Targeting the transferrin receptor to transport antisense oligonucleotides across the mammalian blood-brain barrier.

Antisense oligonucleotides (ASOs) are promising therapeutics for treating various neurological disorders. However, ASOs are unable to readily cross the mammalian blood-brain barrier (BBB) and therefore need to be delivered intrathecally to the central nervous system (CNS). Here, we engineered a human transferrin receptor 1 (TfR1) binding molecule, the oligonucleotide transport vehicle (OTV), to transport a tool ASO across the BBB in human TfR knockin (TfRmu/hu KI) mice and nonhuman primates. Intravenous injection and systemic delivery of OTV to TfRmu/hu KI mice resulted in sustained knockdown of the ASO target RNA, Malat1, across multiple mouse CNS regions and cell types, including endothelial cells, neurons, astrocytes, microglia, and oligodendrocytes. In addition, systemic delivery of OTV enabled Malat1 RNA knockdown in mouse quadriceps and cardiac muscles, which are difficult to target with oligonucleotides alone. Systemically delivered OTV enabled a more uniform ASO biodistribution profile in the CNS of TfRmu/hu KI mice and greater knockdown of Malat1 RNA compared with a bivalent, high-affinity TfR antibody. In cynomolgus macaques, an OTV directed against MALAT1 displayed robust ASO delivery to the primate CNS and enabled more uniform biodistribution and RNA target knockdown compared with intrathecal dosing of the same unconjugated ASO. Our data support systemically delivered OTV as a potential platform for delivering therapeutic ASOs across the BBB.

Limb development genes underlie variation in human fingerprint patterns.

Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized "pattern-block" correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning.

Impact of Race and Health Insurance Status on Response to Neoadjuvant Chemotherapy for Breast Cancer Patients.

We evaluated how race, insurance status, and other sociodemographic, tumor, and treatment variables influenced the response to neoadjuvant chemotherapy (NAC) in breast cancer. We performed an IRB-approved retrospective review of 298 breast cancer patients treated with NAC from 2006-2018 at our institution. Univariable and multivariable binary logistic regression analyses were performed to estimate the effects of race, insurance status, and other variables on outcomes. Outcomes of interest included pathologic complete response (pCR), partial response (pPR), and any response (pCR or pPR). Sixty-nine patients (23%) identified as African American. One hundred sixty-eight (57%) patients had private insurance, 71 (24%) had Medicare, 40 (14%) had Medicaid, and 17 (6%) had no insurance. Insurance status was a predictor for any clinical response to NAC in both univariable and multivariable analyses (p<0.01), where odds of pCR or pPR were lower for patients with Medicare compared to private insurance (OR 0.32, 95% CI: 0.15-0.70, p<0.01). Other variables significant for the response to NAC included body mass index, hormone receptor status, clinical group stage, and Ki-67. Race did not influence the response to NAC. Insurance provider, body mass index, hormone receptor status, clinical group stage, and Ki-67 may be useful predictors of treatment outcomes. Future studies that assess the impacts of insurance status and other identified factors on treatment response may help evaluate outcomes in at-risk populations with factors that preclude full benefit from NAC.

Machine Learning-Guided Prediction of Central Anterior Chamber Depth Using Slit Lamp Images from a Portable Smartphone Device.

There is currently no objective portable screening modality for narrow angles in the community. In this prospective, single-centre image validation study, we used machine learning on slit lamp images taken with a portable smartphone device (MIDAS) to predict the central anterior chamber depth (ACD) of phakic patients with undilated pupils. Patients 60 years or older with no history of laser or intraocular surgery were recruited. Slit lamp images were taken with MIDAS, followed by anterior segment optical coherence tomography (ASOCT; Casia SS-1000, Tomey, Nagoya, Japan). After manual annotation of the anatomical landmarks of the slit lamp photos, machine learning was applied after image processing and feature extraction to predict the ACD. These values were then compared with those acquired from the ASOCT. Sixty-six eyes (right = 39, 59.1%) were included for analysis. The predicted ACD values formed a strong positive correlation with the measured ACD values from ASOCT (R2 = 0.91 for training data and R2 = 0.73 for test data). This study suggests the possibility of estimating central ACD using slit lamp images taken from portable devices.

Comparison of Genome-Wide Association Scans for Quantitative and Observational Measures of Human Hair Curvature.

Previous genetic studies on hair morphology focused on the overall morphology of the hair using data collected by self-report or researcher observation. Here, we present the first genome-wide association study (GWAS) of a micro-level quantitative measure of hair curvature. We compare these results to GWAS results obtained using a macro-level classification of observable hair curvature performed in the same sample of twins and siblings of European descent. Observational data were collected by trained observers, while quantitative data were acquired using an Optical Fibre Diameter Analyser (OFDA). The GWAS for both the observational and quantitative measures of hair curvature resulted in genome-wide significant signals at chromosome 1q21.3 close to the trichohyalin (TCHH) gene, previously shown to harbor variants associated with straight hair morphology in Europeans. All genetic variants reaching genome-wide significance for both GWAS (quantitative measure lead single-nucleotide polymorphism [SNP] rs12130862, p = 9.5 × 10-09; observational measure lead SNP rs11803731, p = 2.1 × 10-17) were in moderate to very high linkage disequilibrium (LD) with each other (minimum r2 = .45), indicating they represent the same genetic locus. Conditional analyses confirmed the presence of only one signal associated with each measure at this locus. Results from the quantitative measures reconfirmed the accuracy of observational measures.

The Effect of Patient Education and Telemedicine Reminders on Adherence to Eye Drops for Glaucoma.

PURPOSE: To determine the improvement in patient adherence to topical ocular hypotensive therapy by introducing a personalized illustrated medication reference chart and telereminder. DESIGN: Prospective randomized controlled clinical trial. PARTICIPANTS: Fifty-nine patients with glaucoma who were using at least 3 or more eye drops were recruited from the ophthalmology clinic at the National University Hospital of Singapore. METHODS: Participants were randomized into 3 groups: control, reference chart only, and reference chart with telereminder. They completed a survey on demographics, barriers to glaucoma medication adherence, and self-adherence (measured by the Morisky adherence scale) before and 6 weeks after intervention. Logistic regression analysis was performed on the barriers that contribute to nonadherence and paired t tests were conducted for the preimplementation and postimplementation effects of intervention on adherence score. MAIN OUTCOME MEASURES: Changes in mean adherence score based on the Morisky adherence scale before and after intervention in participants from all 3 groups. RESULTS: In our study, 71% of participants who were nonadherent to medications had multiple barriers to adherence, with lack of self-efficacy and forgetfulness being the most common factors. Only the reference chart with telereminder group showed a statistically significant increase in mean adherence score, from 7.18 to 7.69 (P = 0.047). CONCLUSIONS: Adherence to medication in chronic diseases like glaucoma is an important healthcare issue to address. Most of these patients have poor adherence because of multiple factors, and hence interventions aimed at improving adherence should be multifaceted to target these barriers.

Surge capacity of intensive care units in case of acute increase in demand caused by COVID-19 in Australia.

OBJECTIVES: To assess the capacity of intensive care units (ICUs) in Australia to respond to the expected increase in demand associated with COVID-19. DESIGN: Analysis of Australian and New Zealand Intensive Care Society (ANZICS) registry data, supplemented by an ICU surge capability survey and veterinary facilities survey (both March 2020). SETTINGS: All Australian ICUs and veterinary facilities. MAIN OUTCOME MEASURES: Baseline numbers of ICU beds, ventilators, dialysis machines, extracorporeal membrane oxygenation machines, intravenous infusion pumps, and staff (senior medical staff, registered nurses); incremental capability to increase capacity (surge) by increasing ICU bed numbers; ventilator-to-bed ratios; number of ventilators in veterinary facilities. RESULTS: The 191 ICUs in Australia provide 2378 intensive care beds during baseline activity (9.3 ICU beds per 100 000 population). Of the 175 ICUs that responded to the surge survey (with 2228 intensive care beds), a maximal surge would add an additional 4258 intensive care beds (191% increase) and 2631 invasive ventilators (120% increase). This surge would require additional staffing of as many as 4092 senior doctors (245% increase over baseline) and 42 720 registered ICU nurses (269% increase over baseline). An additional 188 ventilators are available in veterinary facilities, including 179 human model ventilators. CONCLUSIONS: The directors of Australian ICUs report that intensive care bed capacity could be near tripled in response to the expected increase in demand caused by COVID-19. But maximal surge in bed numbers could be hampered by a shortfall in invasive ventilators and would also require a large increase in clinician and nursing staff numbers.

Genome-wide association analysis links multiple psychiatric liability genes to oscillatory brain activity.

Oscillatory activity is crucial for information processing in the brain, and has a long history as a biomarker for psychopathology. Variation in oscillatory activity is highly heritable, but current understanding of specific genetic influences remains limited. We performed the largest genome-wide association study to date of oscillatory power during eyes-closed resting electroencephalogram (EEG) across a range of frequencies (delta 1-3.75 Hz, theta 4-7.75 Hz, alpha 8-12.75 Hz, and beta 13-30 Hz) in 8,425 subjects. Additionally, we performed KGG positional gene-based analysis and brain-expression analyses. GABRA2-a known genetic marker for alcohol use disorder and epilepsy-significantly affected beta power, consistent with the known relation between GABAA interneuron activity and beta oscillations. Tissue-specific SNP-based imputation of gene-expression levels based on the GTEx database revealed that hippocampal GABRA2 expression may mediate this effect. Twenty-four genes at 3p21.1 were significant for alpha power (FDR q < .05). SNPs in this region were linked to expression of GLYCTK in hippocampal tissue, and GNL3 and ITIH4 in the frontal cortex-genes that were previously implicated in schizophrenia and bipolar disorder. In sum, we identified several novel genetic variants associated with oscillatory brain activity; furthermore, we replicated and advanced understanding of previously known genes associated with psychopathology (i.e., schizophrenia and alcohol use disorders). Importantly, these psychopathological liability genes affect brain functioning, linking the genes' expression to specific cortical/subcortical brain regions.

Variation and Heritability in Hair Diameter and Curvature in an Australian Twin Sample.

Hair diameter and curvature are two characteristics of human scalp hair used in forensic contexts. While previous data show that subjective categorization of hair curvature is highly heritable, the heritability of objectively measured curvature and diameter, and variability of hair characteristics within each individual have not yet been studied. The present study measured hair diameter and curvature using an optical fiber diameter analyzer in a sample of 2,332 twins and siblings. Heritability was estimated using maximum likelihood structural equation modeling. Results show sex differences in the magnitude of genetic influence for mean diameter and curvature, with the vast majority of the variance accounted for by genetic effects in males (diameter = 86%, curvature = 53%) and females (diameter = 77%, curvature = 61%). The consistency of diameter (variance within an individual) was also highly heritable, but did not show sex limitation, with 68% of the variance accounted for by genetic factors. Moderate phenotypic correlations were seen between diameter and consistency (r = 0.3) but there was little correlation between diameter and curvature (r = -0.13). A bivariate Cholesky analysis was used to estimate the genetic and environmental correlations between hair diameter and consistency, yielding genetic correlations of r gF = 0.27 for females and r gM = 0.25 for males.

Attitudes toward waste to energy facilities and impacts on diversion in Ontario, Canada.

Despite progress in residential waste diversion, residual waste - that fraction which cannot be recycled or composted - must continue to be managed by municipalities. Zero waste and environmental groups worry that waste-to-energy (WtE) incinerators discourage diversion, while both incineration and landfill have been stigmatized in the popular consciousness such that WtE incinerators in particular are being cancelled more often than they are approved. We conducted a mail-back survey of 217 residents in Toronto, Durham and Peel, Ontario, to understand attitudes toward diversion, levels of support for WtE incineration and WtE landfill (landfill gas recovery) facilities, and predictors of facility support. Contrary to experiences elsewhere, diversion seems threatened by WtE when measured as attitudes with 18%, and 14% agreeing that they would be less inclined to divert recyclable/compostable materials if they knew materials went to a WtE landfill or incinerator. When forced to choose between four options landfill or incineration with and without energy recovery, WtE incineration is most preferred (65%) and landfill without WtE is the least preferred option (61%). However, measurement has a large influence on public opinion results in the sense that support for WtE incineration drops to 43% when asked as a "vote in favor" question and to only 36% when measured as a 4-item index of support. When the indexes of support for landfill and WtE incineration are modeled, the prominence of odor in the landfill model distinguishes it from the WtE incinerator model which is dominated more by community and concern about health effects. Implications for policy are discussed, particularly mandatory diversion targets to accompany WtE.

Population Dynamics of Aspergillus Section Nigri Species on Vineyard Samples of Grapes and Raisins.

Several species of Aspergillus section Nigri, including potential mycotoxin producers, are common residents of grape vineyards, but the relative population size of individual species throughout the growing season is difficult to determine using traditional isolation and identification methods. Using a quantitative droplet digital PCR (ddPCR) method in combination with dilution plating, total Aspergillus section Nigri populations and relative proportions of A. niger, A. welwitschiae, A. carbonarius, and A. tubingensis were measured from vineyard samples without the need for identifying individual fungal isolates. Grapes were sampled from two raisin vineyards (vineyards A and B) at berry set, veraison, harvest, and raisin stages in two consecutive years. Plate counts showed that the total population of Aspergillus section Nigri present on the fruit increased from berry set to raisin and became a larger component of the total recovered fungal population in both vineyards in both years. Results from ddPCR analysis showed that the relative proportion of A. carbonarius among the four species assayed increased later in the season (harvest and raisin) in comparison to earlier in the season (berry set and veraison). Total fungal and Aspergillus section Nigri plate counts were not significantly different between vineyards in either year. However, vineyard A generally showed higher proportions of A. carbonarius in harvest and raisin samples than vineyard B. This coincided with higher incidence and levels of ochratoxin A in vineyard A harvest and raisin fruit than in vineyard B fruit. This work demonstrates that this ddPCR method is a useful tool for culture-independent monitoring of populations of mycotoxigenic Aspergillus species during grape and raisin production.

Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept.

Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders.

Occurrence of ochratoxin a contamination and detection of ochratoxigenic Aspergillus species in retail samples of dried fruits and nuts.

Ochratoxin A (OTA) is a mycotoxin produced by several species of Aspergillus and Penicillium and is a potential contaminant of a wide variety of food products. To determine the incidence of OTA contamination in dried fruits and tree nuts, retail packaged and bulk raisins, dates, figs, prunes, almonds, pistachios, and walnuts were collected from small and large supermarkets in seven areas of the United States between 2012 and 2014. Of the 665 samples analyzed, OTA was detected in 48 raisin samples, 4 fig samples, 4 pistachio samples, and 1 date sample. OTA contamination levels ranged from 0.28 to 15.34 ng/g in dried fruits and 1.87 to 890 ng/g in pistachios; two raisin samples and one pistachio sample exceeded the European Union regulatory limit of 10 ng/g. PCR detection of potential OTA-producing Aspergillus species revealed the presence of A. niger, A. welwitschiae, and A. carbonarius in 20, 7, and 7 of the 57 OTA-contaminated samples, respectively. However, OTA-producing A. carbonarius was isolated from only one raisin sample, and no other OTA-producing Aspergillus species were found. These results suggest that raisins are more frequently contaminated with low levels of OTA than are other dried fruits and nuts and that Aspergillus species are the likely source of that contamination.

Assessment of nutrient intakes of picky-eating Chinese preschoolers using a modified food frequency questionnaire.

BACKGROUND: Dietary assessment is crucial for monitoring nutritional status of young children. This study applied a modified Chinese food frequency questionnaire (FFQ) to assess nutrient intakes of young picky-eating Hong Kong children. METHODS: Nutrient intakes were obtained by FFQ and 3-day food record (3DFR) in 29 picky-eating children aged 44.8±9.2 months who participated in a randomised controlled trial of a new milk formula. RESULTS: When compared with 3DFR, FFQ over-reported energy intake by 283 kcal (26.5%) at baseline and 237 kcal (21.4%) at end-of-study, and also overestimated intakes of carbohydrates, proteins and fats. At baseline, FFQ and 3DFR classified 34.4%-65.5% of subjects into the same tertiles for most nutrients. These methods showed weak-to-moderate agreement in measuring most nutrients, with 3DFR showing a trend towards a systematic increase in the differences with increasing nutrient intake. CONCLUSION: Our FFQ shows promising results for assessing nutrient intakes in picky-eating Chinese preschoolers.

Ultrasound of the hands and feet for rheumatological disorders: influence on clinical diagnostic confidence and patient management.

PURPOSE: The purpose of the study was to quantify the impact that ultrasound (US) of the hands and feet has on the rheumatologists' diagnostic confidence and on patient management. MATERIALS AND METHODS: There were 62 consecutive referrals from two rheumatologists for US of the hands and/or feet for this prospective controlled observational study. Measurements of diagnostic confidence for both specific clinical findings as well as overall diagnosis using a Likert scale were made both before and after the US examination in each case. Proposed management was also recorded before US and then with the benefit of the US result. McNemar's test was performed to determine differences in diagnostic certainty and proposed management before and after US. RESULTS: The physician certainty for specific clinical findings increased significantly following US for synovitis (9.7 vs 38.7%), tenosynovitis (9.7 vs 46.8%), erosions (1.6 vs 58.1%), enthesitis (50.0 vs 83.9%) and other (53.2 vs 77.4%). The physician certainty for overall diagnosis increased significantly for seronegative arthritis (46.8 vs 61.3%), inflammatory osteoarthritis (46.8 vs 87.1%), and primary osteoarthritis (46.8 vs 73.0%). A total of 88.7% of patients had disease-modifying antirheumatic drugs as a proposed management option before US vs 48.4% after US. Before US, 4.8% of patients had non-steroidal anti-inflammatory drug as a proposed management option versus 45.2% after US. CONCLUSION: Ultrasound of the hands and/or feet significantly influenced the rheumatologists' diagnostic confidence in specific clinical findings and management plans.

Metastasis to the breast from an adenocarcinoma of the colon.

Metastases to the breast from extramammary malignancies are rare. We report a case of metastasis to the breast from a colonic adenocarcinoma in a 50-year-old man who was 6 years status after a right hemicolectomy for T3N1M1 adenocarcinoma of the ascending colon. Sonographic evaluation of the right breast lump showed a hypoechoic mass with slightly irregular margins, but there was no internal vascularity. Chest CT also documented a poorly enhancing suspicious mass in the right breast. The diagnosis of adenocarcinoma metastasis to the breast was achieved with sonographically guided core biopsy.

Abdominal manifestations of extranodal lymphoma: spectrum of imaging findings.

OBJECTIVE: The purpose of this article is to illustrate the spectrum of appearances of extranodal lymphoma in the abdomen using cross-sectional imaging techniques. CONCLUSION: Extranodal lymphoma in the abdomen can mimic other neoplastic or inflammatory conditions. Although a definitive diagnosis is possible only with biopsy, it is important to consider extranodal lymphoma in the presence of certain imaging appearances in the appropriate clinical setting for the correct diagnosis, accurate staging, and optimal management.

Postoperative evaluation of the knee after autologous chondrocyte implantation: what radiologists need to know.

Articular cartilage lesions occur commonly. Cartilage is relatively avascular and is unable to self-repair. A chondral lesion may become symptomatic. It may lead to osteoarthritis and increased morbidity. The aim of cartilage repair is to restore hyaline cartilage. There are many types of cartilage repair surgery, most of which result in fibrocartilage repair tissue that is suboptimal. Autologous chondrocyte implantation has been shown to produce hyaline-type repair tissue. Magnetic resonance (MR) imaging is performed preoperatively to define the ulcer and postoperatively to evaluate the technical success of implantation and the state of cartilage healing and to identify potential complications. Features of the autologous chondrocyte implantation graft that are assessed include the degree of filling by repair tissue, its integration with native cartilage and subchondral bone, the character of the graft substance and surface, and the underlying bone. MR arthrography is superior to unenhanced MR imaging because intraarticular contrast material allows the recipient site to be physically separated from adjacent structures so that it can be characterized more accurately. MR imaging and arthroscopy are complementary investigations in the follow-up of an autologous chondrocyte implantation in the knee. The appearance of the knee after autologous chondrocyte implantation varies among individuals and according to the time-course of healing. Familiarity with the surgical procedure and imaging appearance is essential for an accurate postsurgical assessment.