Rapid QC-MS: Interactive Dashboard for Synchronous Mass Spectrometry Data Acquisition Quality Control.

Consistently collecting high-quality liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS) data is a time-consuming hurdle for untargeted workflows. Analytical controls such as internal and biological standards are commonly included in high-throughput workflows, helping researchers recognize low-integrity specimens regardless of their biological source. However, evaluating these standards as data are collected has remained a considerable bottleneck─in both person-hours and accuracy. Here we present Rapid QC-MS, an automated, interactive dashboard for assessing LC-MS/MS data quality. Minutes after a new data file is written, a browser-viewable dashboard is updated with quality control results spanning multiple performance dimensions such as instrument sensitivity, in-run retention time shifts, and mass accuracy drift. Rapid QC-MS provides interactive visualizations that help users recognize acute deviations in these performance metrics, as well as gradual drifts over periods of hours, days, months, or years. Rapid QC-MS is open-source, simple to install, and highly configurable. By integrating open-source Python libraries and widely used MS analysis software, it can adapt to any LC-MS/MS workflow. Rapid QC-MS runs locally and offers optional remote quality control by syncing with Google Drive. Furthermore, Rapid QC-MS can operate in a semiautonomous fashion, alerting users to specimens with potentially poor analytical integrity via frequently used messaging applications. Initially developed for integration with Thermo Orbitrap workflows, Rapid QC-MS offers a fast, straightforward approach to help users collect high-quality untargeted LC-MS/MS data by eliminating many of the most time-consuming steps in manual data curation. Download for free: https://github.com/czbiohub-sf/Rapid-QC-MS.

The perceptions and adoption of environmentally sustainable practices among anesthesiologists-a qualitative study.

PURPOSE: Previous surveys of anesthesiologists showed that despite a strong interest in implementing environmentally sustainable anesthetic practices, less than a third do so. Qualitative understanding of the capability, opportunity, and motivational factors that influence "green" behavior will inform the design of effective interventions to promote environmentally sustainable practices in the operating room (OR). METHODS: We conducted 23 semistructured interviews with anesthesiologists, with data saturation achieved. Applying the Behavior Change Wheel, interview questions addressed "capability," "opportunity," and "motivation" determinants of behavior. RESULTS: Preference for sevoflurane and syringe reuse were most commonly cited as existing environmentally sustainable anesthetic practices. Several participants reported lack of knowledge and feedback as impediments to sustainable anesthetic practices. Reported physical barriers included inadequate recycling facilities and abundance of supplies. Interviewees also discussed the importance of habitual behavior in improving skill sets and reducing cognitive load required to perform environmentally sustainable practices. General awareness of environmental issues and aggregation of marginal gains were reasons for environmentally sustainable measures in the OR. Organizational practice and culture played a significant role in the propagation of sustainable anesthetic practices, with senior staff often carrying a greater influence. While the majority preferred a top-down approach to effect change, others favored the use of incentives. CONCLUSION: This study provides insight into the factors that influence the adoption of environmentally sustainable practices in the OR. Measures to promote these practices include education and training, feedback on efforts, engagement of senior anesthetists as role models and for change management, environmental restructuring, and policy designs that balance a top-down vs bottom-up approach to influencing change.

RéSUMé: OBJECTIF: Des enquêtes antérieures auprès d'anesthésiologistes ont montré que, malgré un vif intérêt pour la mise en œuvre de pratiques anesthésiques durables sur le plan environnemental, moins d'un tiers les mettent en pratique. La compréhension qualitative de la capacité, des possibilités et des facteurs de motivation qui influencent les comportements « verts ¼ éclairera la conception d'interventions efficaces pour promouvoir des pratiques durables sur le plan environnemental en salle d'opération. MéTHODE: Nous avons mené 23 entretiens semi-structurés avec des anesthésiologistes, avec une saturation des données atteinte. En appliquant la roue du changement de comportement, les questions d'entrevue portaient sur les déterminants du comportement liés à la « capacité ¼, à l'« occasion ¼ et à la « motivation ¼. RéSULTATS: La préférence pour le sévoflurane et la réutilisation des seringues ont été le plus souvent citées comme des pratiques anesthésiques durables. Plusieurs participants ont signalé que le manque de connaissances et de rétroaction constituait un obstacle à des pratiques anesthésiques durables. Parmi les obstacles physiques signalés, mentionnons l'insuffisance des installations de recyclage et l'abondance des fournitures. Les personnes interrogées ont également discuté de l'importance du comportement habituel pour améliorer les compétences et réduire la charge cognitive requise pour mettre en œuvre des pratiques durables. La prise de conscience générale des questions environnementales et l'agrégation des gains marginaux étaient les raisons citées pour lesquelles des mesures écologiquement viables ont été prises en salle d'opération. La pratique organisationnelle et la culture ont joué un rôle important dans la diffusion de pratiques anesthésiques durables, les cadres supérieurs ayant souvent une plus grande influence. Alors que la majorité préférerait une approche descendante pour apporter des changements, d'autres étaient en faveur de l'utilisation d'incitatifs. CONCLUSION: Cette étude donne un aperçu des facteurs qui influencent l'adoption de pratiques durables sur le plan environnemental en salle d'opération. Les mesures visant à promouvoir ces pratiques comprennent l'éducation et la formation, la rétroaction sur les efforts, l'engagement des anesthésistes plus établis ou senior en tant que modèles et gestionnaires du changement, la restructuration environnementale et la conception de politiques qui équilibrent une approche descendante vs une approche ascendante pour influencer le changement.

An fMRI study of cognitive planning before and after symptom provocation in pediatric obsessive-compulsive disorder.

BACKGROUND: Pediatric obsessive-compulsive disorder (OCD) has been associated with poorer planning in laboratory, school and home settings. It is unclear whether this impairment is a standalone cognitive issue or the result of OCD symptoms. No study has examined the influence of provoked distress on planning performance and neural correlates in pediatric OCD. METHODS: Before and after a symptom provocation task, youth with OCD (n = 23; 9 boys; mean age ± standard deviation 15.1 ± 2.6 years) and matched healthy controls (n = 23) completed the Tower of London task during functional MRI scanning. RESULTS: During planning, participants with OCD recruited the left superior frontal gyrus to a greater extent than healthy controls after symptom provocation (group × time point interaction; t 44 = 5.22, p < 0.001). In a seeded, region of interest-constrained, functional connectivity analysis, we identified greater connectivity between the left superior frontal gyrus and the right middle frontal gyrus, left precuneus and left inferior parietal lobule in participants with OCD than healthy controls. We also identified greater connectivity between the right amygdala and right medial frontal gyrus in patients with OCD than healthy controls, but only before symptom provocation. LIMITATIONS: The fixed-order design of the study and the number of participants taking medication (n = 20) should be noted. CONCLUSION: Participants with OCD demonstrated greater amygdalar-cortical connectivity before symptom provocation, while sustaining greater recruitment and connectivity of task-related planning areas throughout the task. These results suggest that brain activity and connectivity is altered after symptom provocation, in the absence of impaired planning performance.

Burnout in anaesthesiology residents: A systematic review of its prevalence and stressors.

BACKGROUND: Burnout is an occupational hazard precipitated by chronic exposure to excessive work-related stress. It can have negative impacts on the health and safety of patients and clinicians. Anaesthesiologists are at a high risk of burnout; anaesthetic residents especially may experience higher levels of stress as a result of training requirements and postgraduate examinations. However, the scale of burnout among anaesthesiology residents is not well evaluated. OBJECTIVES: To determine the prevalence of burnout and identify risk factors contributing to it among anaesthesiology residents worldwide and evaluate preventive strategies at institutional and departmental levels. DESIGN: A systematic review without meta-analysis. DATA SOURCES: We searched PubMed, Embase, Scopus and PsycInfo for English language articles published up to 24 May 2021. ELIGIBILITY CRITERIA: The inclusion criteria for qualitative analysis were a reported burnout prevalence in anaesthesiology residents and the use of an assessment tool. Exclusion criteria were reviews/meta-analyses/correspondence, non-English articles, articles without anaesthesiology residents and lacking information on burnout prevalence and metrics for assessment. RESULTS: Twelve studies met the inclusion criteria; seven studies utilised the 22-item Maslach Burnout Inventory Human Services Survey (MBI-HSS) and five utilised the abbreviated Maslach Burnout Inventory (aMBI). The reported burnout prevalence among anaesthesiology residents varied between 2.7 and 67.0% (median = 24.7%). Differences in burnout criteria contributed significantly to methodological heterogeneity. Factors predisposing to burnout included long working hours, poor workplace relationships, professional examinations and adverse clinical events. Protected rest time and restricted work hours were identified as effective strategies to prevent burnout. Other preventive strategies include mindfulness and resilience courses, as well as departmental initiatives such as exercise. CONCLUSION: Burnout is common amongst anaesthesiology residents. Standardised tools and diagnostic criteria are needed to distinguish methodological heterogeneity from true heterogeneity in study populations. Interventions have been proposed to improve management strategies to minimise burnout anaesthesiology residents. PROSPERO REFERENCE: CRD42019140472.

Ten quick tips for making things findable.

The distribution of scholarly content today happens in the context of an immense deluge of information found on the internet. As a result, researchers face serious challenges when archiving and finding information that relates to their work. Library science principles provide a framework for navigating information ecosystems in order to help researchers improve findability of their professional output. Here, we describe the information ecosystem which consists of users, context, and content, all 3 of which must be addressed to make information findable and usable. We provide a set of tips that can help researchers evaluate who their users are, how to archive their research outputs to encourage findability, and how to leverage structural elements of software to make it easier to find information within and beyond their publications. As scholars evaluate their research communication strategies, they can use these steps to improve how their research is discovered and reused.

Race and ethnicity in pediatric OCD: An exploratory study of a clinical North American sample.

BACKGROUND: Influences of race and ethnicity have received limited attention in pediatric obsessive-compulsive disorder (OCD), despite noted importance in other psychiatric diseases. We sought to compare racially defined groups presenting to a North American tertiary care pediatric OCD subspecialty clinic. METHODS: Clinician-rated and parent/child-reported information was extracted from a research data registry comprising OCD-affected youth assessed between 2011 and 2018. The study population was aggregated into racial groups, defined as Caucasian, Asian, and "other." Country of origin and spoken language were used as ethnicity proxies. Obsessivecompulsive disorder phenotype, clinical course, and family environment were compared, with inclusion of mixed Asian-Caucasians in post-hoc analyses. RESULTS: Asian youth reported significantly later ages of OCD symptom onset, clinical diagnosis, and treatment compared with Caucasian youth and were significantly less likely to have participated in OCD-specific treatment, despite similar clinician recommendation rates. Obsessivecompulsive disorder severity and comorbidities did not differ across groups. Asian parents reported significantly higher levels of family blame and conflict than Caucasian parents, but similar prevalence of OCD family history. CONCLUSIONS: Clinically relevant differences were identified between Asians and Caucasians, highlighting the need for individualized care that respects the influences of ethnicity and race in pediatric OCD. Replication and future study of additional racial groups is warranted.

Neurocognitive risk markers in pediatric obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) has complex genetic underpinnings, particularly in its early-onset form, which places siblings at a 10-fold increased risk of developing the disorder. Examination for neurocognitive markers preceding pediatric OCD onset has not been conducted, although markers have been identified in adult OCD. This study compared neurocognition across groups of OCD-affected youth (n = 87), unaffected siblings of those with early-onset OCD (n = 67), and healthy controls (HC; n = 79). METHODS: A total of 233 participants aged 6-18 years old completed standardized neurocognitive tests of cognitive flexibility, decision making, planning, response inhibition, spatial working memory, attention, recognition nonverbal memory, and intelligence. They were administered the Anxiety Disorders Interview Schedule-Parent version (ADIS-P) and completed self-report anxiety and OCD questionnaires. Linear mixed-effects models tested for differences between groups, adjusting for age, gender, IQ, state anxiety, and ethnicity, and accounting for random effects of family membership. RESULTS: OCD-affected youth and unaffected siblings performed significantly worse on planning in comparison to HCs (Cohen's d = 0.74; 95% CI = [0.11, 1.36]; Cohen's d = 0.75; 95% CI = [0.12, 1.38], respectively; omnibus group effect p = .007). No other significant between-group differences were identified. CONCLUSIONS: Neurocognitive performance differences between groups identified planning as a preexisting trait marker of pediatric OCD, while no other domain presented as a marker of pediatric OCD. This differs from adult OCD, which is associated with broader cognitive impairments. Investigating longitudinal trajectories and predictive significance of neurocognition in those affected by, and at risk for, early-onset OCD is warranted. Ideally, this will enhance individualized risk stratification and inform future prevention and early intervention strategies.

Cognitive-behavioral therapy booster treatment in pediatric obsessive-compulsive disorder: A utilization assessment pilot study.

BACKGROUND: Cognitive-behavioral therapy (CBT) for pediatric obsessivecompulsive disorder (OCD) is effective, although many individuals report they need continued support after completing treatment. METHODS: Six monthly drop-in booster sessions were offered to 94 youth with OCD and their parents who previously had completed a 12-week group family-based CBT program (GF-CBT). This report describes program utilization rates and participant satisfaction levels. RESULTS: Twenty-three percent (n = 22) of invited youths with OCD attended ≥1 booster session; 63% of attendees participated in >1 session. The mean number of attended sessions was 2.84 (standard deviation = 1.74). No significant group differences between booster attendees and non-attendees were found in terms of age, sex, ethnicity, parental education, or symptom severity at baseline or end of GF-CBT. Booster session attendees were more likely to have comorbidities than non-attendees (82% vs 58%; P = .045). Most participants were recent treatment completers (59%). Based on participant feedback, booster sessions were valuable, with perceived benefits related to peer interaction and support, skills review, and homework development. CONCLUSIONS: Cognitive-behavioral therapy booster sessions for pediatric OCD seem to be an acceptable approach that a significant percentage of recent treatment completers would utilize. Further research is needed to examine program efficacy and to draw conclusions about key program features.

Academic skills in pediatric obsessive-compulsive disorder: A preliminary study.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a prevalent and debilitating illness that often begins in childhood and has a significant impact on the functioning of youth and their families. Given that schooling represents a considerable portion of youth's lives and is a key contributor to their development, identifying impacts of OCD on school performance is important. METHODS: The present study evaluated academic skill differences in OCD-affected youth age 7 to 18 (n = 25) compared with matched healthy controls (HCs; n = 25), as captured via standardized testing. Analysis of variance was used to examine group effects on the outcome variables. RESULTS: In comparison with HCs, OCD-affected youth presented with significantly poorer performance in math calculation (P = .029), although mean scores fell in the normative range. Thirty-six percent of the OCD group were in the Below Average range, compared with 12% of the HCs (P = .047). There were no significant between-group differences in word reading or spelling. Academic skills were not associated with symptom severity. CONCLUSIONS: Findings suggest that underperformance in math may be present in a higher-than-expected proportion of OCD-affected youth. Further studies of academic skills are warranted to replicate the current findings and to examine roles of academic enhancers in this vulnerable population.

The neuron-specific IIS/FOXO transcriptome in aged animals reveals regulatory mechanisms of cognitive aging.

Cognitive decline is a significant health concern in our aging society. Here, we used the model organism C. elegans to investigate the impact of the IIS/FOXO pathway on age-related cognitive decline. The daf-2 Insulin/IGF-1 receptor mutant exhibits a significant extension of learning and memory span with age compared to wild-type worms, an effect that is dependent on the DAF-16 transcription factor. To identify possible mechanisms by which aging daf-2 mutants maintain learning and memory with age while wild-type worms lose neuronal function, we carried out neuron-specific transcriptomic analysis in aged animals. We observed downregulation of neuronal genes and upregulation of transcriptional regulation genes in aging wild-type neurons. By contrast, IIS/FOXO pathway mutants exhibit distinct neuronal transcriptomic alterations in response to cognitive aging, including upregulation of stress response genes and downregulation of specific insulin signaling genes. We tested the roles of significantly transcriptionally-changed genes in regulating cognitive functions, identifying novel regulators of learning and memory. In addition to other mechanistic insights, a comparison of the aged vs young daf-2 neuronal transcriptome revealed that a new set of potentially neuroprotective genes is upregulated; instead of simply mimicking a young state, daf-2 may enhance neuronal resilience to accumulation of harm and take a more active approach to combat aging. These findings suggest a potential mechanism for regulating cognitive function with age and offer insights into novel therapeutic targets for age-related cognitive decline.

A review of COVID-19-related thrombosis and anticoagulation strategies specific to the Asian population.

The coronavirus disease 2019 (COVID-19) pandemic has placed an immense burden on healthcare systems worldwide. There is intensive research targeted at better understanding of the virus pathogenicity, development of effective treatment strategies and vaccines against COVID-19. It is increasingly being recognised that the pathogenicity of COVID-19 extends beyond the respiratory system. In severe cases, there can be widespread activation of the immune system, vascular injury and a resultant pro-thrombotic state. Severe COVID-19 is widely regarded as a risk factor for venous thromboembolism. Interim European and American guidelines have been created to guide anticoagulation strategies in COVID-19 patients. However, it is unclear if these guidelines can be extrapolated directly to Asians, in whom there are differences in the baseline risk of thrombosis and bleeding. Our review article aimed to summarise the current understanding of arteriovenous thromboembolic complications in COVID-19 and discuss management strategies for prevention and treatment of thrombotic events in Asian COVID-19 patients.

Single-Laboratory Validation of an Immunoaffinity Column Cleanup LC Method for the Analysis of Aflatoxins and Ochratoxin A in Cannabis Plant Material, Resins, Vapes, Isolates, and Edible Products.

BACKGROUND: Potential fungal infection of cannabis plants during drying has raised concerns of resulting mycotoxin contamination in leaves and flowers and subsequent contamination of derived products including cannabis-containing edible products. Validated routine methods are essential to monitor cannabis and cannabis products to ensure consumer safety consistent with long-standing controls for mycotoxins such as aflatoxins and ochratoxin A in foodstuffs. OBJECTIVE: To provide single-laboratory validation data to demonstrate the suitability of a method for determining aflatoxins and ochratoxin A in cannabis plant material, resins, vapes, isolates, and edible products such as chocolate. METHOD: Extraction of solid and liquid matrixes with acetonitrile:water, centrifugation, and then dilution of an aliquot of supernatant with phosphate-buffered saline solution containing Tween 20 surfactant. Cleanup by passing through an immunoaffinity column containing antibodies to both aflatoxins and ochratoxin A and analyzing in a single LC chromatographic run with fluorescence detection. RESULTS: For within-day analysis, recoveries were in the range 77 to 99% with RSDs from 0.7 to 9.6% for aflatoxin B1. Similarly, ochratoxin A recoveries were from 64 to 94% and RSDs from 0.9 to 9.5% for mycotoxin mixtures spiked into cannabis flowers, resins, vapes, isolates, chocolate, gummies, edible oils, and beverages. CONCLUSIONS: A method for the determination of aflatoxins and ochratoxin A was successfully developed and single-laboratory validation data has been presented for cannabis plant material, resins, vapes, isolates, and edible products. HIGHLIGHTS: A multi-mycotoxin immunoaffinity column cleanup with LC-fluorescence has been validated and shown to be suitable for routine control of aflatoxins and ochratoxin A in cannabis flowers and a diverse range of edible cannabis products.

An Integrated Genomic, Proteomic, and Immunopeptidomic Approach to Discover Treatment-Induced Neoantigens.

All nucleated mammalian cells express major histocompatibility complex (MHC) proteins that present peptides on cell surfaces for immune surveillance. These MHC-presented peptides (pMHC) are necessary for directing T-cell responses against cells harboring non-self antigens derived from pathogens or from somatic mutations. Alterations in tumor-specific antigen repertoires - particularly novel MHC presentation of mutation-bearing peptides (neoantigens) - can be potent targets of anti-tumor immune responses. Here we employed an integrated genomic and proteomic antigen discovery strategy aimed at measuring how interferon gamma (IFN-γ) alters antigen presentation, using a human lymphoma cell line, GRANTA-519. IFN-γ treatment resulted in 126 differentially expressed proteins (2% of all quantified proteins), which included components of antigen presentation machinery and interferon signaling pathways, and MHC molecules themselves. In addition, several proteasome subunits were found to be modulated, consistent with previous reports of immunoproteasome induction by IFN-γ exposure. This finding suggests that a modest proteomic response to IFN-γ could create larger alteration to cells' antigen/epitope repertoires. Accordingly, MHC immunoprecipitation followed by mass spectrometric analysis of eluted peptide repertoires revealed exclusive signatures of IFN-γ induction, with 951 unique peptides reproducibly presented by MHC-I and 582 presented by MHC-II. Furthermore, an additional set of pMHCs including several candidate neoantigens, distinguished control and the IFN-γ samples by their altered relative abundances. Accordingly, we developed a classification system to distinguish peptides which are differentially presented due to altered expression from novel peptides resulting from changes in antigen processing. Taken together, these data demonstrate that IFN-γ can re-shape antigen repertoires by identity and by abundance. Extending this approach to models with greater clinical relevance could help develop strategies by which immunopeptide repertoires are intentionally reshaped to improve endogenous or vaccine-induced anti-tumor immune responses and potentially anti-viral immune responses.

Mindfulness-based skills training group for parents of obsessive-compulsive disorder-affected children: A caregiver-focused intervention.

BACKGROUND AND PURPOSE: Parents of children with obsessive-compulsive disorder (OCD) report significant emotional and socio-occupational impacts. There is, however, currently insufficient support for these parents. This study examined a mindfulness-based intervention for parents of OCD-affected children, investigating its feasibility and impact on parental ability to tolerate their child's OCD-related distress, in addition to exploring potential indirect effects. MATERIALS AND METHODS: Parents of OCD-affected children (n = 39) completed an eight-week baseline observation period followed by eight, weekly manualized mindfulness-based intervention group sessions. Measures of parental tolerance of child distress, dispositional mindfulness, family accommodation, family functioning, and OCD symptom severity were collected. RESULTS: In comparison to the baseline observation period, parental tolerance of child distress and dispositional mindfulness significantly improved following mindfulness training. No other temporal differences were observed. Parents reported high satisfaction. CONCLUSION: Mindfulness-based skills training for parents of OCD-affected youth appears to be feasible and to significantly increase tolerance related to the child's distress. CLINICAL TRIAL REGISTRATION NUMBER: NCT03212703.

Who listens and who doesn't? Factors associated with adherence to antibiotic stewardship intervention in a Singaporean tertiary hospital.

INTRODUCTION: Antibiotic stewardship programmes (ASPs) can improve patient outcomes by prospective audit and feedback with interventions. However, adherence to ASP interventions is not mandatory. Identifying factors associated with improved adherence may help to enhance ASP recommendations and activities. METHODS: A retrospective cohort study was conducted, comprising all ASP interventions performed as part of the prospective audit and feedback strategy in our institution (an acute tertiary-care hospital in Singapore) from January 2016 to July 2018. Adherence to ASP intervention was ascertained based on documented compliance with the recommended interventions within 48h. Factors associated with adherence to ASP interventions, such as patient demographics, clinical condition, type of infection, and characteristics of ASP interventions were identified using the χ2 test for categorical variables. On multivariate analysis, factors independently associated with adherence to ASP intervention were identified using logistic regression. RESULTS: Adherence to ASP intervention was 81.9% (5758/7028). On univariate and multivariate analysis, interventions coupled with direct communication via phone call (adjusted odds ratio [aOR] 1.61, 95% CI 1.23-2.08) were associated with higher odds of adherence, whereas admission to a surgical unit, intervention involving carbapenem use, and recommendation to de-escalate or discontinue antibiotics were associated with lower odds of adherence to ASP interventions. CONCLUSION: Although adherence rates to ASP interventions were relatively high, interventions made to the surgical unit and recommendations related to carbapenem use were not so well received. Interventions communicated verbally via phone call were well received, highlighting the need for a close working relationship between ASP teams and hospital physicians.

The utility of voriconazole therapeutic drug monitoring in a multi-racial cohort in Southeast Asia.

OBJECTIVES: Voriconazole serum concentration, which is affected by several factors, is associated with treatment response and toxicity. There is paucity of data on voriconazole therapeutic drug monitoring (TDM) among Southeast Asians, who exhibit a higher prevalence of CYP2C19-poor metabolisers compared with Caucasians and East Asians. Hence, there are concerns for higher risk of voriconazole accumulation and toxicity. We aim to determine the utility of voriconazole TDM through establishing: (1) proportion of patients achieving therapeutic troughs without dose adjustments; (2) characterisation of patients with sub-therapeutic, therapeutic and supra-therapeutic levels; (3) appropriate dose titrations/dose required for therapeutic troughs; (4) correlation between troughs and adverse events, treatment response/fungal breakthrough. PATIENTS AND METHODS: A single-centre retrospective analysis of data from adults (≥21 years old) with ≥1 voriconazole trough measured at Singapore General Hospital from 2015 to 2017 was performed. RESULTS: Thirty-two patients (45.7%) among 70 patients achieved therapeutic troughs (defined as 2.0-5.5 mg/L) without dose adjustments. Eleven patients (15.7%) experienced hepatotoxicity (troughs 0.5 to >7.5 mg/L). Neurotoxicity occurred in three patients (4.3%) (troughs ≥6.7 mg/L) and all patients had symptom resolution upon dose reduction. Treatment failure of invasive fungal infection appeared less in patients with therapeutic troughs compared with sub-therapeutic troughs (11.4% vs. 14.2%). Two patients experienced treatment failure despite supra-therapeutic voriconazole troughs. CONCLUSIONS: TDM should be implemented due to significant unpredictability in dose exposure. TDM can reduce unnecessary switches to alternatives due to intolerability and rule in the possibility of resistant organisms in the event of treatment failure despite therapeutic troughs, alerting clinicians to switch to alternatives promptly.

TagGraph reveals vast protein modification landscapes from large tandem mass spectrometry datasets.

Although mass spectrometry is well suited to identifying thousands of potential protein post-translational modifications (PTMs), it has historically been biased towards just a few. To measure the entire set of PTMs across diverse proteomes, software must overcome the dual challenges of covering enormous search spaces and distinguishing correct from incorrect spectrum interpretations. Here, we describe TagGraph, a computational tool that overcomes both challenges with an unrestricted string-based search method that is as much as 350-fold faster than existing approaches, and a probabilistic validation model that we optimized for PTM assignments. We applied TagGraph to a published human proteomic dataset of 25 million mass spectra and tripled confident spectrum identifications compared to its original analysis. We identified thousands of modification types on almost 1 million sites in the proteome. We show alternative contexts for highly abundant yet understudied PTMs such as proline hydroxylation, and its unexpected association with cancer mutations. By enabling broad characterization of PTMs, TagGraph informs as to how their functions and regulation intersect.

Neural correlates of symptom provocation in pediatric obsessive-compulsive disorder.

OBSESSIVE-COMPULSIVE DISORDER: (OCD)-affected adults and children exhibit three to four symptom dimensions with distinct but overlapping neural correlates. No symptom provocation behavioural or imaging study has examined all symptom dimensions in a pediatric OCD sample. METHOD: Clinically diagnosed pediatric OCD-affected participants (n = 25) as well as age, gender and Tanner pubertal stage-matched healthy controls (HCs; n = 24) (total sample: mean age = 14.77 ±â€¯2.93 years; age range = 9-18 years; 35% male) viewed alternating blocks of OCD symptom provocation (Contamination, Bad Thoughts, and Just Right symptom dimensions), Fear, Neutral and Rest (i.e. fixation) conditions during functional magnetic resonance imaging. A region-of-interest analysis used seeds based upon results of an adult OCD meta-analysis RESULTS: OCD participants found OCD symptom-related stimuli bothersome, particularly when compared to controls in the "Just Right" symptom dimension. Pediatric OCD patients exhibited greater recruitment of the left superior temporal gyrus (STG) than healthy controls during combined symptom provocation versus neutral conditions. CONCLUSION: Findings suggest involvement of the temporal poles rather than in classic cortico-striatal-thalamico-cortical circuits in pediatric OCD during symptom provocation.

A case-control study of sleep disturbances in pediatric obsessive-compulsive disorder.

BACKGROUND: Sleep disturbances, including delayed sleep phase disorder (DSPD) and disorders of sleep initiation and maintenance (DIMS), have repeatedly been identified in adult obsessive-compulsive disorder (OCD). These disturbances have not been well-characterized objectively in pediatric OCD. METHODS: Thirty OCD-affected youth (8-18 yrs, 40% male) and 30 age and gender-matched healthy controls (HCs) completed the Sleep Disturbances Scale for Children (SDSC), and one week of continuous actigraphy with concurrent sleep diary documentation. A subsample completed the Children's Sleep Hygiene Scale (CSHS) and Sleep Attitudes and Beliefs Scale (SABS). RESULTS: Seventy-two percent of OCD participants reported sleep disturbances versus 15% of HC participants (p < 0.001). Convergent actigraphy results suggested DIMS but not DSPD were common. DISCUSSION: The parents of OCD-affected children seem to be successfully controlling bedtimes, preventing circadian rhythm system disruptions. OCD status does adversely impact, however, the perisleep arousal system. These results have important clinical implications, suggesting sleep problems may be best managed through direct treatment of OCD symptoms. It is recommended that all pediatric OCD patients be screened for sleep disturbances to inform treatment plan development.