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Bis(monoacylglycero)phosphates (BMPs), a class of lipids highly enriched within endolysosomal organelles, are key components of the lysosomal intraluminal vesicles responsible for activating sphingolipid catabolic enzymes. While BMPs are understudied relative to other phospholipids, recent reports associate BMP dysregulation with a variety of pathological states including neurodegenerative diseases and lysosomal storage disorders. Since the dramatic lysosomal remodeling characteristic of cellular transformation could impact BMP abundance and function, we employed untargeted lipidomics approaches to identify and quantify BMP species in several in vitro and in vivo models of breast cancer and comparative non-transformed cells and tissues. We observed lower BMP levels within transformed cells relative to normal cells, and consistent enrichment of docosahexaenoic acid (22:6) fatty acyl chain-containing BMP species in both human- and mouse-derived mammary tumorigenesis models. Our functional analysis points to a working model whereby 22:6 BMPs serve as reactive oxygen species scavengers in tumor cells, protecting lysosomes from oxidant-induced lysosomal membrane permeabilization. Our findings suggest that breast tumor cells might divert polyunsaturated fatty acids into BMP lipids as part of an adaptive response to protect their lysosomes from elevated reactive oxygen species levels, and raise the possibility that BMP-mediated lysosomal protection is a tumor-specific vulnerability that may be exploited therapeutically.

OBJECTIVE: Surgical education is changing in an era of new regulations and evolving training cultures. We sought to understand the factors that affect operative experiences during otolaryngology residency. METHODS: From December 2019 to December 2020, five otolaryngology training programs used the SIMPL OR smartphone application to evaluate residents after each operation. Residents and attendings rated the trainees autonomy on a 4-level Zwisch scale, performance on a 5-level scale, and case complexity on a 3-level scale. We examined associations between ratings of autonomy and performance with variables including postgraduate year (PGY), case complexity, gender, week of the academic year (AY), and whether multiple procedures were logged. RESULTS: 78 attendings and 92 residents logged 2984 evaluations. PGY level and week of the AY were positively associated with attending ratings of autonomy and performance (PGY3 vs. PGY2: B = 0.63, p

The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species but acts poorly toward non-transformed cells derived from multiple tissues. Here, we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate, and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Our observations expose a key vulnerability intrinsic to cancer stem cells and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment.

Adults have been shown to favor stable causal relationships – those that hold robustly across background contexts – in their actions and causal/explanatory generalizations (Vasilyeva et al, 2018). Here we explore how this preference develops. We present results from one study with 141 4-7-year-olds investigating whether children pay attention to causal stability when they explain observations and design interventions in novel contexts. We report developmental shifts in reliance on causal stability in a range of inferential tasks, highlight the important role of perceived average causal strength in determining children’s causal preferences, and discuss the implications of our findings for theories of early causal learning. To our knowledge, this is the first study exploring the role of stability in children’s causal reasoning.

PurposeTo examine the short-term efficacy and safety of gonioscopy-assisted transluminal trabeculotomy (GATT) in a series of patients who developed glaucoma following vitreoretinal surgery.Patients and methodsRetrospective case series of consecutive patients aged above 18 years with secondary open-angle glaucoma following vitreoretinal surgery who had undergone GATT between January 2015 and June 2019. Eyes were excluded if there is

While genetic variants are known to be associated with overall gene abundance in stimulated immune cells, less is known about their effects on alternative isoform usage. By analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to influenza infection and type 1 interferon stimulation. We identified more than a thousand quantitative trait loci (QTLs) associated with alternate isoform usage (isoQTLs), many of which are independent of expression QTLs (eQTLs) for the same gene. Compared with eQTLs, isoQTLs are enriched for splice sites and untranslated regions, but depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs explain a significant proportion of the disease heritability attributed to common genetic variants. At the ERAP2 locus, we shed light on the function of the gene and how two frequent, highly differentiated haplotypes with intermediate frequencies could be maintained by balancing selection. At baseline and following type 1 interferon stimulation, the major haplotype is associated with low ERAP2 expression caused by nonsense-mediated decay, while the minor haplotype, known to increase Crohn's disease risk, is associated with high ERAP2 expression. In response to influenza infection, we found two uncharacterized isoforms expressed from the major haplotype, likely the result of multiple perfectly linked variants affecting the transcription and splicing at the locus. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in innate immune responses and, in the case of ERAP2, may confer a historical fitness advantage in response to virus.

AimTo determine if poor access to healthcare is associated with increased cytomegalovirus (CMV) retinitis risk among patients with HIV with CD4 counts of 30-min travel time, 95% CI 1.08 to 13.8) and lower income (OR 1.22 per US$50 less income, 95% CI 1.02 to 1.47).ConclusionsCD4 count, low income and longer travel time to clinic were significant risk factors for CMV retinitis among patients with HIV in a resource-limited setting. These results suggest that reducing blindness from CMV retinitis should focus on increasing accessibility of screening examinations to poor and hard-to-reach patients.

ImportanceCytomegalovirus (CMV) retinitis is a leading cause of blindness in many developing countries, likely the result of inadequate screening. Telemedicine screening for CMV retinitis instituted at the point of care for human immunodeficiency virus (HIV) infection may allow for earlier detection.ObjectivesTo determine the diagnostic accuracy of retinal photography in detecting CMV retinitis at the point of HIV care and to characterize the clinical manifestations of CMV retinitis detected through the screening program.Design, setting, and participantsWe enrolled 103 participants from a population of 258 patients with HIV and a CD4 level of less than 100/μL treated at an HIV clinic in Thailand from June 2010 through June 2012. We captured mosaic fundus photographs through a dilated pupil using a digital fundus camera. An experienced on-site ophthalmologist masked to the results of the fundus images subsequently examined each eye with indirect ophthalmoscopy and recorded the clinical findings on a standardized form. Three remote graders evaluated each image for CMV retinitis.InterventionFundus photography and indirect ophthalmoscopy.Main outcomes and measuresSensitivity and specificity of telemedicine relative to indirect ophthalmoscopy for diagnosis of CMV retinitis and clinical features of CMV retinitis lesions.ResultsSixteen patients (15.5%) were diagnosed as having CMV retinitis, of whom 5 (31%) had bilateral disease. Of the 21 eyes (10.2%) with CMV retinitis, 7 (33%) had visual symptoms. Retinitis lesions occupied less than 10% of the total retinal surface area in 13 of 21 eyes (62%) and did not involve the posterior pole (ie, zone 1) in 15 of 21 eyes (71%). Mean logMAR visual acuity in affected eyes was 0.41 (95% CI, 0.11-0.71; Snellen equivalent, 20/50 [95% CI, 20/25-20/100]). The mean sensitivity for the 3 remote graders in detecting CMV retinitis on fundus photography was 30.2% (95% CI, 10.5%-52.4%), and mean specificity was 99.1% (95% CI, 97.8%-100.0%). The CMV retinitis lesions missed by the remote graders (false-negative findings) were more likely to be small (P = .001) and located in the peripheral retina (P = .04).Conclusions and relevancePatients undergoing screening at a clinic for HIV treatment had less extensive retinitis than patients in recent reports from an ophthalmology clinic. Retinal photography with the camera used in this study was not highly sensitive in detecting CMV retinitis but may identify disease with an immediate threat to vision. Improved accuracy will require a camera that can more easily image the peripheral retina.

PurposeTo determine risk factors predictive of retinal detachment in patients with cytomegalovirus (CMV) retinitis in a setting with limited access to ophthalmic care.DesignCase-control study.MethodsSixty-four patients with CMV retinitis and retinal detachment were identified from the Ocular Infectious Diseases and Retina Clinics at Chiang Mai University. Three control patients with CMV retinitis but no retinal detachment were selected for each case, matched by calendar date. The medical records of each patient were reviewed, with patient-level and eye-level features recorded for the clinic visit used to match cases and controls, and also for the initial clinic visit at which CMV retinitis was diagnosed. Risk factors for retinal detachment were assessed separately for each of these time points using multivariate conditional logistic regression models that included 1 eye from each patient.ResultsPatients with a retinal detachment were more likely than controls to have low visual acuity (odds ratio [OR], 1.24 per line of worse vision on the logMAR scale; 95% confidence interval [CI], 1.16-1.33) and bilateral disease (OR, 2.12; 95% CI, 0.92-4.90). Features present at the time of the initial diagnosis of CMV retinitis that predicted subsequent retinal detachment included bilateral disease (OR, 2.68; 95% CI, 1.18-6.08) and lesion size (OR, 2.64 per 10% increase in lesion size; 95% CI, 1.41-4.94).ConclusionBilateral CMV retinitis and larger lesion sizes, each of which is a marker of advanced disease, were associated with subsequent retinal detachment. Earlier detection and treatment may reduce the likelihood that patients with CMV retinitis develop a retinal detachment.

ImportanceCytomegalovirus (CMV) retinitis continues to be a leading cause of blindness in many developing countries. Telemedicine holds the potential to increase the number of people screened for CMV retinitis, but it is unclear whether nonophthalmologists could be responsible for interpreting fundus photographs captured in a telemedicine program.ObjectiveTo determine the accuracy of nonophthalmologist photographic graders in diagnosing CMV retinitis from digital fundus photographs.Design, setting, and participantsFifteen nonexpert graders each evaluated 182 mosaic retinal images taken from the eyes of patients with AIDS who were evaluated at the Ocular Infectious Diseases Clinic at Chiang Mai University in Chiang Mai, Thailand.Main outcomes and measuresGraders diagnosed each image as CMV retinitis present, CMV retinitis absent, or unknown. The results from each grader were compared with those of an indirect ophthalmoscopic examination from an experienced on-site ophthalmologist as well as with the consensus grade given by a panel of CMV retinitis experts.ResultsRelative to the on-site ophthalmologist, the sensitivity of remote CMV retinitis diagnosis by nonexpert graders ranged from 64.0% to 95.5% (mean, 84.1%; 95% CI, 78.6%-89.6%)), and the specificity ranged from 65.6% to 92.5% (mean, 82.3%; 95% CI, 76.6%-88.0%)). Agreement between nonexpert and expert graders was high: the mean sensitivity and specificity values of nonexpert diagnosis using expert consensus as the reference standard were 93.2% (95% CI, 90.6%-95.8%) and 88.4% (95% CI, 85.4%-91.1%), respectively. Mean intrarater reliability also was high (mean Cohen κ, 0.83; 95% CI, 0.78-0.87).Conclusions and relevanceThe sensitivity and specificity of remote diagnosis of CMV retinitis by nonexpert graders was variable, although several nonexperts achieved a level of accuracy comparable to that of CMV retinitis experts. More intensive training and periodic evaluations would be required if nonexperts are to be used in clinical practice.

Sexual dimorphism in body weight, fat distribution, and metabolic disease has been attributed largely to differential effects of male and female gonadal hormones. Here, we report that the number of X chromosomes within cells also contributes to these sex differences. We employed a unique mouse model, known as the "four core genotypes," to distinguish between effects of gonadal sex (testes or ovaries) and sex chromosomes (XX or XY). With this model, we produced gonadal male and female mice carrying XX or XY sex chromosome complements. Mice were gonadectomized to remove the acute effects of gonadal hormones and to uncover effects of sex chromosome complement on obesity. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had up to 2-fold increased adiposity and greater food intake during daylight hours, when mice are normally inactive. Mice with two X chromosomes also had accelerated weight gain on a high fat diet and developed fatty liver and elevated lipid and insulin levels. Further genetic studies with mice carrying XO and XXY chromosome complements revealed that the differences between XX and XY mice are attributable to dosage of the X chromosome, rather than effects of the Y chromosome. A subset of genes that escape X chromosome inactivation exhibited higher expression levels in adipose tissue and liver of XX compared to XY mice, and may contribute to the sex differences in obesity. Overall, our study is the first to identify sex chromosome complement, a factor distinguishing all male and female cells, as a cause of sex differences in obesity and metabolism.

BACKGROUND: Lung cancer survivors are at an increased risk for recurrence and the development of secondary tumors and other comorbid conditions. However, little is known about lung cancer survivors' risk behaviors and the effect of these behaviors on overall health perceptions. OBJECTIVE: The purpose of this study was to describe the prevalence of health risk behaviors among non-small cell lung cancer survivors and their relationship perception to overall health. METHODS: One hundred forty-two survivors of non-small cell lung cancer with a minimum of 5 years disease free completed a battery of questionnaires to assess perception of health status and self-reported risk behaviors (smoking, exposure to secondhand smoke, alcohol use) and weight before and after diagnosis. Urinary cotinine level was used to verify smoking status, and actual height and weight were obtained to determine overweight status (body mass index, >/=25). Descriptive statistics and logistic regression were used to analyze the data. RESULTS: Seventy percent of participants reported their health as good to excellent. Although 81% quit smoking after diagnosis, 13.4% continued to smoke and 28% reported exposure to secondhand smoke. Approximately half the sample (58%) drank alcohol (16.3% quit after diagnosis) and was overweight (51%). A strong agreement between current smoking and exposure to secondhand smoke was observed. In a multivariate analysis, smoking (odds ratio [OR], 7.02; CI, 2.45 to 20.13), exposure to secondhand smoke (OR, 5.37; CI, 2.42 to 11.95), alcohol use (OR, 9.04; CI, 3.28 to 24.92), and overweight (OR, 8.51; CI, 3.44 to 21.10) were independent predictors of perceived poor health status. CONCLUSION: Although most lung cancer survivors have made healthy lifestyle changes, a substantial proportion has not. Our findings suggest the need for multiple risk factor interventions to decrease risk behaviors and improve overall health after a cancer diagnosis.