Do we need high temporal resolution modelling of exposure in urban areas? A test case.

Roadside concentrations of harmful pollutants such as NOx are highly variable in both space and time. This is rarely considered when assessing pedestrian and cyclist exposures. We aim to fully describe the spatio-temporal variability of exposures of pedestrians and cyclists travelling along a road at high resolution. We evaluate the value added of high spatio-temporal resolution compared to high spatial resolution only. We also compare high resolution vehicle emissions modelling to using a constant volume source. We highlight conditions of peak exposures, and discuss implications for health impact assessments. Using the large eddy simulation code Fluidity we simulate NOx concentrations at a resolution of 2 m and 1 s along a 350 m road segment in a complex real-world street geometry including an intersection and bus stops. We then simulate pedestrian and cyclist journeys for different routes and departure times. For the high spatio-temporal method, the standard deviation in 1 s concentration experienced by pedestrians (50.9 µg.m-3) is nearly three times greater than that predicted by the high-spatial only (17.5 µg.m-3) or constant volume source (17.6 µg.m-3) methods. This exposure is characterised by low concentrations punctuated by short duration, peak exposures which elevate the mean exposure and are not captured by the other two methods. We also find that the mean exposure of cyclists on the road (31.8 µg.m-3) is significantly greater than that of cyclists on a roadside path (25.6 µg.m-3) and that of pedestrians on a sidewalk (17.6 µg.m-3). We conclude that ignoring high resolution temporal air pollution variability experienced at the breathing time scale can lead to a mischaracterization of pedestrian and cyclist exposures, and therefore also potentially the harm caused. High resolution methods reveal that peaks, and hence mean exposures, can be meaningfully reduced by avoiding hyper-local hotspots such as bus stops and junctions.

Reconstruction of the Corticospinal Tract in Patients with Motor-Eloquent High-Grade Gliomas Using Multilevel Fiber Tractography Combined with Functional Motor Cortex Mapping.

BACKGROUND AND PURPOSE: Tractography of the corticospinal tract is paramount to presurgical planning and guidance of intraoperative resection in patients with motor-eloquent gliomas. It is well-known that DTI-based tractography as the most frequently used technique has relevant shortcomings, particularly for resolving complex fiber architecture. The purpose of this study was to evaluate multilevel fiber tractography combined with functional motor cortex mapping in comparison with conventional deterministic tractography algorithms. MATERIALS AND METHODS: Thirty-one patients (mean age, 61.5 [SD, 12.2] years) with motor-eloquent high-grade gliomas underwent MR imaging with DWI (TR/TE = 5000/78 ms, voxel size = 2 × 2 × 2 mm3, 1 volume at b = 0 s/mm2, 32 volumes at b = 1000 s/mm2). DTI, constrained spherical deconvolution, and multilevel fiber tractography-based reconstruction of the corticospinal tract within the tumor-affected hemispheres were performed. The functional motor cortex was enclosed by navigated transcranial magnetic stimulation motor mapping before tumor resection and used for seeding. A range of angular deviation and fractional anisotropy thresholds (for DTI) was tested. RESULTS: For all investigated thresholds, multilevel fiber tractography achieved the highest mean coverage of the motor maps (eg, angular threshold = 60°; multilevel/constrained spherical deconvolution/DTI, 25% anisotropy threshold = 71.8%, 22.6%, and 11.7%) and the most extensive corticospinal tract reconstructions (eg, angular threshold = 60°; multilevel/constrained spherical deconvolution/DTI, 25% anisotropy threshold = 26,485 mm3, 6308 mm3, and 4270 mm3). CONCLUSIONS: Multilevel fiber tractography may improve the coverage of the motor cortex by corticospinal tract fibers compared with conventional deterministic algorithms. Thus, it could provide a more detailed and complete visualization of corticospinal tract architecture, particularly by visualizing fiber trajectories with acute angles that might be of high relevance in patients with gliomas and distorted anatomy.

Spasticity-related pain in children/adolescents with cerebral palsy. Part 2: IncobotulinumtoxinA efficacy results from a pooled analysis.

PURPOSE: This pooled analysis of data from three Phase 3 studies investigated the effects of incobotulinumtoxinA on spasticity-related pain (SRP) in children/adolescents with uni-/bilateral cerebral palsy (CP). METHODS: Children/adolescents (ambulant and non-ambulant) were evaluated for SRP on increasingly difficult activities/tasks 4 weeks after each of four incobotulinumtoxinA injection cycles (ICs) using the Questionnaire on Pain caused by Spasticity (QPS; six modules specific to lower limb [LL] or upper limb [UL] spasticity and respondent type [child/adolescent, interviewer, or parent/caregiver]). IncobotulinumtoxinA doses were personalized, with all doses pooled for analysis. RESULTS: QPS key item responses were available from 331 and 155 children/adolescents with LL- and UL-spasticity, respectively, and 841/444 (LL/UL) of their parents/caregivers. IncobotulinumtoxinA efficacy was evident with the first IC. Efficacy was sustained and became more robust with further subsequent ICs. By Week 4 of the last (i.e. fourth) IC, 33.8-53.3% of children/adolescents reported complete SRP relief from their baseline pain for respective QPS items. Children/adolescents reported reductions in mean LL SRP intensity at levels that surpassed clinically meaningful thresholds. Similarly, parents/caregivers observed complete SRP relief and less frequent SRP with incobotulinumtoxinA. Similar results were found for UL SRP. CONCLUSION: These findings indicate that incobotulinumtoxinA could bring considerable benefit to children/adolescents with spasticity by reducing SRP, even during strenuous activities.

Botulinum neurotoxin type A in the interdisciplinary treatment of sialorrhea in adults and children-update and practice recommendations.

Sialorrhea is defined as a chronic excessive flow of saliva from the mouth, often with adverse consequences for health and quality of life of patients. In addition to currently used non-drug treatment and systemic drugs, intraglandular Botulinum Neurotoxin A (BoNT/A) injections have been examined in case studies, controlled trials and clinical practice. Two pivotal Phase III trials recently led to market approval in the USA and EU for IncobotulinumtoxinA [Xeomin®, IncoBoNT/A, Clostridium botulinum neurotoxin type A (150 kD), free from complexing proteins, Merz Pharmaceuticals GmbH] for treatment of chronic sialorrhea in adults and pediatric patients. This review provides a multidisciplinary approach to discuss the current state of sialorrhea therapy as well as benefits and current limitations of BoNT/A injections. A consensus regarding treatment recommendations made available to physicians in Germany in 2022 has now been updated here for presentation to an international audience. This review provides a framework including a flow chart for patient selection, recommendations for dosing and the injection process, as well as a discussion of therapeutic goals, long-term benefits and safety aspects. This review is aimed at supporting physicians in developing multidisciplinary and individualized treatment approaches to achieve optimal benefits for patients.

Safety Profile and Lack of Immunogenicity of IncobotulinumtoxinA in Pediatric Spasticity and Sialorrhea: A Pooled Analysis.

IncobotulinumtoxinA, a pure botulinumtoxinA formulation, is free of accessory proteins. This analysis provides pooled safety data from phase 3 trials of children/adolescents (2-17 years), investigating incobotulinumtoxinA for the treatment of spasticity associated with cerebral palsy (at doses ≤20 U/kg (max. 500 U) per injection cycle (IC) for ≤6 ICs; three trials) or sialorrhea associated with neurologic disorders (at total doses of 20-75 U per IC for ≤4 ICs; one trial) for ≤96 weeks. Safety endpoints included the incidences of different types of treatment-emergent adverse events (TEAEs) and immunogenicity. IncobotulinumtoxinA dose groups were combined. Of 1159 patients (mean age 7.3 years, 60.4% males) treated with incobotulinumtoxinA, 3.9% experienced treatment-related TEAEs, with the most common being injection site reactions (1.3%) (both indications), muscular weakness (0.7%) (spasticity), and dysphagia (0.2%) (sialorrhea). Two patients (0.2%) experienced a treatment-related treatment-emergent serious adverse event, and 0.3% discontinued the study due to treatment-related TEAEs. No botulinumtoxinA-naïve patients developed neutralizing antibodies (NAbs) after incobotulinumtoxinA. All children/adolescents with known pre-treatment status and testing positive for Nabs at final visit (n = 7) were previously treated with a botulinumtoxinA other than incobotulinumtoxinA. IncobotulinumtoxinA was shown to be safe, with very few treatment-related TEAEs in a large, diverse cohort of children/adolescents with chronic conditions requiring long-term treatment and was without new NAb formation in treatment-naïve patients.

Spasticity-related pain in children/adolescents with cerebral palsy. Part 1: Prevalence and clinical characteristics from a pooled analysis.

PURPOSE: A large prospective database from three Phase 3 studies allowed the study of spasticity-related pain (SRP) in pediatric cerebral palsy (CP). METHODS: Baseline (pretreatment) SRP data occurring during different activities in children/adolescents (aged 2-17 years, ambulant/nonambulant) with uni-/bilateral spastic CP was obtained using the Questionnaire on Pain caused by Spasticity (QPS; six modules specific to spasticity level [lower limb (LL) or upper limb (UL)] and type of respondent [child/adolescent, interviewer, or parent/caregiver]). RESULTS: At baseline, 331 children/adolescents with LL- and 155 with UL-spasticity completed at least one key item of their modules; LL/UL QPS modules of parent/caregivers were at least partially completed (key items) by 841/444 parents/caregivers. SRP with at least one activity at baseline was self-reported in 81.9% /69.7% (LLs/ULs) of children/adolescents with spasticity. Parents/caregivers observed LL/UL SRP behaviors in 85.9% /77.7% of their children, with multiple body regions affected. SRP negatively affected the great majority of the children in various ways. Child/adolescent-reported mean SRP intensity and parent/caregiver-observed mean SRP behavior frequencies were higher for LLs than ULs, and the level of SRP increased with more physically demanding activities. CONCLUSION: These data suggest SRP is more common and intense in pediatric CP than generally thought, emphasizing the need for effective, long-term pain management.

[Stroke alarm-Arterial ischemic stroke as one of the most time-critical emergencies in children and adolescents]. / Notfall-Neuropädiatrie ­ Der arteriell ischämische Schlaganfall als einer der zeitkritischsten Notfälle bei Kindern und Jugendlichen.

Arterial ischemic stroke in childhood and adolescence is one of the most time-critical emergencies in pediatrics. Nevertheless, it is often diagnosed with a considerable time delay which may be associated with low awareness, the sometimes nonspecific clinical presentation with a wide variety of differential diagnoses, and less established 'acute care structures'. The revascularisation strategies in adult stroke care are also potential and promising treatment options for children, even if available evidence is still limited. In the post-acute phase, the etiological work-up is complex due to the multitude of risk factors to be considered. But it is essential to identify each child's individual risk profile as it determines secondary prevention, risk of recurrence and outcome. Long-term care in a multiprofessional, interdisciplinary team must take into account the bio-psycho-social aspects to integrate the child into its social and educational, and later professional environment.

Safety and efficacy of repeat long-term incobotulinumtoxinA treatment for lower limb or combined upper/lower limb spasticity in children with cerebral palsy.

PURPOSE: The open-label phase 3 "Treatment with IncobotulinumtoxinA in Movement Open-Label" (TIMO) study investigated longer-term safety and efficacy of incobotulinumtoxin A in children/adolescents with cerebral palsy (CP). METHODS: Patients on standard treatment, with unilateral or bilateral lower limb (LL) or combined upper limb (UL)/LL spasticity received four incobotulinumtoxinA injection cycles (16 or 20 Units/kg bodyweight total [maximum 400 or 500 Units] per cycle depending on ambulatory status/clinical pattern treated), each followed by 12-16 weeks' observation. Treatment for pes equinus was mandatory; flexed knee or adducted thigh were options for unilateral treatment and/or ULs for unilateral/bilateral treatment. The primary endpoint was safety; changes in Ashworth Scale and Gross Motor Function Measure-66 scores, and Global Impression of Change Scale scores at week 4 of each injection cycle were also evaluated. RESULTS: IncobotulinumtoxinA (≤500 Units for ≤98 weeks) was safe, well-tolerated, and effective across all endpoints for multipattern treatment of LL and combined LL/UL spasticity in ambulant/nonambulant children/adolescents with CP. Treatment effects increased with each injection cycle. No new/unexpected safety concerns were identified. CONCLUSION: IncobotulinumtoxinA showed a good safety and tolerability profile, with efficacy over multiple clinical presentations. As an adjunct treatment, it offers an effective, individualized treatment option for pediatric CP-related spasticity.

Timing of maternal immune activation and sex influence schizophrenia-relevant cognitive constructs and neuregulin and GABAergic pathways.

Maternal immune activation (MIA) during pregnancy is an established environmental risk factor for schizophrenia. Timing of immune activation exposure as well as sex of the exposed offspring are critical factors in defining the effects of MIA. However, the specificity of MIA on the component structure of schizophrenia, especially cognition, has been difficult to assess due to a lack of translational validity of maze-like testing paradigms. We aimed to assess cognitive domains relevant to schizophrenia using highly translational touchscreen-based tasks in male and female mice exposed to the viral mimetic, poly(I:C) (5 mg/k, i.p.), during early (gestational day (GD) 9-11) and late (GD13-15) gestational time points. Gene expression of schizophrenia candidate pathways were assessed in fetal brain immediately following poly(I:C) exposure and in adulthood to identify its influence on neurodevelopmental processes. Sex and window specific alterations in cognitive performance were found with the early window of MIA exposure causing female-specific disruptions to working memory and reduced perseverative behaviour, while late MIA exposure caused male-specific changes to working memory and deficits in reversal learning. GABAergic specification marker, Nkx2.1 gene expression was reduced in fetal brains and reelin expression was reduced in adult hippocampus of both early and late poly(I:C) exposed mice. Neuregulin and EGF signalling were initially upregulated in the fetal brain, but were reduced in the adult hippocampus, with male mice exposed in the late window showing reduced Nrg3 expression. Serine racemase was reduced in both fetal and adult brain, but again, adult reductions were specific to male mice exposed at the late time point. Overall, we show that cognitive constructs relevant to schizophrenia are altered by in utero exposure to maternal immune activation, but are highly dependent on the timing of infection and the sex of the offspring. Glutamatergic and epidermal growth factor pathways were similarly altered by MIA in a timing and sex dependent manner, while MIA-induced GABAergic deficits were independent of timing or sex.

Test-Retest Reliability and Construct Validity of the German Translation of the Gait Outcome Assessment List (GOAL) Questionnaire for Children with Ambulatory Cerebral Palsy.

The Gait Outcome Assessment List (GOAL) is a patient or caregiver-reported assessment of gait-related function across different domains of the International Classification of Functioning, Disability, and Health (ICF) developed for ambulant children with cerebral palsy (CP). So far, the questionnaire is only available in English. The aim of this study was to translate the GOAL into German and to evaluate its reliability and validity by studying the association between GOAL scores and gross motor function as categorized by the gross motor function classification system (GMFCS) in children with cerebral palsy (CP). The GOAL was administered to primary caregivers of n = 91 children and adolescents with CP (n = 32, GMFCS levels I; n = 27, GMFCS level II; and n = 32, GMFCS level III) and n = 15 patients were capable of independently completing the whole questionnaire (GMFCS level I). For assessing test-retest reliability, the questionnaire was completed for a second time 2 weeks after the first by the caregivers of n = 36 patients. Mean total GOAL scores decreased significantly with increasing GMFCS levels with scores of 71 (95% confidence interval [CI]: 66.90-74.77) for GMFCS level I, 56 (95% CI: 50.98-61.86) for GMFCS level II, and 45 (95% CI: 40.58-48.48) for GMFCS level III, respectively. In three out of seven domains, caregivers rated their children significantly lower than children rated themselves. The test-retest reliability was excellent as was internal consistency given the GOAL total score. The German GOAL may serve as a much needed patient-reported outcome measure of gait-related function in ambulant children and adolescents with CP.

[Exacerbation of working conditions due to the economic pressures of hospitals : Mandatory staffing ratios for physicians?] / Verschärfung der Arbeitsbedingungen durch Kostendruck der Krankenhäuser : Verpflichtende Personalschlüssel für Ärzte?

BACKGROUND: In current hospital-based urological care, economic pressure and its influence on urological working and further training conditions are a main point of criticism among young urologists. Against the background of a growing need for young talent in our specialist discipline, there is an urgent need for action. With the introduction of the lower limits for nursing staff, there is now a threat of a reduction in the number of physicians with the aim of reducing costs for business reasons. OBJECTIVE: A mandatory staffing ratio is often mentioned to counteract the downsizing in German clinics. The role of the lower staffing limit is explained in the following article. MATERIALS AND METHODS: We have analyzed the current draft laws of the federal government, as well as position papers and statements from federal political representatives such as the Marburger Bund, Bundesverband Deutscher Urologen and the German Medical Association (Bundesärztekammer) since 2018. RESULTS AND CONCLUSION: The analysis of current developments in nursing policy shows that the first step is a needs-based assessment of personnel and subsequent financing in the clinic setting. With adequate staffing, as in the traffic light scheme of the German Medical Association, not only would clinics position themselves as attractive employers and training centers for large parts of the urological medical profession, but would also significantly improve working conditions, patient care and patient safety. Medical training must remain an essential part of everyday hospital life.

IncobotulinumtoxinA for the treatment of lower-limb spasticity in children and adolescents with cerebral palsy: A phase 3 study.

PURPOSE: Investigate the efficacy and safety of multipattern incobotulinumtoxinA injections in children/adolescents with lower-limb cerebral palsy (CP)-related spasticity. METHODS: Phase 3 double-blind study in children/adolescents (Gross Motor Function Classification System - Expanded and Revised I-V) with unilateral or bilateral spastic CP and Ashworth Scale (AS) plantar flexor (PF) scores ⩾ 2 randomized (1:1:2) to incobotulinumtoxinA (4, 12, 16 U/kg, maximum 100, 300, 400 U, respectively) for two 12- to 36-week injection cycles. Two clinical patterns were treated. Pes equinus (bilateral or unilateral) was mandatory; if unilateral, treatment included flexed knee or adducted thigh. ENDPOINTS: Primary: AS-PF change from baseline to 4 weeks; Coprimary: investigator-rated Global Impression of Change Scale (GICS)-PF at 4 weeks; Secondary: investigator's, patient's, and parent's/caregiver's GICS, Gross Motor Function Measure-66 (GMFM-66). RESULTS: Among 311 patients, AS-PF and AS scores in all treated clinical patterns improved from baseline to 4-weeks post-injection and cumulatively across injection cycles. GICS-PF and GICS scores confirmed global spasticity improvements. GMFM-66 scores indicated better motor function. No significant differences between doses were evident. Treatment was well-tolerated, with no unexpected treatment-related adverse events or neutralising antibody development. CONCLUSION: Children/adolescents with lower-limb spasticity experienced multipattern benefits from incobotulinumtoxinA, which was safe and well-tolerated in doses up to 16 U/kg, maximum 400 U.

Real-life outcomes after artificial urinary sphincter explantation in women suffering from severe stress incontinence.

PURPOSE: Artificial urinary sphincter (AUS) implantation in female patients results in high satisfaction rates and high functional outcomes, but implantation can be challenging and explantation of the device is fairly common. The objective of this study was to review outcomes after AUS explantation in women. METHODS: This is a retrospective, monocentric study of all women who underwent open or laparoscopic AUS implantation between November 1994 and July 2019, and patients with AUS explantation were included. Management after AUS explantation using descriptive analysis was assessed. RESULTS: Over a span of 26 years, 111 women had an AUS implanted by a single surgeon. Of these surgeries, 35 explantations in 29 patients were later required: 20 initial AUSs, nine revised AUSs and six reimplanted AUS (rAUSs). The median time to explantation was 15.5 month (± 0.55). After explantation, 13 rAUSs in 10 patients were successful and two attempts failed. The median time between explantation and rAUS was 8 months (± 0.95). At the last follow-up, five patients still had their rAUS and six rAUSs had required explantation after a median time of 6.5 months (± 0.65). Surgery was still possible for 12 patients who did not have a rAUS: three cystectomies, one bladder neck closure with continent urinary diversion, and six mid-urethral slings or adjustable continence therapy balloon implantations. Among the 23 patients who did not need a cystectomy or a bladder neck closure with continent urinary diversion, four were completely dry (17.4%), 11 were improved (47.8%), and eight (34.8%) experienced unchanged incontinence with the post-explantation management. Limitations include retrospective design, heterogeneous management over time and a relatively small population of patients in our cohort. CONCLUSION: Reimplantation of an AUS after an explantation seems feasible after at least 6 months. However, the surgery will be more difficult and satisfaction is not guaranteed. Multicenter databases should be created to help surgeons and patients decide on appropriate management strategies after explantation of an AUS.

Detection of Optic Neuritis on Routine Brain MRI without and with the Assistance of an Image Postprocessing Algorithm.

BACKGROUND AND PURPOSE: At times, there is a clinical need for using routine brain MR imaging performed close to the time of onset of patients' visual symptoms to firmly establish the diagnosis of optic neuritis. Our aim was to assess the diagnostic performance of radiologists in detecting optic neuritis on routine brain MR images and whether this performance could be enhanced using a postprocessing algorithm. MATERIALS AND METHODS: In this retrospective case-control study of 60 patients (37 women, 23 men; mean age, 47.2 [SD, 17.9] years), 2 blinded neuroradiologists evaluated T2-weighted FLAIR and contrast-enhanced T1WI from brain MR imaging for the presence of imaging evidence of optic neuritis. Images were processed using an image-processing algorithm that aimed to selectively accentuate the signal intensity of diseased optic nerves. We assessed the effect of image processing on the contrast-to-noise ratio between the optic nerves and normal-appearing white matter and on the diagnostic performance of the neuroradiologists, including the interobserver reliability. RESULTS: The average sensitivity of readers was 55%, 56.5%, and 30.0% on FLAIR, coronal contrast-enhanced T1WI, and axial contrast-enhanced T1WI, respectively. Sensitivities were lower in the absence of fat saturation on FLAIR (P = .001) and coronal contrast-enhanced T1WI (P = .04). Processing increased the contrast-to-noise ratio of diseased (P value range = .03 to <.001) but not of control optic nerves. Processing did not improve the sensitivity but improved the specificity and positive predictive value. Interobserver agreement improved from slight to good. CONCLUSIONS: Detection of optic neuritis on routine brain MR imaging is challenging. Specificity, positive predictive value, and interobserver agreement can be improved by postprocessing of MR images.

Outcomes of artificial urinary sphincter in female with neurological stress urinary incontinence: a long-term follow-up.

PURPOSE: To report the outcomes of AUS in women with neurological SUI resulting from intrinsic sphincter deficiency after a follow-up from 3 to 20 years. METHODS: The charts of female with moderate to severe neurological SUI who underwent open or laparoscopic AUS implantation between November 1994 and July 2014 were reviewed retrospectively. All patients were operated by a single experienced surgeon. Primary endpoint was a postoperative continence categorized as complete continence (no pads used), improved incontinence or unchanged incontinence. RESULTS: Twenty-three women (mean age 54 years, range 19-77) underwent open or laparoscopic AUS implantation. At the last follow-up, 7 (30.4%) initial artificial urinary sphincters remained in situ and 9 (39.1%) patients had at least one revision or reimplantation. Sixteen patients were fully continent (69.6%), four (17.4%) had improved incontinence and three (13.0%) had unchanged incontinence. After a median follow-up of 11.6 years (3-22), 8 (34.8%) explanations in 7 patients and 16 (69.6%) revisions in 11 patients occurred. The average time without explanation or revision was 10.9 and 8.5 years, respectively. Survival rates without AUS explanation were 94.4%, 76.5%, 72.8%, 50% and without revision were 83.3%, 64.7%, 45.5% and 16.7% at 5, 10, 15 and 20 years, respectively. CONCLUSION: Although all methods are imperfect at best, AUS remain toward our experience a good way to achieve long-term continence in female patients suffering from neurological SUI with preserved manual dexterity.

Pathway-Based Approaches for Assessing Biological Hazards of Complex Mixtures of Contaminants: A Case Study in the Maumee River.

Assessment of ecological risks of chemicals in the field usually involves complex mixtures of known and unknown compounds. We describe the use of pathway-based chemical and biological approaches to assess the risk of chemical mixtures in the Maumee River (OH, USA), which receives a variety of agricultural and urban inputs. Fathead minnows (Pimephales promelas) were deployed in cages for 4 d at a gradient of sites along the river and adjoining tributaries in 2012 and during 2 periods (April and June) in 2016, in conjunction with an automated system to collect composite water samples. More than 100 industrial chemicals, pharmaceuticals, and pesticides were detected in water at some of the study sites, with the greatest number typically found near domestic wastewater treatment plants. In 2016, there was an increase in concentrations of several herbicides from April to June at upstream agricultural sites. A comparison of chemical concentrations in site water with single chemical data from vitro high-throughput screening (HTS) assays suggested the potential for perturbation of multiple biological pathways, including several associated with induction or inhibition of different cytochrome P450 (CYP) isozymes. This was consistent with direct effects of water extracts in an HTS assay and induction of hepatic CYPs in caged fish. Targeted in vitro assays and measurements in the caged fish suggested minimal effects on endocrine function (e.g., estrogenicity). A nontargeted mass spectroscopy-based analysis suggested that hepatic endogenous metabolite profiles in caged fish covaried strongly with the occurrence of pesticides and pesticide degradates. These studies demonstrate the application of an integrated suite of measurements to help understand the effects of complex chemical mixtures in the field. Environ Toxicol Chem 2021;40:1098-1122. © 2020 SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Staged complex abdominal wall hernia repair in morbidly obese patients.

PURPOSE: The repair of complex abdominal wall hernias in morbidly obese patients is often associated with a higher risk of complications and hernia recurrences. Improvement in obesity and its associated metabolic complications are hypothesized to improve hernia repair outcomes. This study analyzes outcomes from morbidly obese patients who underwent bariatric surgery with staged complex abdominal wall reconstruction at Creighton University Medical Center (CUMC). METHODS: This retrospective study included morbidly obese patients with complex abdominal wall hernia, who underwent bariatric surgery with staged abdominal wall reconstruction. Data points collected included patient demographics, obesity-related co-morbidities, pre-operative BMI, EBMIL at 12 months, hernia characteristics, postoperative complications, BMI at time of hernia repair, and hernia recurrence. RESULTS: Twelve patients with an average BMI of 48 and complex abdominal wall hernias (mean width 14.0 cm) met inclusion criteria. Seven patients (58%) had significant loss of domain. Bariatric procedures included six laparoscopic sleeve gastrectomies (LSG), three laparoscopic Roux-en-Y gastric bypasses (LRNYGB), and three revisional procedures (2 vertical band gastroplasties to LRNYGB and 1 LRNYGB revision). At 12-month follow-up, the mean excess BMI loss (EBMIL) was 64.6%. The average time to staged complex abdominal wall reconstruction was 22.3 months. Two non-elective hernia repairs were performed due to one incarceration and one strangulation. There were no recurrences after an average follow-up of 21.9 months. CONCLUSIONS: In this study, staged mesh repair of complex abdominal wall hernias after bariatric surgery in morbidly obese patients was associated with acceptable morbidity and no hernia recurrences at approximately 1.5 year follow-up.

Nutritional status of children with cerebral palsy attending rehabilitation centers.

AIM: To describe the nutritional status of children with cerebral palsy (CP) from rehabilitation and therapeutic centers in Argentina, and to analyze their risk of undernutrition based on their Gross Motor Function Classification System (GMFCS) level. METHOD: This was a cross-sectional study with data collected from 321 children (196 males, 125 females) with CP age 2 to 19 years (mean age 9y 3mo, SD 4y 5mo) from 17 rehabilitation and therapeutic centers in five Argentine provinces. Nutritional status was defined by height, weight, and body mass index for age z-scores using World Health Organization growth charts. Odds ratios were used to evaluate the association between GMFCS level and nutritional status. RESULTS: Of the children with CP studied, 52.4% were in GMFCS levels IV and V. Regarding the nutritional status, 41.7% were normal, 19.0% had moderate undernutrition, 33.9% severe undernutrition, 2.5% overweight, and 2.8% obese. When compared to those in GMFCS levels I to III, the odds of children in GMFCS levels IV and V having moderate undernutrition are four times greater and the odds of having severe undernutrition are 14 times greater. INTERPRETATION: There is a high prevalence of undernutrition associated with CP (GMFCS levels IV and V) among children in rehabilitation and therapeutic centers in Argentina. Risk of severe undernutrition increases with increased motor compromises.

Bazedoxifene - a promising brain active SERM that crosses the blood brain barrier and enhances spatial memory.

Over 20 years of accumulated evidence has shown that the major female sex hormone 17ß-estradiol can enhance cognitive functioning. However, the utility of estradiol as a therapeutic cognitive enhancer is hindered by its unwanted peripheral effects (carcinogenic). Selective estrogen receptor modulators (SERMs) avoid the unwanted effects of estradiol by acting as estrogen receptor antagonists in some tissues such as breast and uterus, but as agonists in others such as bone, and are currently used for the treatment of osteoporosis. However, understanding of their actions in the brain are limited. The third generation SERM bazedoxifene has recently been FDA approved for clinical use with an improved biosafety profile. However, whether bazedoxifene can enter the brain and enhance cognition is unknown. Using mice, the current study aimed to explore if bazedoxifene can 1) cross the blood-brain barrier, 2) rescue ovariectomy-induced hippocampal-dependent spatial memory deficit, and 3) activate neural estrogen response element (ERE)-dependent gene transcription. Using liquid chromatography-mass spectrometry (LC-MS), we firstly demonstrate that a peripheral injection of bazedoxifene can enter the brain. Secondly, we show that an acute intraperitoneal injection of bazedoxifene can rescue ovariectomy-induced spatial memory deficits. And finally, using the ERE-luciferase reporter mouse, we show in vivo that bazedoxifene can activate the ERE in the brain. The evidence shown here suggest bazedoxifene could be a viable cognitive enhancer with promising clinical applicability.