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2.
J Hazard Mater ; 400: 122870, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-32947725

RESUMO

Polychlorinated aromatic compounds (PCACs) pose significant remediation challenges, since their high soil affinities preclude mobile-phase partitioning and subsurface extraction. To enhance partitioning and desorption, subsurface temperatures are raised using a technique called thermal conduction heating-soil vapor extraction (TCH-SVE). While this technique improves PCAC partitioning, it can also promote several degradation reactions under temperatures typical of low-temperature TCH-SVE (200-400 °C). While these reactions are labile, the extent to which they occur in flow-through TCH-SVE is unclear. The current research used bench-scale, flow-through TCH-SVE to assess relative importance of three removal pathways: (1) target volatilization, (2) reductive dechlorination, and (3) oxidation via OH-addition. Pentachlorophenol was used as a representative PCAC, and pathway contributions, extents, and regioselectivity were examined as a function of temperature (225-375 °C) and gas-phase oxygen content (air vs. nitrogen). Across treatments, OH-addition and dechlorination occurred in parallel and accounted for significantly more removal than PCP volatilization. OH-addition byproducts had highest yields (regardless of oxygen content) and were consistent with surface-mediated OH production and ring addition. OH-addition increased with temperature while volatilization and dechlorination decreased. Notable exceptions occurred between 225 and 325 °C (where dechlorination dropped 10-fold) and 325 and 375 °C (where OH-addition fell 75%), signifying major mechanism shifts in these intervals.

3.
J Urol ; : 101097JU0000000000001377, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32945696

RESUMO

PURPOSE: Obesity is a well-known risk factor for kidney cancer incidence. However, a number of studies have demonstrated more favorable kidney cancer prognosis in patients with elevated body mass index (BMI) conferring a survival advantage, termed 'the obesity paradox'. We aimed to evaluate the association between BMI and kidney cancer outcomes (progression-free survival (PFS), cancer specific survival (CSS), and overall survival (OS)). MATERIALS AND METHODS: A computerized systematic search of Medline, EMBASE, Proquest, Pubmed, and Google scholar for literature published in English was performed between its inception and December 2018 and Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were used for reporting. RESULTS: Overall, 34 publications comprising a total of 50,717 patients were included in the analysis. The majority assessed the association between BMI and CSS. Overweight and obese patients were associated with improved CSS compared to patients with normal BMI (HR 0.85, 95% confidence interval (CI) 0.79-0.93). A similar trend was demonstrated for PFS (HR 0.68, 95% CI 0.59-0.78) and OS (HR 0.66, 95% CI 0.55-0.79). On the contrary, the underweight group was associated with inferior CSS (HR 2.16, 95% CI 1.15-4.04). Main drawbacks limiting the interpretation were the retrospective design in the majority of studies, heterogeneity in study population, BMI classification, and covariates in multivariate analysis. CONCLUSIONS: This is the largest systematic review of evaluating the potential phenomenon of the obesity paradox in kidney cancer outcomes. It demonstrated a favorable effect of BMI on kidney cancer outcomes. However, due to significant heterogeneity of studies, multicenter prospective studies and further research on the fundamental biological mechanisms are warranted to confirm the significance of BMI on kidney cancer prognosis.

4.
Birth Defects Res ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32935482

RESUMO

Proteus syndrome is a mosaic genetic overgrowth disorder caused by a postzygotic, mosaic activating mutation in AKT1. Rare prenatal presentations include segmental tissue overgrowth, and skeletal and CNS anomalies. We present the first report of prenatally diagnosed and molecularly confirmed Proteus syndrome. Prenatal imaging identified megalencephaly, brain and eye malformations, focal soft tissue enlargement, and ambiguous genitalia. Exome sequencing performed on cultured amniocytes demonstrated an AKT1 pathogenic variant consistent with Proteus syndrome, and postnatal examination confirmed the diagnosis. Postnatal Sanger sequencing could not identify the AKT1 pathogenic variant. This case underscores the importance of prenatal exome sequencing on cultured amniocytes for mosaic overgrowth disorders, as well as provides additional information on the prenatal phenotype of Proteus syndrome, and highlights the impact of prenatal diagnosis on postnatal management.

6.
Sleep ; 2020 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-32918472

RESUMO

STUDY OBJECTIVES: To determine whether actigraphy-assessed indices of sleep are associated with cognitive performance in women, and explore whether these associations vary by race/ethnicity. METHODS: Participants were 1,126 postmenopausal community-dwelling females (mean age 65 years) from the observational Study of Women's Health Across the Nation (SWAN); 25% were black, 46% white, 13% Chinese, 11% Japanese, and 5% Hispanic. Actigraphy-assessed sleep measures included total sleep time, wake after sleep onset, and fragmentation. Cognitive measures included immediate and delayed verbal memory, working memory, and information processing speed. All measures were assessed in conjunction with SWAN annual visit 15. RESULTS: Across the sample, after covariate adjustment, greater wake after sleep onset and fragmentation were concurrently associated with slower information processing speed. Black participants had significantly worse sleep relative to other race/ethnic groups. Significant race/sleep interactions were observed; in black, but not white, participants, greater fragmentation was concurrently associated with worse verbal memory and slower information processing speed, and greater wake after sleep onset was concurrently associated with slower information processing speed. Sleep-cognitive performance associations were not different in Chinese and Japanese participants relative to white participants. CONCLUSIONS: Greater wakefulness and fragmentation during sleep are concurrently associated with slower information processing. Sleep continuity impacted concurrent cognitive performance in black, but not white, women. This effect may not have been detected in white women because their sleep was largely within the normal range. Future longitudinal studies in diverse samples are critical to further understand whether race/ethnicity moderates the influence of sleep on cognitive performance.

7.
J Rheumatol ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934137

RESUMO

OBJECTIVE: To examine the efficacy and safety of pegloticase in combination with methotrexate in patients with uncontrolled gout in an exploratory, open-label clinical trial (NCT03635957) prior to a randomized, controlled trial. METHODS: A multicenter, open-label, efficacy and safety study of pegloticase with methotrexate cotreatment was conducted in patients with uncontrolled gout. Patients were administered oral methotrexate (15 mg/week) and folic acid (1 mg/day) 4 weeks prior to and throughout pegloticase treatment. The primary study outcome was the proportion of responders, defined as sUA <6 mg/dL for ≥80% of the time during month 6 (weeks 20, 22, and 24). All analyses were performed on a modified intent-to-treat population, defined as patients who received ≥1 pegloticase infusion. RESULTS: Seventeen patients were screened and 14 patients (all men, average age: 49.3 ± 8.7 years) were enrolled. On Day 1, mean sUA was 9.2 ± 2.5 mg/dL and 12 of the 14 patients had visible tophi. At the 6 month timepoint, 11/14 (78.6%, 95%CI 49.2-95.3%) met the responder definition, with 3 patients discontinuing after meeting protocol-defined treatment discontinuation rules (pre-infusion sUA values greater than 6 mg/dL at 2 consecutive scheduled visits). All patients tolerated methotrexate. No new safety concerns were identified. CONCLUSION: In this study, an increased proportion of patients maintained therapeutic response at 6 months when treated concomitantly with methotrexate and pegloticase when compared to the previously reported 42% using pegloticase alone. These results support the need for a randomized study of methotrexate or placebo with pegloticase to validate these open label findings.

8.
Lancet ; 396(10252): 684-692, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32891212

RESUMO

BACKGROUND: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings. METHODS: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 µg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11. FINDINGS: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred. INTERPRETATION: Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be. FUNDING: BioMarin Pharmaceutical.

9.
Artigo em Inglês | MEDLINE | ID: mdl-32888375

RESUMO

Mosaic genetic mutations may be somatic, germline, or "gonosomal" and have the potential to cause genetic syndromes, disorders, or malformations. Mutations can occur at any point in embryonic development and the timing determines the extent of distribution of the mutation throughout the body and different tissue types. The eye and visual pathway offer a unique opportunity to study somatic and gonosomal mosaic mutations as the eye consists of tissues derived from all three germ layers allowing disease pathology to be assessed with noninvasive imaging. In this review, we describe systemic and ocular manifestations in a child with mosaic Coffin-Siris syndrome. The patient presented with a significant medical history of accommodative esotropia and hyperopia, macrocephaly, polydactyly, global developmental delay, hypotonia, ureteropelvic junction (UPJ) obstruction, and brain MRI abnormalities. The ophthalmic findings in this patient were nonspecific, however, they are consistent with ocular manifestations reported in other patients with Coffin-Siris syndrome. We also review ophthalmic findings of select mosaic chromosomal and single-gene disorders. Ophthalmic assessment alongside clinical genetic testing may play an important role in diagnosis of genetic syndromes as well as understanding disease pathology, particularly when mosaicism plays a role.

10.
PLoS One ; 15(8): e0237603, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841261

RESUMO

BACKGROUND/PURPOSE: To date, studies examining polymicrobial infections in ocular disease have mostly been limited to keratitis or endophthalmitis. We characterized polybacterial infections compared to monobacterial infections in prior clinical studies evaluating besifloxacin ophthalmic suspension 0.6% for the treatment of bacterial conjunctivitis and report on associated microbiological outcomes. METHODS: In this post-hoc analysis, microbiological data for subjects with conjunctivitis due to one or more than one bacterial species in three previous studies (two vehicle-, one active-controlled) of besifloxacin were extracted. Bacterial species identified at baseline were deemed causative if their colony count equaled or exceeded species-specific prespecified threshold criteria. In subjects with polybacterial infections, the fold-increase over threshold was used to rank order the contribution of individual species. Baseline pathogens and their minimum inhibitory concentrations (MICs) for common ophthalmic antibiotics were compared by infection type, as were microbial eradication rates following treatment with besifloxacin. RESULTS: Of 1041 subjects with culture-confirmed conjunctivitis, 17% had polybacterial and 83% had monobacterial conjunctivitis at baseline. In polybacterial compared to monobacterial infections, Haemophilus influenzae and Streptococcus pneumoniae were identified less frequently as the dominant infecting species (P = 0.042 and P<0.001, respectively), whereas Streptococcus mitis/S. mitis group was identified more frequently as dominant (P<0.001). Viral coinfection was also identified more frequently in polybacterial infections (P<0.001). Staphylococcus aureus was the most common coinfecting species in polybacterial infections and the second most common dominant species in such infections. With few exceptions, MICs for individual species were comparable regardless of infection type. Clinical microbial eradication rates with besifloxacin were high regardless of infection type (P≤0.016 vs vehicle at follow-up visits). CONCLUSIONS: Approximately one in five subjects with bacterial conjunctivitis are infected with more than one bacterial species underscoring the need for a broad-spectrum antibiotic for such infections. Besifloxacin treatment resulted in robust eradication rates of these infections comparable to monobacterial infections. TRIAL REGISTRATION: NCT000622908, NCT00347932, NCT00348348.

11.
Adv Ther ; 37(10): 4209-4219, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32767182

RESUMO

INTRODUCTION: The safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) have been characterized using data from clinical trials. METHODS: We further characterized the safety and tolerability of nintedanib in patients with IPF in clinical practice using the global pharmacovigilance database. The database included spontaneously reported adverse events and data collected via solicited reporting in patients treated with nintedanib from 15 October 2014 to 15 October 2018. Adverse events were coded using the Medical Dictionary for Regulatory Activities. Cumulative exposure to nintedanib was estimated on the basis of sales data. RESULTS: Cumulative exposure to nintedanib was estimated as 60,107 patient-years. Diarrhea was the most frequent event (301.6 events per 1000 patient-years). Most (97.0%) diarrhea events were non-serious. The median (25th, 75th percentile) time to onset of the first diarrhea event was 60 (11, 182) days. Elevated liver enzyme or bilirubin levels were reported at a rate of 31.5 events per 1000 patient-years. Bleeding was reported at a rate of 36.8 events per 1000 patient-years; 81.0% of events were non-serious. Major cardiovascular adverse events were reported at a rate of 13.4 events per 1000 patient-years and myocardial infarction at a rate of 4.3 events per 1000 patient-years. Gastrointestinal perforation was reported at a rate of 1.0 event per 1000 patient-years. CONCLUSIONS: On the basis of pharmacovigilance data collected over 4 years, the safety profile of nintedanib in patients with IPF was consistent with that observed in clinical trials and described in the product label, with no new safety concerns observed.

12.
Orphanet J Rare Dis ; 15(1): 204, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32762706

RESUMO

BACKGROUND: Perinatal and infantile hypophosphatasia (HPP) are associated with respiratory failure and respiratory complications. Effective management of such complications is of key clinical importance. In some infants with HPP, severe tracheobronchomalacia (TBM) contributes to respiratory difficulties. The objective of this study is to characterize the clinical features, investigations and management in these patients. METHODS: We report a case series of five infants with perinatal HPP, with confirmed TBM, who were treated with asfotase alfa and observed for 3-7 years. Additionally, we reviewed respiratory function data in a subgroup of patients with perinatal and infantile HPP included in the clinical trials of asfotase alfa, who required high-pressure respiratory support (positive end-expiratory pressure [PEEP] ≥6 cm H2O and/or peak inspiratory pressure ≥18 cm H2O) during the studies. RESULTS: The case series showed that TBM contributed significantly to respiratory morbidity, and prolonged respiratory support with high PEEP was required. However, TBM improved over time, allowing weaning of all patients from ventilator use. The review of clinical trial data included 20 patients and found a high degree of heterogeneity in PEEP requirements across the cohort; median PEEP was 8 cm H2O at any time and some patients presented with high PEEP (≥8 cm H2O) over periods of more than 6 months. CONCLUSION: In infants with HPP presenting with persistent respiratory complications, it is important to screen for TBM and initiate appropriate respiratory support and treatment with asfotase alfa at an early stage. TRIAL REGISTRATION: ClinicalTrials.gov numbers: NCT00744042 , registered 27 August 2008; NCT01205152 , registered 17 September 2010; NCT01176266 , registered 29 July 2010.

14.
Sci Data ; 7(1): 258, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32759965

RESUMO

Mapping the causal effects of one brain region on another is a challenging problem in neuroscience that we approached through invasive direct manipulation of brain function together with concurrent whole-brain measurement of the effects produced. Here we establish a unique resource and present data from 26 human patients who underwent electrical stimulation during functional magnetic resonance imaging (es-fMRI). The patients had medically refractory epilepsy requiring surgically implanted intracranial electrodes in cortical and subcortical locations. One or multiple contacts on these electrodes were stimulated while simultaneously recording BOLD-fMRI activity in a block design. Multiple runs exist for patients with different stimulation sites. We describe the resource, data collection process, preprocessing using the fMRIPrep analysis pipeline and management of artifacts, and provide end-user analyses to visualize distal brain activation produced by site-specific electrical stimulation. The data are organized according to the brain imaging data structure (BIDS) specification, and are available for analysis or future dataset contributions on openneuro.org including both raw and preprocessed data.

15.
Artigo em Inglês | MEDLINE | ID: mdl-32783764

RESUMO

Background: No previous studies have determined the incidence of acute kidney injury (AKI) in trauma patients treated with vancomycin + meropenem (VM) versus vancomycin + cefepime (VC). The purpose of this study was to fill this gap. Methods: A series of 99 patients admitted to an American College of Surgeons-verified level 1 trauma center over a two-year period who received VC or VM for >48 hours were reviewed retrospectively. Exclusion criteria were existing renal dysfunction or on renal replacement therapy. The primary outcome was AKI as defined by a rise in serum creatinine (SCr) to 1.5 times baseline. Multi-variable analysis was performed to control for factors associated with AKI (age, obesity, gender, length of stay [LOS], nephrotoxic agent(s), and baseline SCr), with significance defined as p < 0.05. Results: The study population was 50 ± 19 years old, 76% male, with a median LOS of 21 [range 15-39] days, and baseline SCr of 0.9 ± 0.2 mg/dL. Antibiotics, diabetes mellitus, and Injury Severity Score were independent predictors of AKI (odds ratio [OR] 4.4; 95% confidence interval [CI] 1.4-12; OR 9.3; 95% CI 1-27; OR 1.2; 95% CI 1.023-1.985, respectively). The incidence of AKI was higher with VM than VC (10/26 [38%] versus 14/73 [19.1%]; p = 0.049). Conclusions: The renal toxicity of vancomycin is potentiated by meropenem relative to cefepime in trauma patients. We recommend caution when initiating vancomycin combination therapy, particularly with meropenem.

16.
Artigo em Inglês | MEDLINE | ID: mdl-32743891

RESUMO

The ligands L1 and L2 form trinuclear self-assembled complexes with Cu2+ (i.e. [(L1 )2 Cu3 ]6+ or [(L2 )2 Cu3 ]6+ ) both of which act as a host to a variety of anions. Inclusion of long aliphatic chains on these ligands allows the assemblies to extract anions from aqueous media into organic solvents. Phosphate can be removed from water efficiently and highly selectively, even in the presence of other anions.

17.
Artigo em Inglês | MEDLINE | ID: mdl-32861817

RESUMO

PURPOSE/OBJECTIVES: In 2009, the Radiation Therapy Oncology Group (RTOG) genitourinary (GU) members published a consensus atlas for contouring prostate pelvic nodal clinical target volumes (CTV). Data has emerged further informing nodal recurrence patterns. The objective of this study is to provide an updated prostate pelvic nodal consensus atlas. MATERIALS/METHODS: A literature review was performed abstracting data on nodal recurrence patterns. Data was presented to a panel of international experts, including radiation oncologists, radiologists, and urologists. After data review, participants contoured nodal CTVs on three cases: post-operative, intact node positive, and intact node negative. Radiation oncologist contours were analyzed qualitatively using count maps which provided a visual assessment of controversial regions and quantitatively analyzed using Sorensen-Dice similarity coefficients, and Hausdorff distances compared with the 2009 RTOG atlas. Diagnostic radiologists generated a reference table outlining considerations for determining clinical node positivity. RESULTS: Eighteen radiation oncologists' contours (54 CTVs) were included. Two urologists' volumes were examined in a separate analysis. The mean CTV for the post-op case was 302 cc, intact node positive case was 409 cc, and intact node negative case 342 cc. Compared to the original RTOG consensus, the mean Sorensen-Dice similarity coefficient for the post-op case was 0.63 (SD 0.13), intact node positive case was 0.68 (SD 0.13), and intact node negative case 0.66 (SD 0.18). The mean Hausdorff Distance (in cm) for the post-op case was 0.24 (SD 0.13), the intact node positive case was 0.23 (SD 0.09), and intact node negative case 0.33 (SD 0.24). Four regions of CTV controversy were identified and consensus for each of these areas was reached. CONCLUSIONS: Discordance with the 2009 RTOG consensus atlas was seen in a group of experienced NRG Oncology and international GU radiation oncologists. To address areas of variability and account for new data, an updated NRG Oncology consensus contour atlas was developed.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32810917

RESUMO

PURPOSE: Sleep disturbances are common, particularly in middle aged women. Prescription medications for this indication are increasingly used, despite uncertain safety. This study assessed prescription medication use for sleep among a cohort of women with and without sleep disturbances. METHODS: We examined reports of sleep disturbance and sleep medication use among pre- and early peri-menopausal womenassessed annually or biennially since 1996. Women self-reported medications at visits, and we identified medications that have been used primarily for sleep disturbances. They reported on difficulties falling and staying asleep, and early morning wakening. Sleep medication use across 20 years of follow-up was examined for all women and by race/ethnicity. Women who reported data for both sleep disturbance and sleep medication use were included in the analyses.. RESULTS: Among participants in a cohort of 3302 women who were enrolled prior to their menopause transition, 3082 women were included in the analytic sample and 2531 (82%) reported sleep disturbances. They were more likely to endorse higher anxiety and pain scores and more comorbid conditions than women without sleep disturbances. Baseline characteristics were similar among women who did and did not use sleep medications. Among women reporting a sleep disturbance at baseline, 2.5% reported sleep medication use, increasing to 8% over 20 years. However, the proportion of women reporting sleep medication use who did not report a sleep disturbance remained low, approximately 1% to 2% over the entire follow-up. Increases in sleep medication use was observed across women of all race/ethnicities. CONCLUSIONS: The use of sleep medications among women reporting sleep disturbance grew over the last 20 years. Growth was observed across women of all race/ethnicities.

19.
Eur J Pediatr ; 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32627057

RESUMO

Neurally adjusted ventilatory assist (NAVA) ventilation allows patients to determine their peak inspiratory pressure and tidal volume on a breath-by-breath basis. Apprehension exists about premature neonates' ability to self-regulate breath size. This study describes peak pressure and tidal volume distribution of neonates on NAVA and non-invasive NAVA. This is a retrospective study of stored ventilator data with exploratory analysis. Summary statistics were calculated. Distributional assessment of peak pressure and tidal volume were evaluated, overall and per NAVA level. Over 1 million breaths were evaluated from 56 subjects. Mean peak pressure was 16.4 ± 6.4 in the NAVA group, and 15.8 ± 6.4 in the NIV-NAVA group (t test, p < 0.001). Mean tidal volume was 3.5 ± 2.7 ml/kg.Conclusion:In neonates on NAVA, most pressures and volumes were within or lower than recommended ranges with pressure-limited or volume-guarantee ventilation. What is known: • Limiting peak inspiratory pressures or tidal volumes are the main strategies to minimize ventilator-induced lung injury in neonates. Neurally adjusted ventilatory assist allows neonates to regulate their own peak inspiratory pressures and tidal volumes on a breath-to-breath basis using neural feedback. What is new: • When neonates chose the size of their breaths based on neural feedback, the majority of peak inspiratory pressures and tidal volumes were within or lower than the recommended peak inspiratory pressure or tidal volume ranges with pressure-limited or volume guarantee ventilation.

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