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IntroductionAvailable evidence is mixed concerning associations between smoking status and COVID-19 clinical outcomes. Effects of nicotine replacement therapy (NRT) and vaccination status on COVID-19 outcomes in smokers are unknown.MethodsElectronic health record data from 104 590 COVID-19 patients hospitalized February 1, 2020 to September 30, 2021 in 21 U.S. health systems were analyzed to assess associations of smoking status, in-hospital NRT prescription, and vaccination status with in-hospital death and ICU admission.ResultsCurrent (n = 7764) and never smokers (n = 57 454) did not differ on outcomes after adjustment for age, sex, race, ethnicity, insurance, body mass index, and comorbidities. Former (vs never) smokers (n = 33 101) had higher adjusted odds of death (aOR, 1.11; 95% CI, 1.06-1.17) and ICU admission (aOR, 1.07; 95% CI, 1.04-1.11). Among current smokers, NRT prescription was associated with reduced mortality (aOR, 0.64; 95% CI, 0.50-0.82). Vaccination effects were significantly moderated by smoking status; vaccination was more strongly associated with reduced mortality among current (aOR, 0.29; 95% CI, 0.16-0.66) and former smokers (aOR, 0.47; 95% CI, 0.39-0.57) than for never smokers (aOR, 0.67; 95% CI, 0.57, 0.79). Vaccination was associated with reduced ICU admission more strongly among former (aOR, 0.74; 95% CI, 0.66-0.83) than never smokers (aOR, 0.87; 95% CI, 0.79-0.97).ConclusionsFormer but not current smokers hospitalized with COVID-19 are at higher risk for severe outcomes. SARS-CoV-2 vaccination is associated with better hospital outcomes in COVID-19 patients, especially current and former smokers. NRT during COVID-19 hospitalization may reduce mortality for current smokers.ImplicationsPrior findings regarding associations between smoking and severe COVID-19 disease outcomes have been inconsistent. This large cohort study suggests potential beneficial effects of nicotine replacement therapy on COVID-19 outcomes in current smokers and outsized benefits of SARS-CoV-2 vaccination in current and former smokers. Such findings may influence clinical practice and prevention efforts and motivate additional research that explores mechanisms for these effects.

BackgroundThere is mixed evidence about the relations of current versus past cancer with severe COVID-19 outcomes and how they vary by patient and cancer characteristics.MethodsElectronic health record data of 104,590 adult hospitalized patients with COVID-19 were obtained from 21 United States health systems from February 2020 through September 2021. In-hospital mortality and ICU admission were predicted from current and past cancer diagnoses. Moderation by patient characteristics, vaccination status, cancer type, and year of the pandemic was examined.Results6.8% of the patients had current (n = 7,141) and 6.5% had past (n = 6,749) cancer diagnoses. Current cancer predicted both severe outcomes but past cancer did not; adjusted odds ratios (aOR) for mortality were 1.58 [95% confidence interval (CI), 1.46-1.70] and 1.04 (95% CI, 0.96-1.13), respectively. Mortality rates decreased over the pandemic but the incremental risk of current cancer persisted, with the increment being larger among younger vs. older patients. Prior COVID-19 vaccination reduced mortality generally and among those with current cancer (aOR, 0.69; 95% CI, 0.53-0.90).ConclusionsCurrent cancer, especially among younger patients, posed a substantially increased risk for death and ICU admission among patients with COVID-19; prior COVID-19 vaccination mitigated the risk associated with current cancer. Past history of cancer was not associated with higher risks for severe COVID-19 outcomes for most cancer types.ImpactThis study clarifies the characteristics that modify the risk associated with cancer on severe COVID-19 outcomes across the first 20 months of the COVID-19 pandemic. See related commentary by Egan et al., p. 3.

Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.

Hepatitis E virus is a common cause of acute viral hepatitis. We analyzed reports of hepatitis E outbreaks among forcibly displaced populations in sub-Saharan Africa during 2010-2020. Twelve independent outbreaks occurred, and >30,000 cases were reported. Transmission was attributed to poor sanitation and overcrowding.

Main objectiveThere is limited information on how patient outcomes have changed during the COVID-19 pandemic. This study characterizes changes in mortality, intubation, and ICU admission rates during the first 20 months of the pandemic.Study design and methodsUniversity of Wisconsin researchers collected and harmonized electronic health record data from 1.1 million COVID-19 patients across 21 United States health systems from February 2020 through September 2021. The analysis comprised data from 104,590 adult hospitalized COVID-19 patients. Inclusion criteria for the analysis were: (1) age 18 years or older; (2) COVID-19 ICD-10 diagnosis during hospitalization and/or a positive COVID-19 PCR test in a 14-day window (+/- 7 days of hospital admission); and (3) health system contact prior to COVID-19 hospitalization. Outcomes assessed were: (1) mortality (primary), (2) endotracheal intubation, and (3) ICU admission.Results and significanceThe 104,590 hospitalized participants had a mean age of 61.7 years and were 50.4% female, 24% Black, and 56.8% White. Overall risk-standardized mortality (adjusted for age, sex, race, ethnicity, body mass index, insurance status and medical comorbidities) declined from 16% of hospitalized COVID-19 patients (95% CI: 16% to 17%) early in the pandemic (February-April 2020) to 9% (CI: 9% to 10%) later (July-September 2021). Among subpopulations, males (vs. females), those on Medicare (vs. those on commercial insurance), the severely obese (vs. normal weight), and those aged 60 and older (vs. younger individuals) had especially high mortality rates both early and late in the pandemic. ICU admission and intubation rates also declined across these 20 months.ConclusionsMortality, intubation, and ICU admission rates improved markedly over the first 20 months of the pandemic among adult hospitalized COVID-19 patients although gains varied by subpopulation. These data provide important information on the course of COVID-19 and identify hospitalized patient groups at heightened risk for negative outcomes.Trial registrationClinicalTrials.gov Identifier: NCT04506528 (https://clinicaltrials.gov/ct2/show/NCT04506528).

ObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.MethodsConfounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses.ResultsOur analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.SignificanceOur results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.

BackgroundMultidisciplinary and multisectoral approaches such as One Health and related concepts (e.g., Planetary Health, EcoHealth) offer opportunities for synergistic expertise to address complex health threats. The connections between humans, animals, and the environment necessitate collaboration among sectors to comprehensively understand and reduce risks and consequences on health and wellbeing. One Health approaches are increasingly emphasized for national and international plans and strategies related to zoonotic diseases, food safety, antimicrobial resistance, and climate change, but to date, the possible applications in clinical practice and benefits impacting human health are largely missing.MethodsIn 2018 the "Application of the One Health Approach to Global Health Centers" conference held at the Albert Einstein College of Medicine convened experts involved in One Health policy and practice. The conference examined issues relevant to One Health approaches, sharing examples of challenges and successes to guide application to medical school curricula and clinical practice for human health. This paper presents a synthesis of conference proceedings, framed around objectives identified from presentations and audience feedback.Findings and recommendationsThe following objectives provide opportunities for One Health involvement and benefits for medical schools and global health centers by: 1) Improving One Health resource sharing in global health and medical education; 2) Creating pathways for information flow in clinical medicine and global health practice; 3) Developing innovative partnerships for improved health sector outcomes; and 4) Informing and empowering health through public outreach. These objectives can leverage existing resources to deliver value to additional settings and stakeholders through resource efficiency, more holistic and effective service delivery, and greater ability to manage determinants of poor health status. We encourage medical and global health educators, practitioners, and students to explore entry points where One Health can add value to their work from local to global scale.

IntroductionHIV self-testing (HIVST) in outpatient departments (OPD) is a promising strategy for HIV testing in Malawi, given high OPD patient volumes and substantial wait times. To evaluate the relative cost and expected impact of facility-based HIVST (FB-HIVST) at OPDs in Malawi for increasing HIV status awareness, we conducted an economic evaluation of an HIVST cluster-randomized controlled trial.MethodsA cluster-randomized trial was conducted at 15 sites in Malawi from September 2017 to February 2018 with three arms: 1) Standard provider-initiated-testing-and-counselling (PITC); 2) Optimized PITC (additional provider training and job-aids) and 3) FB-HIVST (HIVST demonstration, distribution and kit use in OPD, private kit interpretation and optional HIV counselling). The total production cost per newly identified positive and per person newly initiated on ART were calculated by study arm. These were calculated as the total cost of testing everyone divided by the number of newly identified positives; and the total cost of testing everyone divided by the number of those initiated on ART. Cost-outcomes were calculated under three cost scenarios: (1) full study costs, (2) routine implementation costs and (3) routine implementation + reduced cost for HIVST kits.ResultsThe average cost per person newly diagnosed in the full study cost scenario was $101, $156 and $189, and cost per person initiated on ART was $121, $156 and $279 for Standard PITC, Optimized PITC and FB-HIVST respectively. In the routine implementation cost scenario, the average cost per person newly diagnosed was reduced to $83, and $93, and cost per person initiated on ART to $83, and $137 for Optimized PITC and FB-HIVST respectively. In the negotiated HIVST cost scenario, the average cost per person newly diagnosed was reduced to $55 and cost per person newly initiated on ART reduced to $81 in the FB-HIVST arm.ConclusionsWhile the cost per new ART initiation through FB-HIVST was higher than Standard PITC, FB-HIVST could become cost-saving compared to PITC if the cost of kits is reduced or if treatment linkage rate were increased in the FB-HIVST arm. For high volume OPDs, HIVST may increase facility capacity and increase the number of newly diagnosed positives.

Unusually large outbreaks of mumps across the United States in 2016 and 2017 raised questions about the extent of mumps circulation and the relationship between these and prior outbreaks. We paired epidemiological data from public health investigations with analysis of mumps virus whole genome sequences from 201 infected individuals, focusing on Massachusetts university communities. Our analysis suggests continuous, undetected circulation of mumps locally and nationally, including multiple independent introductions into Massachusetts and into individual communities. Despite the presence of these multiple mumps virus lineages, the genomic data show that one lineage has dominated in the US since at least 2006. Widespread transmission was surprising given high vaccination rates, but we found no genetic evidence that variants arising during this outbreak contributed to vaccine escape. Viral genomic data allowed us to reconstruct mumps transmission links not evident from epidemiological data or standard single-gene surveillance efforts and also revealed connections between apparently unrelated mumps outbreaks.

BackgroundMedia reporting on communicable diseases has been demonstrated to affect the perception of the public. Communicable disease reporting related to foreign-born persons has not yet been evaluated.ObjectiveExamine how political leaning in the media affects reporting on tuberculosis (TB) in foreign-born persons.MethodsHealthMap, a digital surveillance platform that aggregates news sources on global infectious diseases, was used. Data was queried for media reports from the U.S. between 2011-2019, containing the term "TB" or "tuberculosis" and "foreign born", "refugee (s)," or "im (migrants)." Reports were reviewed to exclude duplicates and non-human cases. Each media source was rated using two independent media bias indicators to assess political leaning. Forty-six non-tuberculosis reports were randomly sampled and evaluated as a control. Two independent reviewers performed sentiment analysis on each report.ResultsOf 891 TB-associated reports in the US, 46 referenced foreign-born individuals, and were included in this analysis. 60.9% (28) of reports were published in right-leaning news media and 6.5% (3) of reports in left-leaning media, while 39.1% (18) of the control group reports were published in left- leaning media and 10.9% (5) in right-leaning media (p < .001). 43% (20) of all study reports were posted in 2016. Sentiment analysis revealed that right-leaning reports often portrayed foreign-born persons negatively.ConclusionPreliminary data from this pilot suggest that political leaning may affect reporting on TB in US foreign-born populations. Right-leaning news organizations produced the most reports on TB, and the majority of these reports portrayed foreign-born persons negatively. In addition, the control group comprised of non-TB, non-foreign born reports on communicable diseases featured a higher percentage of left-leaning news outlets, suggesting that reporting on TB in foreign-born individuals may be of greater interest to right-leaning outlets. Further investigation both in the U.S. and globally is needed.

BackgroundTo apply a novel method to adjust for HIV knowledge as an unmeasured confounder for the effect of unsafe injection on future HIV testing.MethodsThe data were collected from 601 HIV-negative persons who inject drugs (PWID) from a cohort in San Francisco. The panel-data generalized estimating equations (GEE) technique was used to estimate the adjusted risk ratio (RR) for the effect of unsafe injection on not being tested (NBT) for HIV. Expert opinion quantified the bias parameters to adjust for insufficient knowledge about HIV transmission as an unmeasured confounder using Bayesian bias analysis.ResultsExpert opinion estimated that 2.5%-40.0% of PWID with unsafe injection had insufficient HIV knowledge; whereas 1.0%-20.0% who practiced safe injection had insufficient knowledge. Experts also estimated the RR for the association between insufficient knowledge and NBT for HIV as 1.1-5.0. The RR estimate for the association between unsafe injection and NBT for HIV, adjusted for measured confounders, was 0.96 (95% confidence interval: 0.89,1.03). However, the RR estimate decreased to 0.82 (95% credible interval: 0.64, 0.99) after adjusting for insufficient knowledge as an unmeasured confounder.ConclusionOur Bayesian approach that uses expert opinion to adjust for unmeasured confounders revealed that PWID who practice unsafe injection are more likely to be tested for HIV - an association that was not seen by conventional analysis.

We examined correlates of late and delayed initiation of antiretroviral therapy (ART) in British Columbia, Canada. From December 2013 to December 2015 we recruited treatment-naïve people living with HIV who initiated ART within the previous year. 'Late initiation' was defined as CD4 cell count ≤500 cells/µL at ART initiation and 'delayed initiation' as ≥1 year between HIV diagnosis and initiation. Multivariable logistic regression assessed independent correlates of late and delayed initiation. Of 87 participants, 44 (51%) initiated late and 22 (26%) delayed initiation. Delayed initiation was positively associated with older age (adjusted odds ratio [AOR]: 1.06 per year, 95% confidence interval [95% CI]: 1.01-1.12) and inversely associated with wanting to start ART at diagnosis (AOR: 0.06, 95% CI: 0.02-0.21). Variables associated with late initiation were older age (AOR: 1.09 per year, 95% CI: 1.03-1.15) and medical reason(s) for initiation (AOR: 5.00, 95% CI: 1.41-17.86). Late initiation was less likely among those with greater perceived ART efficacy (AOR 0.94, 95% CI: 0.90-0.98) and history of incarceration (AOR: 0.12, 95% CI: 0.03-0.56). Disparities in timing of initiation were observed for age, perceived ART efficacy, and history of incarceration. Enhanced health services that address these factors may facilitate earlier treatment initiation.

BackgroundThe purpose of this study was to identify global trends in Listeria monocytogenes epidemiology using ProMED reports. ProMED is a publicly available, global outbreak reporting system that uses both informal and formal sources. In the context of Listeria, ProMED reports on atypical findings such as higher than average case counts, events from unusual sources, and multinational outbreaks.MethodsKeywords "Listeria" and "listeriosis" were utilized in the ProMED search engine covering the years 1996-2018. Issue date, countries involved, source, suspected and confirmed case counts, and fatalities were extracted. Data unique to each event, including commentary by content experts, were evaluated. When multiple reports regarding the same outbreak or recall were obtained, the last report pertaining to that outbreak was utilized. Rates of Listeria events over time were compared using a normal approximation to the Poisson distribution; p

Infectious disease outbreaks play an important role in global morbidity and mortality. Real-time epidemic forecasting provides an opportunity to predict geographic disease spread as well as case counts to better inform public health interventions when outbreaks occur. Challenges and recent advances in predictive modeling are discussed here. We identified data needs in the areas of epidemic surveillance, mobility, host and environmental susceptibility, pathogen transmissibility, population density, and healthcare capacity. Constraints in standardized case definitions and timely data sharing can limit the precision of predictive models. Resource-limited settings present particular challenges for accurate epidemic forecasting due to the lack of granular data available. Incorporating novel data streams into modeling efforts is an important consideration for the future as technology penetration continues to improve on a global level. Recent advances in machine-learning, increased collaboration between modelers, the use of stochastic semi-mechanistic models, real-time digital disease surveillance data, and open data sharing provide opportunities for refining forecasts for future epidemics. Epidemic forecasting using predictive modeling is an important tool for outbreak preparedness and response efforts. Despite the presence of some data gaps at present, opportunities and advancements in innovative data streams provide additional support for modeling future epidemics.

This invited editorial introduces a special issue of Epidemiology & Infection while also discussing advances in emerging infectious diseases.

BackgroundFormate is an important metabolite that serves as a donor of one-carbon groups to the intracellular tetrahydrofolate pool. However, little is known of its circulating concentrations or of their determinants.ObjectiveThis study aimed to define formate concentrations and their determinants in a healthy young population.DesignSerum formate was measured in 1701 participants from the Trinity Student Study. The participants were men and women, aged 18 to 28 y, enrolled at Trinity College, Dublin. Formate concentrations were compared with other one-carbon metabolites, vitamin status, potential formate precursors, genetic polymorphisms, and lifestyle factors.ResultsSerum formate concentrations ranged from 8.7 to 96.5 µM, with a mean of 25.9 µM. Formate concentrations were significantly higher in women than in men; oral contraceptive use did not further affect them. There was no effect of smoking or of alcohol ingestion, but the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) 677C→T (rs1801133) polymorphism was associated with a significantly decreased formate concentration. Formate was positively associated with potential metabolic precursors (serine, methionine, tryptophan, choline) but not with glycine. Formate concentrations were positively related to serum folate and negatively related to serum vitamin B-12.ConclusionsFormate concentrations were sensitive to the concentrations of metabolic precursors. In view of the increased susceptibility of women with the TT genotype of MTHFR to give birth to infants with neural tube defects as well as the effectiveness of formate supplementation in decreasing the incidence of folate-resistant neural tube defects in susceptible mice, it will be important to understand how this genotype decreases the serum formate concentration. This trial was registered at www.clinicaltrials.gov as NCT03305900.

A remarkable feature of human vision is that the retina and brain have evolved circuitry to extract useful spatial and spectral information from signals originating in a photoreceptor mosaic with trichromatic constituents that vary widely in their relative numbers and local spatial configurations. A critical early transformation applied to cone signals is horizontal-cell-mediated lateral inhibition, which imparts a spatially antagonistic surround to individual cone receptive fields, a signature inherited by downstream neurons and implicated in color signaling. In the peripheral retina, the functional connectivity of cone inputs to the circuitry that mediates lateral inhibition is not cone-type specific, but whether these wiring schemes are maintained closer to the fovea remains unsettled, in part because central retinal anatomy is not easily amenable to direct physiological assessment. Here, we demonstrate how the precise topography of the long (L)-, middle (M)-, and short (S)-wavelength-sensitive cones in the human parafovea (1.5° eccentricity) shapes perceptual sensitivity. We used adaptive optics microstimulation to measure psychophysical detection thresholds from individual cones with spectral types that had been classified independently by absorptance imaging. Measured against chromatic adapting backgrounds, the sensitivities of L and M cones were, on average, receptor-type specific, but individual cone thresholds varied systematically with the number of preferentially activated cones in the immediate neighborhood. The spatial and spectral patterns of these interactions suggest that interneurons mediating lateral inhibition in the central retina, likely horizontal cells, establish functional connections with L and M cones indiscriminately, implying that the cone-selective circuitry supporting red-green color vision emerges after the first retinal synapse.SIGNIFICANCE STATEMENT We present evidence for spatially antagonistic interactions between individual, spectrally typed cones in the central retina of human observers using adaptive optics. Using chromatic adapting fields to modulate the relative steady-state activity of long (L)- and middle (M)-wavelength-sensitive cones, we found that single-cone detection thresholds varied predictably with the spectral demographics of the surrounding cones. The spatial scale and spectral pattern of these photoreceptor interactions were consistent with lateral inhibition mediated by retinal horizontal cells that receive nonselective input from L and M cones. These results demonstrate a clear link between the neural architecture of the visual system inputs-cone photoreceptors-and visual perception and have implications for the neural locus of the cone-specific circuitry supporting color vision.

Adaptive optics is a relatively new field, yet it is spreading rapidly and allows new questions to be asked about how the visual system is organized. The editors of this feature issue have posed a series of question to scientists involved in using adaptive optics in vision science. The questions are focused on three main areas. In the first we investigate the use of adaptive optics for psychophysical measurements of visual system function and for improving the optics of the eye. In the second, we look at the applications and impact of adaptive optics on retinal imaging and its promise for basic and applied research. In the third, we explore how adaptive optics is being used to improve our understanding of the neurophysiology of the visual system.

Backgrounds and aimsLow concentrations of plasma HDL-C are associated with the development of atherosclerotic cardiovascular diseases and type 2 diabetes. Here we aimed to explore the relationship between the in vivo fractional synthesis of triglycerides (fTG) in subcutaneous (s.q.) abdominal adipose tissue (AT), HDL-C concentrations and HDL particle size composition in non-diabetic humans.MethodsThe fTG in s.q. abdominal AT was measured in 16 non-diabetic volunteers (7 women, 9 men; Age: 49 ± 20 years; BMI: 31 ± 5 kg/m; Fasting Plasma Glucose: 90 ± 10 mg/dl) after (2)H2O labeling. HDL-C concentration and subclasses, large (L-HDL), intermediate (I-HDL) and small (S-HDL) were measured.ResultsLinear regression analyses demonstrated significant associations of fTG with plasma concentration of HDL-C (r = 0.625,p = 0.009) and percent contribution of L-HDL (r = 0.798,p

Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.

PurposeTo determine the light sensitivity of poorly reflective cones observed in retinas of normal subjects, and to establish a relationship between cone reflectivity and perceptual threshold.MethodsFive subjects (four male, one female) with normal vision were imaged longitudinally (7-26 imaging sessions, representing 82-896 days) using adaptive optics scanning laser ophthalmoscopy (AOSLO) to monitor cone reflectance. Ten cones with unusually low reflectivity, as well as 10 normally reflective cones serving as controls, were targeted for perceptual testing. Cone-sized stimuli were delivered to the targeted cones and luminance increment thresholds were quantified. Thresholds were measured three to five times per session for each cone in the 10 pairs, all located 2.2 to 3.3° from the center of gaze.ResultsCompared with other cones in the same retinal area, three of 10 monitored dark cones were persistently poorly reflective, while seven occasionally manifested normal reflectance. Tested psychophysically, all 10 dark cones had thresholds comparable with those from normally reflecting cones measured concurrently (P = 0.49). The variation observed in dark cone thresholds also matched the wide variation seen in a large population (n = 56 cone pairs, six subjects) of normal cones; in the latter, no correlation was found between cone reflectivity and threshold (P = 0.0502).ConclusionsLow cone reflectance cannot be used as a reliable indicator of cone sensitivity to light in normal retinas. To improve assessment of early retinal pathology, other diagnostic criteria should be employed along with imaging and cone-based microperimetry.

Breast tumors often show profound sensitivity to exogenous oxidative stress. Investigational agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) induces aryl hydrocarbon receptor (AhR)-mediated DNA damage in certain breast cancer cells. Since AhR agonists often elevate intracellular oxidative stress, we hypothesize that 5F 203 increases reactive oxygen species (ROS) to induce DNA damage, which thwarts breast cancer cell growth. We found that 5F 203 induced single-strand break formation. 5F 203 enhanced oxidative DNA damage that was specific to breast cancer cells sensitive to its cytotoxic actions, as it did not increase oxidative DNA damage or ROS formation in nontumorigenic MCF-10A breast epithelial cells. In contrast, AhR agonist and procarcinogen benzo[a]pyrene and its metabolite, 1,6-benzo[a]pyrene quinone, induced oxidative DNA damage and ROS formation, respectively, in MCF-10A cells. In sensitive breast cancer cells, 5F 203 activated ROS-responsive kinases: c-Jun-N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38). AhR antagonists (alpha-naphthoflavone, CH223191) or antioxidants (N-acetyl-l-cysteine, EUK-134) attenuated 5F 203-mediated JNK and p38 activation, depending on the cell type. Pharmacological inhibition of AhR, JNK, or p38 attenuated 5F 203-mediated increases in intracellular ROS, apoptosis, and single-strand break formation. 5F 203 induced the expression of cytoglobin, an oxidative stress-responsive gene and a putative tumor suppressor, which was diminished with AhR, JNK, or p38 inhibition. Additionally, 5F 203-mediated increases in ROS production and cytoglobin were suppressed in AHR100 cells (AhR ligand-unresponsive MCF-7 breast cancer cells). Our data demonstrate 5F 203 induces ROS-mediated DNA damage at least in part via AhR, JNK, or p38 activation and modulates the expression of oxidative stress-responsive genes such as cytoglobin to confer its anticancer action.

BackgroundNeural tube defects (NTDs), which are among the most common congenital malformations, are influenced by environmental and genetic factors. Low maternal folate is the strongest known contributing factor, making variants in genes in the folate metabolic pathway attractive candidates for NTD risk. Multiple studies have identified nominally significant allelic associations with NTDs. We tested whether associations detected in a large Irish cohort could be replicated in an independent population.MethodsReplication tests of 24 nominally significant NTD associations were performed in racially/ethnically matched populations. Family-based tests of fifteen nominally significant single nucleotide polymorphisms (SNPs) were repeated in a cohort of NTD trios (530 cases and their parents) from the United Kingdom, and case-control tests of nine nominally significant SNPs were repeated in a cohort (190 cases, 941 controls) from New York State (NYS). Secondary hypotheses involved evaluating the latter set of nine SNPs for NTD association using alternate case-control models and NTD groupings in white, African American and Hispanic cohorts from NYS.ResultsOf the 24 SNPs tested for replication, ADA rs452159 and MTR rs10925260 were significantly associated with isolated NTDs. Of the secondary tests performed, ARID1A rs11247593 was associated with NTDs in whites, and ALDH1A2 rs7169289 was associated with isolated NTDs in African Americans.ConclusionsWe report a number of associations between SNP genotypes and neural tube defects. These associations were nominally significant before correction for multiple hypothesis testing. These corrections are highly conservative for association studies of untested hypotheses, and may be too conservative for replication studies. We therefore believe the true effect of these four nominally significant SNPs on NTD risk will be more definitively determined by further study in other populations, and eventual meta-analysis.

In humans, experimental access to single sensory receptors is difficult to achieve, yet it is crucial for learning how the signals arising from each receptor are transformed into perception. By combining adaptive optics microstimulation with high-speed eye tracking, we show that retinal function can be probed at the level of the individual cone photoreceptor in living eyes. Classical psychometric functions were obtained from cone-sized microstimuli targeted to single photoreceptors. Revealed psychophysically, the cone mosaic also manifests a variable sensitivity to light across its surface that accords with a simple model of cone light capture. Because this microscopic grain of vision could be detected on the perceptual level, it suggests that photoreceptors can act individually to shape perception, if the normally suboptimal relay of light by the eye's optics is corrected. Thus the precise arrangement of cones and the exact placement of stimuli onto those cones create the initial retinal limits on signals mediating spatial vision.

ObjectiveWe aimed to evaluate the impact of a novel noninvasive oral pressure therapy (OPT) (Winx®, ApniCure) system on polysomnographic measures of sleep-disordered breathing, sleep architecture, and sleep stability in obstructive sleep apnea (OSA).Subjects and methodsA 4-week, multicenter, prospective, open-label, randomized, crossover, first-night order of control vs treatment, single-arm trial was conducted in five American Academy of Sleep Medicine (AASM) - accredited sleep clinics and one research laboratory. Sixty-three subjects (analysis cohort) were studied from a screening cohort of 367 subjects. The analysis cohort was 69.8% men, ages 53.6±8.9 years (mean±SD), body mass index of 32.3±4.5kg/m(2), with mild to severe OSA. At treatment initiation, subjects received random assignment to one night with and one without (control) treatment, and they were assessed again following 28 nights of treatment. Breathing and sleep architecture were assessed each night based on blind scoring by a single centralized scorer using AASM criteria.ResultsAverage nightly usage across the take-home period was 6.0±1.4h. There were no severe or serious device-related adverse events (AEs). Median apnea-hypopnea index (AHI) was 27.5 events per hour on the control night, 13.4 events per hour on the first treatment night, and 14.8 events per hour after 28days of treatment. A clinically significant response (treatment AHI ⩽10/h and ⩽50% of control values) was seen in 20 of the 63 subjects evaluated. Rapid eye movement percentage (REM%) was significantly increased, and N1%, stage shifts to N1 sleep, overall stage shifts, total awakenings, and arousals per hour were all significantly reduced at both treatment nights compared to controls. Mean Epworth sleepiness scale (ESS) was significantly reduced from 12.1 to 8.6 (Cohen d effect size, 0.68) in those untreated for two or more weeks prior to OPT study participation and remained unchanged in subjects who directly switched from continuous positive airway pressure (CPAP) therapy to OPT.ConclusionClinically significant improvements in sleep quality and continuity, AHI, ODI, ESS, and overall clinical status were achieved in an easily identified subgroup. OPT was safe and well-tolerated and nightly usage was high.

The occipital lobes were obtained after death from six adult subjects with monocular visual loss. Flat-mounts were processed for cytochrome oxidase (CO) to reveal metabolic activity in the primary (V1) and secondary (V2) visual cortices. Mean V1 surface area was 2643 mm2 (range, 1986-3477 mm2). Ocular dominance columns were present in all cases, having a mean width of 863 microm. There were 78-126 column pairs along the V1 perimeter. Human column patterns were highly variable, but in at least one person they resembled a scaled-up version of macaque columns. CO patches in the upper layers were centered on ocular dominance columns in layer 4C, with one exception. In this individual, the columns in a local area resembled those present in the squirrel monkey, and no evidence was found for column/patch alignment. In every subject, the blind spot of the contralateral eye was conspicuous as an oval region without ocular dominance columns. It provided a precise landmark for delineating the central 15 degrees of the visual field. A mean of 53.1% of striate cortex was devoted to the representation of the central 15 degrees. This fraction was less than the proportion of striate cortex allocated to the representation of the central 15 degrees in the macaque. Within the central 15 degrees, each eye occupied an equal territory. Beyond this eccentricity, the contralateral eye predominated, occupying 63% of the cortex. In one subject, monocular visual loss began at age 4 months, causing shrinkage of ocular dominance columns. In V2, which had a larger surface area than V1, CO stripes were present but could not be classified as thick or thin.