Lack of Cas13a inhibition by anti-CRISPR proteins from Leptotrichia prophages.

CRISPR systems are prokaryotic adaptive immune systems that use RNA-guided Cas nucleases to recognize and destroy foreign genetic elements. To overcome CRISPR immunity, bacteriophages have evolved diverse families of anti-CRISPR proteins (Acrs). Recently, Lin et al. (2020) described the discovery and characterization of 7 Acr families (AcrVIA1-7) that inhibit type VI-A CRISPR systems. We detail several inconsistencies that question the results reported in the Lin et al. (2020) study. These include inaccurate bioinformatics analyses and bacterial strains that are impossible to construct. Published strains were provided by the authors, but MS2 bacteriophage plaque assays did not support the published results. We also independently tested the Acr sequences described in the original report, in E. coli and mammalian cells, but did not observe anti-Cas13a activity. Taken together, our data and analyses prompt us to question the claim that AcrVIA1-7 reported in Lin et al. are type VI anti-CRISPR proteins.

Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike.

A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant, BA.2.86, has emerged and spread to numerous countries worldwide, raising alarm because its spike protein contains 34 additional mutations compared with its BA.2 predecessor1. We examined its antigenicity using human sera and monoclonal antibodies (mAbs). Reassuringly, BA.2.86 was no more resistant to human sera than the currently dominant XBB.1.5 and EG.5.1, indicating that the new subvariant would not have a growth advantage in this regard. Importantly, sera from people who had XBB breakthrough infection exhibited robust neutralizing activity against all viruses tested, suggesting that upcoming XBB.1.5 monovalent vaccines could confer added protection. Although BA.2.86 showed greater resistance to mAbs to subdomain 1 (SD1) and receptor-binding domain (RBD) class 2 and 3 epitopes, it was more sensitive to mAbs to class 1 and 4/1 epitopes in the 'inner face' of the RBD that is exposed only when this domain is in the 'up' position. We also identified six new spike mutations that mediate antibody resistance, including E554K that threatens SD1 mAbs in clinical development. The BA.2.86 spike also had a remarkably high receptor affinity. The ultimate trajectory of this new SARS-CoV-2 variant will soon be revealed by continuing surveillance, but its worldwide spread is worrisome.

Proteomic profiling identifies novel proteins for genetic risk of severe COVID-19: the Atherosclerosis Risk in Communities Study.

BACKGROUND: Genome-wide association studies have identified six genetic variants associated with severe COVID-19, yet the mechanisms through which they may affect disease remains unclear. We investigated proteomic signatures related to COVID-19 risk variants rs657152 (ABO), rs10735079 (OAS1/OAS2/OAS3), rs2109069 (DPP9), rs74956615 (TYK2), rs2236757 (IFNAR2) and rs11385942 (SLC6A20/LZTFL1/CCR9/FYCO1/CXCR6/XCR1) as well as their corresponding downstream pathways that may promote severe COVID-19 in risk allele carriers and their potential relevancies to other infection outcomes. METHODS: A DNA aptamer-based array measured 4870 plasma proteins among 11 471 participants. Linear regression estimated associations between the COVID-19 risk variants and proteins with correction for multiple comparisons, and canonical pathway analysis was conducted. Cox regression assessed associations between proteins identified in the main analysis and risk of incident hospitalized respiratory infections (2570 events) over a 20.7-year follow-up. RESULTS: The ABO variant rs657152 was associated with 84 proteins in 7241 white participants with 24 replicated in 1671 Black participants. The TYK2 variant rs74956615 was associated with ICAM-1 and -5 in white participants with ICAM-5 replicated in Black participants. Of the 84 proteins identified in the main analysis, seven were significantly associated with incident hospitalized respiratory infections including Ephrin type-A receptor 4 (hazard ratio (HR): 0.87; P = 2.3 × 10-11) and von Willebrand factor type A (HR: 1.17; P = 1.6x10-13). CONCLUSIONS: Novel proteomics signatures and pathways for COVID-19-related risk variants TYK2 and ABO were identified. A subset of these proteins predicted greater risk of incident hospitalized pneumonia and respiratory infections. Further studies to examine these proteins in COVID-19 patients are warranted.

Pixel walking along the boreal forest-Arctic tundra ecotone: Large scale ground-truthing of satellite-derived greenness (NDVI).

In this Technical Advance, we describe a novel method to improve ecological interpretation of remotely sensed vegetation greenness measurements that involved sampling 24,395 Landsat pixels (30 m) across 639 km of Alaska's central Brooks Range. The method goes well beyond the spatial scale of traditional plot-based sampling and thereby more thoroughly relates ground-based observations to satellite measurements. Our example dataset illustrates that, along the boreal-Arctic boundary, vegetation with the greatest Landsat Normalized Difference Vegetation Index (NDVI) is taller than 1 m, woody, and deciduous; whereas vegetation with lower NDVI tends to be shorter, evergreen, or non-woody. The field methods and associated analyses advance efforts to inform satellite data with ground-based vegetation observations using field samples collected at spatial scales that closely match the resolution of remotely sensed imagery.

Cotyledon-Specific Flow Evaluation of Rhesus Macaque Placental Injury Using Ferumoxytol Dynamic Contrast-Enhanced MRI.

BACKGROUND: Recently, dynamic contrast-enhanced (DCE) MRI with ferumoxytol as contrast agent has recently been introduced for the noninvasive assessment of placental structure and function throughout. However, it has not been demonstrated under pathological conditions. PURPOSE: To measure cotyledon-specific rhesus macaque maternal placental blood flow using ferumoxytol DCE MRI in a novel animal model for local placental injury. STUDY TYPE: Prospective animal model. SUBJECTS: Placental injections of Tisseel (three with 0.5 mL and two with 1.5 mL), monocyte chemoattractant protein 1 (three with 100 µg), and three with saline as controls were performed in a total of 11 rhesus macaque pregnancies at approximate gestational day (GD 101). DCE MRI scans were performed prior (GD 100) and after (GD 115 and GD 145) the injection (term = GD 165). FIELD STRENGTH/SEQUENCE: 3 T, T1-weighted spoiled gradient echo sequence (product sequence, DISCO). ASSESSMENT: Source images were inspected for motion artefacts from the mother or fetus. Placenta segmentation and DCE processing were performed for the dynamic image series to measure cotyledon specific volume, flow, and normalized flow. Overall placental histopathology was conducted for controls, Tisseel, and MCP-1 animals and regions of tissue infarctions and necrosis were documented. Visual inspections for potential necrotic tissue were conducted for the two Tisseelx3 animals. STATISTICAL TESTS: Wilcoxon rank sum test, significance level P < 0.05. RESULTS: No motion artefacts were observed. For the group treated with 1.5 mL of Tisseel, significantly lower cotyledon volume, flow, and normalized flow per cotyledon were observed for the third gestational time point of imaging (day ~145), with mean normalized flow of 0.53 minute-1. Preliminary histopathological analysis shows areas of tissue necrosis from a selected cotyledon in one Tisseel-treated (single dose) animal and both Tisseelx3 (triple dose) animals. DATA CONCLUSION: This study demonstrates the feasibility of cotyledon-specific functional analysis at multiple gestational time points and injury detection in a placental rhesus macaque model through ferumoxytol-enhanced DCE MRI. LEVEL OF EVIDENCE: NA TECHNICAL EFFICACY: Stage 2.

A systematic review of postpartum psychosis resulting in infanticide: missed opportunities in screening, diagnosis, and treatment.

PURPOSE: Impacting 1 in 1000 women, untreated postpartum psychosis is associated with a 4% infanticide rate. This systematic review aims to identify factors that are associated with infanticide resulting from psychosis in the puerperal period and pinpoint areas of missed opportunity for intervention. METHODS: A systematic literature review was conducted in accordance with PRISMA guidelines to identify and synthesize cases of maternal infanticide among perinatal females with evidence of postpartum psychosis. Four independent reviewers screened 231 articles identified in searches of three databases (PsycInfo, PubMed, and Web of Science) for studies conducted from 2013 to 2023. RESULTS: Twelve studies were included in the final review. Findings indicate that those experiencing puerperal psychosis have increased incidence of infanticide suggesting missed opportunities for intervention and treatment. Common factors in mothers who committed infanticide as a result of delusions and/or hallucinations associated with PMADs were identified, including lack of standardized screening tools, preference for traditional and/or cultural healing practices, and access to care. CONCLUSION: The current body of evidence supports developing and evaluating clinical interventions aimed at improving maternal mental health outcomes and infant outcomes in perinatal women experiencing puerperal psychosis.

The role of positive affect in asthma control and symptom severity in adolescents.

INTRODUCTION: We test the effects of positive affect and its arousal subscale components of calm, wellbeing, and vigor on asthma control and symptom severity in adolescents with moderate to severe asthma. Additionally, we test whether positive affect (and its arousal components) moderate how stress impacts asthma control and symptom severity. METHODS: Adolescents with asthma (N = 66, ages 12-17) completed brief surveys 4 times a day for 7 days reporting on their positive affect, stress, and asthma symptom severity and conducted a morning peak expiratory flow assessment each day. Asthma control and psychological asthma triggers were assessed at the end of the 7 days. RESULTS: Positive affect moderated the association between stress and asthma control (b = -0.33, p = 0.009) as well as the association between psychological triggers and asthma control (b = -0.74, p = 0.007). When assessing the positive affect arousal components, calm and wellbeing seemed to be driving these effects. Additionally, calm moderated the association between stress and asthma symptom severity (b = -0.33, p = 0.036) as well as the association between psychological triggers and asthma symptom severity (b = -0.75, p = 0.021). CONCLUSIONS: When considering patient stress (e.g., general stress, psychological asthma triggers), positive affect and its arousal components of calm and wellbeing may be helpful for patients with higher levels of stress and/or for patients experiencing greater numbers of psychological triggers.

Pharmacy barriers for transgender and gender diverse young adults.

BACKGROUND: Transgender and gender diverse (TGD) individuals face substantial physical and mental health care barriers. Community pharmacies are one of the most accessible healthcare settings; however, concern for discrimination at the pharmacy has been reported. It is important to gain a better understanding of TGD individual's perspectives and experiences at the pharmacy to ensure optimal and inclusive care. OBJECTIVE: To identify TGD individual experiences and barriers at the pharmacy. METHODS: This IRB-approved qualitative study recruited TGD young adults in the United States between ages 18-29 years old for semi-structured focus group discussions. Questions focused on barriers to obtaining medications at the pharmacy and negative or positive experiences with pharmacists. Interviews were recorded, transcribed, and transcripts were analyzed for common themes amongst participants. RESULTS: Nine 1.5-2-hour focus groups were conducted and included 30 participants (2-6 participants in each group). All participants reported having been prescribed medications by a physician or mental health provider. Participants self-reported issues at pharmacies and with pharmacy personnel. Major themes included issues accessing medications and supplies (needles, syringes), questioning of prescription validity and patient identity, and lack of education or understanding of TGD individuals by pharmacy staff. CONCLUSION: TGD individuals experience barriers at the pharmacy and concerning issues with pharmacy staff. Education, structural competency, and improvements in gender-related data management are necessary for pharmacists and pharmacy staff to provide equitable and inclusive care for TGD individuals.

Reported outcome measures in complex fracture elbow dislocations: a systematic review.

BACKGROUND: Complex elbow fracture dislocations, dislocation with fracture of one or several surrounding bony stabilizers, are difficult to manage and associated with poor outcomes. While many studies have explored treatment strategies but a lack of standardization of patient-reported outcome measures (PROMs) makes cross-study comparison difficult. In this systematic review, we aim to describe what injury patterns, measured outcomes, and associated complications are reported in the complex elbow fracture dislocation literature to provide outcome reporting recommendations that will facilitate improved future cross-study comparison. METHODS: A systematic review was performed per Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. We queried PubMed/MEDLINE, Embase, Web of Science, and Cochrane databases to identify articles published between 2010 and 2022 reporting on adult patients who had a complex elbow fracture dislocation. Pathologic fractures were excluded. A bias assessment using the methodological index for nonrandomized studies criteria was conducted. For each article, patient demographics, injury pattern, outcome measures, and complications were recorded. RESULTS: Ninety-one studies reporting on 3664 elbows (3654 patients) with an elbow fracture and dislocation (weighted mean age 44 years, follow-up of 30 months, 41% female) were evaluated. Of these, the injury pattern was described in 3378 elbows and included 2951 (87%) terrible triad injuries and 72 (2%) transolecranon fracture-dislocations. The three most commonly reported classification systems were: Mason classification for radial head fractures, Regan and Morrey coronoid classification for coronoid fractures, and O'Driscoll classification for coronoid fractures. Range of motion was reported in 87 (96%) studies with most reporting flexion (n = 70), extension (n = 62), pronation (n = 68), or supination (n = 67). Strength was reported in 11 (12%) studies. PROMs were reported in 83 (91%) studies with an average of 2.6 outcomes per study. There were 14 outcome scores including the Mayo Elbow Performance Score (n = 69 [83%]), the Disabilities of Arm, Shoulder and Hand (DASH) score (n = 28 [34%]), the visual analog scale for pain (n = 27 [33%]), QuickDASH score (n = 13 [15.7%]), and Oxford Elbow score (n = 5 [6.0%]). No significance was found between the number of PROMs used per article and the year of publication (P = .313), study type (P = .689), complex fracture pattern (P = .211), or number of elbows included (P = .152). CONCLUSION: There is great heterogeneity in reported PROMs in the complex elbow fracture dislocation literature. Although there is no gold standard PROM for assessing complex elbow fracture dislocations, we recommend the use of at least the Mayo Elbow Performance Score and DASH outcomes measures as well as visual analog scale pain rating scale in future studies to facilitate cross-study comparisons.

The Effect of Socioeconomic Status on Clinical Outcomes and Implant Survivorship After Primary Anatomic and Reverse Total Shoulder Arthroplasty.

BACKGROUND: Low socioeconomic status has been shown to contribute to poor outcomes in patients undergoing joint replacement surgery. However, there is a paucity of studies investigating shoulder arthroplasty. The purpose of this study was to evaluate the effect of socioeconomic status on baseline and postoperative outcome scores and implant survivorship after anatomic and reverse primary total shoulder arthroplasty (TSA). METHODS: A retrospective review of a prospectively-collected single-institution database was performed to identify patients who underwent primary TSA. Zip codes were collected and converted to Area Deprivation Index (ADI) scores. We performed a correlation analysis between national ADI scores and preoperative, postoperative, and pre- to postoperative improvement in range of motion, shoulder strength, and functional outcome scores in patients with minimum 2-year follow-up. Patients were additionally grouped into groups according to their national ADI. Achievement of the MCID, SCB, and PASS and revision-free survivorship were compared between groups. RESULTS: A total of 1,148 procedures including 415 anatomic and 733 reverse total shoulder arthroplasties with a mean age of 64 ± 8.2 and 69.9 ± 8.0 years, respectively, were included. The mean follow-up was 6.3 ± 3.6 years for anatomic and 4.9 ± 2.7 years for reverse TSA. We identified a weak negative correlation between national ADI and most functional outcome scores and range of motion preoperatively (R range 0.07 to 0.16), postoperatively (R range 0.09 to 0.14), and pre- to postoperative improvement (R range 0.01 to 0.17). Thus, greater area deprivation was weakly associated with poorer function preoperatively, poorer final outcomes and poorer improvement in outcomes. There was no difference in the proportion of each ADI group achieving MCID, SCB, and PASS in the anatomic TSA cohort. However, in the reverse TSA cohort, the proportion of patients achieving MCID, SCB, and PASS decreased with greater deprivation. There was no difference in survivorship between ADI groups . CONCLUSIONS: We found a negative effect of low socioeconomic status on baseline and postoperative patient outcomes and range-of-motion; however, the correlations were relatively weak. Patients that reside in socioeconomically deprived areas have poorer functional outcomes before and after TSA and achieve less improvement from surgery. We should strive to identify modifiable factors to improve the success of TSA in socioeconomically deprived areas.

Navigating the journey as a peer reviewer: A roadmap to success.

Peer review is an essential step in scientific progress and clinical improvement, providing opportunity for research to be critically evaluated and improved by one's colleagues. Pharmacists from all job settings are called to serve as peer reviewers in the ever-growing publication landscape of the profession. Despite challenges to engagement such as time and compensation, peer review provides considerable professional development for both authors and reviewers alike. This article will serve as a practical guide for peer reviewers, discussing best practices as well as the handling of different situations that may arise during the process.

Evaluating increases in sensitivity from NORDIC for diverse fMRI acquisition strategies.

As the neuroimaging field moves towards detecting smaller effects at higher spatial resolutions, and faster sampling rates, there is increased attention given to the deleterious contribution of unstructured, thermal noise. Here, we critically evaluate the performance of a recently developed reconstruction method, termed NORDIC, for suppressing thermal noise using datasets acquired with various field strengths, voxel sizes, sampling rates, and task designs. Following minimal preprocessing, statistical activation (t-values) of NORDIC processed data was compared to the results obtained with alternative denoising methods. Additionally, we examined the consistency of the estimates of task responses at the single-voxel, single run level, using a finite impulse response (FIR) model. To examine the potential impact on effective image resolution, the overall smoothness of the data processed with different methods was estimated. Finally, to determine if NORDIC alters or removes temporal information important for modeling responses, we employed an exhaustive leave-p-out cross validation approach, using FIR task responses to predict held out timeseries, quantified using R2. After NORDIC, the t-values are increased, an improvement comparable to what could be achieved by 1.5 voxels smoothing, and task events are clearly visible and have less cross-run error. These advantages are achieved with smoothness estimates increasing by less than 4%, while 1.5 voxel smoothing is associated with increases of over 140%. Cross-validated R2s based on the FIR models show that NORDIC is not measurably distorting the temporal structure of the data under this approach and is the best predictor of non-denoised time courses. The results demonstrate that analyzing 1 run of data after NORDIC produces results equivalent to using 2 to 3 original runs and that NORDIC performs equally well across a diverse array of functional imaging protocols. Significance Statement: For functional neuroimaging, the increasing availability of higher field strengths and ever higher spatiotemporal resolutions has led to concomitant increase in concerns about the deleterious effects of thermal noise. Historically this noise source was suppressed using methods that reduce spatial precision such as image blurring or averaging over a large number of trials or sessions, which necessitates large data collection efforts. Here, we critically evaluate the performance of a recently developed reconstruction method, termed NORDIC, which suppresses thermal noise. Across datasets varying in field strength, voxel sizes, sampling rates, and task designs, NORDIC produces substantial gains in data quality. Both conventional t-statistics derived from general linear models and coefficients of determination for predicting unseen data are improved. These gains match or even exceed those associated with 1 voxel Full Width Half Max image smoothing, however, even such small amounts of smoothing are associated with a 52% reduction in estimates of spatial precision, whereas the measurable difference in spatial precision is less than 4% following NORDIC.

C-H Functionalization of Polyolefins to Access Reprocessable Polyolefin Thermosets.

Upcycling plastic waste into reprocessable materials with performance-advantaged properties would contribute to the development of a circular plastics economy. Here, we modify branched polyolefins and postconsumer polyethylene through a versatile C-H functionalization approach using thiosulfonates as a privileged radical group transfer functionality. Cross-linking the functionalized polyolefins with polytopic amines provided dynamically cross-linked polyolefin networks enabled by associative bond exchange of diketoenamine functionality. A combination of resonant soft X-ray scattering and grazing incidence X-ray scattering revealed hierarchical phase morphology in which diketoenamine-rich microdomains phase-separate within amorphous regions between polyolefin crystallites. The combination of dynamic covalent cross-links and microphase separation results in useful and improved mechanical properties, including a ∼4.5-fold increase in toughness, a reduction in creep deformation at temperatures relevant to use, and high-temperature structural stability compared to the parent polyolefin. The dynamic nature of diketoenamine cross-links provides stress relaxation at elevated temperatures, which enabled iterative reprocessing of the dynamic covalent polymer network with little cycle-to-cycle property fade. The ability to convert polyolefin waste into a reprocessable thermoformable material with attractive thermomechanical properties provides additional optionality for upcycling to enable future circularity.

Effect of Methyl Groups on Formation of Ordered or Layered Graphitic Materials from Aromatic Molecules.

Developing functionally complex carbon materials from small aromatic molecules requires an understanding of how the chemistry and structure of its constituent molecules evolve and crosslink, to achieve a tailorable set of functional properties. Here, molecular dynamics (MD) simulations are used to isolate the effect of methyl groups on condensation reactions during the oxidative process and evaluate the impact on elastic modulus by considering three monodisperse pyrene-based systems with increasing methyl group fraction. A parameter to quantify the reaction progression is designed by computing the number of new covalent bonds formed. Utilizing the previously developed MD framework, it is found that increasing methylation leads to an almost doubling of bond formation, a larger fraction of the new bonds oriented in the direction of tensile stress, and a higher basal plane alignment of the precursor molecules along the direction of tensile stress, resulting in enhanced tensile modulus. Additionally, via experiments, it is demonstrated that precursors with a higher fraction of methyl groups result in a higher alignment of molecules. Moreover, increased methylation results in the lower spread of single molecule alignment which may lead to smaller variations in tensile modulus and more consistent properties in carbon materials derived from methyl-rich precursors.

Soil moisture impacts the tundra carbon balance in a changing climate.

There is growing recognition that soil moisture plays a crucial role in regulating the response of tundra carbon cycling to climate warming.

Effects of Salt on Phase Behavior and Rheological Properties of Alginate-Chitosan Polyelectrolyte Complexes.

Oppositely charged polyelectrolytes often form polyelectrolyte complexes (PECs) due to the association through electrostatic interactions. Obtaining PECs using natural, biocompatible polyelectrolytes is of interest in the food, pharmaceutical, and biomedical industries. In this work, PECs were prepared from two biopolymers, positively charged chitosan and negatively charged alginate. We investigate the changes in the structure and properties of PECs by adding sodium chloride (salt doping) to the system. The shear modulus of PECs can be tuned from ∼10 to 104 Pa by changing the salt concentration. The addition of salt led to a decrease in the water content of the complex phase with increasing shear modulus. However, at a very high salt concentration, the shear modulus of the complex phase decreased but did not lead to the liquid coacervate formation, typical of synthetic polyelectrolytes. This difference in phase behavior has likely been attributed to the hydrophobicity of chitosan and long semiflexible alginate and chitosan chains that restrict the conformational changes. Large amplitude oscillatory shear experiments captured nonlinear responses of PECs. The compositions of the PECs, determined as a function of salt concentration, signify the preferential partitioning of salt into the complex phase. Small-angle X-ray scattering of the salt-doped PECs indicates that the Kuhn length and radius of the alginate-chitosan associated structure qualitatively agree with the captured phase behavior and rheological data. This study provides insights into the structure-property as a function of salt concentration of natural polymer-based PECs necessary for developing functional materials from natural polyelectrolytes.

Facial typicality and attractiveness reflect an ideal dimension of face structure.

Face perception and recognition are important processes for social interaction and communication among humans, so understanding how faces are mentally represented and processed has major implications. At the same time, faces are just some of the many stimuli that we encounter in our everyday lives. Therefore, more general theories of how we represent objects might also apply to faces. Contemporary research on the mental representation of faces has centered on two competing theoretical frameworks that arose from more general categorization research: prototype-based face representation and exemplar-based face representation. Empirically distinguishing between these frameworks is difficult and neither one has been ruled out. In this paper, we advance this area of research in three ways. First, we introduce two additional frameworks for mental representation of categories, varying abstraction and ideal representation, which have not been applied to face perception and recognition before. Second, we fit formal computational models of all four of these theories to human perceptual judgments of the typicality and attractiveness (a strong correlate of typicality) of 100 young adult Caucasian female faces, with the models expressed within a face space derived from facial similarity judgments via multidimensional scaling. Third, we predict the perceived typicality and attractiveness of the faces using these models and compare the predictive performance of each to the empirical data. We found that of all four models, the ideal representation model provided the best account of perceived typicality and attractiveness for the present set of faces, although all models showed discrepancies from the empirical data. These findings demonstrate the relevance of mental categorization processes for representing faces.

Early splenomegaly and septicaemia in homozygous sickle cell disease: A birth cohort study.

BACKGROUND: Patients with homozygous sickle cell disease (HbSS) and clinical splenomegaly by 6 months of age appeared at greater risk of invasive infections after 5 years of the Jamaican Cohort Study. We determined whether this risk remained significant over a longer study period, using a more rigorous definition of infection and examining the contribution of potential confounders. METHODS: Newborn screening of 100,000 consecutive deliveries during 1973-1981 detected 311 births with HbSS. Age at first clinical splenomegaly was used to categorize 285 of these patients in whom this could be determined: at or before 7 months (early), after 7 months (later), or 'never' palpated despite repeated examinations. Infective episodes were confined to 'first infections confirmed by positive culture'. Using a generalized linear model, the risk of septicaemia was assessed in each group, after adjusting for potential confounders. RESULTS: Of 93 'first infections', 42 occurred in 105 subjects in the 'early' group, 49 in 157 subjects in the 'later' group, and two in 23 subjects in the 'never' group; the observed to expected ratio of 1.42, 0.90 and 0.22 was highly significant (p = .003). Assessed as risk ratios, 'early' splenomegaly had a significantly higher risk ratio (RR) for septicaemia (RR = 7.4, confidence interval [CI]: 1.1-50.7, p < .05) when compared to the 'never' group adjusting for vaccine exposure and foetal haemoglobin concentration. The most common organisms were Streptococcus pneumoniae, Salmonella species, Haemophilus influenzae and Staphylococcus aureus. CONCLUSION: Early clinical splenomegaly in HbSS remains a predictor of septicaemia, defining a group that may require closer monitoring.

Analyzing Fluoride Binding by Group 15 Lewis Acids: Pnictogen Bonding in the Pentavalent State.

We report the results of a computational investigation into fluoride binding by a series of pentavalent pnictogen Lewis acids: pnictogen pentahalides (PnX5), tetraphenyl pnictogeniums (PnPh4+), and triphenyl pnictogen tetrachlorocatecholates (PnPh3Cat). Activation strain and energy decomposition analyses of the Lewis adducts not only clearly delineate the electrostatic and orbital contributions to these acid-base interactions but also highlight the importance of Pauli repulsion and molecular flexibility in determining relative Lewis acidity among the pnictogens.

Circadian, Reward, and Emotion Systems in Teens prospective longitudinal study: protocol overview of an integrative reward-circadian rhythm model of first onset of bipolar spectrum disorder in adolescence.

BACKGROUND: Bipolar spectrum disorders (BSDs) are associated with a heightened sensitivity to rewards and elevated reward-related brain function in cortico-striatal circuitry. A separate literature documents social and circadian rhythm disruption in BSDs. Recently, integrated reward-circadian models of BSDs have been proposed. These models draw on work indicating that the two systems influence each other and interact to affect mood functioning. When dysregulated, reward and circadian system signaling may combine to form a positive feedback loop, whereby dysregulation in one system exacerbates dysregulation in the other. Project CREST (Circadian, Reward, and Emotion Systems in Teens) provides a first systematic test of reward-circadian dysregulation as a synergistic and dynamic vulnerability for first onset of BSD and increases in bipolar symptoms during adolescence. METHODS: This NIMH-funded R01 study is a 3-year prospective, longitudinal investigation of approximately 320 community adolescents from the broader Philadelphia area, United States of America. Eligible participants must be 13-16 years old, fluent in English, and without a prior BSD or hypomanic episode. They are being selected along the entire dimension of self-reported reward responsiveness, with oversampling at the high tail of the dimension in order to increase the likelihood of BSD onsets. At Times 1-6, every 6 months, participants will complete assessments of reward-relevant and social rhythm disruption life events and self-report and diagnostic assessments of bipolar symptoms and episodes. Yearly, at Times 1, 3, and 5, participants also will complete self-report measures of circadian chronotype (morningness-eveningness) and social rhythm regularity, a salivary dim light melatonin onset (DLMO) procedure to assess circadian phase, self-report, behavioral, and neural (fMRI) assessments of monetary and social reward responsiveness, and a 7-day ecological momentary assessment (EMA) period. During each EMA period, participants will complete continuous measures of sleep/wake and activity (actigraphy), a daily sleep diary, and three within-day (morning, afternoon, evening) measures of life events coded for reward-relevance and social rhythm disruption, monetary and social reward responsiveness, positive and negative affect, and hypo/manic and depressive symptoms. The fMRI scan will occur on the day before and the DLMO procedure will occur on the first evening of the 7-day EMA period. DISCUSSION: This study is an innovative integration of research on multi-organ systems involved in reward and circadian signaling in understanding first onset of BSD in adolescence. It has the potential to facilitate novel pharmacological, neural, and behavioral interventions to treat, and ideally prevent, bipolar conditions.