bluuebunny/crossref_metadata_2025 huggingface dataset:
Nationwide Survey of Antimicrobial Dispensation and Training in Pharmacies and Nonpharmacy Stores in the Dominican Republic
Authors: Lora Alfredo J Mena , Fermin Rita Rojas , Bisono Bismarck , Flores Talia , Jimenez Mariel , Almonte Marcos , Rodriguez Julia , Bleasdale Susan
Published: November 2020

Background: Antimicrobial use in low- and middle-income countries (LMICs) can play a major role in the development of antimicrobial resistance (AMR). In many LMICs, antimicrobials can be dispensed without prescriptions; they often available in pharmacies and nonpharmacy stores alike. We conducted a nationwide survey to describe the availability and antimicrobial dispensation practices in pharmacies and nonpharmacy stores in the Dominican Republic. Methods: A survey was administered to staff responsible for dispensing antimicrobials at pharmacies and nonpharmacy stores in the Dominican Republic. Stores were randomly selected from March through November 2019 in 7 cities representing all geographic regions of the Dominican Republic. Data on availability of antimicrobials and staff education on antimicrobial use were obtained. Case scenarios with commons symptoms were used to survey staff on antimicrobial use recommendations. Symptoms included dysuria, throat pain, diarrhea, fever, and cough. The availability of antimicrobials ordering by phone and via online delivery was assessed for each store. Results: Staff from 125 stores were invited to participate; 34 pharmacies and 48 nonpharmacy stores participated and 43 refused to participate. Overall, 200 antimicrobial use recommendations were given in pharmacies and 43 in nonpharmacy stores. The most common type of antimicrobial use recommendations were aminopenicillins (Fig. 1). Staff received prior training or education on antimicrobials in 61% of pharmacies and 0% of nonpharmacy stores. Antimicrobial recommendations by case scenario in pharmacies and nonpharmacy stores are shown in Figs. 2 and 3. Antimicrobials are available for phone order in 80% of pharmacies and 90% of nonpharmacy stores. No antimicrobials were available via online delivery apps. Conclusions: Antimicrobials are widely available in the Dominican Republic and can be obtained without a prescription, in person or via delivery. Staff at pharmacy stores recommended different antimicrobials by symptom, whereas staff at nonpharmacy stores commonly recommended aminopenicillins for all symptoms. Training or education on antimicrobial use was common for staff at pharmacy stores but nonexistent for staff at nonpharmacy stores. In LMICs with easy access to antimicrobials, frontline staff in pharmacies and nonpharmacy stores are gatekeepers for antimicrobial use and may represent an important target for outpatient antimicrobial stewardship initiatives.

Funding: None

Disclosures: None
Outbreak of Burkholderia cepacia Complex Due to Multiple Brands of Contaminated Aqueous Chlorhexidine in Hong Kong
Authors: WONG Shuk-Ching , CHENG Vincent Chi-Chung
Published: November 2020

Background: Contaminated chlorhexidine produced by a single company has been implicated in the outbreak or pseudo-outbreak of Burkholderia cepacia complex (BCC). However, simultaneous occurrence of multiple brands of contaminated chlorhexidine supplied by different manufacturers resulting in a persistent outbreak for >1 year has not been well described. Objective: We report an outbreak of BCC with epidemiological investigation and using whole-genome sequencing (WGS) analysis of patient and environmental isolates in Hong Kong. Methods: Upon the investigation of a cohort of renal patients undergoing peritoneal dialysis colonized or infected with BCC in their exit sites, different brands of 0.05% aqueous chlorhexidine (aqCHX) used for exit site dressing, supplied from hospital or purchased from community pharmacies by patients, were cultured. A risk factor analysis for exit-site acquisition of BCC was performed. A site visit to a local manufacturer was conducted to investigate the process of production and to collect environmental samples for culture, which were further analyzed by WGS along with the BCC isolates cultured from patients and aqCHX purchased from community pharmacies. Results: Four patients undergoing peritoneal dialysis had cultures positive for BCC in the exit site swab in September 2019. A snapshot screening revealed 88 (32.0%) of 275 renal dialysis patients colonized with BCC. Of these patients, 47 (17.1%) were newly diagnosed and 41 (14.9%) were known to be colonized or infected with BCC according to retrospective data retrieval from January 1, 2018. A significantly greater proportion of patients with newly diagnosed BCC (cases) had used contaminated aqCHX for exit-site dressing than those with culture negative for BCC (controls): 38 of 47 (80.9%) versus 54 of 187 (28.9%) (P < .001). Of 161 aqCHX samples, 10 brands from 4 manufacturers (purchased from community pharmacies), 125 (77.6%) were culture positive for BCC, whereas all 77 aqCHX samples supplied by the hospital, which are different brands and are produced by different manufacturers, were proven to be sterile. Of the 28 environmental samples taken from a local manufacturer during the site visit, 19 samples (67.9%, 3 collected from the instrument for production of aqCHX and all 16 newly produced aqCHX samples) were culture positive for BCC. WGS revealed 3 major clusters characterized by B. cenocepacia genomovar IIIA ST1547 and 2 novel MLST clusters from 52 patients and 26 environmental isolates selected. Conclusions: This outbreak was terminated by product recall, and the government has decided to take regulatory actions to ensure the sterility of antiseptics, including aqCHX.

Funding: None

Disclosures: None
Pathogens Associated With Repeat Versus Single Central-Line–Associated Bloodstream Infections, Acute-Care Hospitals, NHSN
Authors: Dudeck Margaret A. , Allen-Bridson Katherine , Edwards Jonathan R.
Published: November 2020

Background: The NHSN is the nation’s largest surveillance system for healthcare-associated infections. Since 2011, acute-care hospitals (ACHs) have been required to report intensive care unit (ICU) central-line–associated bloodstream infections (CLABSIs) to the NHSN pursuant to CMS requirements. In 2015, this requirement included general medical, surgical, and medical-surgical wards. Also in 2015, the NHSN implemented a repeat infection timeframe (RIT) that required repeat CLABSIs, in the same patient and admission, to be excluded if onset was within 14 days. This analysis is the first at the national level to describe repeat CLABSIs. Methods: Index CLABSIs reported in ACH ICUs and select wards during 2015–2108 were included, in addition to repeat CLABSIs occurring at any location during the same period. CLABSIs were stratified into 2 groups: single and repeat CLABSIs. The repeat CLABSI group included the index CLABSI and subsequent CLABSI(s) reported for the same patient. Up to 5 CLABSIs were included for a single patient. Pathogen analyses were limited to the first pathogen reported for each CLABSI, which is considered to be the most important cause of the event. Likelihood ratio χ2 tests were used to determine differences in proportions. Results: Of the 70,214 CLABSIs reported, 5,983 (8.5%) were repeat CLABSIs. Of 3,264 nonindex CLABSIs, 425 (13%) were identified in non-ICU or non-select ward locations. Staphylococcus aureus was the most common pathogen in both the single and repeat CLABSI groups (14.2% and 12%, respectively) (Fig. 1). Compared to all other pathogens, CLABSIs reported with Candida spp were less likely in a repeat CLABSI event than in a single CLABSI event (P < .0001). Insertion-related organisms were more likely to be associated with single CLABSIs than repeat CLABSIs (P < .0001) (Fig. 2). Alternatively, Enterococcus spp or Klebsiella pneumoniae and K. oxytoca were more likely to be associated with repeat CLABSIs than single CLABSIs (P < .0001). Conclusions: This analysis highlights differences in the aggregate pathogen distributions comparing single versus repeat CLABSIs. Assessing the pathogens associated with repeat CLABSIs may offer another way to assess the success of CLABSI prevention efforts (eg, clean insertion practices). Pathogens such as Enterococcus spp and Klebsiella spp demonstrate a greater association with repeat CLABSIs. Thus, instituting prevention efforts focused on these organisms may warrant greater attention and could impact the likelihood of repeat CLABSIs. Additional analysis of patient-specific pathogens identified in the repeat CLABSI group may yield further clarification.

Funding: None

Disclosures: None
Patterns and Predictors of UTI Treatment Practices in Nursing Homes
Authors: Ford James H. , Heller Dee , Selle Kathi , Nordman-Oliveira Susan , Robinson Jennifer , Jolles Sally , Uribe-cano Daniela , Crnich Christopher
Published: November 2020

Background: Suspicion of urinary tract infection (UTI) is the most common justification for prescribing antibiotics in nursing homes. More than half of antibiotic prescriptions for treatment of UTI in nursing homes are either unnecessary or inappropriate. Achieving a better understanding of the factors that underlie UTI treatment decisions is necessary to improve the quality of antibiotic prescribing in nursing homes. An ongoing hybrid type 2 effectiveness-implementation cluster randomized trial of a recently developed nursing home UTI recognition and management tool kit provided us with an opportunity to explore the influence of organizational, clinical, and staff attributes on UTI antibiotic prescribing practices in nursing homes. Methods: Data on antibiotic starts for suspected UTIs were collected in 29 nursing homes over a 9-month period. Antibiotic practices evaluated included total antibiotic starts per 1,000 resident days, % antibiotic starts with treatment duration >7 days, % antibiotic starts in which the initial antibiotic choice was a fluoroquinolone, and % antibiotic starts meeting UTI tool-kit criteria of appropriateness. Prior research and bivariate analyses were used to select clinical and organizational attributes as well as individual nursing staff-level retention rates for inclusion in a stepwise linear regression model for each antibiotic practice outcome. Results: In total, 602 UTI antibiotic events were evaluated. Four associations were identified for antibiotic starts including nursing home urine culture rate, ICP status, nonprofit and part-time LPN retention. Nursing homes with higher full-time LPN retention had a lower rate of antibiotic treatment duration >7 days. Full-time CNAs and part-time LPNs retention and for-profit status was associated with the proportion of fluoroquinolone antibiotic starts. No attributes influenced the proportion of antibiotic starts meeting appropriateness criteria (Fig. 1). Urine culture rates are driving overall nursing home antibiotic prescribing. Conclusions: Urine culture practices was strongly associated with UTI treatment rates in nursing homes. A variety of organizational characteristics were also associated with UTI treatment rates as well as other UTI antibiotic prescribing practices. Some of these associations appear paradoxical but may reflect increasing resident acuity and increased capacity to standardize practices through organizational centralization.

Funding: Support for the project provided by the Wisconsin Partnership Program.

Disclosures: None
Peer Comparison Intervention to Improve Antibiotic Prescribing in Dentistry
Authors: Klevens Monina , Roberts Rebecca , Cumming Melissa
Published: November 2020

Background: Dentists prescribe an estimated 13% of outpatient antibiotic courses, many of which may be unnecessary. Health departments are in a unique position to support implementation of antibiotic stewardship across healthcare facilities, including in dental offices. A customized peer comparison message with feedback regarding prescribing frequencies was effective in reducing inappropriate prescribing among primary care physicians in Massachusetts and California. We tested the effect of a peer comparison message for antibiotic prescribing on dentists in the Massachusetts Medicaid program. Methods: We analyzed data from September 2018 to July 2019 for prescriptions of antibiotic courses by dentists to identify the highest prescribing dentists. We used their national provider identifier (NPI) to deduplicate providers and we searched for addresses using the CMS online database. On March 25, 2019, the high prescribers were sent a hard copy letter from the Massachusetts Department of Public Health stating that they were “among the 1% of frequent prescribers.” In addition, the letter provided citations to professional guidelines and prescribing best practices and invited participation in health department–sponsored training for continuing education credits. We tracked the monthly number of antibiotics prescribed by provider before and after the mailing and compared those who received the letter (intervention) to those whose address was either out of state or undeliverable (comparison). Results: Prescribing records for 3,008 dentists were available from September 2018 through July 2019. Most (67%) prescribed <10 antibiotic courses in the 11-month period; the mean monthly antibiotic courses prescribed ranged from 1.2 to 1.6, and the median monthly prescriptions was 0. However, 33% prescribed 10–199 antibiotics, and 1% prescribed >200. Of these 28 comprising the highest 1% , 15 received the intervention letter. The others were either out of state (N = 3) or the letter was returned undelivered (N = 10). The average monthly number of antibiotic courses prescribed before the intervention was similar in the intervention and comparison groups (25.0 and 24.2, respectively). In the 4 months after the intervention, the average did not change in the intervention group but increased slightly in the comparison group (25.2 and 26.2, respectively). The intervention had no significant effect (P = .80). Conclusions: We observed no effect of this peer comparison message among a small sample of dentists in the Massachusetts Medicaid program. This finding may be due to multiple factors, including the small number of the targeted prescribers, the use of a relatively friendly message for communicating with the high prescribers, and the possibility that other forms of communication would be more effective.

Funding: None

Disclosures: None
Pilot Point-Prevalence Survey for Healthcare-Associated Infections in Long-Term Care Hospitals, South Korea, 2018
Authors: Choi Jongrim , Lee Ji Young , Jeong Jae Sim , Lee Sung Eun , Choi Jong Hwa , Kim Sin Jeong , Kim Mi-Na
Published: November 2020

Background: Recently, healthcare-associated infections (HAIs) in long-term care hospitals (LTCHs) have markedly increased, but no infection control policy has been established in South Korea. We investigated the current HAI surveillance system and executed a point-prevalence pilot study in LTCHs. Methods: HAIs were defined by newly established surveillance manual based on McGeer criteria revised in 2012. Three LTCHs in Seoul and Gyeonggi province were voluntarily recruited, and data were collected from up to 50 patients who were hospitalized on August 1. The medical records from September to November 2018 were retrospectively reviewed by a charge nurse for infection control per each hospitals after 1 day of training specific for LTCH surveillance. All data were reviewed by a senior researcher visiting onsite. Results: The participating hospitals had 272.33 ± 111.01 beds. Only 1 hospital had an onsite microbiological laboratory. In total, 156 patients were enrolled and 5 HAIs were detected, for a prevalence rate of 3.2%. The average patient age was 79.04 ± 9.92 years. The HAIs included 2 urinary tract infections, skin and soft-tissue infection, low respiratory infection, and conjunctivitis. Conclusions: This is the first survey of HAI in LTCHs in South Korea. The 3.2% prevalence rate is lower than those from previous reports from the European Union or the United States. This study supports the development of a national HAI surveillance and infection control system in LTCHs, although implementation may be limited due to the lack of laboratory support and infection control infrastructure in Korea.

Funding: None

Disclosures: None
Process Surveillance and Follow-Up Monitoring to Increase Compliance to Standards in Medical Device Reprocessing
Authors: Scott Mark , Wilson Sharon , Bush Kathryn , Control  , Fluet Karin , Gagnon Heather , Herrick Tiffany
Published: November 2020

Background: Effective medical device reprocessing (MDR) is essential in preventing the spread of microorganisms and maintaining patient safety. Alberta Health Services (AHS) is an Alberta-wide, integrated health system, responsible for delivering health services to >4.3 million people living in the province. In 2010, periodic province-wide MDR reviews were initiated by the provincial health system to verify that the cleaning, disinfection, and sterilization of reusable critical and semicritical medical devices met established standards. To date, there have been 3 review cycles; in cycle 3, a follow-up process for tracking and reporting corrective actions was initiated. Methods: As in previous MDR review cycles, cycle 3 included the use of a standardized suite of tools to measure compliance with standards set by Accreditation Canada, the Canadian Standards Association, and the Government of Alberta. Each cycle involved a review of MDR areas completed by trained reviewers. Interrater reliability among reviewers was maintained through training and debriefings following reviews to ensure agreement. Following reviews, reports were generated for areas, zones, and AHS. As part of the corrective actions and follow-up process, identified deficiencies were categorized into 5 themes. Corrective actions were tracked and periodic reports were generated showing the progress of deficiency resolution. Resolution rates (number of resolved deficiencies divided by total number of of deficiencies) were calculated for each of the identified themes as well as overall for cycle 3. Results: Overall compliance for cycle 3 was 93%. Cycle 3 reviews revealed that more than half of the deficiencies (58%) were identified previously in cycle 2. The resolution rates ranged from 78% to 95% for identified deficiencies for 4 of the 5 themes: documentation, technique, PPE/attire/hand hygiene, and other. The theme related to physical infrastructure showed a considerably lower resolution rate of 49%. The corrective action follow-up process showed increased overall resolution rate from 59% at the start of the follow-up process to 82% at its completion. When this resolution rate was applied to the initial survey compliance rate for cycle 3, overall compliance increased to 99%. Conclusions: Monitoring quality of MDR practices is essential in maintaining and improving patient safety. The standardized provincial review process identified common themes and a coordinated approach to support the resolution of many identified deficiencies. Most of those deficiencies were resolved; however, those deficiencies related to physical infrastructure of the MDR department continue to be seen across review cycles. This review process with follow up of these deficiencies can help bring attention to organization leadership and Funding: authorities during budget cycles.

Funding: None

Disclosures: None
Ensuring Effective Judicial Review of EU Soft Law via the Action for Annulment before the EU Courts: a Plea for a Liberal-Constitutional Approach
Authors: Gentile Giulia
Published: November 2020

Judicial review of EU soft law – Liberal-constitutionalism – Principle of effective judicial protection – The liberal-constitutional jurisprudence of the European Court of Justice – Action for annulment – Formalistic understanding of the concept of ‘legally binding effects’ – Preliminary ruling procedure – Limitations of the preliminary ruling procedure in granting effective judicial protection in relation to EU soft law – A plea for a liberal-constitutional reading of Articles 263 and 288 TFEU in relation to direct review of EU soft law
Diagnostik von Lernstörungen: Zeit zum Umdenken
Authors: Mähler Claudia
Published: November 2020

Zusammenfassung. Lernschwierigkeiten beim Erwerb der Schriftsprache oder des Rechnens gehört für ca. ein Drittel aller Grundschulkinder zum schulischen Alltag. Wenn diese Schwierigkeiten länger andauern, wird von Lernschwächen, Lernstörungen oder Lernbehinderungen gesprochen. Die begriffliche Abgrenzung wird aktuell durch verschiedene Klassifikationskriterien in verschiedenen Klassifikationssystemen (ICD-10/11, DSM-5 oder AWMF Leitlinien) sehr erschwert, was Unsicherheiten in der Diagnostik und auch divergierende pädagogische Konsequenzen zur Folge hat. Eine besondere Rolle spielt dabei das sogenannte doppelte Diskrepanzkriterium für die Diagnose einer Lernstörung: Die Leistung eines Kindes muss unter dem nach dem Alter bzw. der Beschulung und der Intelligenz zu erwartenden Niveau liegen. Die Schulleistung muss also erwartungswidrig ausfallen – das betroffene Kind bleibt hinter den für die Klassenstufe typischen Leistungen und auch hinter den eigenen allgemeinen kognitiven Fähigkeiten zurück. Das Kriterium der Diskrepanz der Schulleistung zur Intelligenz wird seit langem kontrovers diskutiert und ist in den Klassifikationssystemen unterschiedlich verankert. Seine Anwendung hat sowohl für die diagnostische als auch für die pädagogische Praxis weitreichende Konsequenzen. Es führt dazu, dass Kinder mit Diskrepanz zwischen Schulleistung und Intelligenz die Diagnose „Lernstörung“ erhalten, Kinder ohne diese Diskrepanz haben eine „Lernschwäche“, beide Gruppen erfahren unterschiedliche schulische und außerschulische Lernförderung. Der vorliegende Beitrag stellt die Berechtigung dieses Kriteriums der Diskrepanz zwischen Schulleistung und Intelligenz anhand empirischer Evidenz in Frage und beleuchtet Konsequenzen sowohl für die bislang gängige Anwendung des doppelten Diskrepanzkriteriums als auch für den Verzicht darauf. Das Fazit dieser Erörterung rät zum Umdenken.
Experimental Insights Into Space Weathering of Phobos: Laboratory Investigation of Sputtering by Atomic and Molecular Planetary Ions
Authors: Szabo P. S. , Biber H. , Jäggi N. , Wappl M. , Stadlmayr R. , Primetzhofer D. , Nenning A. , Mutzke A. , Fleig J. , Mezger K. , Lammer H. , Galli A. , Wurz P. , Aumayr F.
Published: November 2020

Investigating the space weathering of the Martian moon Phobos represents an important step toward understanding the development from its origin to its present‐day appearance. Depending on Phobos’ orbital position, its surface is continuously sputtered by the solar wind and planetary ions that originate in the Martian atmosphere. Based on Mars Atmosphere and Volatile Evolution measurements, it has been proposed that sputtering by planetary O+ and O2+ ions dominates in the Martian tail region, where the planet mostly shadows Phobos from the solar wind. In these models, uncertainties for sputtering yield inputs still exist due to the lack of sufficient analog experiments. Therefore, sputtering measurements with O+, O2+, C+, and CO2+ ions between 1 and 5 keV were performed using augite samples as Phobos analogs. The experimental results for O+ irradiations show smaller mass changes than predicted by SDTrimSP simulations, which probably can be attributed to O implantation enabled by the Fe content of the target. Sputtering with O2+ and CO2+ in the low keV range shows no deviations in the sputtering yields attributable to molecular effects. Therefore, CO2+ ions will most likely be negligible for the sputtering of Phobos according to the current understanding of ion fluxes on the Martian moon. Ultimately, our experiments suggest that the sputtering contribution on Phobos by O ions is about 50% smaller than previously assumed. This does not change the qualitative outcome from previous modeling stating that planetary O ions are by far the dominant sputtering contribution on Phobos in the Martian tail region.
On-screen fingerprint sensor with optically and electrically tailored transparent electrode patterns for use on high-resolution mobile displays
Authors: Kim-Lee Hyun-Joon , Hong Seog Woo , Kim Dong Kyun , Kim Jinmyoung , Kim Hong Suk , Chung Seok-Whan , Cho Eun-Hyoung , Kim Hae-Sung , Lee Byung-Kyu
Published: November 2020

In this study, a mutual capacitive-type on-screen fingerprint sensor, which can recognize fingerprints on a display screen to provide smartphones with full-screen displays with a minimal bezel area, is fabricated. On-screen fingerprint sensors are fabricated using an indium tin oxide transparent conductor with a sheet resistance of ~10 Ω/sq. and a transmittance of ~94% (~86% with the substrate effect) in the visible wavelength range, and assembled onto a display panel. Even at this high transmittance, the electrodes can degrade the display quality when they are placed on the display. The interference between periodic display pixel arrays and sensor patterns can lead to the Moiré phenomenon. It is necessary to find an appropriate sensor pattern that minimizes the Moiré pattern, while maintaining the signal sensitivity. To search for appropriate patterns, a numerical calculation is carried out over wide ranges of pitches and rotation angles. The range is narrowed for an experimental evaluation, which is used to finally determine the sensor design. As the selected sensor pitches are too small to detect capacitance variations, three unit patterns are electrically connected to obtain a unit block generating a larger signal. By applying the selected sensor pattern and circuit driving by block, fingerprint sensing on a display is demonstrated with a prototype built on a commercial smartphone.
Emotional regulation neural circuitry abnormalities in adult bipolar disorder: dissociating effects of long-term depression history from relationships with present symptoms
Authors: Bertocci Michele A. , Bergman Jeffrey , Santos Joao Paulo Lima , Iyengar Satish , Bonar Lisa , Gill Mary Kay , Abdul-waalee Halimah , Bebko Genna , Stiffler Richelle , Lockovich Jeanette , Aslam Haris , Ladouceur Cecile , Merranko John , Diler Rasim , Birmaher Boris , Versace Amelia , Phillips Mary L.
Published: November 2020

Bipolar disorder (BD) is common and debilitating and confounding effects of depression history on neural activity in BD are unknown. We aimed to dissociate neural activity reflecting past depression-load vs. present symptom severity using the Course and Outcome of Bipolar Youth (COBY), a prospective longitudinal cohort study of pediatric-onset BD. In n = 54 COBY (18–32 years), we modeled depression scores over time (up to 17.5 years) using a standardized autoregressive moving average (ARMA) model, followed by k-means cluster analysis. N = 36 healthy participants (HC, 20–36 years) were included. Using two factorial analyses, we parsed the impact of ARMA-defined past depression-load on neural activity from the impact of current symptoms on neural activity (p < 0.001, k > 30) and examined relationships with past and present symptoms (ps FDR-corrected). ARMA identified three COBY groups based on past depression-load. ARMA-defined COBY participants with the greatest past depression-load vs. other groups showed greater activity in right temporoparietal junction, thalamus, insula, premotor cortex, left fusiform gyrus, bilateral precuneus and cerebellum. In contrast, BD-COBY participants vs. HC showed greater activity in left hippocampus, dorsolateral prefrontal cortex, and right somatosensory cortex, plus the above thalamus, premotor cortex and cerebellum; activity positively correlated with present symptom severity in most regions. Past depression-load was related to social cognition and salience perception network activity, potentially reflecting heightened attention to socially relevant distracters, while present symptoms were associated with emotion processing and reappraisal network activity, potentially reflecting abnormal emotional experience and regulation. Differentiating aberrant neural activity related to long-term depression vs. present affective symptoms can help target interventions to networks associated with pathophysiological processes, rather than long-term illness effects.
Extreme enrichment of VNTR-associated polymorphicity in human subtelomeres: genes with most VNTRs are predominantly expressed in the brain
Authors: Linthorst Jasper , Meert Wim , Hestand Matthew S. , Korlach Jonas , Vermeesch Joris Robert , Reinders Marcel J. T. , Holstege Henne
Published: November 2020

The human genome harbors numerous structural variants (SVs) which, due to their repetitive nature, are currently underexplored in short-read whole-genome sequencing approaches. Using single-molecule, real-time (SMRT) long-read sequencing technology in combination with FALCON-Unzip, we generated a de novo assembly of the diploid genome of a 115-year-old Dutch cognitively healthy woman. We combined this assembly with two previously published haploid assemblies (CHM1 and CHM13) and the GRCh38 reference genome to create a compendium of SVs that occur across five independent human haplotypes using the graph-based multi-genome aligner REVEAL. Across these five haplotypes, we detected 31,680 euchromatic SVs (>50 bp). Of these, ~62% were comprised of repetitive sequences with ‘variable number tandem repeats’ (VNTRs), ~10% were mobile elements (Alu, L1, and SVA), while the remaining variants were inversions and indels. We observed that VNTRs with GC-content >60% and repeat patterns longer than 15 bp were 21-fold enriched in the subtelomeric regions (within 5 Mb of the ends of chromosome arms). VNTR lengths can expand to exceed a critical length which is associated with impaired gene transcription. The genes that contained most VNTRs, of which PTPRN2 and DLGAP2 are the most prominent examples, were found to be predominantly expressed in the brain and associated with a wide variety of neurological disorders. Repeat-induced variation represents a sizeable fraction of the genetic variation in human genomes and should be included in investigations of genetic factors associated with phenotypic traits, specifically those associated with neurological disorders. We make available the long and short-read sequence data of the supercentenarian genome, and a compendium of SVs as identified across 5 human haplotypes.
Mitochondrial DNA haplogroups and risk of attention deficit and hyperactivity disorder in European Americans
Authors: Chang Xiao , Liu Yichuan , Mentch Frank , Glessner Joseph , Qu Huiqi , Nguyen Kenny , Sleiman Patrick M. A. , Hakonarson Hakon
Published: November 2020

Although mitochondrial dysfunction has been implicated in the pathophysiology of attention deficit and hyperactivity disorder ADHD, the role of mitochondrial DNA (mtDNA) has not been extensively investigated. To determine whether mtDNA haplogroups influence risk of ADHD, we performed a case-control study comprising 2076 ADHD cases and 5078 healthy controls, all of whom were European decedents recruited from The Children’s Hospital of Philadelphia (CHOP). Associations between eight major European mtDNA Haplogroups and ADHD risk were assessed in three independent European cohorts. Meta-analysis of the three studies indicated that mtDNA haplogroups K (odds ratio = 0.69, P = 2.24 × 10−4, Pcorrected = 1.79 × 10−3) and U (odds ratio = 0.77, P = 8.88 × 10−4, Pcorrected = 7.11 × 10−3) were significantly associated with reduced risk of ADHD. In contrast, haplogroup HHV* (odds ratio = 1.18, P = 2.32 × 10−3, Pcorrected = 0.019) was significantly associated with increased risk of ADHD. Our results provide novel insight into the genetic basis of ADHD, implicating mitochondrial mechanisms in the pathophysiology of this relatively common psychiatric disorder.
Analysis of brain networks and fecal metabolites reveals brain–gut alterations in premenopausal females with irritable bowel syndrome
Authors: Osadchiy Vadim , Mayer Emeran A. , Gao Kan , Labus Jennifer S. , Naliboff Bruce , Tillisch Kirsten , Chang Lin , Jacobs Jonathan P. , Hsiao Elaine Y. , Gupta Arpana
Published: November 2020

Alterations in brain–gut–microbiome (BGM) interactions have been implicated in the pathogenesis of irritable bowel syndrome (IBS). Here, we apply a systems biology approach, leveraging neuroimaging and fecal metabolite data, to characterize BGM interactions that are driving IBS pathophysiology. Fecal samples and resting state fMRI images were obtained from 138 female subjects (99 IBS, 39 healthy controls (HCs)). Partial least-squares discriminant analysis (PLS-DA) was conducted to explore group differences, and partial correlation analysis explored significantly changed metabolites and neuroimaging data. All correlational tests were performed controlling for age, body mass index, and diet; results are reported after FDR correction, withq < 0.05 as significant. Compared to HCs, IBS showed increased connectivity of the putamen with regions of the default mode and somatosensory networks. Metabolite pathways involved in nucleic acid and amino acid metabolism differentiated the two groups. Only a subset of metabolites, primarily amino acids, were associated with IBS-specific brain changes, including tryptophan, glutamate, and histidine. Histidine was the only metabolite positively associated with both IBS-specific alterations in brain connectivity. Our findings suggest a role for several amino acid metabolites in modulating brain function in IBS. These metabolites may alter brain connectivity directly, by crossing the blood–brain-barrier, or indirectly through peripheral mechanisms. This is the first study to integrate both neuroimaging and fecal metabolite data supporting the BGM model of IBS, building the foundation for future mechanistic studies on the influence of gut microbial metabolites on brain function in IBS.
Fine mapping and identification of candidate genes for the peach powdery mildew resistance gene Vr3
Authors: Marimon Neus , Luque Jordi , Arús Pere , Eduardo Iban
Published: November 2020

Powdery mildew is one of the major diseases of peach (Prunus persica), caused by the ascomycete Podosphaera pannosa. Currently, it is controlled through calendar-based fungicide treatments starting at petal fall, but an alternative is to develop resistant peach varieties. Previous studies mapped a resistance gene (Vr3) in interspecific populations between almond (‘Texas’) and peach (‘Earlygold’). To obtain molecular markers highly linked to Vr3 and to reduce the number of candidate genes, we fine-mapped Vr3 to a genomic region of 270 kb with 27 annotated genes. To find evidence supporting one of these positional candidate genes as being responsible of Vr3, we analyzed the polymorphisms of the resequences of both parents and used near-isogenic lines (NILs) for expression analysis of the positional candidate genes in symptomatic or asymptomatic leaves. Genes differentially expressed between resistant and susceptible individuals were annotated as a Disease Resistance Protein RGA2 (Prupe2G111700) or an Eceriferum 1 protein involved in epicuticular wax biosynthesis (Prupe2G112800). Only Prupe2G111700 contained a variant predicted to have a disruptive effect on the encoded protein, and was overexpressed in both heterozygous and homozygous individuals containing the Vr3 almond allele, compared with susceptible individuals. This information was also useful to identify and validate molecular markers tightly linked and flanking Vr3. In addition, the NILs used in this work will facilitate the introgression of this gene into peach elite materials, alone or pyramided with other known resistance genes such as peach powdery mildew resistance gene Vr2.
Clay nanosheet-mediated delivery of recombinant plasmids expressing artificial miRNAs via leaf spray to prevent infection by plant DNA viruses
Authors: Liu Qili , Li Yanpeng , Xu Kedong , Li Dongxiao , Hu Haiyan , Zhou Feng , Song Puwen , Yu Yongang , Wei Qichao , Liu Qian , Wang Weipeng , Bu Ruifang , Sun Haili , Wang Xiaohui , Hao Jianjun , Li Honglian , Li Chengwei
Published: November 2020

Whitefly-transmitted begomoviruses are economically important plant pathogens that cause severe problems in many crop plants, such as tomato, papaya, cotton, and tobacco. Tomato yellow leaf curl virus (TYLCV) is a typical monopartite begomovirus that has been extensively studied, but methods that can efficiently control begomoviruses are still scarce. In this study, we combined artificial microRNA (amiRNA)-mediated silencing technology and clay nanosheet-mediated delivery by spraying and developed a method for efficiently preventing TYLCV infection in tomato plants. We designed three amiRNAs that target different regions of TYLCV to silence virus-produced transcripts. Three plant expression vectors expressing pre-amiRNAs were constructed, and recombinant plasmid DNAs (pDNAs) were loaded onto nontoxic and degradable layered double hydroxide (LDH) clay nanosheets. LDH nanosheets containing multiple pDNAs were sprayed onto plant leaves. We found that the designed amiRNAs were significantly accumulated in leaves 7 days after spraying, while the pDNAs were sustainably detected for 35 days after the spray, suggesting that the LDH nanosheets released pDNAs in a sustained manner, protected pDNAs from degradation and efficiently delivered pDNAs into plant cells. Importantly, when the LDH nanosheets coated with pDNAs were sprayed onto plants infected by TYLCV, both the disease severity and TYLCV viral concentration in sprayed plants were significantly decreased during the 35 days, while the levels of H2O2 were significantly increased in those plants. Taken together, these results indicate that LDH nanosheets loaded with pDNAs expressing amiRNAs can be a sustainable and promising tool for begomovirus control.
Genetic dissection of climacteric fruit ripening in a melon population segregating for ripening behavior
Authors: Pereira Lara , Santo Domingo Miguel , Ruggieri Valentino , Argyris Jason , Phillips Michael A. , Zhao Guangwei , Lian Qun , Xu Yongyang , He Yuhua , Huang Sanwen , Pujol Marta , Garcia-Mas Jordi
Published: November 2020

Melon is as an alternative model to understand fruit ripening due to the coexistence of climacteric and non-climacteric varieties within the same species, allowing the study of the processes that regulate this complex trait with genetic approaches. We phenotyped a population of recombinant inbred lines (RILs), obtained by crossing a climacteric (Védrantais, cantalupensis type) and a non-climcteric variety (Piel de Sapo T111, inodorus type), for traits related to climacteric maturation and ethylene production. Individuals in the RIL population exhibited various combinations of phenotypes that differed in the amount of ethylene produced, the early onset of ethylene production, and other phenotypes associated with ripening. We characterized a major QTL on chromosome 8, ETHQV8.1, which is sufficient to activate climacteric ripening, and other minor QTLs that may modulate the climacteric response. The ETHQV8.1 allele was validated by using two reciprocal introgression line populations generated by crossing Védrantais and Piel de Sapo and analyzing the ETHQV8.1 region in each of the genetic backgrounds. A Genome-wide association study (GWAS) using 211 accessions of the ssp. melo further identified two regions on chromosome 8 associated with the production of aromas, one of these regions overlapping with the 154.1 kb interval containing ETHQV8.1. The ETHQV8.1 region contains several candidate genes that may be related to fruit ripening. This work sheds light into the regulation mechanisms of a complex trait such as fruit ripening.
Open syntaxin overcomes exocytosis defects of diverse mutants in C. elegans
Authors: Tien Chi-Wei , Yu Bin , Huang Mengjia , Stepien Karolina P. , Sugita Kyoko , Xie Xiaoyu , Han Liping , Monnier Philippe P. , Zhen Mei , Rizo Josep , Gao Shangbang , Sugita Shuzo
Published: November 2020

Assembly of SNARE complexes that mediate neurotransmitter release requires opening of a ‘closed’ conformation of UNC-64/syntaxin. Rescue of unc-13/Munc13 mutant phenotypes by overexpressed open UNC-64/syntaxin suggested a specific function of UNC-13/Munc13 in opening UNC-64/ syntaxin. Here, we revisit the effects of open unc-64/syntaxin by generating knockin (KI) worms. The KI animals exhibit enhanced spontaneous and evoked exocytosis compared to WT animals. Unexpectedly, the open syntaxin KI partially suppresses exocytosis defects of various mutants, including snt-1/synaptotagmin, unc-2/P/Q/N-type Ca2+ channel alpha-subunit and unc-31/CAPS, in addition to unc-13/Munc13 and unc-10/RIM, and enhanced exocytosis in tom-1/Tomosyn mutants. However, open syntaxin aggravates the defects of unc-18/Munc18 mutants. Correspondingly, open syntaxin partially bypasses the requirement of Munc13 but not Munc18 for liposome fusion. Our results show that facilitating opening of syntaxin enhances exocytosis in a wide range of genetic backgrounds, and may provide a general means to enhance synaptic transmission in normal and disease states.
Evolutionary and functional genomics of DNA methylation in maize domestication and improvement
Authors: Xu Gen , Lyu Jing , Li Qing , Liu Han , Wang Dafang , Zhang Mei , Springer Nathan M. , Ross-Ibarra Jeffrey , Yang Jinliang
Published: November 2020

DNA methylation is a ubiquitous chromatin feature, present in 25% of cytosines in the maize genome, but variation and evolution of the methylation landscape during maize domestication remain largely unknown. Here, we leverage whole-genome sequencing (WGS) and whole-genome bisulfite sequencing (WGBS) data on populations of modern maize, landrace, and teosinte (Zea mays ssp. parviglumis) to estimate epimutation rates and selection coefficients. We find weak evidence for direct selection on DNA methylation in any context, but thousands of differentially methylated regions (DMRs) are identified population-wide that are correlated with recent selection. For two trait-associated DMRs, vgt1-DMR and tb1-DMR, HiChIP data indicate that the interactive loops between DMRs and respective downstream genes are present in B73, a modern maize line, but absent in teosinte. Our results enable a better understanding of the evolutionary forces acting on patterns of DNA methylation and suggest a role of methylation variation in adaptive evolution.
Armadillo-repeat kinesin1 interacts with Arabidopsis atlastin RHD3 to move ER with plus-end of microtubules
Authors: Sun Jiaqi , Zhang Mi , Qi Xingyun , Doyle Caitlin , Zheng Huanquan
Published: November 2020

In living cells, dynamics of the endoplasmic reticulum (ER) are driven by the cytoskeleton motor machinery as well as the action of ER-shaping proteins such as atlastin GTPases including RHD3 in Arabidopsis. It is not known if the two systems interplay, and, if so, how they do. Here we report the identification of ARK1 (Armadillo-Repeat Kinesin1) via a genetic screen for enhancers of the rhd3 mutant phenotype. In addition to defects in microtubule dynamics, ER organization is also defective in mutants lacking a functional ARK1. In growing root hair cells, ARK1 comets predominantly localize on the growing-end of microtubules and partially overlap with RHD3 in the cortex of the subapical region. ARK1 co-moves with RHD3 during tip growth of root hair cells. We show that there is a functional interdependence between ARK1 and RHD3. ARK1 physically interacts with RHD3 via its armadillo domain (ARM). In leaf epidermal cells where a polygonal ER network can be resolved, ARK1, but not ARK1ΔARM, moves together with RHD3 to pull an ER tubule toward another and stays with the newly formed 3-way junction of the ER for a while. We conclude that ARK1 acts together with RHD3 to move the ER on microtubules to generate a fine ER network.
Resonant inelastic x-ray scattering study of vector chiral ordered kagome antiferromagnet
Authors: Xiong Zijian , Datta Trinanjan , Yao Dao-Xin
Published: November 2020

We study the resonant inelastic x-ray scattering (RIXS) features of vector chiral ordered kagome antiferromagnets. Utilizing a group theoretical formalism that respects lattice site symmetry, we calculated the L-edge magnon contribution for the vesignieite compound BaCu3V2O8(OH)2. We show that polarization dependence of the L-edge RIXS spectrum can be used to track magnon branches. We predict a non-zero L-edge signal in the non-cross π−π polarization channel. At the K-edge, we derived the two-site effective RIXS and Raman scattering operator for two-magnon excitation in vesignieite using the Shastry–Shraiman formalism. Our derivation considers spin-orbit coupling effects in virtual hopping processes. We find vector chiral correlation (four-spin) contribution that is proportional to the RIXS spectrum. Our scattering operator formalism can be applied to a host of non-collinear non-coplanar magnetic materials at both the L and K-edge. We demonstrate that vector chiral correlations can be accessed by RIXS experiments.
Roles of bacteriophages, plasmids and CRISPR immunity in microbial community dynamics revealed using time-series integrated meta-omics
Authors: Martínez Arbas Susana , Narayanasamy Shaman , Herold Malte , Lebrun Laura A. , Hoopmann Michael R. , Li Sujun , Lam Tony J. , Kunath Benoît J. , Hicks Nathan D. , Liu Cindy M. , Price Lance B. , Laczny Cedric C. , Gillece John D. , Schupp James M. , Keim Paul S. , Moritz Robert L. , Faust Karoline , Tang Haixu , Ye Yuzhen , Skupin Alexander , May Patrick , Muller Emilie E. L. , Wilmes Paul
Published: November 2020

Viruses and plasmids (invasive mobile genetic elements (iMGEs)) have important roles in shaping microbial communities, but their dynamic interactions with CRISPR-based immunity remain unresolved. We analysed generation-resolved iMGE–host dynamics spanning one and a half years in a microbial consortium from a biological wastewater treatment plant using integrated meta-omics. We identified 31 bacterial metagenome-assembled genomes encoding complete CRISPR–Cas systems and their corresponding iMGEs. CRISPR-targeted plasmids outnumbered their bacteriophage counterparts by at least fivefold, highlighting the importance of CRISPR-mediated defence against plasmids. Linear modelling of our time-series data revealed that the variation in plasmid abundance over time explained more of the observed community dynamics than phages. Community-scale CRISPR-based plasmid–host and phage–host interaction networks revealed an increase in CRISPR-mediated interactions coinciding with a decrease in the dominant ‘Candidatus Microthrix parvicella’ population. Protospacers were enriched in sequences targeting genes involved in the transmission of iMGEs. Understanding the factors shaping the fitness of specific populations is necessary to devise control strategies for undesirable species and to predict or explain community-wide phenotypes.
Characterizing the contribution of high temperatures to child undernourishment in Sub-Saharan Africa
Authors: Baker Rachel E. , Anttila-Hughes Jesse
Published: November 2020

Despite improvements to global economic conditions, child undernourishment has increased in recent years, with approximately 7.5% of children suffering from wasting. Climate change is expected to worsen food insecurity and increase potential threats to nutrition, particularly in low-income and lower-middle income countries where the majority of undernourished children live. We combine anthropometric data for 192,000 children from 30 countries in Sub-Saharan Africa with historical climate data to directly estimate the effect of temperature on key malnutrition outcomes. We first document a strong negative relationship between child weight and average temperature across regions. We then exploit variation in weather conditions to statistically identify the effects of increased temperatures over multiple time scales on child nutrition. Increased temperatures in the month of survey, year leading up to survey and child lifetime lead to meaningful declines in acute measures of child nutrition. We find that the lifetime-scale effects explain most of the region-level negative relationship between weight and temperature, indicating that high temperatures may be a constraint on child nutrition. We use CMIP5 local temperature projections to project the impact of future warming, and find substantial increases in malnutrition depending on location: western Africa would see a 37% increase in the prevalence of wasting by 2100, and central and eastern Africa 25%.