Linezolid optic neuropathy.

PURPOSE OF REVIEW: In this article, we reviewed 67 reported cases of linezolid optic neuropathy and describe the common characteristics and expectations for recovery with an emphasis on recent findings in the literature. RECENT FINDINGS: Linezolid classically causes a reversible, duration-dependent optic neuropathy. However, in our review, we found only 66.7% of patients recovered complete visual function. Vision loss most commonly affected visual acuity followed by visual field and color vision. We also found patients taking higher doses of linezolid experienced full recovery less often, suggesting a dose-dependent component of linezolid optic neuropathy. Linezolid use has increased in frequency and duration, especially in the treatment of drug-resistant tuberculosis, and data indicate that these patients experience lower rates of complete vision recovery compared with patients taking linezolid for other indications. SUMMARY: Linezolid is an effective medication for treating drug-resistant infections; however, it may result in optic neuropathy. It is reasonable for patients on linezolid to undergo screening examinations, especially those on higher doses or for prolonged duration of therapy.

RLSuite: An Integrative R-Loop Bioinformatics Framework.

We recently described the development of a database of 810 R-loop mapping datasets and used this data to conduct a meta-analysis of R-loops. R-loops are three-stranded nucleic acid structures containing RNA:DNA hybrids and we were able to verify that 30% of expressed genes have an associated R-loop in a location conserved manner.. Moreover, intergenic R-loops map to enhancers, super enhancers and with TAD domain boundaries. This work demonstrated that R-loop mapping via high-throughput sequencing can reveal novel insight into R-loop biology, however the analysis and quality control of these data is a non-trivial task for which few bioinformatic tools exist. Herein we describe RLSuite, an integrative R-loop bioinformatics framework for pre-processing, quality control, and downstream analysis of R-loop mapping data. RLSuite enables users to compare their data to hundreds of public datasets and generate a user-friendly analysis report for sharing with non-bioinformatician colleagues. Taken together, RLSuite is a novel analysis framework that should greatly benefit the emerging R-loop bioinformatics community in a rapidly expanding aspect of epigenetic control that is still poorly understood.

Rust (Puccinia emaculata) Management and Impact on Biomass Yield in Switchgrass.

Rust, putatively caused by Puccinia emaculata, is a widespread and potentially damaging disease of switchgrass, a crop produced as feedstock for livestock and bioenergy. Azoxystrobin, chlorothalonil, and myclobutanil were applied at 1-, 2-, 3-, or 4-week intervals for 12 to 14 weeks to the vegetatively propagated switchgrass cultivar Cloud Nine to assess fungicide selection and application interval for the control of rust as well as the impact of this disease on switchgrass biomass yield. Although rust severity significantly differed among study years, azoxystrobin and myclobutanil were often equally and more effective than chlorothalonil at controlling rust, with superior disease control coming at shorter application intervals compared with extended application intervals. Year, product, application interval, and product × interval significantly impacted dry biomass yield, which was greatest in 2016 and lowest in 2014. Dry biomass yield protection was significantly better with azoxystrobin and myclobutanil applications than with chlorothalonil or no fungicide. Linear regression models with the final disease rating, as well as with the area under disease progress curve in each year, were significant, but coefficients of determination were low to moderate (0.21 < R2 < 0.60), indicating that rust response and subsequent disease impact on dry biomass yield were impacted by other factors. From our models, an estimated 3 to 5% biomass decline was calculated for each 10% increment in rust-related leaf necrosis observed at the final September rating date. With rust-related leaf necrosis ≥80% by 1 September in each of 4 study years, biomass yield may be reduced by 24 to 40% if rust problems are not managed in switchgrass crops.

A Novel Multiplexed Enzyme-Linked Immunosorbent Assay for the Detection of IgG Seroreactivity to Cytomegalovirus (CMV) UL144.

Infection with human cytomegalovirus (CMV) is common and may have grave consequences in transplant recipients and congenitally infected children. Diagnosis of CMV infection is based on detection of specific antibodies and molecular assays. The incorporation of CMV serological assays into diagnostic algorithms requires careful evaluation and interpretation. Very few serological assays measure CMV infection by a specific strain. We developed an enzyme-linked immunosorbent assay (ELISA) using CMV-encoded UL144 as the antigen. UL144 encodes three major genotypes, A, B, and C, and recombinants. The ELISA was developed with the three UL144 proteins and optimized as a multiplex assay. Sera from 55 positive and 59 negative CMV IgG, determined by the clinical microbiology laboratory, were used for evaluation and optimization. A cutoff optical density (OD) that distinguishes UL144 antibody-positive from antibody-negative sera was established. UL144 A, B, C, and combinations of these antigens were detected in sera. An assay threshold of 0.1 was established and, from a total of 303 sera, the overall sensitivity, specificity, and positive and negative predictive values of the multiplex ELISA were 86.72% (95% confidence interval [CI] 79.59% to 92.07%), 96.57% (92.69% to 98.73%), 94.40% (88.45% to 97.38%), and 91.60% (87.50% to 94.44%), respectively. The inter- and intraassay median coefficients of variation were 0.06 (interquartile range [IQR] 0.56, 0.2) and 0.171 (IQR 0.038, 0.302), respectively. No cross-reactivity was observed with HSV-positive CMV-negative sera. This ELISA gives simple and reproducible results for detection of anti-CMV UL144 IgG. It may assist in differentiating natural infection from CMV vaccines that lack UL144, and may provide an important tool for epidemiological studies of CMV strains.

Characteristics and Outcomes of Clinic Visits Immediately Preceding Sepsis Hospitalization.

BACKGROUND: Existing sepsis quality improvement initiatives focus on recognition and treatment of sepsis upon hospital admission. Yet many patients are evaluated in the clinic within 1 day of sepsis hospitalization. OBJECTIVES: To determine the circumstances of clinic visits that precede sepsis hospitalization, including illness severity, whether patients are referred to the hospital, and time lapse and change in illness severity between clinic and hospital evaluation. METHODS: In a retrospective cohort study at a tertiary academic medical center, data from electronic medical records were collected for all adult patients evaluated in an outpatient clinic within 1 day of sepsis hospitalization in 2017. RESULTS: Of 1450 patients hospitalized with sepsis, 118 had an established outpatient provider and a clinic visit within 1 day of admission and thus were included. During the clinic visit, 47 patients (39.8%) had a quick Sequential Organ Failure Assessment (qSOFA) score ≥1, and 59 (50.0%) had vital sign abnormalities. Most (74, 62.7%) were sent directly to the emergency department or hospital. Upon emergency department/hospital presentation, 62 patients (52.5%) had a worsening qSOFA score and/ or vital signs and 27 (22.9%) had worsening of multiple parameters. Median time lapse from clinic to emergency department/hospital evaluation was 3.2 hours. CONCLUSIONS: One in 10 patients hospitalized for sepsis had been evaluated in a clinic within 1 day of admission. At that clinic visit, most patients had an elevated qSOFA score or abnormal vital signs and a majority were sent directly to the emergency department/hospital. Half experienced clinical deterioration between the clinic visit and arrival in the emergency department/hospital.

Causes and characteristics of death in patients with acute hypoxemic respiratory failure and acute respiratory distress syndrome: a retrospective cohort study.

BACKGROUND: Acute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS) are associated with high in-hospital mortality. However, in cohorts of ARDS patients from the 1990s, patients more commonly died from sepsis or multi-organ failure rather than refractory hypoxemia. Given increased attention to lung-protective ventilation and sepsis treatment in the past 25 years, we hypothesized that causes of death may be different among contemporary cohorts. These differences may provide clinicians with insight into targets for future therapeutic interventions. METHODS: We identified adult patients hospitalized at a single tertiary care center (2016-2017) with AHRF, defined as PaO2/FiO2 ≤ 300 while receiving invasive mechanical ventilation for > 12 h, who died during hospitalization. ARDS was adjudicated by multiple physicians using the Berlin definition. Separate abstractors blinded to ARDS status collected data on organ dysfunction and withdrawal of life support using a standardized tool. The primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support. RESULTS: We identified 385 decedents with AHRF, of whom 127 (33%) had ARDS. The most common primary causes of death were sepsis (26%), pulmonary dysfunction (22%), and neurologic dysfunction (19%). Multi-organ failure was present in 70% at time of death, most commonly due to sepsis (50% of all patients), and 70% were on significant respiratory support at the time of death. Only 2% of patients had insupportable oxygenation or ventilation. Eighty-five percent died following withdrawal of life support. Patients with ARDS more often had pulmonary dysfunction as the primary cause of death (28% vs 19%; p = 0.04) and were also more likely to die while requiring significant respiratory support (82% vs 64%; p <  0.01). CONCLUSIONS: In this contemporary cohort of patients with AHRF, the most common primary causes of death were sepsis and pulmonary dysfunction, but few patients had insupportable oxygenation or ventilation. The vast majority of deaths occurred after withdrawal of life support. ARDS patients were more likely to have pulmonary dysfunction as the primary cause of death and die while requiring significant respiratory support compared to patients without ARDS.

CRISPR-based gene editing enables FOXP3 gene repair in IPEX patient cells.

The prototypical genetic autoimmune disease is immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, a severe pediatric disease with limited treatment options. IPEX syndrome is caused by mutations in the forkhead box protein 3 (FOXP3) gene, which plays a critical role in immune regulation. As a monogenic disease, IPEX is an ideal candidate for a therapeutic approach in which autologous hematopoietic stem and progenitor (HSPC) cells or T cells are gene edited ex vivo and reinfused. Here, we describe a CRISPR-based gene correction permitting regulated expression of FOXP3 protein. We demonstrate that gene editing preserves HSPC differentiation potential, and that edited regulatory and effector T cells maintain their in vitro phenotype and function. Additionally, we show that this strategy is suitable for IPEX patient cells with diverse mutations. These results demonstrate the feasibility of gene correction, which will be instrumental for the development of therapeutic approaches for other genetic autoimmune diseases.

Oxygen consumption rate of Caenorhabditis elegans as a high-throughput endpoint of toxicity testing using the Seahorse XFe96 Extracellular Flux Analyzer.

Caenorhabditis elegans presents functioning, biologically relevant phenotypes and is frequently used as a bioindicator of toxicity. However, most C. elegans in vivo effect-assessment methods are laborious and time consuming. Therefore, we developed a novel method to measure the oxygen consumption rate of C. elegans as a sublethal endpoint of toxicity. This protocol was tested by exposing 50 larval stage one C. elegans individuals for 48 h (at 20 °C) to different concentrations of two toxicants i.e. benzylcetyldimethylammonium chloride (BAC-C16) and cadmium (Cd). Following exposures, the oxygen consumption rate of the C. elegans individuals were measured using the high-throughput functionality of the Seahorse XFe96 Extracellular Flux Analyzer. Dose-response curves for BAC-C16 (R2 = 0.93; P = 0.001) and Cd (R2 = 0.98; P = 0.001) were created. Furthermore, a strong, positive correlation was evidenced between C. elegans oxygen consumption rate and a commonly used, ecologically relevant endpoint of toxicity (growth inhibition) for BAC-C16 (R2 = 0.93; P = 0.0001) and Cd (R2 = 0.91; P = 0.0001). The data presented in this study show that C. elegans oxygen consumption rate can be used as a promising functional measurement of toxicity.

Transmission of Coxiella burnetii by ingestion in mice.

Coxiella burnetii, the causative agent of Q fever, is widely present in dairy products around the world. It has been isolated from unpasteurised milk and cheese and can survive for extended periods of time under typical storage conditions for these products. Although consumption of contaminated dairy products has been suggested as a potential route for transmission, it remains controversial. Given the high prevalence of C. burnetii in dairy products, we sought to examine the feasibility of transmitting the major sequence types (ST16, ST8 and ST20) of C. burnetii circulating in the United States. We delivered three strains of C. burnetii, comprising each sequence type, directly into the stomachs of immunocompetent BALB/c mice via oral gavage (OG) and assessed them for clinical symptoms, serological response and bacterial dissemination. We found that mice receiving C. burnetii by OG had notable splenomegaly only after infection with ST16. A robust immune response and persistence in the stomach and mesenteric lymph nodes were observed in mice receiving ST16 and ST20 by OG, and dissemination of C. burnetii to peripheral tissues was observed in all OG infected mice. These findings support the oral route as a mode of transmission for C. burnetii.

Behaviour change, weight loss and remission of Type 2 diabetes: a community-based prospective cohort study.

AIM: To quantify the association between behaviour change and weight loss after diagnosis of Type 2 diabetes, and the likelihood of remission of diabetes at 5-year follow-up. METHOD: We conducted a prospective cohort study in 867 people with newly diagnosed diabetes aged 40-69 years from the ADDITION-Cambridge trial. Participants were identified via stepwise screening between 2002 and 2006, and underwent assessment of weight change, physical activity (EPAQ2 questionnaire), diet (plasma vitamin C and self-report), and alcohol consumption (self-report) at baseline and 1 year after diagnosis. Remission was examined at 5 years after diabetes diagnosis via HbA1c level. We constructed log binomial regression models to quantify the association between change in behaviour and weight over both the first year after diagnosis and the subsequent 1-5 years, as well as remission at 5-year follow-up. RESULTS: Diabetes remission was achieved in 257 participants (30%) at 5-year follow-up. Compared with people who maintained the same weight, those who achieved ≥ 10% weight loss in the first year after diagnosis had a significantly higher likelihood of remission [risk ratio 1.77 (95% CI 1.32 to 2.38; p<0.01)]. In the subsequent 1-5 years, achieving ≥10% weight loss was also associated with remission [risk ratio 2.43 (95% CI 1.78 to 3.31); p<0.01]. CONCLUSION: In a population-based sample of adults with screen-detected Type 2 diabetes, weight loss of ≥10% early in the disease trajectory was associated with a doubling of the likelihood of remission at 5 years. This was achieved without intensive lifestyle interventions or extreme calorie restrictions. Greater attention should be paid to enabling people to achieve weight loss following diagnosis of Type 2 diabetes.

Neurodevelopmental profile of siblings with Angelman syndrome due to pathogenic UBE3A variants.

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder caused by a lack of expression of the maternally inherited UBE3A gene on chromosome 15. Individuals with AS due to a UBE3A mutation are more likely to have siblings who also have AS compared with those with AS due to other cytogenetic/molecular mechanisms, but it is unknown whether the developmental outcome of siblings who have AS is similar. METHODS: Through an ongoing AS Natural History Study, we identified seven pairs of siblings with AS due to a UBE3A mutation. We compared the neurodevelopment of the first-born and second-born siblings with AS participants who have a UBE3A mutation and have either typically developing siblings or no siblings. RESULTS: Second-born AS participants due to a UBE3A mutation were more likely to be diagnosed at an earlier age. With the exception of higher expressive language scores among the second-born participants, no other differences were observed in the developmental and adaptive functioning skills across the different groups. CONCLUSIONS: The presence of an older sibling with the same neurodevelopmental disorder is associated with an earlier age of diagnosis and may be associated with an improvement in expressive language skills; the developmental outcome of siblings with AS due to a UBE3A mutation is otherwise comparable.

Author Correction: Forearc carbon sink reduces long-term volatile recycling into the mantle.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: Forearc carbon sink reduces long-term volatile recycling into the mantle.

Change history: In this Article, the original affiliation 2 was not applicable and has been removed. In addition, in the Acknowledgements there was a statement missing and an error in a name. These errors have been corrected online.

Forearc carbon sink reduces long-term volatile recycling into the mantle.

Carbon and other volatiles in the form of gases, fluids or mineral phases are transported from Earth's surface into the mantle at convergent margins, where the oceanic crust subducts beneath the continental crust. The efficiency of this transfer has profound implications for the nature and scale of geochemical heterogeneities in Earth's deep mantle and shallow crustal reservoirs, as well as Earth's oxidation state. However, the proportions of volatiles released from the forearc and backarc are not well constrained compared to fluxes from the volcanic arc front. Here we use helium and carbon isotope data from deeply sourced springs along two cross-arc transects to show that about 91 per cent of carbon released from the slab and mantle beneath the Costa Rican forearc is sequestered within the crust by calcite deposition. Around an additional three per cent is incorporated into the biomass through microbial chemolithoautotrophy, whereby microbes assimilate inorganic carbon into biomass. We estimate that between 1.2 × 108 and 1.3 × 1010 moles of carbon dioxide per year are released from the slab beneath the forearc, and thus up to about 19 per cent less carbon is being transferred into Earth's deep mantle than previously estimated.

Novel Plate Design to Improve Mandibular and Maxillary Reconstruction with the Osteocutaneous Fibula Flap.

Virtual surgical planning (VSP) has improved the accuracy and efficiency of craniofacial reconstruction using the osteocutaneous free fibula flap. Despite this, challenges remain in translating the VSP to a real-world construct due to small changes that can occur after osteotomies of the mandible or maxilla. Poor execution of the VSP can lead to malocclusion, undesirable aesthetics, or poor bony contact at the sites of osteosynthesis. We describe a novel technique using Selective LASER Melted plates to achieve maximum control and accuracy of complex, virtually planned reconstructions of the mandible and maxilla.

An association analysis of sow parity, live-weight and back-fat depth as indicators of sow productivity.

Understanding how critical sow live-weight and back-fat depth during gestation are in ensuring optimum sow productivity is important. The objective of this study was to quantify the association between sow parity, live-weight and back-fat depth during gestation with subsequent sow reproductive performance. Records of 1058 sows and 13 827 piglets from 10 trials on two research farms between the years 2005 and 2015 were analysed. Sows ranged from parity 1 to 6 with the number of sows per parity distributed as follows: 232, 277, 180, 131, 132 and 106, respectively. Variables that were analysed included total born (TB), born alive (BA), piglet birth weight (BtWT), pre-weaning mortality (PWM), piglet wean weight (WnWT), number of piglets weaned (Wn), wean to service interval (WSI), piglets born alive in subsequent farrowing and sow lactation feed intake. Calculated variables included the within-litter CV in birth weight (LtV), pre-weaning growth rate per litter (PWG), total litter gain (TLG), lactation efficiency and litter size reared after cross-fostering. Data were analysed using linear mixed models accounting for covariance among records. Third and fourth parity sows had more (P0.05). Heavier sow live-weight throughout gestation was associated with an increase in PWM (P0.05). In conclusion, this study showed that sow parity, live-weight and back-fat depth can be used as indicators of reproductive performance. In addition, this study also provides validation for future development of a benchmarking tool to monitor and improve the productivity of modern sow herd.

Global burden of hearing impairment and ear disease.

BACKGROUND: Hearing loss can present at birth or be acquired as a result of illness, middle-ear disease, injury, age, overuse of certain medications, and/or induced by exposure to damaging noise levels. There are serious short-term consequences for people living with hearing impairment, including the effects on language acquisition, education, employment and overall wellbeing. There are also complex long-term implications. OBJECTIVES: This review aimed to present some of the leading causes of ear disease and hearing loss globally, and to identify their impact at both an individual and societal level.

Reaching rural veterans: a new mechanism to connect rural, low-income US Veterans with resources and improve food security.

BACKGROUND: Rural, low-income US veterans face additional barriers to accessing food and resources compared to urban veterans. Based on both social-ecological and cultural competence approaches, the Reaching Rural Veterans (RRV) pilot intervention built on the existing infrastructure of food pantries to improve food security and connect rural, low-income veterans with resources. This article describes the process of implementing and evaluating RRV. METHODS: Five rural food pantries within each of two states, Indiana and Kentucky, received training in cultural competence and held monthly outreach events where food and services were offered to veterans. Veteran adult participants completed an assessment at baseline and 3-month follow-up that measured food security using the US Household Food Security Survey Module and self-reported resource enrollment. Repeated measures logistic regression models evaluated the odds of improving food security and resource enrollment from baseline to follow-up (significance P < 0.05). RESULTS: RRV recruited 234 participants; 53% completed the follow-up assessment. At follow-up, the odds of household (P = 0.009) and adult (P = 0.01) food security increased, as did enrollment in one or more of the following resources: Temporary Assistance for Needy Families, Supplemental Security Income, General Assistance or Assistance from the Township Trustee (P = 0.005). CONCLUSIONS: RRV yielded promising preliminary results of improved food security and resource use.

Is the aging human ovary still ticking?: Expression of clock-genes in luteinized granulosa cells of young and older women.

BACKGROUND: It has been shown - mostly in animal models - that circadian clock genes are expressed in granulosa cells and in corpora luteum and might be essential for the ovulatory process and steroidogenesis. OBJECTIVE: We sought to investigate which circadian clock genes exist in human granulosa cells and whether their expression and activity decrease during aging of the ovary. STUDY DESIGN: Human luteinized granulosa cells were isolated from young (age 18-33) and older (age 39-45) patients who underwent in-vitro fertilization treatment. Levels of clock genes expression were measured in these cells 36 h after human chorionic gonadotropin stimulation. METHODS: Human luteinized granulosa cells were isolated from follicular fluid during oocyte retrieval. The mRNA expression levels of the circadian genes CRY1, CRY2, PER1, PER2, CLOCK, ARNTL, ARNTL2, and NPAS2 were analyzed by quantitative polymerase chain reaction. RESULTS: We found that the circadian genes CRY1, CRY2, PER1, PER2, CLOCK, ARNTL, ARNTL2, and NPAS2, are expressed in cultured human luteinized granulosa cells. Among these genes, there was a general trend of decreased expression in cells from older women but it reached statistical significance only for PER1 and CLOCK genes (fold change of 0.27 ± 0.14; p = 0.03 and 0.29 ± 0.16; p = 0.05, respectively). CONCLUSIONS: This preliminary report indicates that molecular circadian clock genes exist in human luteinized granulosa cells. There is a decreased expression of some of these genes in older women. This decline may partially explain the decreased fertility and steroidogenesis of reproductive aging.