Techniques to increase lumbar puncture success in newborn babies: the NeoCLEAR RCT.

Background: Lumbar puncture is an essential tool for diagnosing meningitis. Neonatal lumbar puncture, although frequently performed, has low success rates (50-60%). Standard technique includes lying infants on their side and removing the stylet 'late', that is, after the needle is thought to have entered the cerebrospinal fluid. Modifications to this technique include holding infants in the sitting position and removing the stylet 'early', that is, following transection of the skin. To the best of our knowledge, modified techniques have not previously been tested in adequately powered trials. Objectives: The aim of the Neonatal Champagne Lumbar punctures Every time - An RCT (NeoCLEAR) trial was to compare two modifications to standard lumbar puncture technique, that is, use of the lying position rather than the sitting position and of 'early' rather than 'late' stylet removal, in terms of success rates and short-term clinical, resource and safety outcomes. Methods: This was a multicentre 2 × 2 factorial pragmatic non-blinded randomised controlled trial. Infants requiring lumbar puncture (with a working weight ≥ 1000 g and corrected gestational age from 27+0 to 44+0 weeks), and whose parents provided written consent, were randomised by web-based allocation to lumbar puncture (1) in the sitting or lying position and (2) with early or late stylet removal. The trial was powered to detect a 10% absolute risk difference in the primary outcome, that is, the percentage of infants with a successful lumbar puncture (cerebrospinal fluid containing < 10,000 red cells/mm3). The primary outcome was analysed by modified intention to treat. Results: Of 1082 infants randomised (sitting with early stylet removal, n = 275; sitting with late stylet removal, n = 271; lying with early stylet removal, n = 274; lying with late stylet removal, n = 262), 1076 were followed up until discharge. Most infants were term born (950/1076, 88.3%) and were aged < 3 days (936/1076, 87.0%) with a working weight > 2.5 kg (971/1076, 90.2%). Baseline characteristics were balanced across groups. In terms of the primary outcome, the sitting position was significantly more successful than lying [346/543 (63.7%) vs. 307/533 (57.6%), adjusted risk ratio 1.10 (95% confidence interval 1.01 to 1.21); p = 0.029; number needed to treat = 16 (95% confidence interval 9 to 134)]. There was no significant difference in the primary outcome between early stylet removal and late stylet removal [338/545 (62.0%) vs. 315/531 (59.3%), adjusted risk ratio 1.04 (95% confidence interval 0.94 to 1.15); p = 0.447]. Resource consumption was similar in all groups, and all techniques were well tolerated and safe. Limitations: This trial predominantly recruited term-born infants who were < 3 days old, with working weights > 2.5 kg. The impact of practitioners' seniority and previous experience of different lumbar puncture techniques was not investigated. Limited data on resource use were captured, and parent/practitioner preferences were not assessed. Conclusion: Lumbar puncture success rate was higher with infants in the sitting position but was not affected by timing of stylet removal. Lumbar puncture is a safe, well-tolerated and simple technique without additional cost, and is easily learned and applied. The results support a paradigm shift towards sitting technique as the standard position for neonatal lumbar puncture, especially for term-born infants during the first 3 days of life. Future work: The superiority of the sitting lumbar puncture technique should be tested in larger populations of premature infants, in those aged > 3 days and outside neonatal care settings. The effect of operators' previous practice and the impact on family experience also require further investigation, alongside in-depth analyses of healthcare resource utilisation. Future studies should also investigate other factors affecting lumbar puncture success, including further modifications to standard technique. Trial registration: This trial is registered as ISRCTN14040914 and as Integrated Research Application System registration 223737. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/106) and is published in full in Health Technology Assessment; Vol. 27, No. 33. See the NIHR Funding and Awards website for further award information.

Newborn babies are more susceptible to getting meningitis, and this can be fatal or have lifelong complications. A lumbar puncture is an essential test for diagnosing meningitis. Lumbar puncture involves taking a small amount of spinal fluid from the lower back using a needle. Analysing the fluid confirms or excludes meningitis, allowing the right treatment to be given. Lumbar punctures are commonly performed in newborns, but are technically difficult. In 50­60% of lumbar punctures in newborns, either no fluid is obtained or the sample is mixed with blood, making analysis less reliable. No-one knows which is the best technique, and so practice varies. The baby can be held lying on their side or sat up, and the 'stylet', which is a thin piece of metal that sits inside (and aids insertion of) the needle, can be removed either soon after passing through the skin (i.e. 'early stylet removal') or once the tip is thought to have reached the spinal fluid (i.e. 'late stylet removal'). We wanted to find the best technique for lumbar puncture in newborns. Therefore, we compared sitting with lying position, and 'early' with 'late' stylet removal. We carried out a large trial in newborn care and maternity wards in 21 UK hospitals. With parental consent, we recruited 1082 full-term and premature babies who needed a lumbar puncture. Our results demonstrated that the sitting position was more successful than lying position, but the timing of stylet removal did not affect success. In summary, the sitting position is an inexpensive, safe, well-tolerated and easily learned way to improve lumbar puncture success rates in newborns. Our results strongly support using this technique in newborn babies worldwide.

Family Well-Being During the COVID-19 Pandemic: The Risks of Financial Insecurity and Coping.

During the COVID-19 pandemic, families have experienced unprecedented financial and social disruptions. We studied the impact of preexisting psychosocial factors and pandemic-related financial and social disruptions in relation to family well-being among N = 4091 adolescents and parents during early summer 2020, participating in the Adolescent Brain Cognitive DevelopmentSM Study. Poorer family well-being was linked to prepandemic psychosocial and financial adversity and was associated with pandemic-related material hardship and social disruptions to routines. Parental alcohol use increased risk for worsening of family relationships, while a greater endorsement of coping strategies was mainly associated with overall better family well-being. Financial and mental health support may be critical for family well-being during and after a widespread crisis, such as the COVID-19 pandemic.

A practice-led assessment of landscape restoration potential in a biodiversity hotspot.

Effective restoration planning tools are needed to mitigate global carbon and biodiversity crises. Published spatial assessments of restoration potential are often at large scales or coarse resolutions inappropriate for local action. Using a Tanzanian case study, we introduce a systematic approach to inform landscape restoration planning, estimating spatial variation in cost-effectiveness, based on restoration method, logistics, biomass modelling and uncertainty mapping. We found potential for biomass recovery across 77.7% of a 53 000 km2 region, but with some natural spatial discontinuity in moist forest biomass, that was previously assigned to human causes. Most areas with biomass deficit (80.5%) were restorable through passive or assisted natural regeneration. However, cumulative biomass gains from planting outweighed initially high implementation costs meaning that, where applicable, this method yielded greater long-term returns on investment. Accounting for ecological, funding and other uncertainty, the top 25% consistently cost-effective sites were within protected areas and/or moderately degraded moist forest and savanna. Agro-ecological mosaics had high biomass deficit but little cost-effective restoration potential. Socio-economic research will be needed to inform action towards environmental and human development goals in these areas. Our results highlight value in long-term landscape restoration investments and separate treatment of savannas and forests. Furthermore, they contradict previously asserted low restoration potential in East Africa, emphasizing the importance of our regional approach for identifying restoration opportunities across the tropics. This article is part of the theme issue 'Understanding forest landscape restoration: reinforcing scientific foundations for the UN Decade on Ecosystem Restoration'.

Longitudinal assessment of brain structure and behaviour in youth with rapid weight gain: Potential contributing causes and consequences.

OBJECTIVE: Independent of weight status, rapid weight gain has been associated with underlying brain structure variation in regions associated with food intake and impulsivity among pre-adolescents. Yet, we lack clarity on how developmental maturation coincides with rapid weight gain and weight stability. METHODS: We identified brain predictors of 2-year rapid weight gain and its longitudinal effects on brain structure and impulsivity in the Adolescent Brain Cognitive DevelopmentSM Study®. Youth were categorized as Healthy Weight/Weight Stable (WSHW , n = 527) or Weight Gainers (WG, n = 221, >38lbs); 63% of the WG group were healthy weight at 9-to-10-years-old. RESULTS: A fivefold cross-validated logistic elastic-net regression revealed that rapid weight gain was associated with structural variation amongst 39 brain features at 9-to-10-years-old in regions involved with executive functioning, appetitive control and reward sensitivity. Two years later, WG youth showed differences in change over time in several of these regions and performed worse on measures of impulsivity. CONCLUSIONS: These findings suggest that brain structure in pre-adolescence may predispose some to rapid weight gain and that weight gain itself may alter maturational brain change in regions important for food intake and impulsivity. Behavioural interventions that target inhibitory control may improve trajectories of brain maturation and facilitate healthier behaviours.

Assessment of infant position and timing of stylet removal to improve lumbar puncture success in neonates (NeoCLEAR): an open-label, 2 × 2 factorial, randomised, controlled trial.

BACKGROUND: Newborn infants are the highest-risk age group for bacterial meningitis. Lumbar punctures are therefore frequently performed in neonates, but success rates are low (50-60%). In Neonatal Champagne Lumbar punctures Every time-A Randomised Controlled Trial (NeoCLEAR), we sought to optimise infant lumbar puncture by evaluating two modifications to traditional technique: sitting position versus lying down and early stylet removal (stylet removal after transecting the subcutaneous tissue) versus late stylet removal. METHODS: NeoCLEAR was an open-label, 2 × 2 factorial, randomised, controlled trial, conducted in 21 UK neonatal and maternity units. Infants requiring lumbar puncture at 27+0 to 44+0 weeks corrected gestational age and weighing 1000 g or more were randomly assigned (1:1:1:1) to sitting position and early stylet removal, sitting position and late stylet removal, lying position and early stylet removal, or lying position and late stylet removal using a 24/7, web-based, secure, central randomisation system. Block randomisation was stratified within site by corrected gestational age (27+0 to 31+6 weeks, 32+0 to 36+6 weeks, 37+0 to 40+6 weeks, or 41+0 to 44+0 weeks), using variable block sizes of four and eight with equal frequency. Laboratory staff were masked to allocation. The primary outcome was successful first lumbar puncture, defined as obtaining a cerebrospinal fluid sample with a red blood cell count of less than 10 000 cells per µL. The primary and secondary (including safety) outcomes were analysed by the groups to which infants were assigned regardless of deviation from the protocol or allocation received, but with exclusion of infants who were withdrawn before data collection or who did not undergo lumbar puncture (modified intention-to-treat analysis). This study is registered with ISRCTN, ISRCTN14040914. FINDINGS: Between Aug 3, 2018, and Aug 31, 2020, 1082 infants were randomly assigned to sitting (n=546) or lying (n=536), and early (n=549) or late (n=533) stylet removal. 1076 infants were followed-up until discharge and included in the modified intention-to-treat analysis. 961 (89%) infants were term, and 936 (87%) were younger than 3 days. Successful first lumbar puncture was more frequently observed in sitting than in lying position (346 [63·7%] of 543 vs 307 [57·6%] of 533; adjusted risk ratio 1·10 [95% CI 1·01 to 1·21], p=0·029; number needed to treat=16). Timing of stylet removal had no discernible effect on the primary outcome (338 [62·0%] of 545 infants in the early stylet removal group and 315 [59·3%] of 531 in the late stylet removal group had a successful first lumbar puncture; adjusted risk ratio 1·04 [95% CI 0·94-1·15], p=0·45). Sitting was associated with fewer desaturations than was lying (median lowest oxygen saturations during first lumbar puncture 93% [IQR 89-96] vs 90% [85-94]; median difference 3·0% [2·1-3·9], p<0·0001). One infant from the sitting plus late stylet removal group developed a scrotal haematoma 2 days after lumbar puncture, which was deemed to be possibly related to lumbar puncture. INTERPRETATION: NeoCLEAR is the largest trial investigating paediatric lumbar puncture so far. Success rates were improved when sitting rather than lying. Sitting lumbar puncture is safe, cost neutral, and well tolerated. We predominantly recruited term neonates younger than 3 days; other populations warrant further study. Neonatal lumbar puncture is commonly performed worldwide; these results therefore strongly support the widespread adoption of sitting technique for neonatal lumbar puncture. FUNDING: UK National Institute for Health and Care Research.

Access to quality health resources and environmental toxins affect the relationship between brain structure and BMI in a sample of pre and early adolescents.

Background: Environmental resources are related to childhood obesity risk and altered brain development, but whether these relationships are stable or if they have sustained impact is unknown. Here, we utilized a multidimensional index of childhood neighborhood conditions to compare the influence of various social and environmental disparities (SED) on body mass index (BMI)-brain relationships over a 2-year period in early adolescence. Methods: Data were gathered the Adolescent Brain Cognitive Development Study® (n = 2,970, 49.8% female, 69.1% White, no siblings). Structure magnetic resonance imaging (sMRI), anthropometrics, and demographic information were collected at baseline (9/10-years-old) and the 2-year-follow-up (11/12-years-old). Region of interest (ROIs; 68 cortical, 18 subcortical) estimates of cortical thickness and subcortical volume were extracted from sMRI T1w images using the Desikan atlas. Residential addresses at baseline were used to obtain geocoded estimates of SEDs from 3 domains of childhood opportunity index (COI): healthy environment (COIHE), social/economic (COISE), and education (COIED). Nested, random-effects mixed models were conducted to evaluate relationships of BMI with (1) ROI * COI[domain] and (2) ROI * COI[domain] * Time. Models controlled for sex, race, ethnicity, puberty, and the other two COI domains of non-interest, allowing us to estimate the unique variance explained by each domain and its interaction with ROI and time. Results: Youth living in areas with lower COISE and COIED scores were heavier at the 2-year follow-up than baseline and exhibited greater thinning in the bilateral occipital cortex between visits. Lower COISE scores corresponded with larger volume of the bilateral caudate and greater BMI at the 2-year follow-up. COIHE scores showed the greatest associations (n = 20 ROIs) with brain-BMI relationships: youth living in areas with lower COIHE had thinner cortices in prefrontal regions and larger volumes of the left pallidum and Ventral DC. Time did not moderate the COIHE x ROI interaction for any brain region during the examined 2-year period. Findings were independent of family income (i.e., income-to-needs). Conclusion: Collectively our findings demonstrate that neighborhood SEDs for health-promoting resources play a particularly important role in moderating relationships between brain and BMI in early adolescence regardless of family-level financial resources.

A Comprehensive Overview of the Physical Health of the Adolescent Brain Cognitive Development Study Cohort at Baseline.

Physical health in childhood is crucial for neurobiological as well as overall development, and can shape long-term outcomes into adulthood. The landmark, longitudinal Adolescent Brain Cognitive Development StudySM (ABCD study®), was designed to investigate brain development and health in almost 12,000 youth who were recruited when they were 9-10 years old and will be followed through adolescence and early adulthood. The overall goal of this paper is to provide descriptive analyses of physical health measures in the ABCD study at baseline, including but not limited to sleep, physical activity and sports involvement, and body mass index. Further this summary will describe how physical health measures collected from the ABCD cohort compare with current normative data and clinical guidelines. We propose this data set has the potential to facilitate clinical recommendations and inform national standards of physical health in this age group. This manuscript will also provide important information for ABCD users and help guide analyses investigating physical health including new avenues for health disparity research as it pertains to adolescent and young adult development.

Longitudinal Impact of Childhood Adversity on Early Adolescent Mental Health During the COVID-19 Pandemic in the ABCD Study Cohort: Does Race or Ethnicity Moderate Findings?

BACKGROUND: During the COVID-19 pandemic in the United States, mental health among youth has been negatively affected. Youth with a history of adverse childhood experiences (ACEs), as well as youth from minoritized racial-ethnic backgrounds, may be especially vulnerable to experiencing COVID-19-related distress. The aims of this study are to examine whether exposure to pre-pandemic ACEs predicts mental health during the COVID-19 pandemic in youth and whether racial-ethnic background moderates these effects. METHODS: From May to August 2020, 7983 youths (mean age, 12.5 years; range, 10.6-14.6 years) in the Adolescent Brain Cognitive Development (ABCD) Study completed at least one of three online surveys measuring the impact of the pandemic on their mental health. Data were evaluated in relation to youths' pre-pandemic mental health and ACEs. RESULTS: Pre-pandemic ACE history significantly predicted poorer mental health across all outcomes and greater COVID-19-related stress and impact of fears on well-being. Youths reported improved mental health during the pandemic (from May to August 2020). While reporting similar levels of mental health, youths from minoritized racial-ethnic backgrounds had elevated COVID-19-related worry, stress, and impact on well-being. Race and ethnicity generally did not moderate ACE effects. Older youths, girls, and those with greater pre-pandemic internalizing symptoms also reported greater mental health symptoms. CONCLUSIONS: Youths who experienced greater childhood adversity reported greater negative affect and COVID-19-related distress during the pandemic. Although they reported generally better mood, Asian American, Black, and multiracial youths reported greater COVID-19-related distress and experienced COVID-19-related discrimination compared with non-Hispanic White youths, highlighting potential health disparities.

Disparities in Excess Mortality Associated with COVID-19 - United States, 2020.

The COVID-19 pandemic has disproportionately affected Hispanic or Latino, non-Hispanic Black (Black), non-Hispanic American Indian or Alaska Native (AI/AN), and non-Hispanic Native Hawaiian or Other Pacific Islander (NH/PI) populations in the United States. These populations have experienced higher rates of infection and mortality compared with the non-Hispanic White (White) population (1-5) and greater excess mortality (i.e., the percentage increase in the number of persons who have died relative to the expected number of deaths for a given place and time) (6). A limitation of existing research on excess mortality among racial/ethnic minority groups has been the lack of adjustment for age and population change over time. This study assessed excess mortality incidence rates (IRs) (e.g., the number of excess deaths per 100,000 person-years) in the United States during December 29, 2019-January 2, 2021, by race/ethnicity and age group using data from the National Vital Statistics System. Among all assessed racial/ethnic groups (non-Hispanic Asian [Asian], AI/AN, Black, Hispanic, NH/PI, and White populations), excess mortality IRs were higher among persons aged ≥65 years (426.4 to 1033.5 excess deaths per 100,000 person-years) than among those aged 25-64 years (30.2 to 221.1) and those aged <25 years (-2.9 to 14.1). Among persons aged <65 years, Black and AI/AN populations had the highest excess mortality IRs. Among adults aged ≥65 years, Black and Hispanic persons experienced the highest excess mortality IRs of >1,000 excess deaths per 100,000 person-years. These findings could help guide more tailored public health messaging and mitigation efforts to reduce disparities in mortality associated with the COVID-19 pandemic in the United States,* by identifying the racial/ethnic groups and age groups with the highest excess mortality rates.

Meaningful associations in the adolescent brain cognitive development study.

The Adolescent Brain Cognitive Development (ABCD) Study is the largest single-cohort prospective longitudinal study of neurodevelopment and children's health in the United States. A cohort of n = 11,880 children aged 9-10 years (and their parents/guardians) were recruited across 22 sites and are being followed with in-person visits on an annual basis for at least 10 years. The study approximates the US population on several key sociodemographic variables, including sex, race, ethnicity, household income, and parental education. Data collected include assessments of health, mental health, substance use, culture and environment and neurocognition, as well as geocoded exposures, structural and functional magnetic resonance imaging (MRI), and whole-genome genotyping. Here, we describe the ABCD Study aims and design, as well as issues surrounding estimation of meaningful associations using its data, including population inferences, hypothesis testing, power and precision, control of covariates, interpretation of associations, and recommended best practices for reproducible research, analytical procedures and reporting of results.

Otorhinolaryngology litigation in England: 727 clinical negligence cases against the National Health Service.

INTRODUCTION: Litigation against the National Health Service (NHS) in England is rising. The aim of this study was to determine the incidence and characteristics of otorhinolaryngology clinical negligence claims in England. METHODS: A retrospective review was undertaken of all clinical negligence claims in England held by NHS Resolution relating to otorhinolaryngology between April 2013 and April 2018. Analysis was performed using information for cause, patient injury and claim cost. Where claim information was adequately detailed, the authors categorised claims by subspecialty, diagnosis and surgery. RESULTS: A total number of 727 claims were identified with an estimated potential cost of £108 million. Out of these, 463 were closed claims. Including open claim reserves, the mean cost of a claim was £148 923. Head and neck surgery was the subspecialty with the highest number of claims (n = 313, 43%) and highest cost (£51.5 million) followed by otology (n = 171, £24.5 million) and rhinology (n = 171, £13.6 million). Over half of claims were associated with an operation (n = 429, 59%) where mastoid surgery (n = 46) and endoscopic sinus surgery (n = 46) were equally associated with the greatest number of claims. The most frequent causes for clinical negligence claims included failure or delay to diagnose (n = 178, 25%), failure or delay to treat (n = 136, 19%), intra-operative complications (n = 130, 18%) and failure of the consent process (n = 107, 15%). DISCUSSION: Clinical negligence claims in otorhinolaryngology are related to several different components of patient management and are not limited to postoperative complications. This study highlights the importance of robust pathways in out-patient diagnostics and the consenting process in order to deliver better patient care and reduce the impact of litigation. Keywords informed consent, malpractice, clinical negligence claims, litigation, otolaryngology.

Outpatient management of heart valve disease following the COVID-19 pandemic: implications for present and future care.

The established processes for ensuring safe outpatient surveillance of patients with known heart valve disease (HVD), echocardiography for patients referred with new murmurs and timely delivery of surgical or transcatheter treatment for patients with severe disease have all been significantly impacted by the novel coronavirus pandemic. This has created a large backlog of work and upstaging of disease with consequent increases in risk and cost of treatment and potential for worse long-term outcomes. As countries emerge from lockdown but with COVID-19 endemic in society, precautions remain that restrict 'normal' practice. In this article, we propose a methodology for restructuring services for patients with HVD and provide recommendations pertaining to frequency of follow-up and use of echocardiography at present. It will be almost impossible to practice exactly as we did prior to the pandemic; thus, it is essential to prioritise patients with the greatest clinical need, such as those with symptomatic severe HVD. Local procedural waiting times will need to be considered, in addition to usual clinical characteristics in determining whether patients requiring intervention would be better suited having surgical or transcatheter treatment. We present guidance on the identification of stable patients with HVD that could have follow-up deferred safely and suggest certain patients that could be discharged from follow-up if waiting lists are triaged with appropriate clinical input. Finally, we propose that novel models of working enforced by the pandemic-such as increased use of virtual clinics-should be further developed and evaluated.

Association of lead-exposure risk and family income with childhood brain outcomes.

Socioeconomic factors influence brain development and structure, but most studies have overlooked neurotoxic insults that impair development, such as lead exposure. Childhood lead exposure affects cognitive development at the lowest measurable concentrations, but little is known about its impact on brain development during childhood. We examined cross-sectional associations among brain structure, cognition, geocoded measures of the risk of lead exposure and sociodemographic characteristics in 9,712 9- and 10-year-old children. Here we show stronger negative associations of living in high-lead-risk census tracts in children from lower- versus higher-income families. With increasing risk of exposure, children from lower-income families exhibited lower cognitive test scores, smaller cortical volume and smaller cortical surface area. Reducing environmental insults associated with lead-exposure risk might confer greater benefit to children experiencing more environmental adversity, and further understanding of the factors associated with high lead-exposure risk will be critical for improving such outcomes in children.

Intraindividual Dynamic Network Analysis - Implications for Clinical Assessment.

A network analysis approach to psychopathology regards symptoms as mutually interacting components of a multifaceted system (Borsboom & Cramer, 2013). Although several studies using this approach have examined comorbidity between disorders using cross-sectional samples, a direct application of the network analysis approach to intraindividual dynamic relations between symptoms in a complex, comorbid case has not been reported. The current article describes an intraindividual dynamic network analysis (IDNA) approach to understanding the psychopathology of an individual using dynamic (over time) lead-lag interrelations between symptoms. Multivariate time series data were utilized to create and examine an intraindividual, lag-1 network of the partial, day-to-day relations of symptoms in an individual with comorbid mood and anxiety disorders. Characteristics of the network, including centrality indices, stability, dynamic processes between symptoms, and their implications for clinical assessment are described. Additional clinical implications and future directions for IDNA, including the potential incremental validity of this assessment approach for empirically-based idiographic assessment and personalized treatment planning, are discussed. This person-specific IDNA approach may be especially useful in complex and comorbid cases.

Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides.

A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.

The clinical application of suicide risk assessment: A theory-driven approach.

The interpersonal theory of suicide posits that thwarted belongingness (TB) and perceived burdensomeness (PB) increase suicide ideation; however, studies have found mixed results regarding this hypothesis among psychiatric inpatients. This study aimed to (a) demonstrate how assessing TB and PB using the Interpersonal Needs Questionnaire (INQ) can provide clinically useful information and (b) investigate how statistical methodology may impact the clinical application of the INQ. Participants were 139 (Sample 1) and 104 (Sample 2) psychiatric inpatients. In both samples, ordinal logistic regression results indicated TB and PB, separately, were significant predictors of suicide ideation-related outcomes; however, when examined as simultaneous predictors, TB was no longer a significant predictor. The interaction between TB and PB was not significant for either sample. Despite this, TB and PB scores provided clinically relevant information about suicide ideation-related outcomes. For example, the highest scores on TB and PB indicated a 93% and 95% chance of having some level of distress due to suicide ideation (Sample 1), a 91% and 92% chance of having some level of desire for death, and a 79% and 84% chance of having some level of desire for suicide, respectively (Sample 2). This study also proposes clinical cutoff scores for the INQ (for TB and PB, respectively, cutoff scores were 22 and 17 for distress due to suicide ideation, 33 and 17 for desire for death, and 31 and 22 for desire for suicide). Although these results indicate that multicollinearity between TB and PB may create interpretational ambiguity for clinicians, TB and PB may each be useful separate predictors of suicide ideation-related outcomes in psychiatric inpatient settings and should be incorporated into suicide risk assessment. KEY PRACTITIONER MESSAGE: The 15-item Interpersonal Needs Questionnaire (an assessment of thwarted belongingness and perceived burdensomeness) should be incorporated into suicide risk assessment. Among psychiatric inpatients, greater thwarted belongingness and perceived burdensomeness, as separate predictors, were associated with increased levels of distress due to suicide ideation, desire for death, and desire for suicide. The highest scores on thwarted belongingness and perceived burdensomeness indicated a 79% to 95% chance of experiencing an elevated level of distress due to suicide ideation, desire for death, or desire for suicide. Recommended clinical cutoff scores were provided. For example, thwarted belongingness cutoff score of 31 and perceived burdensomeness cutoff score of 22 maximized the sensitivity and specificity of the INQ to detect some level of desire for suicide.

Automated Registration of Multimodal Optic Disc Images: Clinical Assessment of Alignment Accuracy.

PURPOSE: To determine the accuracy of automated alignment algorithms for the registration of optic disc images obtained by 2 different modalities: fundus photography and scanning laser tomography. MATERIALS AND METHODS: Images obtained with the Heidelberg Retina Tomograph II and paired photographic optic disc images of 135 eyes were analyzed. Three state-of-the-art automated registration techniques Regional Mutual Information, rigid Feature Neighbourhood Mutual Information (FNMI), and nonrigid FNMI (NRFNMI) were used to align these image pairs. Alignment of each composite picture was assessed on a 5-point grading scale: "Fail" (no alignment of vessels with no vessel contact), "Weak" (vessels have slight contact), "Good" (vessels with <50% contact), "Very Good" (vessels with >50% contact), and "Excellent" (complete alignment). Custom software generated an image mosaic in which the modalities were interleaved as a series of alternate 5×5-pixel blocks. These were graded independently by 3 clinically experienced observers. RESULTS: A total of 810 image pairs were assessed. All 3 registration techniques achieved a score of "Good" or better in >95% of the image sets. NRFNMI had the highest percentage of "Excellent" (mean: 99.6%; range, 95.2% to 99.6%), followed by Regional Mutual Information (mean: 81.6%; range, 86.3% to 78.5%) and FNMI (mean: 73.1%; range, 85.2% to 54.4%). CONCLUSIONS: Automated registration of optic disc images by different modalities is a feasible option for clinical application. All 3 methods provided useful levels of alignment, but the NRFNMI technique consistently outperformed the others and is recommended as a practical approach to the automated registration of multimodal disc images.