Search

Rod and cone photoreceptor cells are specialized neurons responsible for transforming the information reaching the eyes in the form of photons into the language of neuronal activity. Rods are the most prevalent photoreceptor type, primarily responsible for light detection under conditions of limited illumination. Here we demonstrate that human rods have a morphological organization unique among all described species, whereby the cell soma extends alongside the light-sensitive outer segment compartment to form a structure we have termed the "accessory inner segment." These structures have two striking features: they are reinforced by a massive microtubular cytoskeleton and contain electron-dense adhesions that mediate their attachment to outer segments. Given that the spacing of human rod photoreceptors is sparser than in most other species, the accessory inner segment likely provides mechanical support to the closely apposed outer segment. This discovery expands our understanding of the human retina and directs future studies of human photoreceptor function in health and disease. Ultrastructural analysis of human retinas reveals that the inner segment of human rods extends alongside the outer segment to form the "accessory inner segment," a unique microtubule-based structure that forms adhesions to the outer segment. [ABSTRACT FROM AUTHOR]

The iBerry Study, a Dutch population-based high-risk cohort (n = 1022) examines the transition from subclinical symptoms to psychiatric disorders in adolescents. Here, we present the first follow-up measurement, approximately 3 years after baseline assessment and 5 years after the screening based on self-reported emotional and behavioral problems (SDQ-Y). We give an update on the data collection, details on the (non)response, and the results on psychopathology outcomes. The first follow-up (2019–2022) had a response rate of 79% (n = 807). Our results at baseline (mean age 15.0 years) have shown the effectiveness of using the SDQ-Y to select a cohort oversampled for the risk of psychopathology. At first follow-up (mean age 18.1 years), the previously administered SDQ-Y remains predictive for selecting adolescents at risk. At follow-up, 47% of the high-risk adolescents showed significant mental health problems based on self- and parent reports and 46% of the high-risk adolescents met the criteria for multiple DSM-5 diagnoses. Compared to low-risk adolescents, high-risk adolescents had a sevenfold higher odds of significant emotional and behavioral problems at follow-up. Comprehensive assessment on psychopathology, substance abuse, psychotic symptoms, suicidality, nonsuicidal self-injury, addiction to social media and/or video gaming, and delinquency, as well as social development, and the utilization of healthcare and social services were conducted. This wave, as well as the ones to follow, track these adolescents into their young adulthood to identify risk factors, elucidate causal mechanisms, and discern pathways leading to both common and severe mental disorders. Results from the iBerry Study will provide leads for preventive interventions. [ABSTRACT FROM AUTHOR]

Pelvic venous reflux and obstruction can lead to chronic pelvic pain and extra-pelvic varicosities. This paper will discuss the contemporary understanding of this pathophysiology and its clinical manifestations. It will review evidence-based clinical and imaging criteria of pelvic venous disorders, data supporting benefit from venous interventions, criticisms of the available data and highlight evidence research gaps that exist. Finally, it will argue that comparative outcomes research utilizing standardized patient selection for embolization and stenting, embolization treatment strategies that eliminate the pelvic varices (at least to start), and clinically relevant outcome measures are necessary to establish the benefit of vascular treatments. [ABSTRACT FROM AUTHOR]

Balloon angioplasty for recoarctation of the aorta is routinely performed in young children and is considered successful when the systolic gradient is reduced to < 10 mmHg. IMPACT defines acute procedural success solely based on a final gradient of < 10 mmHg and stratifies participating institutions based on these acute outcomes. Between February 2012 and December 2020, IMPACT data was analyzed for 110 coarctation interventions. Electronic medical records were reviewed, and primary endpoints were one of the following: (1) final analysis end date (June 2021), (2) patient death, or (3) most recent transcatheter or surgical reintervention. 64 (58.2%) interventions had a post-procedure CA gradient < 10 mmHg. Comparison of clinical patient outcome for acute success demonstrated no significant relationship using IMPACT (p = 0.70) criteria. There was no statistically significant difference between clinical success and failure for: pre- and post-treatment systolic gradients; absolute or percent change in systolic gradient; and pre-treatment aorta diameter. Clinical outcome and patient age did show a significant difference (p = 0.0093) with better clinical outcomes in older patients. Our analysis did not reveal a statistically significant difference between IMPACT criteria for successful treatment of CA and clinical outcome. These findings underscore a need to identify other clinical metrics that better predict outcome following CA balloon angioplasty treatment. [ABSTRACT FROM AUTHOR]

Multilevel modeling (MLM) is commonly used in psychological research to model clustered data. However, data in applied research usually violate one of the essential assumptions of MLM—homogeneity of variance. While the fixed-effect estimates produced by the maximum likelihood method remain unbiased, the standard errors for the fixed effects are misestimated, resulting in inaccurate inferences and inflated or deflated type I error rates. To correct the bias in fixed effects standard errors and provide valid inferences, small-sample corrections such as the Kenward-Roger (KR) adjustment and the adjusted cluster-robust standard errors (CR-SEs) with the Satterthwaite approximation for t tests have been used. The current study compares KR with random slope (RS) models and the adjusted CR-SEs with ordinary least squares (OLS), random intercept (RI) and RS models to analyze small, heteroscedastic, clustered data using a Monte Carlo simulation. Results show the KR procedure with RS models has large biases and inflated type I error rates for between-cluster effects in the presence of level 2 heteroscedasticity. In contrast, the adjusted CR-SEs generally yield results with acceptable biases and maintain type I error rates close to the nominal level for all examined models. Thus, when the interest is only in within-cluster effect, any model with the adjusted CR-SEs could be used. However, when the interest is to make accurate inferences of the between-cluster effect, researchers should use the adjusted CR-SEs with RS to have higher power and guard against unmodeled heterogeneity. We reanalyzed an example in Snijders & Bosker (2012) to demonstrate the use of the adjusted CR-SEs with different models. [ABSTRACT FROM AUTHOR]

Background: Insomnia is more common as people age. Several common hypnotics used to treat insomnia often do not adequately alleviate sleep issues in older adults and may be associated with negative residual effects such as an increased risk of falls, cognitive impairment, automobile accidents, and lack of response to auditory stimuli. The objective of these analyses of three clinical studies was to investigate the efficacy and safety of the dual orexin-receptor antagonist lemborexant (LEM) in older adults. Methods: Study E2006-G000-304 (Study 304; NCT02783729) was a randomized, double-blind, placebo (PBO)-controlled, active-comparator trial where subjects with insomnia disorder received LEM 5 mg (LEM5), LEM 10 mg (LEM10), zolpidem tartrate extended-release 6.25 mg (ZOL), or PBO for 30 days. In crossover Study E2006-E044-106 (Study 106; NCT02583451), healthy subjects (good sleepers) received LEM 2.5 mg, LEM5, LEM10, or PBO for eight nights or zopiclone on days 1 and 8 (and PBO on days 2–7). In crossover Study E2006-A001-108 (Study 108; NCT03008447), healthy subjects received a single dose of LEM5, LEM10, PBO, or ZOL. Sleep assessments included polysomnography-based latency to persistent sleep (LPS), wake after sleep onset (WASO), WASO in the second half of the night (WASO2H), sleep efficiency, postural stability, middle-of-the-night and next-day cognitive performance, middle-of-the-night auditory awakening threshold and return-to-sleep latency, and driving performance. Results: Overall, 453 of 1006 (45%; Study 304), 24 of 48 (50%; Study 106), and 28 of 56 (50%; Study 108) subjects were aged ≥ 65 years. In Study 304, LEM decreased (improved) LPS, WASO, and WASO2H from baseline more than ZOL and PBO; subjects treated with LEM had greater increases in sleep efficiency (improved) than with ZOL or PBO. In both Studies 304 and 108, postural stability was not impaired at waketime in subjects who received LEM compared with PBO. At waketime, LEM did not impair memory compared with PBO. In Study 108, following middle-of-the-night awakening, LEM and ZOL did not affect subjects' ability to awaken to auditory stimuli; LEM did not affect tests of memory and attention. In Study 106, LEM did not impair next-day driving performance in healthy elderly compared with PBO. LEM was well tolerated in subjects aged ≥ 65 years. Conclusions: LEM provided benefits on sleep variables without next-morning residual effects in subjects aged ≥ 65 years, supporting LEM as a treatment option for older adults with insomnia. Trial Registration Numbers and Dates of Registration: Study 304: ClinicalTrials.gov identifier, NCT02783729, date of registration, 26 May 2016. Study 106: ClinicalTrials.gov identifier, NCT02583451, date of registration, 22 October 2015. Study 108: ClinicalTrials.gov identifier, NCT03008447, date of registration, 2 January 2017. Plain Language Summary: The prevalence of insomnia increases with age; however, some hypnotics used for treating insomnia do not adequately resolve sleep problems in older adults and may be associated with adverse residual effects. Specifically, some hypnotics pose safety concerns in this population of patients who are generally more vulnerable to treatment-related effects, including increasing the risk of falls, risks of cognitive impairment, automobile accidents, and unresponsiveness to auditory stimuli. Safer and more effective insomnia medications are needed to reduce sleep problems with improved side-effect profiles. This analysis of lemborexant clinical studies conducted in adult subjects at least 65 years old found the drug to be effective without impairing memory, attention or balance the following day compared with placebo. These subjects were normal sleepers (for age) or had insomnia disorder. Furthermore, lemborexant was not associated with impaired ability to drive the next morning or awaken to loud middle-of-the-night sounds. Lemborexant was well tolerated in these older adults, similar to findings for adults aged at least 18 years. These findings indicate that lemborexant may be an appropriate treatment option for insomnia in older adults. [ABSTRACT FROM AUTHOR]

Introduction: Most European infant national immunization programs (NIPs) recommend pneumococcal conjugate vaccines (PCVs), which currently cover 10–15 serotypes administered in a three-dose schedule (two primary plus one booster). Recently, a PCV covering 20 serotypes that is administered in a four-dose schedule (three primary plus one booster) was licensed. Methods: An online survey was administered to collect data from health care providers (HCPs) and caregivers of children aged 0–5 (including expectant mothers) in four European countries (Germany, France, Spain, and Greece). All caregiver respondents had a shared or full responsibility to make health decisions for their child. Data on opinions, perceptions, and openness to a change in childhood vaccination dosing schedules were collected, along with demographic information for HCPs as well as caregivers. Results: A total of 601 HCPs and 1954 caregivers were recruited across the four countries. Nearly all HCPs (93%) agreed that broader serotype coverage against pneumococcal disease for children is a significant unmet need, and 92% had a "sense of urgency" to vaccinate children. Both HCPs and caregivers were supportive of an additional PCV dose and doctor visit, assuming it provided at least 20% more serotype coverage than what is currently available. Caregivers strongly agreed on the importance of full vaccination for pneumococcal disease, even if an extra dose and visit to the doctor was required. Conclusions: HCPs and caregivers were virtually unanimous in their support for a PCV with broader serotype coverage and showed a subsequent willingness to include an extra infant dose/visit. These results can help guide broader discussions regarding public health policy and vaccine administration in the context of important efforts to reduce the global disease burden associated with pneumococcal disease. [ABSTRACT FROM AUTHOR]

Background: Antibiotic use remains common for the treatment of lower respiratory tract infections. The objective of this study was to evaluate the impact of antibiotic use on the duration and severity of acute lower respiratory tract infection (LRTI). Participants: Adult patients presenting to US primary or urgent care sites with a chief complaint of cough and symptoms consistent with LRTI. Main Measures: Collected data included demographics, comorbidities, symptoms, and 48 viral and bacterial respiratory pathogens by PCR. Severity of signs/symptoms was reported for up to 28 days using diaries and text messages. Interpolation was used where data were missing. Key Results: Of 718 patients with baseline data, 29% had an antibiotic prescribed at baseline. The most common antibiotics were amoxicillin-clavulanate, azithromycin, doxycycline, and amoxicillin in 85% of patients. Provision of an antibiotic had no effect on the duration or overall severity of cough, including in patients with viral, bacterial, and mixed infections. Receipt of an antibiotic did reduce the likelihood of a follow-up visit (14.1% vs 8.2%, aOR 0.47, 95% CI 0.26–0.84), perhaps by removing the motivation of getting an antibiotic at a follow-up visit. However, they were also more likely to receive a systemic corticosteroid (31.9% vs 4.5%, p < 0.001) and were also more likely to receive an albuterol inhaler (22.7% vs 7.6%, p < 0.001). Patients believed that receiving an antibiotic would reduce the duration of their illness by nearly 4 days. Conclusions: In this large prospective study in the US primary and urgent care setting, antibiotics had no measurable impact on the severity or duration of cough due to acute LRTI. Patients had unrealistic expectations regarding the duration of LRTI and the effect of antibiotics which should be the target of antibiotic stewardship efforts. [ABSTRACT FROM AUTHOR]

Transcranial magnetic stimulation (TMS) and electroencephalography (EEG) are non-invasive techniques used for neuromodulation and recording brain electrical activity, respectively. The integration of TMS-EEG has emerged as a valuable tool for investigating the complex mechanisms involved in age-related disorders, such as mild cognitive impairment (MCI) and Alzheimer's disease (AD). By systematically synthesizing TMS-EEG studies, this review aims to shed light on the neurophysiological mechanisms underlying MCI and AD, while also exploring the practical applications of TMS-EEG in clinical settings. PubMed, ScienceDirect, and PsychInfo were selected as the databases for this review. The 22 eligible studies included a total of 592 individuals with MCI or AD as well as 301 cognitively normal adults. TMS-EEG assessments unveiled specific patterns of corticospinal excitability, plasticity, and brain connectivity that distinguished individuals on the AD spectrum from cognitively normal older adults. Moreover, the TMS-induced EEG features were observed to be correlated with cognitive performance and the presence of AD pathological biomarkers. The comprehensive examination of the existing studies demonstrates that the combination of TMS and EEG has yielded valuable insights into the neurophysiology of MCI and AD. This integration shows great potential for early detection, monitoring disease progression, and anticipating response to treatment. Future research is of paramount importance to delve into the potential utilization of TMS-EEG for treatment optimization in individuals with MCI and AD. [ABSTRACT FROM AUTHOR]

Respiratory infections caused by the human fungal pathogen Aspergillus fumigatus are a major cause of mortality for immunocompromised patients. Exposure to these pathogens occurs through inhalation, although the role of the respiratory epithelium in disease pathogenesis has not been fully defined. Employing a primary human airway epithelial model, we demonstrate that fungal melanins potently block the post-translational secretion of the chemokines CXCL1 and CXCL8 independent of transcription or the requirement of melanin to be phagocytosed, leading to a significant reduction in neutrophil recruitment to the apical airway both in vitro and in vivo. Aspergillus-derived melanin, a major constituent of the fungal cell wall, dampened airway epithelial chemokine secretion in response to fungi, bacteria, and exogenous cytokines. Furthermore, melanin muted pathogen-mediated calcium fluxing and hindered actin filamentation. Taken together, our results reveal a critical role for melanin interaction with airway epithelium in shaping the host response to fungal and bacterial pathogens. Here, Reedy et al. use a human airway culture model to show that fungal melanin blocks the secretion of pro-inflammatory chemokines resulting in diminished immune responses to Aspergillus fumigatus and Pseudomonas aeruginosa. [ABSTRACT FROM AUTHOR]

Face-processing timing differences may underlie visual social attention differences between autistic and non-autistic people, and males and females. This study investigates the timing of the effects of neurotype and sex on face-processing, and their dependence on age. We analysed EEG data during upright and inverted photographs of faces from 492 participants from the Longitudinal European Autism Project (141 neurotypical males, 76 neurotypical females, 202 autistic males, 73 autistic females; age 6–30 years). We detected timings of sex/diagnosis effects on event-related potential amplitudes at the posterior–temporal channel P8 with Bootstrapped Cluster-based Permutation Analysis and conducted Growth Curve Analysis (GCA) to investigate the timecourse and dependence on age of neural signals. The periods of influence of neurotype and sex overlapped but differed in onset (respectively, 260 and 310 ms post-stimulus), with sex effects lasting longer. GCA revealed a smaller and later amplitude peak in autistic female children compared to non-autistic female children; this difference decreased in adolescence and was not significant in adulthood. No age-dependent neurotype difference was significant in males. These findings indicate that sex and neurotype influence longer latency face processing and implicates cognitive rather than perceptual processing. Sex may have more overarching effects than neurotype on configural face processing. [ABSTRACT FROM AUTHOR]

EF skills play a central role in the etiology and maintenance of anxiety, but it is unclear whether they act as moderators or mediators in the relation between early behavioral inhibition (BI) and later anxiety. The current study tested two models by examining whether two executive functions (EF) skills (cognitive flexibility and working memory) assessed at age 6 acted as moderators or mediators in the relation between BI at 5 years and anxiety symptoms at 7 years. The sample consisted of 422 children from the Quebec Longitudinal Study of Child Development. We tested the moderation model, main and interaction effects using hierarchical multiple regression analyses and the mediation model with the product of coefficients test. Results showed that higher BI at 5 years predicted high anxiety at 7 years only at low levels of cognitive flexibility or working memory at 6 years. This suggests that high levels of cognitive flexibility or working memory at 6 years may act as protective factors. In contrast, neither cognitive flexibility nor working memory at age 6 acted as mediators in the association between BI at 5 years and anxiety at 7 years. Results support the hypothesis that goal-driven cognitive control processes act as moderators and promote adaptive functioning by dampening the effect of early BI on later anxiety. [ABSTRACT FROM AUTHOR]

Cloverleaf skull deformity or Kleeblattschadel syndrome is a severe condition where multiple cranial sutures are absent and prematurely fused, leading to a trilobate head shape. The remaining open sutures or fontanelles compensate for rapid brain expansion, while the constricted fused calvarium restricts brain growth and results in increased intracranial pressure. Recent data show that early posterior cranial and foramen magnum decompression positively affects infants with cloverleaf skulls. However, long-term sequelae are still rarely discussed. We hereby report a child who developed secondary metopic craniosynostosis after posterior cranial decompression, which required a front-orbital advancement and cranial remodelling as a definitive procedure. [ABSTRACT FROM AUTHOR]

Background: The objective of this network meta-analysis was to compare rates of clinical response and mortality for empiric oral antibiotic regimens in adults with mild-moderate community-acquired pneumonia (CAP). Methods: We searched PubMed, Cochrane, and the reference lists of systematic reviews and clinical guidelines. We included randomized trials of adults with radiologically confirmed mild to moderate CAP initially treated orally and reporting clinical cure or mortality. Abstracts and studies were reviewed in parallel for inclusion in the analysis and for data abstraction. We performed separate analyses by antibiotic medications and antibiotic classes and present the results through network diagrams and forest plots sorted by p-scores. We assessed the quality of each study using the Cochrane Risk of Bias framework, as well as global and local inconsistency. Results: We identified 24 studies with 9361 patients: six at low risk of bias, six at unclear risk, and 12 at high risk. Nemonoxacin, levofloxacin, and telithromycin were most likely to achieve clinical response (p-score 0.79, 0.71, and 0.69 respectively), while penicillin and amoxicillin were least likely to achieve clinical response. Levofloxacin, nemonoxacin, azithromycin, and amoxicillin-clavulanate were most likely to be associated with lower mortality (p-score 0.85, 0.75, 0.74, and 0.68 respectively). By antibiotic class, quinolones and macrolides were most effective for clinical response (0.71 and 0.70 respectively), with amoxicillin-clavulanate plus macrolides and beta-lactams being less effective (p-score 0.11 and 0.22). Quinolones were most likely to be associated with lower mortality (0.63). All confidence intervals were broad and partially overlapping. Conclusion: We observed trends toward a better clinical response and lower mortality for quinolones as empiric antibiotics for CAP, but found no conclusive evidence of any antibiotic being clearly more effective than another. More trials are needed to inform guideline recommendations on the most effective antibiotic regimens for outpatients with mild to moderate CAP. [ABSTRACT FROM AUTHOR]

Purpose: The myocardial creep is a phenomenon in which the heart moves from its original position during stress-dynamic PET myocardial perfusion imaging (MPI) that can confound myocardial blood flow measurements. Therefore, myocardial motion correction is important to obtain reliable myocardial flow quantification. However, the clinical importance of the magnitude of myocardial creep has not been explored. We aimed to explore the prognostic value of myocardial creep quantified by an automated motion correction algorithm beyond traditional PET-MPI imaging variables. Methods: Consecutive patients undergoing regadenoson rest-stress [82Rb]Cl PET-MPI were included. A newly developed 3D motion correction algorithm quantified myocardial creep, the maximum motion at stress during the first pass (60 s), in each direction. All-cause mortality (ACM) served as the primary endpoint. Results: A total of 4,276 patients (median age 71 years; 60% male) were analyzed, and 1,007 ACM events were documented during a 5-year median follow-up. Processing time for automatic motion correction was < 12 s per patient. Myocardial creep in the superior to inferior (downward) direction was greater than the other directions (median, 4.2 mm vs. 1.3–1.7 mm). Annual mortality rates adjusted for age and sex were reduced with a larger downward creep, with a 4.2-fold ratio between the first (0 mm motion) and 10th decile (11 mm motion) (mortality, 7.9% vs. 1.9%/year). Downward creep was associated with lower ACM after full adjustment for clinical and imaging parameters (adjusted hazard ratio, 0.93; 95%CI, 0.91–0.95; p < 0.001). Adding downward creep to the standard PET-MPI imaging model significantly improved ACM prediction (area under the receiver operating characteristics curve, 0.790 vs. 0.775; p < 0.001), but other directions did not (p > 0.5). Conclusions: Downward myocardial creep during regadenoson stress carries additional information for the prediction of ACM beyond conventional flow and perfusion PET-MPI. This novel imaging biomarker is quantified automatically and rapidly from stress dynamic PET-MPI. [ABSTRACT FROM AUTHOR]

This exploratory study uses epistemic network analysis (ENA) to examine the use of extended reality (XR) technologies embedded in post-secondary classes, one in a traditional setting and the other a place-based setting, to examine climate change while utilizing a socioscientific issues (SSI) approach. One group used a virtual reality (VR) application on their smartphones in a traditional class setting to explore four different locations on the Outer Banks of North Carolina, USA (OBX). A second group used an augmented reality (AR) application on their smartphones while visiting the same four locations. Qualitative data was collected after each experience. Analysis of each group's networks indicated that both forms of technology engaged students in the SSI and were beneficial to their learning. However, differences in the networks revealed that virtual reality students made stronger connections between the technology, the physical impacts of climate change, and the political/socioeconomic aspects of climate change. In contrast, the augmented reality students made stronger connections between the technology and learning in general. Implications for practice and future research will be discussed. [ABSTRACT FROM AUTHOR]

Measurement invariance (MI) of a psychometric scale is a prerequisite for valid group comparisons of the measured construct. While the invariance of loadings and intercepts (i.e., scalar invariance) supports comparisons of factor means and observed means with continuous items, a general belief is that the same holds with ordered-categorical (i.e., ordered-polytomous and dichotomous) items. However, as this paper shows, this belief is only partially true—factor mean comparison is permissible in the correctly specified scalar invariance model with ordered-polytomous items but not with dichotomous items. Furthermore, rather than scalar invariance, full strict invariance—invariance of loadings, thresholds, intercepts, and unique factor variances in all items—is needed when comparing observed means with both ordered-polytomous and dichotomous items. In a Monte Carlo simulation study, we found that unique factor noninvariance led to biased estimations and inferences (e.g., with inflated type I error rates of 19.52%) of (a) the observed mean difference for both ordered-polytomous and dichotomous items and (b) the factor mean difference for dichotomous items in the scalar invariance model. We provide a tutorial on invariance testing with ordered-categorical items as well as suggestions on mean comparisons when strict invariance is violated. In general, we recommend testing strict invariance prior to comparing observed means with ordered-categorical items and adjusting for partial invariance to compare factor means if strict invariance fails. [ABSTRACT FROM AUTHOR]

Introduction: A 20-valent pneumococcal conjugate vaccine (PCV20) was recently recommended for use among US children. We evaluated the cost-effectiveness of PCV20 among children aged 6 years with chronic medical conditions (CMC+) and children aged 6 years with immunocompromising conditions (IC) versus one and two doses of 23-valent pneumococcal polysaccharide vaccine (PPSV23), respectively. Methods: A probabilistic model was employed to depict 10-year risk of clinical outcomes and economic costs of pneumococcal disease, reduction in life years from premature death, and expected impact of vaccination among one cohort of children with CMC+ and IC aged 6 years. Vaccine uptake was assumed to be 20% for both PCV20 and PPSV23. Cost per quality-adjusted life year (QALY) gained was evaluated from the US societal and healthcare system perspectives; deterministic and probabilistic sensitivity analyses (DSA/PSA) were also conducted. Results: Among the 226,817 children with CMC+ aged 6 years in the US, use of PCV20 (in lieu of PPSV23) was projected to reduce the number cases of pneumococcal disease by 5203 cases, medical costs by US$8.7 million, and nonmedical costs by US$6.2 million. PCV20 was the dominant strategy versus PPSV23 from both the healthcare and societal perspectives. In the PSA, 99.9% of the 1000 simulations yielded a finding of dominance for PCV20. Findings in analyses of children with IC aged 6 years in the USA were comparable (i.e., PCV20 was the dominant vaccination strategy). Scenario analyses showed that increasing PCV20 uptake to 100% could potentially prevent > 22,000 additional cases of pneumococcal disease and further reduce medical and nonmedical costs by US$70.0 million among children with CMC+ and IC. Conclusions: Use of PCV20 among young children with CMC+ and IC in the USA would reduce the clinical burden of pneumococcal disease and yield overall cost savings from both the US healthcare system and societal perspectives. Higher PCV20 uptake could further reduce the number of pneumococcal disease cases in this population. [ABSTRACT FROM AUTHOR]

The van der Waals heterostructures have evolved as novel materials for complementing the Si-based semiconductor technologies. Group-10 noble metal dichalcogenides (e.g., PtS2, PtSe2, PdS2, and PdSe2) have been listed into two-dimensional (2D) materials toolkit to assemble van der Waals heterostructures. Among them, PdSe2 demonstrates advantages of high stability in air, high mobility, and wide tunable bandgap. However, the regulation of p-type doping of PdSe2 remains unsolved problem prior to fabricating p–n junction as a fundamental platform of semiconductor physics. Besides, a quantitative method for the controllable doping of PdSe2 is yet to be reported. In this study, the doping level of PdSe2 was correlated with the concentration of Lewis acids, for example, SnCl4, used for soaking. Considering the transfer characteristics, the threshold voltage (the gate voltage corresponding to the minimum drain current) increased after SnCl4 soaking treatment. PdSe2 transistors were soaked in SnCl4 solutions with five different concentrations. The threshold voltages from the as-obtained transfer curves were extracted for linear fitting to the threshold voltage versus doping concentration correlation equation. This study provides in-depth insights into the controllable p-type doping of PdSe2. It may also push forward the research of the regulation of conductivity behaviors of 2D materials. [ABSTRACT FROM AUTHOR]

Copyright of Fire Ecology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The kagome metals AV3Sb5 (A = K, Rb, Cs) present an ideal sandbox to study the interrelation between multiple coexisting correlated phases such as charge order and superconductivity. So far, no consensus on the microscopic nature of these states has been reached as the proposals struggle to explain all their exotic physical properties. Among these, field-switchable electric magneto-chiral anisotropy (eMChA) in CsV3Sb5 provides intriguing evidence for a rewindable electronic chirality, yet the other family members have not been likewise investigated. Here, we present a comparative study of magneto-chiral transport between CsV3Sb5 and KV3Sb5. Despite their similar electronic structure, KV3Sb5 displays negligible eMChA, if any, and with no field switchability. This is in stark contrast to the non-saturating eMChA in CsV3Sb5 even in high fields up to 35 T. In light of their similar band structures, the stark difference in eMChA suggests its origin in the correlated states. Clearly, the V kagome nets alone are not sufficient to describe the physics and the interactions with their environment are crucial in determining the nature of their low-temperature state. [ABSTRACT FROM AUTHOR]

Cristae are high‐curvature structures in the inner mitochondrial membrane (IMM) that are crucial for ATP production. While cristae‐shaping proteins have been defined, analogous lipid‐based mechanisms have yet to be elucidated. Here, we combine experimental lipidome dissection with multi‐scale modeling to investigate how lipid interactions dictate IMM morphology and ATP generation. When modulating phospholipid (PL) saturation in engineered yeast strains, we observed a surprisingly abrupt breakpoint in IMM topology driven by a continuous loss of ATP synthase organization at cristae ridges. We found that cardiolipin (CL) specifically buffers the inner mitochondrial membrane against curvature loss, an effect that is independent of ATP synthase dimerization. To explain this interaction, we developed a continuum model for cristae tubule formation that integrates both lipid and protein‐mediated curvatures. This model highlighted a snapthrough instability, which drives IMM collapse upon small changes in membrane properties. We also showed that cardiolipin is essential in low‐oxygen conditions that promote PL saturation. These results demonstrate that the mechanical function of cardiolipin is dependent on the surrounding lipid and protein components of the IMM. Synopsis: Dedicated proteins are known to control the architecture of the inner mitochondrial membrane; however, the role of specific lipids is less well defined. Here, a combination of methods including tomography and lipidomics is used to characterise the role of lipid composition in defining cristae architecture. As lipid ratios change, a critical breakpoint phenocopies the loss of cristae‐shaping proteins in the IMM of yeast mitochondria.Phospholipid saturation controls membrane mechanical properties and modulates ATP synthase oligomerization.The mitochondria‐specific lipid cardiolipin functionally compensates for increased phospholipid saturation and is required for cristae formation in low‐oxygen environments.A mathematical model for cristae membrane tubules predicts a snap‐through instability mediated by both protein and lipid‐encoded curvatures. [ABSTRACT FROM AUTHOR]

The binding and interaction of proteins with nucleic acids such as DNA and RNA constitutes a fundamental biochemical and biophysical process in all living organisms. Identifying and visualizing such temporal interactions in cells is key to understanding their function. To image sites of these events in cells across scales, we developed a method, named PROMPT for PROximal Molecular Probe Transfer, which is applicable to both light and correlative electron microscopy. This method relies on the transfer of a bound photosensitizer from a protein known to associate with specific nucleic acid sequence, allowing the marking of the binding site on DNA or RNA in fixed cells. The method produces a fluorescent mark at the site of their interaction, that can be made electron dense and reimaged at high resolution in the electron microscope. As proof of principle, we labeled in situ the interaction sites between the histone H2B and nuclear DNA. As an example of application for specific RNA localizations we labeled different nuclear and nucleolar fractions of the protein Fibrillarin to mark and locate where it associates with RNAs, also using electron tomography. While the current PROMPT method is designed for microscopy, with minimal variations, it can be potentially expanded to analytical techniques. [ABSTRACT FROM AUTHOR]

The cloverleaf skull deformity remains among the most complicated craniofacial conditions to successfully manage. Many cases achieve largely unsatisfactory outcomes due to the requirement for frequent reoperation on the cranial vault and failure to deal with all the elements of the craniofaciostenosis in a timely fashion. Early cranial vault surgery without addressing the cranial base deformity and its attendant cerebrospinal fluid flow changes is invariably challenging and disappointing. A recent focus on the expansion of the posterior cranial vault as a primary procedure with the greater volume change allows a delay in fronto-orbital advancement and reduced need for repeat surgery. We herein describe three cases of complex multisuture craniosynostosis with cloverleaf skull deformity who underwent neonatal posterior cranial vault decompression along with foramen magnum decompression. Our report examines the safety and rationale for this pre-emptive surgical approach to simultaneously deal with the cranial vault and craniocervical junction abnormalities and thus change the early trajectory of these complex cases. [ABSTRACT FROM AUTHOR]

Background: Understanding which patient-reported outcome measures are being collected and utilized in clinical practice and research for patients with neck pain will help to inform recommendations for a core set of measures that provide value to patients and clinicians during diagnosis, clinical decision-making, goal setting and evaluation of responsiveness to treatment. Therefore, the aim of this study was to conduct a review of systematic reviews using a qualitative synthesis on the use of patient-reported outcome measures (PROMs) for patients presenting with neck pain to physical therapy. Methods: An electronic search of systematic reviews and guideline publications was performed using MEDLINE (OVID), Embase (Elsevier), CINAHL Complete (EBSCOhost), and Web of Science (Clarivate) databases to identify reviews that evaluated physical therapy interventions or interventions commonly performed by a physical therapist for individuals with neck pain and included at least one patient-reported outcome measure. The frequency and variability in which the outcome measures were reported among the studies in the review and the constructs for which they measured were evaluated. The evaluation of a core set of outcome measures was assessed. Risk of bias and quality assessment was performed using A Measurement Tool to Assess systematic Reviews 2. Results: Of the initial 7,003 articles, a total of 37 studies were included in the final review. Thirty-one PROMs were represented within the 37 reviews with eleven patient-reported outcome measures in three or more reviews. The eleven PROMs assessed the constructs of disability, pain intensity, psychosocial factors and quality of life. The greatest variability was found amongst individual measures assessing psychosocial factors. Assessment of psychosocial factors was the least represented construct in the included studies. Overall, the most frequently utilized patient reported outcome measures were the Neck Disability Index, Visual Analog Scale, and Numeric Pain Rating Scale. The most frequently used measures evaluating the constructs of disability, pain intensity, quality of life and psychosocial functioning included the Neck Disability Index, Visual Analog Scale, Short-Form-36 health survey and Fear Avoidance Belief Questionnaire respectively. Overall risk of bias and quality assessment confidence levels ranged from critically low (2 studies), low (12 studies), moderate (8 studies), and high (15 studies). Conclusion: This study identified a core set of patient-reported outcome measures that represented the constructs of disability, pain intensity and quality of life. This review recommends the collection and use of the Neck Disability Index and the Numeric Pain Rating Scale or Visual Analog Scale. Recommendation for a QoL measure needs to be considered in the context of available resources and administrative burden. Further research is needed to confidently recommend a QoL and psychosocial measure for patients presenting with neck pain. Other measures that were not included in this review but should be further evaluated for patients with neck pain are the Patient Reported Outcomes Measurement Information System (PROMIS) Physical function, PROMIS Pain Interference and the Optimal Screening for Prediction of Referral and Outcome Yellow Flag (OSPRO-YF) tool. [ABSTRACT FROM AUTHOR]

Anisotropic and efficient transport of ions under external stimuli governs the operation and failure mechanisms of energy-conversion systems and microelectronics devices. However, fundamental understanding of ion hopping processes is impeded by the lack of atomically precise materials and probes that allow for the monitoring and control at the appropriate time- and length- scales. In this work, using in-situ transmission electron microscopy, we directly show that oxygen ion migration in vacancy ordered, semiconducting SrFeO2.5 epitaxial thin films can be guided to proceed through two distinctly different diffusion pathways, each resulting in different polymorphs of SrFeO2.75 with different ground electronic properties before reaching a fully oxidized, metallic SrFeO3 phase. The diffusion steps and reaction intermediates are revealed by means of ab-initio calculations. The principles of controlling oxygen diffusion pathways and reaction intermediates demonstrated here may advance the rational design of structurally ordered oxides for tailored applications and provide insights for developing devices with multiple states of regulation. Control of ion diffusion is instrumental in understanding the behavior and structural transformations of transition metal oxides. Here, the authors use in-situ TEM to reveal the atomic-scale evolution of the topotactic phase transition in BM-SFO triggered by the migration of oxygen ions under an external stimulus. [ABSTRACT FROM AUTHOR]

Purpose: Facial trauma in women is complex with physical, psychosocial, and cultural influences impacting clinical presentations. Although multifactorial, assaults and falls are principally reported as the main causes. Methods: A retrospective review was conducted from January 2012 to January 2017 at the Women and Children's Hospital and Royal Adelaide Hospital, Adelaide. All maxillofacial fractures in women that attended or were referred to the unit were included in this study. The primary objective was to analyse epidemiological trends of facial fractures and clinical outcomes in the South Australian female population. Results: There is a bimodal distribution of facial fractures at 25–35 years and 65 + years. Indigenous females were 19.5 years younger than non-indigenous females (30.5 vs 49.9, P < 0.001). Approximately half the cohort had a fall-related facial fracture, followed by assault (26.2%), and sports (10.3%). There was a higher proportion of non-alcohol-related trauma from assaults than alcohol-related assaults (72.5% vs 27.5%, P < 0.001). Over half (58.0%) of the cohort had a midface fracture. The elderly had increased odds of 1.9 fold for facial fractures in winter, largely from falls, compared to younger women. Associated injuries were present in almost half the elderly women with 2.6 times the risk compared to younger women. Younger women had higher incidences of surgical intervention (52.6% vs 14.3%, P < 0.05). Conclusions: Young women disproportionately experience larger incidences of non-alcohol-related assaults requiring operative intervention of the mandible, whereas elderly women principally suffer fall-related facial fractures with higher rates of associated injuries. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) actions are mediated through binding to its cell-surface receptor, the GH receptor (GHR), with consequent activation of downstream signalling. However, nuclear GHR localisation has also been observed and is associated with increased cancer cell proliferation. Here we investigated the functional implications of nuclear translocation of the GHR in the human endometrial cancer cell-line, RL95-2, and human mammary epithelial cell-line, MCF-10A. We found that following GH treatment, the GHR rapidly translocates to the nucleus, with maximal localisation at 5–10 min. Combined immunoprecipitation-mass spectrometry analysis of RL95-2 whole cell lysates identified 40 novel GHR binding partners, including the transcriptional regulator, HMGN1. Moreover, microarray analysis demonstrated that the gene targets of HMGN1 were differentially expressed following GH treatment, and co-immunoprecipitation showed that HMGN1 associates with the GHR in the nucleus. Therefore, our results suggest that GHR nuclear translocation might mediate GH actions via interaction with chromatin factors that then drive changes in specific downstream transcriptional programs. [ABSTRACT FROM AUTHOR]

The transport paths of O during intergranular oxidation in binary Ni-Cr were investigated. To isolate the selective oxidation of Cr, oxidation was performed with a CO/CO2 gas mixture in which the oxygen partial pressure was kept under the NiO dissociation pressure. A combination of electron microscopy and atom probe tomography (APT) was used to study the nanometer-scale details of the passivation and penetrative intergranular oxidation processes at high-energy grain boundaries. Oxygen transport towards the terminating oxidation front is elucidated with dedicated usage of oxygen tracer exchange experiments. Secondary ion mass spectroscopy and APT support classical theories of internal oxidation, revealing preferred transport paths at the oxide/alloy interface with sub-nanometer resolution. [ABSTRACT FROM AUTHOR]

Purpose: Belize has among the highest cervical cancer incidence and mortality rates of Latin American and Caribbean countries. This study evaluates the perspectives of key stakeholders for cervical cancer screening in Belize and identifies the barriers and facilitators for providing equitable access to prevention services. Methods: Semi-structured interviews discussing cervical cancer screening were conducted with key stakeholders across the six districts of Belize in 2018. Interviews were transcribed, coded, and analyzed thematically; themes were organized by levels of the social-ecological model. Results: We conducted 47 interviews with health care providers (45%), administrators (17%), government officials (25%), and other stakeholders (13%). Majority (78%) of interviews were from the public sector. Perceived barriers to cervical cancer screening were identified across multiple levels: (1) Individual Patient: potential delays in Pap smear results and fear of a cancer diagnosis; (2) Provider: competing clinician responsibilities; (3) Organizational: insufficient space and training; (4) Community: reduced accessibility in rural areas; and (5) Policy: equipment and staffing budget limitations. The main facilitators we identified included the following: (1) at the Community level: resource-sharing between public and private sectors and dedicated rural outreach personnel; (2) at the Policy level: free public screening services and the establishment of population-based screening. Conclusion: Despite free, publicly available cervical cancer screening in Belize, complex barriers affect access and completion of management when abnormal screening tests are identified. Provider workload, education outreach, and additional funding for training and facilities are potential areas for strengthening this program and increasing detection and management for cervical cancer control. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether treatment of anal high-grade squamous intraepithelial lesions (HSIL), vs active monitoring, is effective in reducing incidence of anal cancer in persons living with HIV, the US National Cancer Institute funded the Phase III ANal Cancer/HSIL Outcomes Research (ANCHOR) clinical trial. As no established patient-reported outcomes (PRO) tool exists for persons with anal HSIL, we sought to estimate the construct validity and responsiveness of the ANCHOR Health-Related Symptom Index (A-HRSI). Methods: The construct validity phase enrolled ANCHOR participants who were within two weeks of randomization to complete A-HRSI and legacy PRO questionnaires at a single time point. The responsiveness phase enrolled a separate cohort of ANCHOR participants who were not yet randomized to complete A-HRSI at three time points: prior to randomization (T1), 14–70 (T2), and 71–112 (T3) days following randomization. Results: Confirmatory factor analysis techniques established a three-factor model (i.e., physical symptoms, impact on physical functioning, impact on psychological functioning), with moderate evidence of convergent validity and strong evidence of discriminant validity in the construct validity phase (n = 303). We observed a significant moderate effect for changes in A-HRSI impact on physical functioning (standardized response mean = 0.52) and psychological symptoms (standardized response mean = 0.60) from T2 (n = 86) to T3 (n = 92), providing evidence of responsiveness. Conclusion: A-HRSI is a brief PRO index that captures health-related symptoms and impacts related to anal HSIL. This instrument may have broad applicability in other contexts assessing individuals with anal HSIL, which may ultimately help improve clinical care and assist providers and patients with medical decision-making. [ABSTRACT FROM AUTHOR]

Ebola virus (EBOV) infection induces the formation of membrane-less, cytoplasmic compartments termed viral factories, in which multiple viral proteins gather and coordinate viral transcription, replication, and assembly. Key to viral factory function is the recruitment of EBOV polymerase, a multifunctional machine that mediates transcription and replication of the viral RNA genome. We show that intracellularly reconstituted EBOV viral factories are biomolecular condensates, with composition-dependent internal exchange dynamics that likely facilitates viral replication. Within the viral factory, we found the EBOV polymerase clusters into foci. The distance between these foci increases when viral replication is enabled. In addition to the typical droplet-like viral factories, we report the formation of network-like viral factories during EBOV infection. Unlike droplet-like viral factories, network-like factories are inactive for EBOV nucleocapsid assembly. This unique view of EBOV propagation suggests a form-to-function relationship that describes how physical properties and internal structures of biomolecular condensates influence viral biogenesis. Here, the authors characterized the phase separation properties and internal structures of intracellular viral factories induced by Ebola virus and correlated these properties to important steps of viral biogenesis. [ABSTRACT FROM AUTHOR]

Severe outbreaks and deaths have been linked to the emergence and global spread of fluoroquinolone-resistant Clostridioides difficile over the past two decades. At the same time, metronidazole, a nitro-containing antibiotic, has shown decreasing clinical efficacy in treating C. difficile infection (CDI). Most metronidazole-resistant C. difficile exhibit an unusual resistance phenotype that can only be detected in susceptibility tests using molecularly intact heme. Here, we describe the mechanism underlying this trait. We find that most metronidazole-resistant C. difficile strains carry a T-to-G mutation (which we term PnimBG) in the promoter of gene nimB, resulting in constitutive transcription. Silencing or deleting nimB eliminates metronidazole resistance. NimB is related to Nim proteins that are known to confer resistance to nitroimidazoles. We show that NimB is a heme-dependent flavin enzyme that degrades nitroimidazoles to amines lacking antimicrobial activity. Furthermore, occurrence of the PnimBG mutation is associated with a Thr82Ile substitution in DNA gyrase that confers fluoroquinolone resistance in epidemic strains. Our findings suggest that the pandemic of fluoroquinolone-resistant C. difficile occurring over the past few decades has also been characterized by widespread resistance to metronidazole. Detection of resistance to the antibiotic metronidazole in C. difficile often requires the presence of heme in the media, for unclear reasons. Here, the authors show that most metronidazole-resistant strains carry a mutation that promotes expression of a heme-dependent enzyme that degrades nitroimidazoles, and the mutation often co-occurs with an amino-acid substitution in DNA gyrase that confers resistance to another class of antibiotics, fluoroquinolones. [ABSTRACT FROM AUTHOR]

Tau protein aggregates in several neurodegenerative disorders, referred to as tauopathies. The tau isoforms observed in post mortem human brain aggregates is used to classify tauopathies. However, distinguishing tauopathies ante mortem remains challenging, potentially due to differences between insoluble tau in aggregates and soluble tau in body fluids. Here, we demonstrated that tau isoforms differ between tauopathies in insoluble aggregates, but not in soluble brain extracts. We therefore characterized post-translational modifications of both the aggregated and the soluble tau protein obtained from post mortem human brain tissue of patients with Alzheimer's disease, cortico-basal degeneration, Pick's disease, and frontotemporal lobe degeneration. We found specific soluble signatures for each tauopathy and its specific aggregated tau isoforms: including ubiquitination on Lysine 369 for cortico-basal degeneration and acetylation on Lysine 311 for Pick's disease. These findings provide potential targets for future development of fluid-based biomarker assays able to distinguish tauopathies in vivo. Post-translational modifications on tau protein in the brain could distinguish primary tauopathies. Here, the authors assess insoluble and soluble tau extracted from post mortem human tauopathy brains and show 4R/3R tau isoform ratio in aggregates is associated with specific modifications on soluble tau protein. [ABSTRACT FROM AUTHOR]

Natural disturbances, like those caused by fires or large herbivores, can strongly affect forest ecosystems. Managers can emulate such disturbance effects, for example, with prescribed fire or domestic livestock. This might benefit species of conservation importance, including capercaillie Tetrao urogallus. We tested this idea using two management trials in a Scots pine Pinus sylvestris forest in Scotland. One trial (blocked design with 25 replicates) in small plots (0.07 ha) tested the effects of prescribed burning or mowing alongside a control. The other compared cattle grazing in two large plots (6 ha and 14 ha) with a control. We measured capercaillie habitat quality indicators, namely, in both trials: cover of bilberry Vaccinium myrtillus; and in the burning and mowing trial: biomass of arthropods taken by capercaillie chicks, and capercaillie dung. Monitoring took place before treatments, and afterwards over a 12–13 year period. Bilberry cover increased following burning and mowing, peaking at 1.4 times control values, six years post-treatment. In one of the cattle plots, similar bilberry increases were recorded throughout the post-treatment period. However, the other cattle plot showed no such change, perhaps reflecting different competitive interactions among field layer plants. Capercaillie dung and spider biomass increased markedly in burnt and mown areas, and ant biomass just in burnt areas. Unexpectedly, bilberry also increased strongly in control areas of both trials, reflecting wider successional changes. Our results suggest that any of these techniques could be used to improve capercaillie habitat quality, but should be delivered alongside monitoring, so that their effects can be evaluated in particular contexts. [ABSTRACT FROM AUTHOR]

Introduction: Respiratory syncytial virus (RSV) is an important cause of severe respiratory illness in older adults and adults with respiratory or cardiovascular comorbidities. Published estimates of its incidence and prevalence in adult groups vary widely. This article reviews the potential limitations affecting RSV epidemiology studies and suggests points to consider when evaluating or designing them. Methods: Studies reporting the incidence or prevalence of RSV infection in adults in high-income Western countries from 2000 onwards were identified via a rapid literature review. Author-reported limitations were recorded, together with presence of other potential limitations. Data were synthesized narratively, with a focus on factors affecting incidence estimates for symptomatic infection in older adults. Results: A total of 71 studies met the inclusion criteria, most in populations with medically attended acute respiratory illness (ARI). Only a minority used case definitions and sampling periods tailored specifically to RSV; many used influenza-based or other criteria that are likely to result in RSV cases being missed. The great majority relied solely on polymerase chain reaction (PCR) testing of upper respiratory tract samples, which is likely to miss RSV cases compared with dual site sampling and/or addition of serology. Other common limitations were studying a single season, which has potential for bias due to seasonal variability; failure to stratify results by age, which underestimates the burden of severe disease in older adults; limited generalizability beyond a limited study setting; and absence of measures of uncertainty in the reporting of results. Conclusions: A significant proportion of studies are likely to underestimate the incidence of RSV infection in older adults, although the effect size is unclear and there is also potential for overestimation. Well-designed studies, together with increased testing for RSV in patients with ARI in clinical practice, are required to accurately capture both the burden of RSV and the potential public health impact of vaccines. [ABSTRACT FROM AUTHOR]

The "Snowball Earths" were cataclysmic events during the late Neoproterozoic's Cryogenian period (720-635 Ma) in which most, if not all, of Earth's surface was covered in ice. Paleoenvironmental reconstructions of these events utilize isotopic systems, such as Δ17O and barium isotopes of barites. Other isotopic systems, such as zinc (Zn), can reflect seawater composition or environmental conditions (e.g., temperature changes) and biological productivity. We report here a multi-isotopic C, O, and Zn data set for carbonates deposited immediately after the Marinoan glaciation (635 Ma) from the Otavi Group in northern Namibia. In this study, we chemically separated calcite and non-calcitic carbonate phases, finding isotopically distinct carbon and oxygen isotopes. These could reflect changes in the source seawater composition and conditions during carbonate formation. Our key finding is largescale Zn isotopic variations over the oldest parts of the distal foreslope cap carbonate sections. The magnitude of variation is larger than any found throughout post-snowball cap carbonates to date, and in a far shorter sequence. This shows a heretofore undiscovered difficulty for Zn isotopic interpretations. The primary Zn sources are likely to be aeolian or alluvial, associated with the massive deglaciation related run-off from the thawing continent and a greater exposed surface for atmospheric aerosol entrainment. The samples with the lightest Zn isotopic compositions (δ66Zn < 0.3 ‰) potentially reflect hydrothermally sourced Zn dominating the carbonates' Zn budget. This finding is likely unique to the oldest carbonates, when the meltwater lid was thinnest and surface waters most prone to upwelling of hydrothermally dominated Snowball Earth brine. On the other hand, local variations could be related to bioproductivity affecting the Zn isotopic composition of the seawater. Similarly, fluctuations in sea-level could bring the depositional site below and above a redoxcline, causing isotopic variations. These variations in Zn isotope ratios preclude the estimation of a global Zn isotopic signature, potentially indicating localized resumption of export production. [ABSTRACT FROM AUTHOR]

Public transport network design deals with finding efficient network solution(s) from a set of alternatives that best satisfies the often-conflicting objectives of stakeholders like passengers and operators. This work presents a simulation-based optimization (SBO) model for designing public transport networks. The work's novelty is in developing such a network design model that fully accounts for the stochastic behavior of commuters on the transit network. The SBO discipline solves decision-based problems like the transit network design problem (TNDP) by combining simulation and optimization models. The proposed model integrates a disaggregated activity-based travel demand simulation with a multi-objective network optimization algorithm. Trip-based travel demand models are commonly used to represent traveler behavior in the literature. The approach limits its ability to accommodate the stochastic realities of traveler behavior in a transit network design solution. Using activity-based simulation instead makes it possible to account for a more realistic traveler behavior, especially real-time decisions made in response to changing network dynamics which ultimately affect the distribution of demand over time on the network. The proposed model is applied to the improved design of the integrated public transport network in the City of Cape Town, South Africa. The results show SBO can design efficient network solutions that reflect the objectives of network stakeholders. [ABSTRACT FROM AUTHOR]

Pregnant refugee patients are especially vulnerable to adverse perinatal outcomes. Detailed characterization of this heterogenous population will identify risk factors and thus guide contextualized initiatives for improved patient care. A retrospective cohort study of obstetrical refugee patients at a tertiary-care hospital in Toronto, Ontario. Of 196 pregnant refugees, 48% were fluent English speaking, 57% had poor social support, and 42% lived in a shelter. Eighty-seven percent started prenatal care after the first trimester, which was associated with delivery of a large-for-gestational-age infant (p = 0.043). Sixteen percent experienced family violence, which was associated with poor fetal aggregate outcomes (p = 0.03). There were significantly higher rates of pre-eclampsia and Cesarean sections in refugee versus non-refugee patients (p < 0.05). Pregnant refugees are at risk for psychosocial challenges and experience significantly worse obstetrical outcomes compared with non-refugees. Quality improvement initiatives should focus on access to early prenatal care, stable housing, and support for victims of family violence. [ABSTRACT FROM AUTHOR]