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Introduction: There have been no prior trials directly comparing the efficacy of different calcitonin gene-related peptide (CGRP) antagonists for migraine prevention. Reported are the results from the first head-to-head study of two CGRP antagonists, galcanezumab (monoclonal antibody) versus rimegepant (gepant), for the prevention of episodic migraine., Methods: In this 3-month, double-blind, double-dummy study, participants were randomized (1:1) to subcutaneous (SC) galcanezumab 120 mg per month (after a 240 mg loading dose) and a placebo oral disintegrating tablet (ODT) every other day (q.o.d.) or to rimegepant 75 mg ODT q.o.d. and a monthly SC placebo. The primary endpoint was the proportion of participants with a ≥ 50% reduction in migraine headache days per month from baseline across the 3-month double-blind treatment period. Key secondary endpoints were overall mean change from baseline in: migraine headache days per month across 3 months and at month 3, 2, and 1; migraine headache days per month with acute migraine medication use; Migraine-Specific Quality of Life Questionnaire Role Function-Restrictive domain score at month 3; and a ≥ 75% and 100% reduction from baseline in migraine headache days per month across 3 months., Results: Of 580 randomized participants (galcanezumab: 287, rimegepant: 293; mean age: 42 years), 83% were female and 81% Caucasian. Galcanezumab was not superior to rimegepant in achieving a ≥ 50% reduction from baseline in migraine headache days per month (62% versus 61% respectively; P = 0.70). Given the pre-specified multiple testing procedure, key secondary endpoints cannot be considered statistically significant. Overall, treatment-emergent adverse events were reported by 21% of participants, with no significant differences between study intervention groups., Conclusions: Galcanezumab was not superior to rimegepant for the primary endpoint; however, both interventions demonstrated efficacy as preventive treatments in participants with episodic migraine. The efficacy and safety profiles observed in galcanezumab-treated participants were consistent with previous studies., Trial Registration: ClinTrials.gov-NCT05127486 (I5Q-MC-CGBD)., (© 2023. The Author(s).)

Characteristics of an acid soil cultivated with Urochloa brizantha cv. Marandu were evaluated in relation to two types of fertilization: a conventional one, chemical based on nitrogen and potassium, and a biofertilizer, based on microalgae biomass. The results were compared among three treatments, control, conventional, and biological fertilization, with seven replications each. The study evaluated microalgae community, total carbon and nitrogen contents, mineral nitrogen, and enzymatic activity. Chlorella vulgaris showed the highest organism density, which can be explained by its rapid growth and high resistance. The highest species diversity was detected in the control 1,380,938 org cm -3 and biological 1,841,250 org cm -3 treatments, with the latter showing a higher density of cyanobacteria, especially Pseudanabaena limnetica with 394,554 org cm -3 . The soil treated with chemical fertilization showed higher nitrate (9.14 mg NKg -1 NO 3 - -N) and potassium (52.32 mg dm -3 ) contents. The highest levels of sulfur (21.73 mg dm -3 ) and iron (96.46 mgdm -3 ) were detected in the biological treatment. The chemical treatment showed higher activity of the enzymes acid phosphatase, acetylglucosaminidase, and sulfatase, while α-glucosidase and leucine aminopeptidase stood out in the biological treatment. Soil properties were not significantly affected by the treatments. The use of microalgae biomass derived from wastewater treatment from milking parlors was evaluated and presented as a promising biofertilizer for agriculture, following the line of recovering nutrient-rich wastes. In this sense, although many challenges need to be overcome, the results suggest that microalgal-based fertilizers could lead to low-impact agriculture., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Avalglucosidase alfa (AVAL) was approved in the United States (2021) for patients with late-onset Pompe disease (LOPD), aged ≥ 1 year. In the present study, pharmacokinetic (PK) simulations were conducted to propose alternative dosing regimens for pediatric LOPD patients based on a bodyweight cut-off. Population PK (PopPK) analysis was performed using nonlinear mixed effect modeling approach on pooled data from three clinical trials with LOPD patients, and a phase 2 study (NCT03019406) with infantile-onset Pompe disease (IOPD: 1-12 years) patients. A total of 2257 concentration-time points from 91 patients (LOPD, n = 75; IOPD, n = 16) were included in the analysis. The model was bodyweight dependent allometric scaling with time varying bodyweight included on clearance and distribution volume. Simulations were performed for two dosing regimens (20 mg/kg or 40 mg/kg) with different bodyweight cut-off (25, 30, 35 and 40 kg) by generating virtual pediatric (1-17 years) and adult patients. Corresponding simulated individual exposures (maximal concentration, C max and area under the curve in the 2-week dosing interval, AUC 2W ), and distributions were calculated. It was found that dosing of 40 mg/kg and 20 mg/kg in pediatric patients < 30 kg and ≥ 30 kg, respectively, achieved similar AVAL exposure (based on AUC 2W ) to adult patients receiving 20 mg/kg. PK simulations conducted on the basis of this model provided supporting data for the currently approved US labelling for dosing adapted bodyweight in LOPD patients ≥ 1 year by USFDA., (© 2023. The Author(s).)

Background: Acute occlusion of the posterior sagittal sinus may lead to dramatic increase in intracranial pressure (ICP), refractory to standard treatment. Hybrid vascular bypass of cranial venous outflow into the internal jugular vein (IJV) has seldom been described for this in recent neurosurgical literature., Objective: To describe creation of a novel vascular bypass shunt from the superior sagittal sinus (SSS) to internal jugular vein (IJV) utilizing a covered stent-Dacron graft construct for control of refractory ICP., Methods: We illustrate a patient with refractory ICP increases after acute sinus ligation that was performed to halt torrential bleeding from intraoperative injury. A temporary shunt was created that successfully controlled ICP. From the promising results of the temporary shunt, we utilized a prosthetic hybrid bypass graft to function as a shunt from the sagittal sinus to IJV. Yet the associated anticoagulation led to complications and a poor outcome., Results: Rapid and sustained ICP reduction can be expected after sagittal sinus-to-jugular bypass shunt placement in acute sinus occlusion. Details of the surgical technique are described. Heparin anticoagulation, while imperative, is also associated with worrisome complications., Conclusion: Acute occlusion of posterior third of sagittal sinus carries a very malignant clinical course. Intractable intracranial hypertension from acute sinus occlusion may be effectively treated with a SSS-IJV bypass shunt. A covered stent construct provides an effective vascular bypass conduit. However, the anticoagulation risk can lead to fatal outcomes. The neurosurgeon must always strive for primary repair of an injured sinus., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

To determine whether a classification based on the contour of the photoplethysmography signal (PPGc) can detect changes in systolic arterial blood pressure (SAP) and vascular tone. Episodes of normotension (SAP 90-140 mmHg), hypertension (SAP > 140 mmHg) and hypotension (SAP < 90 mmHg) were analyzed in 15 cardiac surgery patients. SAP and two surrogates of the vascular tone, systemic vascular resistance (SVR) and vascular compliance (Cvasc = stroke volume/pulse pressure) were compared with PPGc. Changes in PPG amplitude (foot-to-peak distance) and dicrotic notch position were used to define 6 classes taking class III as a normal vascular tone with a notch placed between 20 and 50% of the PPG amplitude. Class I-to-II represented vasoconstriction with notch placed > 50% in a small PPG, while class IV-to-VI described vasodilation with a notch placed < 20% in a tall PPG wave. 190 datasets were analyzed including 61 episodes of hypertension [SAP = 159 (151-170) mmHg (median 1st-3rd quartiles)], 84 of normotension, SAP = 124 (113-131) mmHg and 45 of hypotension SAP = 85(80-87) mmHg. SAP were well correlated with SVR (r = 0.78, p < 0.0001) and Cvasc (r = 0.84, p < 0.0001). The PPG-based classification correlated well with SAP (r = - 0.90, p < 0.0001), SVR (r = - 0.72, p < 0.0001) and Cvasc (r = 0.82, p < 0.0001). The PPGc misclassified 7 out of the 190 episodes, presenting good accuracy (98.4% and 97.8%), sensitivity (100% and 94.9%) and specificity (97.9% and 99.2%) for detecting episodes of hypotension and hypertension, respectively. Changes in arterial pressure and vascular tone were closely related to the proposed classification based on PPG waveform.Clinical Trial Registration NTC02854852.

The aim of the present study is to estimate the export fluxes of major dissolved species at the scale of the Amazon basin, to identify the main parameters controlling their spatial distribution and to identify the role of discharge variability in the variability of the total dissolved solid (TDS) flux through the hydrological cycle. Data are compiled from the monthly hydrochemistry and daily discharge database of the "Programa Climatologico y Hidrologico de la Cuenca Amazonica de Bolivia" (PHICAB) and the HYBAM observatories from 34 stations distributed over the Amazon basin (for the 1983-1992 and 2000-2012 periods, respectively). This paper consists of a first global observation of the fluxes and temporal dynamics of each geomorphological domain of the Amazon basin. Based on mean interannual monthly flux calculations, we estimated that the Amazon basin delivered approximately 272 × 10(6) t year(-1) (263-278) of TDS during the 2003-2012 period, which represents approximately 7 % of the continental inputs to the oceans. This flux is mainly made up by HCO3, Ca and SiO2, reflecting the preferential contributions of carbonate and silicate chemical weathering to the Amazon River Basin. The main tributaries contributing to the TDS flux are the Marañon and Ucayali Rivers (approximately 50 % of the TDS production over 14 % of the Amazon basin area) due to the weathering of carbonates and evaporites drained by their Andean tributaries. An Andes-sedimentary area-shield TDS flux (and specific flux) gradient is observed throughout the basin and is first explained by the TDS concentration contrast between these domains, rather than variability in runoff. This observation highlights that, under tropical context, the weathering flux repartition is primarily controlled by the geomorphological/geological setting and confirms that sedimentary areas are currently active in terms of the production of dissolved load. The log relationships of concentration vs discharge have been characterized over all the studied stations and for all elements. The analysis of the slope of the relationship within the selected contexts reveals that the variability in TDS flux is mainly controlled by the discharge variability throughout the hydrological year. At the outlet of the basin, a clockwise hysteresis is observed for TDS concentration and is mainly controlled by Ca and HCO3 hysteresis, highlighting the need for a sampling strategy with a monthly frequency to accurately determine the TDS fluxes of the basin. The evaporite dissolution flux tends to be constant, whereas dissolved load fluxes released from other sources (silicate weathering, carbonate weathering, biological and/or atmospheric inputs) are mainly driven by variability in discharge. These results suggest that past and further climate variability had or will have a direct impact on the variability of dissolved fluxes in the Amazon. Further studies need to be performed to better understand the processes controlling the dynamics of weathering fluxes and their applicability to present-day concentration-discharge relationships at longer timescales.

The dioxin and dioxin-like compounds are regarded as one of the most toxic group of environmental contaminants. Food for the commercial market is regularly monitored for their dioxin levels and the concentration allowed in food is strictly regulated. Less is known about locally caught fish from recreational fishing, which is often brought home for consumption. This can be fish caught from nearby lakes or streams or fish with marine origin close to industrial areas or harbours that are not regularly monitored for their dioxin levels. In this study, we established collaboration with schools in 13 countries. We received 203 samples of 29 different fish species of which Atlantic cod was the most abundant followed by brown trout and pollock. In general, the majority of samples from the participating countries had low concentrations (between 0.1 and 0.2 pg/g chemical-activated luciferase gene expression toxic equivalency wet weight (CALUX TEQ w.w.)) of dioxins and dioxin-like PCBs. Only 18 samples had concentrations above 1 pg/g CALUX TEQ w.w., and only 2 dab samples had concentration above maximum levels set by the European Commission. The Atlantic cod samples showed a significant reduction in the concentrations of dioxins with increasing latitude indicating less contamination of dioxin and dioxin-like compounds in the north of Norway. The results indicate that a moderate consumption of self-caught fish at presumed non-contaminated sites does not represent a major risk for exposure to dioxins or dioxin-like compounds at concentrations associated with adverse health effects. Recreational fishermen should, however, obtain knowledge about local fish consumption advice.

A population pharmacokinetic analysis was conducted to characterize the pharmacokinetics of fexofenadine in Japanese pediatric patients (6 months through 16 years) with perennial allergic rhinitis or atopic dermatitis. The dataset was composed of 515 patients (including 109 adults), for a total of 1,080 concentration-time points. The analysis was performed with NONMEM using the SAEM method. Several structural models and residual error models were evaluated. The relationship between the individual estimates and the potential covariates was then investigated: demographic and pathophysiologic characteristics were tested as potential model covariates (forward selection method). The qualification of the model was performed using visual predictive check and bootstrap. A two-compartment disposition model with first-order absorption best fitted the data. The inter-individual variability was modeled through an exponential error model for all parameters (except for ka for which no inter-individual term could be estimated), while a proportional error model was used to model the residual variability. The final model included two covariates on elimination clearance and one on the intercompartmental clearance. CL/F was related to BSA and patient's age (expressed in months) Q/F was also related to BSA. Once the model was correctly qualified, exposure parameters such as Cmax and AUCτ were computed and compared between each age sub-group and between Japanese and Caucasians patients. These comparisons did not reveal any major difference (less than 50 %) between subgroups.

Background: Flexible endoscopy is an integral part of surgical care. Exposure to endoscopic procedures varies greatly in surgical training. The Society of American Gastrointestinal and Endoscopic Surgeons has developed the Fundamentals of Endoscopic Surgery (FES), which serves to teach and assess the fundamental knowledge and skills required to practice flexible endoscopy of the gastrointestinal tract. This report describes the validity evidence in the development of the FES cognitive examination., Methods: Core areas in the practice of gastrointestinal endoscopy were identified through facilitated expert focus groups to establish validity evidence for the test content. Test items then were developed based on the content areas. Prospective enrollment of participants at various levels of training and experience was used for beta testing. Two FES cognitive test versions then were developed based on beta testing data. The Angoff and contrasting group methods were used to determine the passing score. Validity evidence was established through correlation of experience level with examination score., Results: A total of 220 test items were developed in accordance with the defined test blueprint and formulated into two versions of 120 questions each. The versions were administered randomly to 363 participants. The correlation between test scores and training level was high (r = 0.69), with similar results noted for contrasting groups based on endoscopic rotation and endoscopic procedural experience. Items then were selected for two test forms of 75 items each, and a passing score was established., Conclusions: The FES cognitive examination is the first test with validity evidence to assess the basic knowledge needed to perform flexible endoscopy. Combined with the hands-on skills examination, this assessment tool is a key component for FES certification.

Background: The Global Operative Assessment of Laparoscopic Skill (GOALS) is one validated metric utilized to grade laparoscopic skills and has been utilized to score recorded operative videos. To facilitate easier viewing of these recorded videos, we are developing novel techniques to enable surgeons to view these videos. The objective of this study is to determine the feasibility of utilizing widespread current consumer-based technology to assist in distributing appropriate videos for objective evaluation., Methods: Videos from residents were recorded via a direct connection from the camera processor via an S-video output via a cable into a hub to connect to a standard laptop computer via a universal serial bus (USB) port. A standard consumer-based video editing program was utilized to capture the video and record in appropriate format. We utilized mp4 format, and depending on the size of the file, the videos were scaled down (compressed), their format changed (using a standard video editing program), or sliced into multiple videos. Standard available consumer-based programs were utilized to convert the video into a more appropriate format for handheld personal digital assistants. In addition, the videos were uploaded to a social networking website and video sharing websites., Results: Recorded cases of laparoscopic cholecystectomy in a porcine model were utilized. Compression was required for all formats. All formats were accessed from home computers, work computers, and iPhones without difficulty. Qualitative analyses by four surgeons demonstrated appropriate quality to grade for these formats., Conclusions: Our preliminary results show promise that, utilizing consumer-based technology, videos can be easily distributed to surgeons to grade via GOALS via various methods. Easy accessibility may help make evaluation of resident videos less complicated and cumbersome.

Background: Natural orifice transluminal endoscopic surgery (NOTES) makes it possible to perform intraperitoneal surgical procedures with a minimal number of access points in the abdominal wall. Currently, it is not possible to perform these interventions without the help of abdominal wall entryways, so these procedures are hybrids fusing minilaparoscopy and transluminal endoscopic surgery. This report presents a prospective clinical series of 25 patients who underwent transvaginal hybrid cholecystectomy for cholelithiasis., Methods: The study comprised a clinical series of 25 consecutive nonrandomized women who underwent a fusion transvaginal NOTES and minilaparoscopy procedure with two trocars for cholelithiasis: one 5-mm umbilical trocar and one 3-mm trocar in the upper left quadrant. The study had no control group., Results: The scheduled surgical intervention was performed for all 25 women. No intraoperative complications occurred. One patient had mild hematuria that resolved in less than 12 h, but no other complications occurred during an average follow-up period of 140 days. Of the 25 women, 20 were discharged in 24 h, and 5 were discharged less than 12 h after the procedure., Conclusion: Hybrid transvaginal cholecystectomy, combining NOTES and minilaparoscopy, is a good surgical model for minimally invasive surgery. It can be performed in surgical settings where laparoscopy is practiced regularly using the instruments normally used for endoscopy and laparoscopic surgery. Due to the reproducibility of the intervention and the ease of vaginal closure, hybrid transvaginal cholecystectomy will permit further development of NOTES in the future.