemporally closer to outbreak reports than chance alone suggests (P < 0.001) unlike control term candidates (P = 0.40).

Conclusions

Conjunctivitis outbreaks can be detected using temporal scan analysis of Google search data alone, with more than 80% detected before an outbreak report's issuance date, some as early as the reported outbreak's start date. Future approaches using data from smaller regions, social media, and more search terms may improve sensitivity further and cross-validate detected candidates, allowing identification of candidate conjunctivitis epidemics from Internet search data potentially to complementarily benefit traditional reporting and detection systems to improve epidemic awareness.

The concept of a morphogen - a molecule that specifies two or more cell fates in a concentration-dependent manner - is paradigmatic in developmental biology. Much remains unknown, however, about the existence of morphogens in the developing vertebrate central nervous system (CNS), including the mouse dorsal telencephalic midline (DTM). Bone morphogenetic proteins (BMPs) are candidate DTM morphogens, and our previous work demonstrated BMP4 sufficiency to induce one DTM cell fate - that of choroid plexus epithelial cells (CPECs) - in a mouse embryonic stem cell (mESC) culture system. Here we used BMP4 in a modified mESC culture system to derive a second DTM fate, the cortical hem (CH). CH and CPEC markers were induced by BMP4 in a concentration-dependent manner consistent with in vivo development. BMP4 concentrations that led to CH fate also promoted markers for Cajal-Retzius neurons, which are known CH derivatives. Interestingly, single BMP4 administrations also sufficed for appropriate temporal regulation of CH, CPEC, and cortical genes, with initially broad and overlapping dose-response profiles that sharpened over time. BMP4 concentrations that yielded CH- or CPEC-enriched populations also had different steady-state levels of phospho-SMAD1/5/8, suggesting that differences in BMP signaling intensity underlie DTM fate choice. Surprisingly, inactivation of the cortical selector gene Lhx2 did not affect DTM expression levels, dose-response profiles, or timing in response to BMP4, although neural progenitor genes were downregulated. These data indicate that BMP4 can act as a classic morphogen to orchestrate both spatial and temporal aspects of DTM fate acquisition, and can do so in the absence of Lhx2.

Influenza viruses are associated with a substantial global burden of morbidity and mortality every year. Estimates of influenza-associated mortality often vary between studies due to differences in study settings, methods, and measurement of outcomes. We reviewed 103 published articles assessing population-based influenza-associated mortality through searches of PubMed and Embase, and we identified considerable variation in the statistical methods used across studies. Studies using regression models with an influenza activity proxy applied 4 approaches to estimate influenza-associated mortality. The estimates increased with age and ranged widely, from -0.3-1.3 and 0.6-8.3 respiratory deaths per 100,000 population for children and adults, respectively, to 4-119 respiratory deaths per 100,000 population for older adults. Meta-regression analysis identified that study design features were associated with the observed variation in estimates. The estimates increased with broader cause-of-death classification and were higher for older adults than for children. The multiplier methods tended to produce lower estimates, while Serfling-type models were associated with higher estimates than other methods. No average estimate of excess mortality could reliably be made due to the substantial variability of the estimates, partially attributable to methodological differences in the studies. Standardization of methodology in estimation of influenza-associated mortality would permit improved comparisons in the future.

Purpose

To measure photoreceptor packing density and S-cone spatial resolution as a function of retinal eccentricity in patients with enhanced S-cone syndrome (ESCS) and to discuss the possible mechanisms supporting their supernormal S-cone acuity.

Methods

We used an adaptive optics scanning laser ophthalmoscope (AOSLO) to characterize photoreceptor packing. A custom non-AO display channel was used to measure L/M- and S-cone-mediated visual acuity during AOSLO imaging. Acuity measurements were obtained using a four-alternative, forced-choice, tumbling E paradigm along the temporal meridian between the fovea and 4° eccentricity in five of six patients and in seven control subjects. L/M acuity was tested by presenting long-pass-filtered optotypes on a black background, excluding wavelengths to which S-cones are sensitive. S-cone isolation was achieved using a two-color, blue-on-yellow chromatic adaptation method that was validated on three control subjects.

Results

Inter-cone spacing measurements revealed a near-uniform cone density profile (ranging from 0.9-1.5 arcmin spacing) throughout the macula in ESCS. For comparison, normal cone density decreases by a factor of 14 from the fovea to 6°. Cone spacing of ESCS subjects was higher than normal in the fovea and subnormal beyond 2°. Compared to the control subjects (n = 7), S-cone-mediated acuities in patients with ESCS were normal near the fovea and became increasingly supernormal with retinal eccentricity. Beyond 2°, S-cone acuities were superior to L/M-cone-mediated acuity in the ESCS cohort, a reversal of the trend observed in normal retinas.

Conclusions

Higher than normal parafoveal cone densities (presumably dominated by S-cones) confer better than normal S-cone-mediated acuity in ESCS subjects.

Purpose

To study cone structure and function in patients with retinitis pigmentosa (RP) owing to mutations in rhodopsin (RHO), expressed in rod outer segments, and mutations in the RP-GTPase regulator (RPGR) gene, expressed in the connecting cilium of rods and cones.

Methods

Four eyes of 4 patients with RHO mutations, 5 eyes of 5 patients with RPGR mutations, and 4 eyes of 4 normal subjects were studied. Cone structure was studied with confocal and split-detector adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral-domain optical coherence tomography. Retinal function was measured using a 543-nm AOSLO-mediated adaptive optics microperimetry (AOMP) stimulus. The ratio of sensitivity to cone density was compared between groups using the Wilcoxon rank-sum test.

Results

AOMP sensitivity/cone density in patients with RPGR mutations was significantly lower than normal (P < 0.001) and lower than patients with RHO mutations (P < 0.015), whereas patients with RHO mutations were similar to normal (P > 0.9).

Conclusions

Retinal sensitivity/cone density was lower in patients with RPGR mutations than normal and lower than patients with RHO mutations, perhaps because cones express RPGR and degenerate primarily, whereas cones in eyes with RHO mutations die secondary to rod degeneration. High-resolution microperimetry can reveal differences in cone degeneration in patients with different forms of RP.

Purpose

To determine the abundance and multimodal visibility of drusen and basal linear deposit (BLinD) in early age-related macular degeneration.

Methods

A 69-year-old white man was imaged by color fundus photography and red free photography, fundus autofluorescence, and optical coherence tomography. From en face images, we determined the drusen field, drusen area, and equivalent diameters of individual drusen. From high-resolution light-microscopic histology (6 months after the last clinic visit), we determined the area of drusen, BLinD, and pre-BLinD in a subretinal pigment epithelium-basal lamina lipid field.

Results

In right and left eyes, respectively, BLinD covered 40% and 46% of the lipid field, versus 21% and 14% covered by drusen. The lipid field was covered 60% to 61% by Drusen + BLinD and 65% to 72% by BLinD + pre-BLinD. In the left eye, the drusen area on color fundus photography (0.18 mm) and red free (0.28 mm) was smaller than the drusen area on histology (1.16 mm). Among drusen confirmed by optical coherence tomography, 55.1% and 56.6% were observed on red free and fundus autofluorescence, respectively.

Conclusion

Basal linear deposit covered 1.9 and 3.4-fold more fundus area than soft drusen, silently increasing progression risk. Improved visualization of BLinD and readouts of the retinal pigment epithelium health over lipid will assist population surveillance, early detection, and trial outcome measures.

BACKGROUND: Many countries/regions implemented strict border measures (e.g., 14-day quarantines) as a blanket policy to prevent COVID-19 importations, while proposed travel bubbles as an alternative to reduce the impact of border controls. We aim to examine the differential importation risks with departure origins and post-arrival controls. METHODS: We developed a Bayesian framework to model disease progress of COVID-19 and the effectiveness of travel measures and inferred the origin-specific disease prevalence among inbound travellers, using data on passengers arriving in Hong Kong and laboratory-confirmed imported cases. We estimated the origin-specific risks of releasing infectious travellers under different control strategies and traveller volumes. We also estimated the risk of having released infectious travellers when a resurgence occurs in departure locations with no imported cases during a certain period. FINDINGS: Under the then strict controls of 14-day quarantine and testing on day 12, the Philippines imposed the greatest importation risk among the studied countries/regions (95.8% of releasing at least one infectious traveller, 95% credible interval (CrI), 94.8-96.6%). This was higher than that from low prevalence countries/regions (e.g., 23.4%, 95% CrI, 21.6-25.3% for Taiwan) if controls relaxed (i.e., 7-day quarantine and test on day 5). Increased traveller volumes and resurgence in departure locations with low prevalence under relaxed controls did not impose a greater importation risk than high prevalence locations under stricter controls. INTERPRETATION: Moderate relaxation of control measures for travellers arriving from low prevalence locations did not impose higher risks of community outbreaks than strict controls on travellers from high prevalence locations. FUNDING: Health and Medical Research Fund, Hong Kong.

Metastatic non-small cell lung cancer (NSCLC) is a highly fatal and immunogenic malignancy. Although the immune system is known to recognize these tumor cells, one mechanism by which NSCLC can evade the immune system is via overexpression of programmed cell death ligand 1 (PD-L1). Recent clinical trials of PD-1 and PD-L1 inhibitors have returned promising clinical responses. Important for personalizing therapy, patients with higher intensity staining for PD-L1 on tumor biopsies responded better. Thus, there has been interest in using PD-L1 tumor expression as a criterion for patient selection. Currently available methods of screening involve invasive tumor biopsy, followed by histological grading of PD-L1 levels. Biopsies have a high risk of complications, and only allow sampling from limited tumor sections, which may not reflect overall tumor heterogeneity. Circulating tumor cell (CTC) PD-L1 levels could aid in screening patients, and could supplement tissue PD-L1 biopsy results by testing PD-L1 expression from disseminated tumor sites. Towards establishing CTCs as a screening tool, we developed a protocol to isolate CTCs at high purity and immunostain for PD-L1. Monitoring of PD-L1 expression on CTCs could be an additional biomarker for precision medicine that may help in determining response to immunotherapies.

Purpose

To compare cone spacing and choriocapillaris (CC) perfusion adjacent to geographic atrophy (GA) in patients with age-related macular degeneration (AMD) and age-similar normal eyes.

Methods

Subjects were imaged using adaptive optics scanning laser ophthalmoscopy (AOSLO), fundus autofluorescence (FAF), and swept-source optical coherence tomography angiography. The GA border was identified using FAF images; CC flow void was analyzed in 1° regions extending from the GA border. A grader masked to CC perfusion selected regions of interest (ROIs) with unambiguous cone mosaics in AOSLO images. At each ROI, cone spacing and CC flow void were converted to Z-scores (standard deviations from the mean of 12 normal eyes aged 50 to 81 years for cone spacing, and 60 normal eyes age 51 to 88 years for CC flow void).

Results

Excluding regions of GA and drusen, CC flow void in eight eyes of six patients with AMD was significantly greater than in four age-similar normal eyes (exact permutation test, P = 0.024). CC flow void was negatively correlated with distance from the GA margin (r = -0.35; 95% confidence interval [CI], -0.53 to -0.12). Increased cone spacing was significantly correlated with CC flow void (r = 0.33; 95% CI, 0.12 to 0.59). Cone spacing was increased in 39% of ROIs, while CC flow void was increased in 96% of ROIs.

Conclusions

In eyes with GA due to AMD, CC hypoperfusion was significantly correlated with, and more extensive than, cone photoreceptor loss. The results suggest that reduced CC perfusion contributes to the development of GA.