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Introduction: This study examined prevalence and correlates of self-reported negative side effects from nicotine vaping product (NVP) use among people who currently or recently vape., Methods: This cross-sectional study analysed data from 3906 adults (aged 18+ years) from the 2020 ITC Four Country Smoking and Vaping Survey (Canada, US, England and Australia) who reported they had ever smoked cigarettes and were either currently vaping daily/weekly or had vaped in the last month. Participants were asked about experiencing and seeking medical advice for any negative side effects from vaping in the past month. Logistic regressions were used to estimate prevalence and identify correlates., Results: Overall, 87.1 % reported no negative side effects from vaping. The most common side effects were throat irritation (5.8 %), cough (5.5 %), and mouth irritation (4.1 %). The top two that led to seeking medical advice were: mouth irritation (46.8 %) and loss of taste (45.2 %). Those more likely to self-report side effects were younger, male, currently smoking (vs quit), vaping for <6 months (vs >1 year), using disposables or cartridges/pods (vs tanks), using vapes with nicotine (vs without nicotine), using menthol/mint flavour (vs sweet flavour), currently smoking (vs quit), believing vaping causes various diseases (e.g., heart disease), and believing that vaping is equally/more harmful than smoking., Conclusion: Negative side effects associated with NVP use were rare and mainly minor in all four countries. Shorter duration of vaping, concurrent smoking while vaping and perceptions of greater vaping harms relative to smoking were associated with more reported negative side effects attributed to vaping., Competing Interests: Declaration of Competing Interest Dr. Cummings has served as a paid expert witness in litigation filed against cigarette manufacturers. None of the other authors has any conflict of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cotadutide is a glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist that may improve kidney function in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). In this phase 2b study, patients with T2D and CKD (estimated glomerular filtration rate [eGFR] of 20 or more and under 90 mL/min per 1.73 m 2 and urinary albumin-to-creatinine ratio [UACR] over 50 mg/g) were randomized 1:1:1:1:1 to 26 weeks' treatment with standard of care plus subcutaneous cotadutide uptitrated to 100, 300, or 600 μg, or placebo daily (double-blind), or the GLP-1 agonist semaglutide 1 mg once weekly (open-label).The co-primary endpoints were absolute and percentage change versus placebo in UACR from baseline to the end of week 14. Among 248 randomized patients, mean age 67.1 years, 19% were female, mean eGFR was 55.3 mL/min per 1.73 m 2 , geometric mean was UACR 205.5 mg/g (coefficient of variation 270.0), and 46.8% were receiving concomitant sodium-glucose co-transporter 2 inhibitors. Cotadutide dose-dependently reduced UACR from baseline to the end of week 14, reaching significance at 300 μg (-43.9% [95% confidence interval -54.7 to -30.6]) and 600 μg (-49.9% [-59.3 to -38.4]) versus placebo; with effects sustained at week 26. Serious adverse events were balanced across arms. Safety and tolerability of cotadutide 600 μg were comparable to semaglutide. Thus, our study shows that in patients with T2D and CKD, cotadutide significantly reduced UACR on top of standard of care with an acceptable tolerability profile, suggesting kidney protective benefits that need confirmation in a larger study., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Data regarding effects of small-quantity-lipid-based nutrient supplements (SQ-LNS) on maternal serum zinc concentrations (SZC) in pregnancy and lactation are limited., Objectives: The objectives of this study were to evaluate the effect of preconception compared with prenatal zinc supplementation (compared with control) on maternal SZC and hypozincemia during pregnancy and early lactation in women in low-resource settings, and assess associations with birth anthropometry., Methods: From ∼100 women/arm at each of 3 sites (Guatemala, India, and Pakistan) of the Women First Preconception Maternal Nutrition trial, we compared SZC at 12- and 34-wk gestation (n = 651 and 838, respectively) and 3-mo postpartum (n = 742) in women randomly assigned to daily SQ-LNS containing 15 mg zinc from ≥3 mo before conception (preconception, arm 1), from ∼12 wk gestation through delivery (early pregnancy, arm 2) or not at all (control, arm 3). Birth anthropometry was examined for newborns with ultrasound-determined gestational age. Statistical analyses were performed separately for each time point., Results: At 12-wk gestation and 3-mo postpartum, no statistical differences in mean SZC were observed among arms. At 34-wk, mean SZC for arms 1 and 2 were significantly higher than for arm 3 (50.3, 50.8, 47.8 μg/dL, respectively; P = 0.005). Results were not impacted by correction for inflammation or albumin concentrations. Prevalence of hypozincemia at 12-wk (<56 μg/dL) was 23% in Guatemala, 26% in India, and 65% in Pakistan; at 34 wk (<50 μg/dL), 36% in Guatemala, 48% in India, and 74% in Pakistan; and at 3-mo postpartum (<66 μg/dL) 79% in Guatemala, 91% in India, and 92% in Pakistan. Maternal hypozincemia at 34-wk was associated with lower birth length-for-age Z-scores (all sites P = 0.013, Pakistan P = 0.008) and weight-for-age Z-scores (all sites P = 0.017, Pakistan P = 0.022)., Conclusions: Despite daily zinc supplementation for ≥7 mo, high rates of maternal hypozincemia were observed. The association of hypozincemia with impaired fetal growth suggests widespread zinc deficiency in these settings. This trial is registered at clinicaltrials.gov as #NCT01883193., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: While a growing number of studies examined the effect of e-cigarette (EC) excise taxes on tobacco use behaviors using cross-sectional surveys or sales data, there are currently no studies that evaluate the impact of EC taxes on smoking and vaping transitions., Methods: Using data from the US arm of the 2016-2020 International Tobacco Control Four Country Smoking and Vaping Survey (ITC 4CV), we employed a multinomial logit model with two-way fixed effects to simultaneously estimate the impacts of cigarette/EC taxes on the change in smoking and vaping frequencies., Results: Our benchmark model suggests that a 10 % increase in cigarette taxes led to an 11 % reduction in smoking frequencies (p < 0.01), while EC taxes did not have a significant effect on smoking frequencies., Conclusion: Our findings suggest that increasing cigarette taxes may serve as an effective means of encouraging people who smoke to cut back on smoking or quit smoking. The impact of increasing EC taxes on smoking transitions is less certain at this time., Competing Interests: Declaration of competing interest KMC has served as a paid expert witness in litigation filed against cigarette manufacturers. GTF has served as an expert witness/consultant for governments defending their country's policies/regulations in litigation. All other authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

South Africa has six species of primates, three of which are bushbabies (family Galagidae). Very little information is available on their parasites due to the lack of longitudinal studies, although Rhipicephalus appendiculatus, Amblyomma hebraeum and Haemaphysalis elliptica were previously reported from the brown greater galago (Otolemur crassicaudatus) in South Africa. During 2014-2019, 83 O. crassicaudatus (70 live-trapped and 13 deceased animals) were checked for the presence of hard ticks, all from Limpopo Province, South Africa. Seventy-three of 83 (88 %) galagos were found to be tick-infested. Among ixodid genera, Haemaphysalis had the highest prevalence (46 % of the bushbabies), followed by Rhipicephalus (25 %) and Ixodes (18 %). In total, ten tick species were identified. Importantly, all infestations were monospecific. Ticks occurred on various body parts of bushbabies, thus no predilection site was noted. In conclusion, while previously only three ixodid species were known to infest bushbabies in South Africa, the present study showed that these animals can be parasitized by a much broader range of hard ticks., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Left ventricular ejection fraction (LVEF) measurement in echocardiography (Echo) using the recommended modified biplane Simpson (MBS) method is operator-dependent and exhibits variability. We aimed to assess the accuracy of a novel fully automated (Auto) artificial intelligence (AI) in view selection and biplane LVEF calculation compared to MBS-Echo, with cardiac magnetic resonance imaging (CMR) as reference., Methods: Each of the 301 consecutive patients underwent CMR and Echo on the same day. LVEF was measured independently by Auto-Echo, MBS-Echo and CMR. Interobserver (n = 40) and test-retest (n = 14) analysis followed., Results: A total of 229 patients (76%) underwent complete analysis. Auto-Echo and MBS-Echo showed high correlations with CMR (R = 0.89 and 0.89) and with each other (R = 0.93). Auto underestimated LVEF (bias: 2.2%; limits of agreement [LOA]: -13.5 to 17.9%), while MBS overestimated it (bias: -2.2%; LOA: 18.6 to 14.1%). Despite comparable areas under the curves of Auto- and MBS-Echo (0.93 and 0.92), 46% (n = 70) of MBS-Echo misclassified LVEF by ≥5% units in patients with a reduced CMR-LVEF <51%. Although LVEF bias variability across different LV function ranges was significant (p < 0.001), Auto-Echo was closer to CMR for patients with reduced LVEF, wall motion abnormalities, and poor image quality than MBS-Echo. The interobserver correlation coefficient of Auto-Echo was excellent compared to MBS-Echo (1.00 vs. <0.91) for different readers. True test-retest variability was higher for MBS-Echo than for Auto-Echo (7.9% vs. 2.5%)., Conclusion: The tested AI has the potential to improve the clinical utility of Echo by reducing user-related variability, providing more accurate and reliable results than MBS., Competing Interests: Declaration of Competing Interest The authors report none., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Preoperative non-invasive mapping of motor function with navigated transcranial magnetic stimulation (nTMS) has become a widely used diagnostic procedure. Determination of the patient-individual resting motor threshold (rMT) is of great importance to achieve reliable results when conducting nTMS motor mapping. Factors which contribute to differences in rMT of brain tumor patients have not been fully investigated., Methods: We included adult patients with all types of de novo and recurrent intracranial lesions, suspicious for intra-axial brain tumors. The outcome measure was the rMT of the upper extremity, defined as the stimulation intensity eliciting motor evoked potentials with amplitudes greater than 50µV in 50 % of applied stimulations., Results: Eighty nTMS examinations in 75 patients (37.5 % female) aged 57.9 ± 14.9 years were evaluated. In non-parametric testing, rMT values were higher in patients with upper extremity paresis (p = 0.024) and lower in patients with high grade gliomas (HGG) (p = 0.001). rMT inversely correlated with patient age (r s =-0.28, p = 0.013) and edema volume (r s =-0.28, p = 0.012) In regression analysis, infiltration of the precentral gyrus (p<0.001) increased rMT values. Values of rMT were reduced in high grade gliomas (p<0.001), in patients taking Levetiracetam (p = 0.019) and if perilesional edema infiltrated motor eloquent brain (p<0.001). Subgroup analyses of glioma patients revealed similar results. Values of rMT did not differ between hand and forearm muscles., Conclusion: Most factors confounding rMT in our study were specific to the lesion. These factors contributed to the variability in cortical excitability and must be considered in clinical work with nTMS to achieve reliable results with nTMS motor mapping., Competing Interests: Declaration of Competing Interest n/a., (Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

We investigated motor control strategies utilized by individuals with recurrent low back pain (rLBP) during active pain and remission periods as well as by back-healthy controls using the Balance-Dexterity Task. Nineteen young adults with rLBP were tested first when they were in pain and then again in symptom remission, and 19 matched controls were also tested. Trunk kinematic coupling and muscle co-activation were examined while participants performed the task by standing on one leg while compressing a spring with a maximum consistent force with the other leg. We found a decreased bilateral external oblique co-activation during the spring condition of the task compared to the stable block condition in people with rLBP compared to back healthy individuals. There was also reduced trunk coupling during the spring condition of the task compared to the stable block condition in both the rLBP active and remission groups, but no group difference between rLBP and back-healthy individuals. When individuals were in active pain, they exhibited more co-activation than when they were in remission, but the co-activation during active pain was not greater than in back-healthy individuals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Acetyl-coenzyme A carboxylase (ACCase) inhibition is an attractive herbicide target. However, issues with fetal developmental toxicity identified at the late stages of the development process can halt progression of previously promising candidates., Objectives: To select and verify predictive lipid biomarkers of ACCase inhibition activity in vivo using liver samples obtained from early stage 7 day repeat dose studies in non-pregnant female Han Wistar rats that could be translated to developmental toxicity endpoints discovered during late-stage studies to provide an early screening tool., Methods: Liver samples from eight rat repeat dose studies, exposed to six ACCase inhibitors from three different chemistries and one alternative mode of action (MoA) that also perturbs lipid biochemistry, were analysed using liquid chromatography - high resolution accurate mass - mass spectrometry. Multivariate and univariate data analysis methods were used for biomarker discovery and validation., Results: A biomarker signature consisting of sixteen lipids biomarkers were selected. Verification of the signature as indicative of ACCase inhibition was established by demonstrating consistent perturbations in the biomarkers using two different ACCase inhibitor chemistries and the lack thereof with an alternate MoA. The fold change profile pattern was predictive of which test substance doses would or would not cause developmental toxicity., Conclusion: A strategy for selecting and verifying a robust signature of lipid biomarkers for predicting a toxicological end point has been described and demonstrated. Differences in lipidomic profiles correlated with developmental toxicity suggesting that indicators of a molecular initiation event resulting in pup developmental toxicity can be predicted from short term, toxicity studies conducted in non-pregnant adult female Han Wistar rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Cigarette filter ventilation and light descriptors are associated with lowered perceptions of risk and smoking more cigarettes per day (CPD). This study examined the relationship between usual cigarette ventilation, perception, and CPD., Methods: A crowdsourced sample (N = 995) of individuals who smoke higher-ventilated (=>20% ventilation) or lower-ventilated (=<10% ventilation) cigarettes identified their usual cigarette as "light" or "full flavor", and reported their average CPD., Results: We found: 1) no association between ventilation status and perception of light versus full flavor (AUC=0.58), with the inaccurate perception being more prevalent in younger individuals (p = 0.041) and those who smoke L&M (73%, p < 0.001) and Camel (61%, p = 0.006) brands; and 2) perception, but not ventilation of usual cigarette, was significantly associated with CPD (p = 0.006), with individuals who perceived their cigarettes as light reporting an average of 13% more cigarettes per day (2.6 CPD), compared to those who perceived their cigarette as full flavor., Conclusions: Perceptions of light versus full-flavor, but not ventilation status, predicted CPD. These findings may inform anti-smoking health communication strategies and smoking cessation interventions., Implications: Tobacco control policies should eradicate the perception of cigarettes as light or full-flavored. Future research investigating the associations between cigarette filter ventilation and smoking behavior should consider the confounding effects that may lie in an individual's perceptions of their cigarettes., Competing Interests: Conflict of interest Although the following activities/relationships do not create a conflict of interest pertaining to this manuscript, in the interest of full disclosure, Dr. Bickel would like to report the following: W. K. Bickel is a principal of HealthSim, LLC; BEAM Diagnostics, Inc.; and Red 5 Group, LLC. In addition, he serves on the scientific advisory board for Sober Grid, Inc., and Ria Health, is a consultant for Alkermes, Inc., and works on a project supported by Indivior, Inc. Dr. Tegge would like to report work on a project supported by Indivior, Inc. Dr. Cummings and Dr. Rees serve as a paid expert witnesses in litigation against cigarette manufacturers. The other authors report no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The protease inhibitor inter-α-inhibitor heavy chain H4 (ITIH4) has been described as an acute-phase reactant and could potentially aid in sepsis monitoring and prognostication., Objectives: To investigate ITIH4 plasma levels in sepsis patients compared with healthy controls and to examine the association between ITIH4 and acute-phase response markers, blood coagulation, and organ dysfunction in sepsis., Methods: We performed a post hoc study to a prospective cohort study. Patients with septic shock (n = 39) were enrolled upon intensive care unit admission. ITIH4 was analyzed using an in-house immunoassay. Standard coagulation parameters, thrombin generation, fibrin formation and lysis, C-reactive protein, organ dysfunction markers, Sequential Organ Failure Assessment score, and disseminated intravascular coagulation (DIC) score were registered. ITIH4 levels were also investigated in a murine Escherichia coli sepsis model., Results: ITIH4 did not display acute-phase behavior as mean ITIH4 levels were not increased in patients with septic shock or in E. coli -infected mice. However, ITIH4 exhibited large interindividual variation in patients with septic shock compared with healthy controls. Low ITIH4 was associated with sepsis-related coagulopathy, including a high DIC score (mean ITIH4: DIC, 203 μg/mL vs non-DIC, 267 μg/mL, P  = .01), low antithrombin ( r  = 0.70, P  < .0001) and decreased thrombin generation (mean ITIH4: first peak thrombin tertile, 210 μg/mL vs third peak thrombin tertile, 303 μg/mL, P  = .01). ITIH4 showed moderate correlation with arterial blood lactate (ρ = -0.50, P  < .001) but only weak correlations with C-reactive protein, alanine transaminase, bilirubin, and Sequential Organ Failure Assessment score (all, ρ < 0.26, P > .05)., Conclusion: ITIH4 is associated with sepsis-related coagulopathy but is not an acute-phase reactant during septic shock., (© 2023 The Authors.)

The influence of thermocycling on the surface deterioration of glazed monolithic high translucent 3Y-TZP dental restorations is still unclear. The purpose of this study therefore was to evaluate low temperature degradation (LTD), elemental release and surface degradation pattern after five years of simulated clinical time. A total of 123 specimens were prepared from second-generation high translucent 3Y-TZP as per ISO 6872:2015 standards (3 mm × 4 mm × 30 mm). They were classified as per glazing and thermocycling protocol; group CPT, DGT and IGT. Glaze materials were applied on one surface of the specimen and subjected to a thermocycling in artificial saliva, four-point bending test, inductively coupled plasma mass spectrometry (ICP-MS), scanning electron microscopy (SEM), energy dispersive x-ray spectroscopy (EDX) and x-ray diffraction (XRD). Flexural strength, characteristic strength and Weibull modulus values were derived from four-point bending test. Descriptive fractographic analysis of surfaces was conducted to observe the surface degradation characteristics and point of failure. Control/no glaze with thermocycling (CPT = 621.5, 1σ = 117.0 MPa) presented higher flexural strength values compared to glaze I with thermocycling (442.4, 1σ = 45.4 MPa) and glaze II with thermocycling (534.3, 1σ = 46.3 MPa). Characteristic strength from Weibull analysis also observed higher values (669.2 MPa) for the control specimens. XRD analysis showed that monoclinic volume fraction (V m  = 11.0, 1σ = 0.7%) was highest in control specimens. Fractographic analysis suggested that there was no correlation between the point of failure initiation and mean flexural strength values. Glazing protected the high translucent 3Y-TZP surface against LTD during thermocycling but negatively impacted on the flexural strength., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: The demographic change results in an ever increasing number of older patients with pre-existing medical conditions who require spinal surgery, and recovery is often severely impaired by procedure-related complications. The purpose of this retrospective study was to determine patients at risk of medical and surgical complications., Method: Using our database, we reviewed 1244 patients with lumbar degenerative disk disease, spinal stenosis, and instability, who had undergone surgery at our department between 2009 and 2014. We screened for medical complications (thromboembolic and cardiac events, pneumonia, and sepsis) and surgical complications (hemorrhage, wound infection, and CSF fistula). Furthermore, a matched 1:1 control group consisted of 103 patients without any surgical and medical complications in the randomly selected period of May 2009 to October 2014., Results: 93 patients (46 women, 47 men), mean age 70 years (range 33-86 years, median 67.4 years), with complications were identified (overall morbidity 7.6 %): 22.6 % (n = 26) had medical complications and 77.4 % (n = 89) surgical complications. In 93 patients (46 females, 47 males), mean age 70 years (range 33-86 years, median 67.4 years), a total of 115 complications were noted (overall morbidity of the 93 patients 7.6 %): 22.6 % (n = 26) medical complications and 77.4 % (n = 89) surgical complications. Age and pre-existing conditions were independently associated with medical complications (p &lt; 0.001). Infections (pneumonia and sepsis) were correlated with multi-segmental interventions (p = 0.009), duration of surgery (p = 0.009), and pre-existing conditions (p = 0.014). Surgical complications were significantly correlated with age (p = 0.016) and duration of surgery (p = 0.014) and occurred significantly more often in patients with instability (p &lt; 0.001). Wound healing disorders were associated with coagulopathy (p = 0.013) and transfusion (p &lt; 0.001)., Conclusions: We identified predictors that help identify patients at risk of medical and surgical complications. These correlations should be taken into account when advising older patients with pre-existing conditions on lumbar spine surgery., Competing Interests: Conflict of interest No conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: The relation between respiratory symptoms and the range of tobacco product use among US adolescents/young adults is not yet clear. This cross-sectional analysis examines tobacco product use and respiratory symptoms in a nationally representative sample of 21,057 adolescents/young adults aged 12-24 years from Wave 4 (2016-17) of the Population Assessment of Tobacco and Health Study., Methods: Presence of functionally important respiratory symptoms was defined by questions regarding wheezing and nighttime cough at a cutoff score associated with poorer functional health status. Past-30-day tobacco use was analyzed 2 ways: never-tobacco users (reference) versus combustible users, noncombustible-only users, and former users; or frequency of use of cigarettes and/or e-cigarettes. Weighted Poisson regression adjusted for past-30-day marijuana use, secondhand smoke exposure, and asthma., Results: Functionally important respiratory symptoms were present in 10.0% overall: 13.8% of combustible users, 9.0% of noncombustible users, 8.2% of noncurrent users and 9.7% of never users. Functionally important respiratory symptoms were associated with combustible tobacco use (relative risk [RR] = 1.52[95% CI 1.29, 1.80]), marijuana use (RR = 1.54[1.34, 1.77]) and secondhand smoke exposure (RR = 1.04[1.03, 1.05]). Higher cigarette smoking frequency was also associated with functionally important respiratory symptoms for frequency categories >14 days/month (eg, RR = 1.93[1.50, 2.49] for 15-29 days/month). Frequency of e-cigarette use was not associated with functionally important respiratory symptoms., Conclusions: During 2016-17, smoking cigarettes, marijuana use, and secondhand smoke exposure were cross-sectionally associated with functionally important respiratory symptoms in adolescents/young adults. Risk increased with increased frequency of cigarette use but not e-cigarette use. Given changes to contemporary e-cigarettes and use, findings may not generalize to newer products., (Copyright © 2022 Academic Pediatric Association. All rights reserved.)

Background: The multicountry Women First trial demonstrated that nutritional supplementation initiated prior to conception (arm 1) or early pregnancy (arm 2) and continued until delivery resulted in significantly greater length at birth and 6 mo compared with infants in the control arm (arm 3)., Objectives: We evaluated intervention effects on infants' longitudinal growth trajectory from birth through 24 mo and identified predictors of length status and stunting at 24 mo., Methods: Infants' anthropometry was obtained at 6, 12, 18, and 24 mo after the Women First trial (registered at clinicaltrials.gov as NCT01883193), which was conducted in low-resource settings: Democratic Republic of Congo, Guatemala, India, and Pakistan. Longitudinal models evaluated intervention effects on infants' growth trajectory from birth to 24 mo, with additional modeling used to identify adjusted predictors for growth trajectories and outcomes at 24 mo., Results: Data for 2337 (95% of original live births) infants were evaluated. At 24 mo, stunting rates were 62.8%, 64.8%, and 66.3% for arms 1, 2, and 3, respectively (NS). For the length-for-age z-score (LAZ) trajectory, treatment arm was a significant predictor, with adjusted mean differences of 0.19 SD (95% CI: 0.08, 0.30; P < 0.001) and 0.17 SD (95% CI: 0.07, 0.27; P < 0.001) for arms 1 and 2, respectively. The strongest predictors of LAZ at 24 mo were birth LAZ <-2 and <-1 to ≥-2, with adjusted mean differences of -0.76 SD (95% CI: -0.93, -0.58; P < 0.001) and -0.47 SD (95% CI: -0.56, -0.38; P < 0.001), respectively. For infants with ultrasound-determined gestational age (n = 1329), the strongest predictors of stunting were birth LAZ <-2 and <-1 to ≥- 2: adjusted relative risk of 1.62 (95% CI: 1.39, 1.88; P < 0.001) and 1.46 (95% CI: 1.31, 1.62; P < 0.001), respectively., Conclusions: Substantial improvements in postnatal growth are likely to depend on improved intrauterine growth, especially during early pregnancy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Covalent Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop as the result of a mutation in cysteine 481 of BTK (C481S), which prevents irreversible binding of the drugs. In the present study we performed preclinical characterization of vecabrutinib, a next-generation noncovalent BTK inhibitor that has ITK-inhibitory properties similar to those of ibrutinib. Unlike ibrutinib and other covalent BTK inhibitors, vecabrutinib showed retention of the inhibitory effect on C481S BTK mutants in vitro, similar to that of wild-type BTK. In the murine Eμ-TCL1 adoptive transfer model, vecabrutinib reduced tumor burden and significantly improved survival. Vecabrutinib treatment led to a decrease in CD8+ effector and memory T-cell populations, whereas the naive populations were increased. Of importance, vecabrutinib treatment significantly reduced the frequency of regulatory CD4+ T cells in vivo. Unlike ibrutinib, vecabrutinib treatment showed minimal adverse impact on the activation and proliferation of isolated T cells. Lastly, combination treatment with vecabrutinib and venetoclax augmented treatment efficacy, significantly improved survival, and led to favorable reprogramming of the microenvironment in the murine Eμ-TCL1 model. Thus, noncovalent BTK/ITK inhibitors, such as vecabrutinib, may be efficacious in C481S BTK mutant CLL while preserving the T-cell immunomodulatory function of ibrutinib., (© 2022 by The American Society of Hematology.)

We previously identified an association of rapid engraftment of patient-derived leukemia cells transplanted into NOD/SCID mice with early relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In a search for the cellular and molecular profiles associated with this phenotype, we investigated the expression of microRNAs (miRNAs) in different engraftment phenotypes and patient outcomes. We found high expression of miR-497 and miR-195 (hereafter miR-497/195) in patient-derived xenograft samples with slow engraftment derived from patients with favorable outcome. In contrast, epigenetic repression and low expression of these miRNAs was observed in rapidly engrafting samples associated with early relapse. Overexpression of miR-497/195 in patient-derived leukemia cells suppressed in vivo growth of leukemia and prolonged recipient survival. Conversely, inhibition of miR-497/195 led to increased leukemia cell growth. Key cell cycle regulators were downregulated upon miR-497/195 overexpression, and we identified cyclin-dependent kinase 4 (CDK4)- and cyclin-D3 (CCND3)-mediated control of G1/S transition as a principal mechanism for the suppression of BCP-ALL progression by miR-497/195. The critical role for miR-497/195-mediated cell cycle regulation was underscored by finding (in an additional independent series of patient samples) that high expression of miR-497/195 together with a full sequence for CDKN2A and CDKN2B (CDKN2A/B) was associated with excellent outcome, whereas deletion of CDKN2A/B together with low expression of miR-497/195 was associated with clearly inferior relapse-free survival. These findings point to the cooperative loss of cell cycle regulators as a new prognostic factor indicating possible therapeutic targets for pediatric BCP-ALL., (© 2021 by The American Society of Hematology.)

This article is the authors' contribution to the tribute issue in honour of Geoffrey Burnstock, the founder of this journal and the field of purinergic signalling. We give a brief account of the results of experimental studies which at the beginning received valuable input from Geoff, who both directly and indirectly influenced our research undertaken over the last two decades. Research into the mechanisms controlling breathing identified ATP as the common mediator of the central and peripheral chemosensory transduction. Studies of the sources and mechanisms of chemosensory ATP release in the CNS suggested that this signalling pathway is universally engaged in conditions of increased metabolic demand by brain glial cells - astrocytes. Astrocytes appear to function as versatile CNS metabolic sensors that detect changes in brain tissue pH, CO 2 , oxygen, and cerebral perfusion pressure. Experimental studies on various aspects of astrocyte biology generated data indicating that the function of these omnipresent glial cells and communication between astrocytes and neurons are governed by purinergic signalling, - first discovered by Geoff Burnstock in the 70's and researched through his entire scientific career., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Adequate gestational weight gain (GWG) is essential for healthy fetal growth. However, in low- and middle-income countries, where malnutrition is prevalent, little information is available about GWG and how it might be modified by nutritional status and interventions., Objective: We describe GWG and its associations with fetal growth and birth outcomes. We also examined the extent to which prepregnancy BMI, and preconception and early weight gain modify GWG, and its effects on fetal growth., Methods: This was a secondary analysis of the Women First Trial, including 2331 women within the Democratic Republic of Congo (DRC), Guatemala, India, and Pakistan, evaluating weight gain from enrollment to ∼12 weeks of gestation and GWG velocity (kg/wk) between ∼12 and 32 weeks of gestation. Adequacy of GWG velocity was compared with 2009 Institute of Medicine recommendations, according to maternal BMI. Early weight gain (EWG), GWG velocity, and adequacy of GWG were related to birth outcomes using linear and Poisson models., Results: GWG velocity (mean ± SD) varied by site: 0.22 ± 0.15 kg/wk in DRC, 0.30 ± 0.23 in Pakistan, 0.31 ± 0.14 in Guatemala, and 0.39 ± 0.13 in India, (P <0.0001). An increase of 0.1 kg/wk in maternal GWG was associated with a 0.13 cm (95% CI: 0.07, 0.18, P <0.001) increase in birth length and a 0.032 kg (0.022, 0.042, P <0.001) increase in birth weight. Compared to women with inadequate GWG, women who had adequate GWG delivered newborns with a higher mean length and weight: 47.98 ± 2.04 cm compared with 47.40 ± 2.17 cm (P <0.001) and 2.864 ± 0.425 kg compared with 2.764 ± 0.418 kg (P <0.001). Baseline BMI, EWG, and GWG were all associated with birth length and weight., Conclusions: These results underscore the importance of adequate maternal nutrition both before and during pregnancy as a potentially modifiable factor to improve fetal growth., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Roux-en-Y gastric bypass (RYGBP) is known to reduce zinc absorption; the effects of vertical sleeve gastrectomy (SG) and its long-term implications on zinc absorption have not yet been studied., Objective: The aim was to evaluate the effects of SG and RYGBP on zinc absorption and zinc status in premenopausal women with severe obesity up to 24 mo after surgery., Methods: Twenty-six premenopausal women undergoing SG [BMI (in kg/m2): 37.3 ± 3.2] and 32 undergoing RYGBP (BMI: 42.0 ± 4.2) were studied. A series of anthropometric, dietary, and zinc status parameters (plasma and hair zinc), and the size of the exchangeable zinc pool (EZP), as well as percentage zinc absorption from a standardized dose using a stable isotope methodology were evaluated in the patients before the surgical procedure and at 12 and 24 mo after SG or RYGBP. SG patients received 15 mg and RYGBP received 25 mg of supplemental Zn/d., Results: In premenopausal women, zinc absorption was decreased by 71.9% and 52.0% in SG and RYGBP, respectively, 24 mo postsurgery, compared with initial values. According to 2-factor repeated-measures ANOVA, time effect was significant (P = <0.0001), but not time × group interaction (P = 0.470). Plasma zinc below the cutoff point of 70 µg/dL increased from 0 to 15.4% and 38.1% in SG and RYGBP, respectively. Mean EZP was significantly reduced 24 mo after surgery, although no time × group interactions were observed. Hair zinc did not change across time or between groups., Conclusions: Both SG and RYGBP have profound effects on zinc absorption capacity, which are not compensated for after 24 mo. Although zinc absorption reduction was similar in both types of surgeries, plasma zinc was more affected in RYGBP than SG, despite greater zinc supplementation in RYGBP.This trial was registered at http://www.isrctn.com as ISRCTN31937503., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Preconceptional maternal small-quantity lipid-based nutrient supplementation (SQLNS) improved intrauterine linear growth in low-resource countries as demonstrated by the Women First Preconception Maternal Nutrition Trial (WF). Fetal growth is dependent on nutrient availability and regulated by insulin-like growth factor 1 (IGF-1) through changes in placental transfer capacity, mediated by the mechanistic target of rapamycin (mTOR) pathway., Objectives: Our objective was to evaluate the role of placental mTOR and IGF-1 signaling on fetal growth in women from 2 low-resource countries with high rates of stunting after they received preconceptional SQLNS., Methods: We studied 48 women from preconception through delivery who were from Guatemala and Pakistan and received SQLNS or not, as part of the WF study. Placental samples were obtained at delivery (control, n = 24; SQLNS, n = 24). Placental protein or mRNA expression of eukaryotic translation initiation factor binding protein-1 (4E-BP1), ribosomal protein S6 (rpS6), AMP-activated protein kinase α (AMPKA), IGF-1, insulin-like growth factor receptor (IGF-1R), and pregnancy associated plasma protein (PAPP)-A, and DNA methylation of the IGF1 promoter were determined. Maternal serum IGF-1, insulin-like growth factor binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, PAPP-A, PAPP-A2, and zinc were measured., Results: Mean ± SEM maternal prepregnancy BMI differed between participants in Guatemala (26.5 ± 1.3) and Pakistan (19.8 ± 0.7) (P < 0.001). In Pakistani participants, SQLNS increased the placental rpS6(T37/46):rpS6 ratio (1.5-fold) and decreased the AMPKA(T172):AMPKA ratio. Placental IGF1 mRNA expression was positively correlated with birth length and birth weight z-scores. Placental PAPP-A (30-fold) and maternal serum zinc (1.2-fold) increased with SQLNS. In Guatemalan participants SQLNS did not influence placental mTOR signaling. Placental IGF-1R protein expression was positively associated with birth length and birth weight z-scores. SQLNS increased placental PAPP-A (40-fold) and maternal serum IGFBP-4 (1.6-fold)., Conclusions: In Pakistani pregnant women with poor nutritional status, preconceptional SQLNS activated placental mTOR and IGF-1 signaling and was associated with improved fetal growth. In contrast, in Guatemalan women SQLNS did not activate placental nutrient-sensing pathways. In populations experiencing childhood stunting, preconceptional SQLNS improves placental function and fetal growth only in the context of poor maternal nutrition. This trial was registered at clinicaltrials.gov as NCT01883193., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Oxidative stress and inflammation are central in the pathophysiology of light-chain amyloid cardiomyopathy (AL-CM). High-density lipoprotein cholesterol (HDLC) is an antioxidant and acts as an anti-inflammatory regulator. In this study, the prognostic value of serum HDL-C was explored in AL-CM., Method: In this prospective single-center study, two hundred consecutive patients with biopsy-confirmed light-chain amyloidosis (AL) and cardiac involvement were enrolled. Patients were classified into low or normal serum HDL-C groups (HDL-C < 40 mg/dL and HDL-C ≥ 40 mg/dL, respectively). Univariate and multivariate Cox models were used to identify predictors of survival. Kaplan-Meier analysis was performed to compare survival between patients with low or normal serum HDL-C., Results: Patients with low serum HDL-C were more likely to present with higher levels of cardiac troponin-T (123.4 ng/L vs. 79.1 ng/L, p = 0.026) and higher levels of N-terminal pro-B-type natriuretic peptide (9146 pg/mL vs. 4945 pg/mL, p = 0.011). Patients were followed for a median follow-up period of 19 months, in which 118 (59%) patients died. The median overall survival times for patients with low or normal serum HDL-C were 7 and 16 months, respectively (p = 0.002). Multivariate analysis demonstrated that serum HDL-C (HR 0.984, 95% CI 0.973-0.994, p = 0.003) was independently associated with prognosis, after adjusting for nephrotic syndrome, hepatic involvement, nutritional state, renal function, SBP, DBP, serum uric acid, total cholesterol, Mayo AL 2004 stage, and treatment with chemotherapy., Conclusions: HDL-C is a novel serum biomarker for disease severity and prognosis in light-chain cardiac amyloidosis., Competing Interests: Declaration of Competing Interest Dr. Alexander has served on advisory boards for Alnylam and Eidos. The other authors report no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Use of nicotine vaping products (NVPs) to replace smoking is often influenced by perceived harmfulness of these products relative to smoking. This study aimed to identify factors that conjointly influenced NVP relative harm perception among smokers and ex-smokers., Methods: Data (n = 11,838) from adult smokers and ex-smokers (quit < 2 years) who participated in the 2016 ITC 4 Country Smoking and Vaping Surveys in Australia, Canada, England and the US were analyzed. Decision tree models were used to classify respondents into those who perceived vaping as less harmful than smoking ("correct" perception) versus otherwise ("incorrect" perception) based on their socio-demographic, smoking and vaping related variables., Results: Decision tree analysis identified nicotine replacement therapy (NRT) harmfulness perceptions relative to smoking, perceived vaping portrayal in the media and other sources as positive, negative or balanced, recency of seeking online vaping information, and age as the key variables that interacted conjointly to classify respondents into those with "correct" versus "incorrect" harm perceptions of vaping relative to smoking (model performance accuracy = 0.70-0.74). In all countries, NRT relative harmfulness perception and vaping portrayal perception were consistently the two most important classifying variables, with other variables showing some country differences., Conclusions: In all four countries, perception of NVP relative harmfulness among smokers and recent ex-smokers is strongly influenced by a combination of NRT relative harmfulness perception and vaping portrayal in the media and other sources. These conjoint factors can serve as useful markers for identifying subgroups more vulnerable to misperception about NVP relative harmfulness to benefit from corrective intervention., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Spinal schwannoma (SS) is the most frequently diagnosed benign spinal tumor, constituting approximately 25 % of all intradural tumors. Aim of our study was to identify factors that potentially affect immediate postoperative neurological outcome, and the rate of functional recovery within 12 months., Methods: Screening of our institutional database yielded 90 consecutive patients (mean age 57.1 years, 39 women [43.3 %]) with newly diagnosed SS between March 1997 and October 2018. We pre- and postoperatively reviewed patient charts, surgical reports, radiographic data, use of IOM, duration of symptoms, histopathology, co-morbidities, radiographic extension, surgical strategy, neurological performance (Japanese Orthopedic Association Score [JOA score] and Frankel Grade Classification)., Results: Mean duration of preoperative symptoms was 3.6 ± 1.6 months. Most common symptoms were local pain (n = 77, 85.6 %). Macroscopic complete resection was achieved in 84 patients (93.3 %). During follow-up, complete recovery from local pain was documented for 41 patients (59.7 %), from radiating pain for 41 (69.5 %; p < 0.001). Postoperatively, 25 (27.7 %) patients developed a new neurological deficit (motor deficits n = 3 and sensory deficits n = 23; one patient developed both); after 12 months, however, motor deficits had abated in all patients, and 16 (69.5 %) patients had completely recovered from sensory deficits. Use of intraoperative monitoring (IOM) was a significant predictor for good functional outcome (p < 0.001)., Conclusion: Resection of SS accompanied by IOM whenever feasible should be advocated. We achieved a high number of complete resections with a low rate of morbidity. New postoperative motor or sensory deficits had a very high rate of complete recovery within 12 months., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Building on published work 1 establishing concurrent validity of a self-report tobacco dependence (TD) index among users of different tobacco products in Wave 1 (W1) of the Population Assessment of Tobacco and Health (PATH) Study, the current study examines prospective relationships with tobacco use behaviors to establish predictive validity of the TD index. Hypotheses suggested high levels of W1 TD would be associated with persistent tobacco use at Wave 2 (W2)., Participants: A U.S. nationally representative sample of 32,320 adult W1 and W2 interviews focused on 11,615 W1 adults who were current established tobacco users and completed the W2 interview., Findings: Higher TD scores and greater changes in TD scores were associated with greater quantity and frequency of tobacco use at the W2 interview for Cigarette Only (n = 7068), Smokeless (smokeless or snus pouches) Only (n = 772), Cigarette plus E-Cigarette (n = 592), and Multiple Products (n = 1866) users, although not significantly so for E-Cigarette Only (n = 367), Cigar Only (traditional, cigarillo, or filtered) (n = 584), or Hookah Only (n = 366) users. Higher TD was associated with decreased odds of successful quitting for Cigarette and Multiple Product users. Higher TD was associated with increased odds of a quit attempt for those in the Hookah and Multiple Products user groups and was not associated with quit attempts or deceased odds of quit success among exclusive E-Cigarette, Cigar, Smokeless and Cigarette plus E-Cigarette users., Conclusion: Support for the predictive validity of the PATH Study measures of adult TD will enable regulatory investigations of TD across several tobacco products., Competing Interests: Declaration of Competing Interest Dr. Cummings has served on a 1-time advisory committee for Pfizer to help them find ways to promote smoking cessation in health care settings and continues to serve as an expert witness on behalf of plaintiffs in litigation against cigarette companies. Dr. Cummings has no other financial links whatsoever to a cigarette company, or other tobacco manufacturer. All other authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Although evidence shows that co-use of cigarettes and cannabis is common, there is little research examining if co-use patterns vary depending on the regulatory environment for cannabis. This study examined patterns of co-use and perceptions of relative harm among cigarette smokers in four countries with different histories, and at different stages of cannabis legalization., Methods: Data are from the 2018 International Tobacco Control 4CV Survey and included 10035 adult cigarette smokers from Canada, United States (US), Australia, and England. At the time of the survey, Canada and the US had relatively more permissive cannabis regulations compared to Australia and England., Results: Among this sample of 10035 cigarette smokers, Canada had the highest rate of cannabis co-use in the last 12 months (36.3%), followed by the US (29.1%), England (21.6%), and Australia (21.4%). Among past 12 month co-users (n = 3134), the US (40.2%) and Canada (35.2%) had the highest rates of daily cannabis use, followed by smokers in England (26.3%) and Australia (21.7%); Australian co-users had the highest rate of infrequent (

Background: Our study evaluated the short-term impact of introducing European Union's tobacco pictorial health warnings (PHWs)., Methods: Longitudinal data were collected at two time-points from adult smokers, participating in the International Tobacco Control (ITC) surveys, conducted in the Netherlands, Australia, Canada, the United Kingdom and the United States. In the Netherlands, textual health warnings (THWs) were replaced by PHWs between both time-points. Health warning policies did not change in the other countries. Data from continuing smokers were used (N = 3,487) and analyzed using Generalized Estimating Equations., Results: Between both time-points, only Dutch smokers showed increases in noticing health warnings (β = 0.712, p < 0.001), self-reports of health warnings leading to a cognitive response such as thinking about smoking health-risks (SHRs) (OR = 1.834, p < 0.001), knowledge about SHRs (β = 0.369, p < 0.001), and avoiding health warnings (OR = 9.869, p < 0.001). However, Dutch smokers showed no changes in attitude towards smoking (β = 0.035, p = 0.518), intention to quit smoking (OR = 0.791, p = 0.157), self-efficacy to quit smoking (β=-0.072, p = 0.286), or reporting that health warnings helped them to resist having a cigarette (OR = 1.091, p = 0.714)., Conclusions: Results suggest that introducing the European PHWs was effective in provoking changes closely related to health warnings, but there was no direct impact on variables more closely related to smoking cessation., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Coordination of the trunk and hips is crucial for successful dynamic balance in many activities of daily living. Persons with recurrent low back pain (rLBP), both while symptomatic and during periods of symptom remission, exhibit dysfunctional muscle activation patterns and coordination of these joints. In a novel dynamic balance task where persons in remission from rLBP exhibit dissociated trunk motion, it is unknown how trunk and hip musculature are coordinated. Activation of hip and trunk muscles were acquired from nineteen persons with and without rLBP during the Balance-Dexterity Task, which involves balancing on one limb while compressing an unstable spring with the other. There were no between-group differences in activation amplitude for any muscle groups tested. In back-healthy control participants, hip and trunk muscle activation amplitudes increased proportionally in response to the added instability of the spring (R = 0.837, p < 0.001). Increases in muscle activation amplitudes in the group in remission from rLBP were not proportional (R = 0.113, p = 0.655). Instead, hip muscle activation in this group was associated with task performance, i.e. dexterous control of the spring (R = 0.676, p = 0.002). These findings highlight atypical coordination of hip and trunk musculature potentially related to task demands in persons with rLBP even during remission from pain., Competing Interests: Declaration of Competing Interests The authors have no conflict of interests to disclose., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Study Objective: Postoperative delirium (POD) is a common neurological system disorder in surgical patients. Anesthesia providers have a wide choice of sedative agents involving different mechanisms in clinical practice, and the incidence of POD varies regarding which sedative agent administered. This network meta-analysis aimed to comprehensively analyze the safety and efficacy of each choice for patients., Design: A network meta-analysis., Setting: Vanderbilt University Medical Center., Measurements: We searched PubMed, EMBASE, Ovid Medline and Cochrane Central Register of Controlled Trials (CENTRAL) through the end of September 2018 with the registration number CRD42018110585. The randomized controlled trials were identified and extracted by two reviewers independently. Commonly used sedative agents such as placebo, sevoflurane, desflurane, isoflurane, dexmedetomidine, propofol, midazolam, and ketamine were assessed in this network meta-analysis and the primary outcome was the incidence of POD. The data were synthesized by network meta-analysis. Pair-wise meta-analyses were conducted using the random-effects model. Each intervention was ranked according to its corresponding surface under the cumulative ranking curve (SUCRA) values. The GRADE framework was undertaken to evaluate the risk of bias., Main Results: We identified 39 RCTs and 5991 patients in this meta-analysis. Dexmedetomidine was found to be the most effective option in reducing POD, compared to midazolam, propofol, desflurane, and sevoflurane. The results revealed that dexmedetomidine was associated with a lower incidence of POD, whereas midazolam was associated with a significantly higher number of patients with delirium. Midazolam and propofol were also associated with a higher incidence of perioperative hypotension and bradycardia., Conclusion: Our study provided meta-analytic evidence and suggested dexmedetomidine could be considered as the most effective sedative agent to reduce POD. However, clinical practitioners still need to weigh the pros and cons before choosing a sedative agent for individual patient., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Anomalous aortic origin of the right coronary artery from the left aortic sinus is a rare congenital anomaly that is generally repaired during adolescence when the condition is associated with symptoms. It is rarely diagnosed in infancy. Similarly, a quadricuspid pulmonary valve is also a rare finding, and there are scant data to evaluate whether this malformation of the pulmonary valve is suitable to be used for a Ross operation. This report describes a case in which both these anomalies coexisted in an infant who underwent a successful Ross-Konno operation., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Human exposure to mercury leads to a variety of pathologies involving numerous organ systems including the immune system. A paucity of epidemiological studies and suitable diagnostic criteria, however, has hampered collection of sufficient data to support a causative role for mercury in autoimmune diseases. Nevertheless, there is evidence that mercury exposure in humans is linked to markers of inflammation and autoimmunity. This is supported by experimental animal model studies, which convincingly demonstrate the biological plausibility of mercury as a factor in the pathogenesis of autoimmune disease., Scope of the Review: In this review, we focus on ability of mercury to elicit inflammatory and autoimmune responses in both humans and experimental animal models., Major Conclusions: Although subtle differences exist, the inflammatory and autoimmune responses elicited by mercury exposure in humans and experimental animal models show many similarities. Proinflammatory cytokine expression, lymphoproliferation, autoantibody production, and nephropathy are common outcomes. Animal studies have revealed significant strain dependent differences in inflammation and autoimmunity suggesting genetic regulation. This has been confirmed by the requirement for individual genes as well as genome wide association studies. Importantly, many of the genes required for mercury-induced inflammation and autoimmunity are also required for idiopathic systemic autoimmunity. A notable difference is that mercury-induced autoimmunity does not require type I IFN. This observation suggests that mercury-induced autoimmunity may arise by both common and specific pathways, thereby raising the possibility of devising criteria for environmentally associated autoimmunity., General Significance: Mercury exposure likely contributes to the pathogenesis of autoimmunity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Glioblastoma multiforme (GBM) is the most common primary brain tumor and has a high recurrence rate. Maximizing the extent of resection (EOR) in recurrent GBM has proved to be the cornerstone of neurosurgical retreatment. The development of surgical microscopes fitted with fluorescein-specific filters has facilitated fluorescein-guided microsurgery and the identification of tumor tissue. Use of fluorescein sodium (FL) in primary high-grade glioma resection has shown promising results. Here, we present our experience with FL and the dedicated surgical microscope filter YELLOW 560 nm in 106 patients with recurrent GBM., Methods: A total of 106 patients with recurrent GBM were included (53 women, 53 men; mean age, 53 years). A total of 5 mg/kg bodyweight of FL was intravenously injected approximately 45 minutes before craniotomy. A YELLOW 560 nm filter (PENTERO 900 [Carl Zeiss Meditec, Oberkochen Germany]) was used for microsurgical tumor resection and resection control. Surgical reports were reviewed regarding the degree of fluorescent staining. Postoperative magnetic resonance images were examined within 48 hours after surgery regarding the EOR and postoperative course regarding neurologic outcome, complications, and any adverse events., Results: Bright fluorescent staining was present in all patients, which markedly enhanced tumor visibility and was deemed helpful for tumor resection. Seventeen patients (16%) showed residual tumor tissue on postoperative magnetic resonance imaging (MRI). Therefore, gross total resection was achieved in 89 patients (84%). No adverse events were registered postoperatively., Conclusions: FL and YELLOW 560 nm are readily available methods for fluorescence-guided tumor resection, similar to contrast enhancement in T1-weighted MRI. FL may improve resection in recurrent GBM with minimal risk, and tumor margins are clearly visualized. FL and the YELLOW 560 nm filter are safe and feasible tools for safe maximal resection of recurrent glioblastoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Reported benefits of maternal nutrition supplements commenced during pregnancy in low-resource populations have typically been quite limited., Objectives: This study tested the effects on newborn size, especially length, of commencing nutrition supplements for women in low-resource populations ≥3 mo before conception (Arm 1), compared with the same supplement commenced late in the first trimester of pregnancy (Arm 2) or not at all (control Arm 3)., Methods: Women First was a 3-arm individualized randomized controlled trial (RCT). The intervention was a lipid-based micronutrient supplement; a protein-energy supplement was also provided if maternal body mass index (kg/m2) was <20 or gestational weight gain was less than recommendations. Study sites were in rural locations of the Democratic Republic of the Congo (DRC), Guatemala, India, and Pakistan. The primary outcome was length-for-age z score (LAZ), with all anthropometry obtained <48 h post delivery. Because gestational ages were unavailable in DRC, outcomes were determined for all 4 sites from WHO newborn standards (non-gestational-age-adjusted, NGAA) as well as INTERGROWTH-21st fetal standards (3 sites, gestational age-adjusted, GAA)., Results: A total of 7387 nonpregnant women were randomly assigned, yielding 2451 births with NGAA primary outcomes and 1465 with GAA outcomes. Mean LAZ and other outcomes did not differ between Arm 1 and Arm 2 using either NGAA or GAA. Mean LAZ (NGAA) for Arm 1 was greater than for Arm 3 (effect size: +0.19; 95% CI: 0.08, 0.30, P = 0.0008). For GAA outcomes, rates of stunting and small-for-gestational-age were lower in Arm 1 than in Arm 3 (RR: 0.69; 95% CI: 0.49, 0.98, P = 0.0361 and RR: 0.78; 95% CI: 0.70, 0.88, P < 0.001, respectively). Rates of preterm birth did not differ among arms., Conclusions: In low-resource populations, benefits on fetal growth-related birth outcomes were derived from nutrition supplements commenced before conception or late in the first trimester. This trial was registered at clinicaltrials.gov as NCT01883193.

Objective: To examine whether mental health problems predict incident use of 12 different tobacco products in a nationally representative sample of youth and young adults., Method: This study analyzed Wave (W) 1 and W2 data from 10,533 12- to 24-year-old W1 never tobacco users in the Population Assessment of Tobacco and Health (PATH) Study. Self-reported lifetime internalizing and externalizing symptoms were assessed at W1. Past 12-month use of cigarettes, electronic nicotine delivery systems (ENDS), traditional cigars, cigarillos, filtered cigars, pipe, hookah, snus pouches, other smokeless tobacco, bidis and kreteks (youth only), and dissolvable tobacco was assessed at W2., Results: In multivariable regression analyses, high-severity W1 internalizing (adjusted odds ratio [AOR] = 1.5, 95% CI = 1.3-1.8) and externalizing (AOR = 1.3, 95% CI = 1.1-1.5) problems predicted W2 onset of any tobacco use compared to no/low/moderate severity. High-severity W1 internalizing problems predicted W2 use onset across most tobacco products. High-severity W1 externalizing problems predicted onset of any tobacco (AOR = 1.6, 95% CI = 1.3-1.8), cigarettes (AOR = 1.4, 95% CI = 1.0-2.0), ENDS (AOR = 1.8, 95% CI = 1.5-2.1), and cigarillos (AOR = 1.5, 95% CI = 1.0-2.1) among youth only., Conclusion: Internalizing and externalizing problems predicted onset of any tobacco use. However, findings differed for internalizing and externalizing problems across tobacco products, and by age, gender, and race/ethnicity. In addition to screening for tobacco product use, health care providers should screen for a range of mental health problems as a predictor of tobacco use. Interventions addressing mental health problems may prevent youth from initiating tobacco use., (Copyright © 2018 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

Background: Cigarette smokers show greater delay discounting (devaluation of delayed consequences) than non-smokers, suggesting that rapid devaluation of the future contributes to tobacco use through a mechanism in which tobacco-related health consequences are too delayed to discourage smoking. However, little work has quantified delay discounting in relation to electronic cigarette (EC) use, a tobacco product that many users believe to pose fewer negative health consequences than cigarettes., Methods: We assessed discounting of delayed monetary rewards in a web-based sample of 976 participants, stratified by both EC use (current and never) and cigarette use (current, former, and never)., Results: Controlling for demographic variance, current EC users generally showed greater discounting than never EC users (p = .019). Current cigarette smokers also showed greater discounting than former and never smokers (p < .001). However, the between-group difference for EC use was much smaller (η p 2  = .006) than for cigarette use (η p 2  = .026). Moreover, differences in discounting in relation to EC use were not statistically apparent in most pairwise comparisons. Most notably, the difference between former smokers who achieved smoking cessation by transitioning to ECs (i.e., exclusive EC users) and those who have never used ECs or cigarettes was nonsignificant and small (η p 2  = .010)., Conclusions: The smaller effect size for the association between delay discounting and current EC use, relative to current cigarette use, suggests that public perception of ECs as a safer alternative to cigarettes attenuates the role of delay discounting in decisions to use ECs., (Copyright © 2018. Published by Elsevier B.V.)

Background: While evidence suggests bidirectional associations between cigarette use and substance (alcohol or drug) use, how these associations are reflected across the range of currently available tobacco products is unknown. This study examined whether ever tobacco use predicted subsequent substance use, and ever substance use predicted subsequent tobacco use among 11,996 U.S. youth (12-17 years) from Waves 1 (2013-2014) and 2 (2014-2015) of the Population Assessment of Tobacco and Health (PATH) Study., Methods: Ever use of cigarettes, e-cigarettes, traditional cigars, cigarillos, filtered cigars, pipe, hookah, snus pouches, smokeless tobacco excluding snus pouches, dissolvable tobacco, bidis, kreteks, alcohol, marijuana, prescription drugs, and other drugs (cocaine and other stimulants, heroin, inhalants, solvents, and hallucinogens) was assessed at Wave 1 followed by past 12-month use assessments at Wave 2. The analyses included covariates (demographics, mental health, sensation seeking, prior use) to mitigate confounding., Results: Ever tobacco use predicted subsequent substance use. The magnitude of the associations was lowest for alcohol, higher for marijuana, and highest for other drugs. Ever substance use also predicted subsequent tobacco use. Specifically, ever alcohol, marijuana, and non-prescribed Ritalin/Adderall use predicted tobacco-product use. Ever e-cigarette and cigarette use exclusively and concurrently predicted subsequent any drug (including and excluding alcohol) use. E-cigarette and cigarette use associations in the opposite direction were also significant; the strongest associations were observed for exclusive cigarette use., Conclusion: Tobacco and substance use prevention efforts may benefit from comprehensive screening and interventions across tobacco products, alcohol, and drugs, and targeting risk factors shared across substances., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: We report on five patients with gadolinium-negative (non-enhancing magnetic resonance imaging-MRI) but 18 F-fluoroethyl tyrosine positron-emission tomography (FET-PET) positive glioma (NEG) undergoing surgery under fluorescence-guidance with fluorescein sodium 10% (FL, Alkon, Germany) in combination with a dedicated light filter (YELLOW 560 nm, Carl Zeiss Meditec, Germany)., Patients and Method: Since 2017, five patients (3 female, 2 male; mean age 45.4 years) underwent fluorescence-guided surgery for supratentorial, intracerebral lesions which showed no contrast-enhancement in the preoperative MRI but were, however, strongly suspicious for gliomas. Accordingly, all patients received a preoperative FET-PET scan and detailed histopathological workup was performed. After giving written informed consent, all patients received 5 mg/kg of FL at the induction of anesthesia. Surgery was conducted under white light and under the YELLOW 560 nm filter. We reviewed the surgical protocols, navigational storage and the image databases of our surgical microscopes for evidence of intraoperative fluorescence that corresponded to the FET-PET positive area., Results: In all patients we found distinct accordances between the FET-PET positive areas and the fluorescing regions within the targeted lesions. Histopathological workup of the fluorescent tissue revealed anaplastic oligodendroglioma, IDH-mutant and 1p/19-codeleted (WHO grade III) (n = 2), anaplastic astrocytoma, IDH-mutant (WHO grade III) (n = 1), oligodendroglioma, IDH-mutant and 1p/19q-codeleted (WHO grade II) (n = 1) and pilocytic astrocytoma (WHO grade I) (n = 1). No adverse events were noted., Discussion and Conclusion: Despite the lack of gadolinium-enhancement in the preoperative MRI, all patients intravenously received FL to guide resection. Irrespective of the final grading, FL was extremely helpful in detecting the lesions and in identifying their border zones. In selected patients with NEG, but strong metabolic activity according to the FET-PET, FL may significantly increase the accuracy of surgery., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau ( VHL ) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E1' in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E1' in addition to a mutation in VHL coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, we show that the mutations induced a dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in VHL exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway., (© 2018 by The American Society of Hematology.)

Objective: To estimate non-invasively the amount, recruitment pattern and discharge frequency of spinal motor neurons (MN) at contraction strength >20% of maximal voluntary contraction (MVC) of small hand muscles., Methods: A peripheral collision technique was used and consisted of supramaximal electrical stimuli at Erb's point and at the wrist, synchronizing descending volleys of action potential during voluntary isometric contractions of the abductor digiti minimi muscle at 20-80% of MVC strength and 1-8 s of contraction duration. Responses of 13 healthy volunteers were quantified and analysed using a recently described model of MN behaviour., Results: A linear relationship between MN discharge and force generation was noticed with R2 = 0.996, and was confirmed using the simulation results (R2 = 0.997) for contraction durations up to 8 s. For each investigated force level, discharge frequency and recruitment pattern were calculated for individual MN., Conclusions: Using this method, MN discharge properties during voluntary activity can be estimated non-invasively., Significance: This method provides new opportunities for the non-invasive study of MN behaviour, and could be expanded to patients with conduction failure and during fatigue., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The FOXO1 transcription factor plays an essential role in the regulation of proliferation and survival programs at early stages of B-cell differentiation. Here, we show that tightly regulated FOXO1 activity is essential for maintenance of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Genetic and pharmacological inactivation of FOXO1 in BCP-ALL cell lines produced a strong antileukemic effect associated with CCND3 downregulation. Moreover, we demonstrated that CCND3 expression is critical for BCP-ALL survival and that overexpression of CCND3 protected BCP-ALL cell lines from growth arrest and apoptosis induced by FOXO1 inactivation. Most importantly, pharmacological inhibition of FOXO1 showed antileukemia activity on several primary, patient-derived, pediatric ALL xenografts with effective leukemia reduction in the hematopoietic, lymphoid, and central nervous system organ compartments, ultimately leading to prolonged survival without leukemia reoccurrence in a preclinical in vivo model of BCP-ALL. These results suggest that repression of FOXO1 might be a feasible approach for the treatment of BCP-ALL., (© 2018 by The American Society of Hematology.)

The cannabis plant and its derivatives have been exploited for centuries for recreational and medicinal purposes, with millions of regular users around the world. The recreational use of cannabis is reflective of its neuropsychiatric effects, such as anxiolysis and euphoria. However, cannabis appears to have an emerging therapeutic role, especially in chronic disease and as an adjunct to cancer treatment. Increasing evidence supports cannabis in the management of chemotherapy-induced nausea and vomiting (CINV) and for pain management; however, studies are limited, particularly by difficulties associated with standardized dosing estimates and inability to accurately assess biologic activities of compounds in cannabis and derivative products. Smoking cannabis has not been proved to be a risk factor in the development of lung cancer, but the data are limited by small studies, misclassification due to self-reporting of use, small numbers of heavy cannabis smokers, and confounding of the risk associated with known causative agents for lung cancer (such as parallel chronic tobacco use). Cannabis and its biologically effective derivatives warrant additional research, ideally, controlled trials in which the cannabidiol and the delta-9-tetrahydrocabinol strength and use are controlled and documented., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

There are not any records on the detection of Toxoplasma gondii and Neospora caninum in tissues of wild birds in the African continent. The aim of the study was to investigate the occurrence of DNA from these protozoan parasites in brain tissue samples collected in years 2014-2015 from 110 wild and domestic birds of 15 orders. Birds came mainly from the province of Limpopo (n=103); the other seven birds came from other five provinces of South Africa. Parasite DNAs were detected by PCR in animal brains. While all samples were negative for N. caninum, T. gondii DNA was detected in three (2.7%) birds: a Red-eyed Dove (Streptopelia semitorquata), a Laughing Dove (S. senegalensis) and a Southern-Yellow-billed Hornbill (Tockus leucomelas), all from Limpopo province. Positive samples were selected for genotyping by a 15 microsatellite markers method in a single multiplex PCR assay. Only the sample from the Red-eyed Dove was successfully genotyped and characterized as type II. This is the first detection of T. gondii in tissue of native African wild birds and the first study focusing on N. caninum in birds from South Africa., (Copyright © 2017. Published by Elsevier B.V.)