Broad Margin Research Articles

Dermatofibrosarcoma Protuberans: The Impact of the Surgical Incision Site in Relation to Tumor Recurrence.

Dermatofibrosarcoma protuberans (DFSP) is a rare, locally invasive cutaneous sarcoma with a high propensity for recurrence, even following complete surgical excision. DFSP exhibits a low metastatic potential and is characterized by a distinctive honeycomb-like architecture composed of uniformly arranged spindle cells that frequently show CD34 immunostaining. Common surgical approaches include wide local excision (WLE), Mohs micrographic surgery (MMS), and, in severe cases, amputation.This literature review explores the impact of the surgical incision site on DFSP recurrence, placing particular emphasis on anatomically challenging regions, such as the head and neck, where achieving tumor-free margins is often difficult due to complex structures and limited tissue for resection. Our primary hypothesis is that DFSP cases arising in these intricate anatomical areas exhibit a higher recurrence risk compared to those on the trunk or extremities, where broader margins are more feasible. To investigate this hypothesis, data from a range of peer-reviewed studies and case reports were analyzed, including diverse patient populations from international sources, institutional case series, and large-scale database analyses, such as the Surveillance, Epidemiology, and End Results (SEER) Program. We evaluated recurrence rates, the adequacy of surgical margins, and anatomical influences across these studies while also focusing on histopathological findings like the presence of fibrosarcomatous (FS) variants, which are known to correlate with aggressive behavior and recurrence. We also reviewed emerging targeted therapies, particularly imatinib, as promising options for managing cases of unresectable or recurrent DFSP, thereby expanding therapeutic choices for clinicians when surgery alone proves inadequate.Our findings suggest a marked increase in recurrence risk for DFSP cases located in the head and neck region, attributed to limitations in achieving wide excision margins in these areas. This review underscores the importance of detailed preoperative planning, precise excision strategies, and individualized approaches based on tumor location to enhance surgical outcomes. Long-term surveillance remains crucial in DFSP management, particularly in high-risk locations, and continued research into targeted therapies offers hope for reducing recurrence rates and improving the quality of life for affected patients.

Topological Reinforcement Adaptive Algorithm (TOREADA) Application to the Alerting of Convulsive Seizures and Validation with Monte Carlo Numerical Simulations

The detection of adverse events—for example, convulsive epileptic seizures—can be critical for patients suffering from a variety of pathological syndromes. Algorithms using remote sensing modalities, such as a video camera input, can be effective for real-time alerting, but the broad variability of environments and numerous nonstationary factors may limit their precision. In this work, we address the issue of adaptive reinforcement that can provide flexible applications in alerting devices. The general concept of our approach is the topological reinforced adaptive algorithm (TOREADA). Three essential steps—embedding, assessment, and envelope—act iteratively during the operation of the system, thus providing continuous, on-the-fly, reinforced learning. We apply this concept in the case of detecting convulsive epileptic seizures, where three parameters define the decision manifold. Monte Carlo-type simulations validate the effectiveness and robustness of the approach. We show that the adaptive procedure finds the correct detection parameters, providing optimal accuracy from a large variety of initial states. With respect to the separation quality between simulated seizure and normal epochs, the detection reinforcement algorithm is robust within the broad margins of signal-generation scenarios. We conclude that our technique is applicable to a large variety of event detection systems.

Phytochemical and Toxicity Evaluation of Methanol Extracts of Leaves and Fruits of Zanthoxylum rhetsa (Rutaceae)

Zanthoxylum rhetsa is extensively utilized in the realm of gastronomy and therapeutics. However, existing literature lacks any documentation concerning the systematic assessment of the toxicity characteristics of the foliage and produce of Z.rhetsa. Consequently, the present inquiry was executed to appraise the immediate toxicity examinations of the methanol extract derived from the leaves and fruits in mice, in accordance with the regulations delineated by the Organization for Economic Cooperation and Development (OECD 420, 2001). In this investigation, a solitary dosage of 5000 mg/kg body mass of the specimen was administered to female mice, as stipulated by the OECD guidelines. Daily surveillance ensued for a total of fourteen days, with the objective of detecting any indications of toxicity or fatality. Upon the culmination of this two-week period, a comprehensive analysis involving hematological, biochemical, and histopathological evaluations was conducted. The outcomes of the immediate toxicity investigations evinced that neither the leaves nor the fruits extract exhibited any morbidity, conspicuous alterations in corporeal mass, nor any discernible impairment in behavioral or motor neural activities in the mice. The haematological and serum biochemical parameters did not exhibit significant disparities from the control groups. These findings were corroborated by histopathological investigations, wherein no abnormalities or pathological alterations were detected in the vital organs. The LD 50 (oral lethal dose) of the samples was determined to exceed 5000 mg/kg body weight. Consequently, the methanol extract of leaf and fruit extract of Z.rhetsa can be regarded as non-toxic and demonstrated a broad margin of safety for its therapeutic application.

WP4.8 - Separating the sheep from the goat - Outcomes Based on Low, High and Extreme Risk NELA scoring

Abstract Background According to the UK National Emergency Laparotomy Audit (NELA), high-risk emergency laparotomy is defined as any patient with a NELA risk score of ≥ 5%, indicating a predicted mortality rate of 5% or higher within 30 days after the procedure. However, scores ranging between 5%-100% fall within the similar ambit of requiring intensive care support. There is a lack of distinction among the patients in the high-risk group with measurable outcomes. Given the broad margin, we stratified NELA mortality into low risk (<5%), high risk (5-50%) and extreme risk (>50%). The study was retrospective, involving 150 laparotomies, and looked at the outcome amongst various stratifications. Methods A retrospective analysis of 150 patients who underwent emergency laparotomy was evaluated against the documented NELA scoring and stratified into categories. Baseline characteristics, encompassing age, usual place of residence, ASA physical status, and NELA score, were analyzed to compare the three groups (low, high and extreme risk). The outcomes under consideration included 30- and 90-day mortality, hospital length of stay, re-operation rates and the length of stay in critical care. Results There existed clear outcomes with the 30-day mortality and re-operation rates between the three groups. Our study highlighted the gap that exists in the clinical prognosis and shared decision-making in patients with high (5-50%) and extreme risk (>50%) NELA scores. Further, we worked out a risk stratification model that could guide consenting these patients. Conclusions Outcomes based on NELA score stratification will only strengthen the shared decision-making process for a patient with an objective understanding of the risks involved.

Preclinical antitumor efficacy of ETN101, a novel oral anticancer agent with Wnt/ß-catenin signaling inhibition, TME modulation, and VEGFR2 targeting for advanced hepatocellular carcinoma treatment.

e16138 Background: Hepatocellular carcinoma (HCC) is an important cancer in worldwide with over 900,000 new cases and approximately 830,000 deaths were reported in 2020. It ranks sixth in global cancer incidence and third in mortality, highlighting its worldwide significance. The high frequency of occurrence and elevated mortality rates contribute to a significant socio-economic burden. However, most patients are diagnosed in the middle and late stages, missing the optimal treatment. Therefore, it is necessary to develop novel, safe, and effective drugs for HCC inhibition, elucidating their mechanisms of action. Methods: Evaluation of ETN101 was utilized in subcutaneous xenograft and orthotopic animal models with human HCC cell lines. ETN101 was administered orally. The tumor volume, tumor weight, and bodyweight were measured, and cancer cell proliferation and apoptosis were also analyzed. The toxicity of ETN101 was investigated through GOT/GPT and histological analysis in the liver and kidney. The signaling mechanism of ETN101 was analyzed through kinase analysis, phosphorylation, in silico docking analysis, and RNA sequencing, both in vitro and in vivo. Results: ETN101 demonstrated approximately 30% tumor inhibition at 10 mg/kg group compared to control. Moreover, 20 mg/kg treatment group also showed significant tumor reduction in all individuals with one complete response (CR). Interestingly, all individuals exhibited CR from 40 to 82 mg/kg treatment groups. During the 10 administrations of Nexavar and Lenvatinib, individuals who showed proliferated tumors persistently were selected, followed by the administration of ETN101. All individuals exhibited either CR or significant reduction in tumor volume upon ETN101. After tracking complete responders for two months, there were no signs of tumor recurrence or metastasis. These results suggested that ETN101 has anticancer effect by regulating Wnt/ß-catenin pathway in tumor microenvironment (TME) with increasing the infiltration of cytotoxic T cells into the tumor. Furthermore, it targets VEGFR2, blocking angiogenesis-related signals to improve therapeutic effects in advanced HCC. Conclusions: Due to lack of effective single drugs for advanced HCC patients, combination therapy is used clinically. We developed ETN101, a monotherapy that targets VEGFR2 and modulates the TME with the same mechanism as the combination therapy. ETN101 also showed excellent efficacy in preclinical study and secured a broad safety margin relative to the effective dose. In addition, ETN101 was effective in those who are not responded to conventional targeted cancer therapies. It is anticipated that ETN101 could serve as a novel therapeutic strategy for advanced HCC patients.

Lethal combination for seedlings: extreme heat drives mortality of drought-exposed high-elevation pine seedlings.

Hotter drought- and biotically-driven tree mortality are expected to increase with climate change in much of the western United States, and species persistence will depend upon ongoing establishment under novel conditions or migration to track ecological niche requirements. High-elevation tree species may be particularly vulnerable to increasing water stress as snowpack declines, increasing the potential for adult mortality and simultaneous regeneration failures. Seedling survival will be determined by ecophysiological limitations in response to changing water availability and temperature. We exposed seedlings from populations of Pinus longaeva, Pinus flexilis, and Pinus albicaulis to severe drought and concurrent temperature stress in common gardens testing timing of drought onset under two different temperature regimes. We monitored seedling functional traits, physiological function, and survival. The combined stressors of water limitation and extreme heat led to conservative water use strategies and declines in physiological function, with these joint stressors ultimately exceeding species' tolerances and leading to complete episodic mortality across all species. Growing conditions were the primary determinant of seedling trait expression, with seedlings exhibiting more drought-resistant traits such as lower specific leaf area in the hottest, driest treatment conditions. Water stress-induced stomatal closure was also widely apparent. Under adequate soil moisture, seedlings endured prolonged exposure to high air and surface temperatures, suggesting broad margins for survival. The critical interaction between soil moisture and temperature suggests that rising temperatures will exacerbate growing season moisture stress. Our results highlight the importance of local conditions over population- and species-level influences in shaping strategies for stress tolerance and resistance to desiccation at this early life stage. By quantifying some of the physiological consequences of drought and heat that lead to seedling mortality, we can better understand the future effects of global change on the composition and distribution of high-elevation conifer forests.

Cadomian tectonic evolution of Iran: records of an unusually hot and broad extensional convergent margin on the northern margin of Gondwana

ABSTRACT The continental crust of Iran is dominated by abundant calc-alkaline and alkaline plutonic and volcanic rocks and by rifted basins filled with mostly terrigenous sedimentary rocks that formed at a Late Ediacaran to Cambrian extensional convergent plate margin along the northern margin of Gondwana. Here we present new zircon U–Pb age, geochemical, and isotopic data from plutonic (granite-granodiorite) and metamorphic (gneiss) rocks in the Kariznou region of NE Iran to provide insights into the nature of the Cadomian convergent margin of Iran. Geochemical data indicate calc-alkaline signatures, characterized by strong depletions in Nb, Ta, P, and Ti and arc-like trace element patterns. New zircon U–Pb ages show that calc-alkaline granitoids and granitic gneiss formed at ~564 to 537 Ma and 538 Ma, respectively. Bulk rock Sr-Nd isotopic data of calc-alkaline rocks have εNd(t) = –5.42 to −5.53 and −6.93 to −7.43 for granite and gneiss, respectively. The gneisses show stronger interaction with and/or re-melting of older continental crust than do granitic rocks. We interpret Kariznou magmatic rocks as forming in association with strong extension accompanied by crustal assimilation. Extension initiated ~570 Ma with the deposition of Late Ediacaran sediments, and magmatism began at 545–535 Ma, generating calc-alkaline magmas. The tectonomagmatic evolution of the Kariznou region encapsulates the prolonged transition of Cadomian Iran from a strongly extensional convergent margin, possibly as a result of oblique oceanic subduction and slab roll-back of the subducting Proto-Tethys oceanic lithosphere, culminating in the formation of an Early Palaeozoic passive margin on the northern side of Gondwana.

Analysis and design approach of wideband digital‐based feedforward ring oscillators

AbstractMulti‐protocol applications and complex systems‐on‐chip demand several clock sources to fulfill all data‐rate requirements. Among the different types of clock sources, LC oscillators dominate the high data‐rate communication standards where frequency stability is a major constraint. In contrast, ring oscillators are preferred for legacy support applications due to their wider tuning range and where stability is not a constraint. Since stability enhancement techniques have been already implemented to ring oscillators, increasing the tuning range of a single ring clock reference might fulfill a broad margin of data rates. This paper presents an analysis and a design approach of wideband digital‐based oscillators based on secondary feedforward paths to support most of the data‐rate requirements inside systems‐on‐chips. Here, we present the inclusion of these auxiliary loops as a tuning range enhancement technique to reduce the total number of required clock references. The presented analysis comprises piece‐wise functions able to accurately predict an FDRO oscillation frequency. Using the piece‐wise model, we present a 15,000 12‐track standard‐cell scalable feedforward oscillator. Auxiliary feedforward inverters allow a maximum 1.5 GHz frequency and a 3 tuning range enhancement while enabling a 100 kHz minimum oscillation frequency. The proposed oscillator occupies an area of 0.05 mm2 in a 180 nm CMOS pure digital node and achieves a 41 ps@1.25 GHz RMS jitter of and a −121 dB FOM.

Feasibility of Perineal Defect Reconstruction with Simplified Fasciocutaneous Inferior Gluteal Artery Perforator (IGAP) Flaps after Tumor Resection of the Lower Rectum: Incidence and Outcome in an Interdisciplinary Approach.

Extralevator abdominoperineal excision (ELAPE) is a relatively new surgical technique for low rectal cancers, enabling a more radical approach than conventional abdominoperineal excision (APE) with a potentially better oncological outcome. To date, no standard exists for reconstruction after extended or extralevator approaches of abdominoperineal (ELAPE) resection for lower gastrointestinal cancer or inflammatory tumors. In the recent literature, techniques with myocutaneous flaps, such as the VY gluteal flap, the pedicled gracilis flap, or the pedicled rectus abdominis flaps (VRAM) are primarily described. We propose a tailored concept with the use of bilateral adipo-fasciocutaneous inferior gluteal artery perforator (IGAP) advancement flaps in VY fashion after ELAPE surgery procedures. This retrospective cohort study analyzes the feasibility of this concept and is, to our knowledge, one of the largest published series of IGAP flaps in the context of primary closure after ELAPE procedures. In a retrospective cohort analysis, we evaluated all the consecutive patients with rectal resections from Jan 2017 to Sep 2021. All the patients with abdominoperineal resection were included in the study evaluation. The primary endpoint of the study was the proportion of plastic reconstruction and inpatient discharge. Out of a total of 560 patients with rectal resections, 101 consecutive patients with ELAPE met the inclusion criteria and were included in the study evaluation. The primary direct defect closure was performed in 72 patients (71.3%). In 29 patients (28.7%), the defect was closed with primary unilateral or bilateral IGAP flaps in VY fashion. The patients' mean age was 59.4 years with a range of 25-85 years. In 84 patients, the indication of the operation was lower rectal cancer or anal cancer recurrence, and non-oncological resections were performed in 17 patients. Surgery was performed in a minimally invasive abdominal approach in combination with open perineal extralevatoric abdominoperineal resection (ELAPE) and immediate IGAP flap reconstruction. The rate of perineal early complications after plastic reconstruction was 19.0%, which needed local revision due to local infection. All these interventions were conducted under general anesthesia (Clavien-Dindo IIIb). The mean length of the hospital stay was 14.4 days after ELAPE, ranging from 3 to 53 days. Since radical resection with a broad margin is the standard choice in primary, sphincter-infiltrating rectal cancer and recurrent anal cancer surgery in combination with ELAPE, the choice technique for pelvic floor reconstruction is under debate and there is no consensus. Using IGAP flaps is a reliable, technical, easy, and safe option, especially in wider defects on the pelvic floor with minimal donor site morbidity and an acceptable complication (no flap necrosis) rate. The data for hernia incidence in the long term are not known.

An insight to treat cardiovascular diseases through phytochemicals targeting PPAR-α.

Peroxisome proliferator-activated receptor-α (PPAR-α) belonging to the nuclear hormone receptor superfamily is a promising target for CVDs which mechanistically improves the production of high-density lipid as well as inhibit vascular smooth muscle cell proliferation. PPAR-α mainly interferes with adenosine monophosphate-activated protein kinase, transforming growth factor-β-activated kinase, and nuclear factor-κB pathways to protect against cardiac complications. Natural products/extracts could serve as a potential therapeutic strategy in CVDs for targeting PPAR-α with broad safety margins. In recent years, the understanding of naturally derived PPAR-α agonists has considerably improved; however, the information is scattered. In vitro and in vivo studies on acacetin, apigenin, arjunolic acid, astaxanthin, berberine, resveratrol, vaticanol C, hispidulin, ginsenoside Rb3, and genistein showed significant effects in CVDs complications by targeting PPAR-α. With the aim of demonstrating the tremendous chemical variety of natural products targeting PPAR-α in CVDs, this review provides insight into various natural products that can work to prevent CVDs by targeting the PPAR-α receptor along with their detailed mechanism.

The Synthetic Collagen-Binding Peptide NIPEP-OSS Delays Mouse Myeloma Progression.

Multiple myeloma (MM) is the second most common hematological malignancy. It is a clonal B-cell disorder characterized by the proliferation of malignant plasma cells in the bone marrow, the presence of monoclonal serum immunoglobulin, and osteolytic lesions. An increasing amount of evidence shows that the interactions of MM cells and the bone microenvironment play a significant role, suggesting that these interactions may be good targets for therapy. The osteopontin-derived collagen-binding motif-bearing peptide NIPEP-OSS stimulates biomineralization and enhances bone remodeling dynamics. Due to its unique targeted osteogenic activity with a broad safety margin, we evaluated the potential of NIPEP-OSS for anti-myeloma activity using MM bone disease (MMBD) animal models. In a 5TGM1-engrafted NSG model, the survival rates of the control and treated groups were significantly different (p = 0.0014), with median survival times of 45 and 57 days, respectively. The bioluminescence analyses showed that myeloma slowly developed in the treated mice compared to the control mice in both models. NIPEP-OSS enhanced bone formation by increasing biomineralization in the bone. We also tested NIPEP-OSS in a well-established 5TGM1-engrafted C57BL/KaLwRij model. Similar to the previous model, the median survival times of the control and treated groups were significantly different (p = 0.0057), with 46 and 63 days, respectively. In comparison with the control, an increase in p1NP was found in the treated mice. We concluded that NIPEP-OSS delays mouse myeloma progression via bone formation in MMBD mouse models.

Two new species of Eurydice Leach, 1815 (Crustacea: Isopoda: Cirolanidae) from the Andaman Islands, northern Indian Ocean

ABSTRACT Eurydice andamanensis sp. nov. and Eurydice mohani sp. nov. are described from intertidal sandy beaches of South Andaman, Andaman Islands. Eurydice andamanensis sp. nov. can be identified by the posterior margin of pleotelson being one-fourth of the pleotelson in width, weakly convex with 11 plumose marginal setae and 4 robust setae; appendix masculina 0.8 times as long as endopod, projecting slightly beyond endopod distal margin by one-third of its length, distally broad, widely rounded, curved medially and mesial margin with 4 small acute cuticular scales; Eurydice mohani sp. nov. can be identified by the posterior margin of pleotelson with 6 plumose marginal setae, pleotelson without distinct depression on anterodorsal surface; appendix masculina 0.4 times as long as endopod, projecting beyond mid-region of endopod by 0.02 of its length, lateral margin with a sinuate notch and apex is rounded. http://www.zoobank.org/urn:lsid:zoobank.org:pub:AFF18D66-4CE3-4D73-BAAA-39083D542008

New constraints on Cenozoic subduction between India and Tibet

The type of lithosphere subducted between India and Tibet since the Paleocene remains controversial; it has been suggested to be either entirely continental, oceanic, or a mixture of the two. As the subduction history of this lost lithosphere strongly shaped Tibetan intraplate tectonism, we attempt to further constrain its nature and density structure with numerical models that aim to reproduce the observed history of magmatism and crustal thickening in addition to present-day plateau properties between 83°E and 88°E. By matching time-evolving geological patterns, here we show that Tibetan tectonism away from the Himalayan syntaxis is consistent with the initial indentation of a craton-like terrane at 55 ± 5 Ma, followed by a buoyant tectonic plate with a thin crust, e.g., a broad continental margin (Himalandia). This new geodynamic scenario can explain the seemingly contradictory observations that had led to competing hypotheses like the subduction of Greater India versus largely oceanic subduction prior to Indian indentation.

Successful Treatment of Complicated Influenza A(H3N2) Virus Infection and Rhabdomyolysis with Compassionate Use of IV Zanamivir

In 2019, EMA licensed intravenous (IV) zanamivir for severe influenza virus infection in children over 6 months as well as adults. Prior to that, it was possible via a compassionate use program. We present successful compassionate use of IV zanamivir in a 14-year-old female with severe influenza A(H3N2) and multi-organ failure, who had failed oral oseltamivir. Her illness was complicated by acute respiratory distress syndrome and rhabdomyolysis requiring extracorporeal membrane oxygenation and hemofiltration. Considering the broad safety margins with neuraminidase inhibitors, an adult dose of 600 mg IV BID was administered in this 60 kg patient. Influenza virus was cleared rapidly and undetectable on day 13. Creatine kinase (CK) values were dropping from 38,000 to 500 within nine days. Given the recent licensure of IV zanamivir, multi-center prospective observational studies in pediatric Intensive Care Unit patients would be beneficial to guide the most appropriate use of IV zanamivir in this vulnerable age group.

Space-time analysis of scientific research on Brosimum alicastrum Swartz

Brosimum alicastrum is a forest species of broad natural distribution in southeastern Mexico, with high potential for animal and human diets, although with incipient forest management. The objective of this study was to analyze the spatial-temporal evolution of basic and applied research where B. alicastrum was the object of study; through a bibliometric analysis of the texts available in the main editorial houses; to identify research areas that are not developed. In 308 texts found from 1883 to 2020, spatial-temporal evolution showed an exponential growth that concentrated the highest productivity from 2002 to 2020 (222 texts) in countries of the Americas. For the case of Mexico, it was found that the research was focused the southeast, which coincides with the natural distribution of the species. However, this research had a low impact (measured by the number of bibliographic citations) as a result of the publication in journals edited in Spanish, while impact journals are led by English-speaking countries, in English. Therefore, the research about B. alicastrum in Latin America has a broad margin of improvement through the publication of texts in English and in journals of greater impact, through the development of research areas that have been slightly explored such as silviculture of the species with special emphasis on its propagation, management in nursery, and forest plantations, which can contribute to food security in each country by ensuring the prime material of an emerging food agro-industry.

Immature chaerilid scorpions from mid-Cretaceous amber of northern Myanmar (Arachnida: Scorpiones: Chaeriloidea)

Extant scorpions of the small family Chaerilidae are very sparse, and they are poorly documented in the fossil record. Here we describe two immature chaerilids from mid-Cretaceous amber of northern Myanmar based on multiple imaging methods. Our specimens can be unambiguously assigned to Chaerilus in family Chaerilidae based on their complete type B trichobothrial pattern, very broad anterior margin of maxillary lobes I, serrated ventral denticle of cheliceral movable finger, presence of pectinal fulcra, and spiniform setae on the ventral surface of tarsi.

Hyporthodus griseofasciatus (Perciformes: Epinephelidae), a new species of deep-water grouper from the west coast of Australia.

A new species of deep-water epinephelid fish is described from the west coast of Australia based on 14 specimens, 99-595 mm standard length. Hyporthodus griseofasciatus sp. nov. is endemic to Western Australia from Barrow Island to Two Peoples Bay in depths of 76-470 m. It has a series of eight grey bands alternating with eight brown bands along the body and the soft dorsal, soft anal and caudal fin margins are pale cream to white. It is distinguished from its nearest congener, H. ergastularius, by the presence of a star-like pattern of radiating lines on the head versus an overall brownish colour in the latter as well as significant differences in the quantitative analyses of 25 morphological characters. The two species have allopatric distributions on either side of the Australian continent. H. griseofasciatus is distinguished from H. octofasciatus by several grey bands being distinctly narrower than other grey bands (vs. all grey bands subequal in the latter) and the presence of broad white margins on the dorsal, caudal and anal fins (vs. narrow or absent in the latter). Some scale counts appear to also differ. Analyses of mitochondrial cytochrome oxidase subunit 1 sequences revealed reciprocally monophyletic clades with fixed differences and genetic distances typical of recently diverged species of fishes.

Pharmacologic Weight Management in the Era of Adolescent Obesity.

Pediatric obesity is a serious health problem in the United States. While lifestyle modification therapy with dietary changes and increased physical activity are integral for the prevention and treatment of mild to moderate obesity in youth, only a modest effect on sustained weight reduction is observed in children and young adults with severe obesity. This underscores the need for additional evidence-based interventions for children and adolescents with severe obesity, including pharmacotherapy, before considering invasive procedures such as bariatric surgery. This publication focuses on recent advances in pharmacotherapy of obesity with an emphasis on medications approved for common and rarer monogenic forms of pediatric obesity. We review medications currently available in the United States, both those approved for weight reduction in children and "off-label" medications that have a broad safety margin. It is intended that this review will provide guidance for practicing clinicians and will encourage future exploration for successful pharmacotherapy and other interventions for obesity in youth.

Adjudicating labor mobility under France’s agreements on the joint management of migration flows: How courts politicize bilateral migration diplomacy

Abstract France’s agreements on the joint management of migration flows (AJMs) figure centrally within studies of bilateral migration agreements. With their origins in friendship and navigation treaties of the late 19th century, the AJMs are successors to the postcolonial, circular mobility conventions of the 1960s, and are uniquely positioned for periodizing the evolution of bilaterally negotiated labor mobilities. Nonetheless, due to the European Union’s reluctance to embrace mass regularization and the EU Member States’ legislative powers over labor markets, they have time and again scotched France’s ambition to leverage preferential labor market entries in exchange for more cooperation over irregular migration. Through documents and statistical data analysis, this Article studies the case of Senegal’s negotiation of additional pathways to France for its lower-skilled workers. At the center is France’s administrative court of appeals, which has confirmed the broad margin of discretion over Art. 42 in the AJM between France and Senegal. This jurisprudence has decoupled the automatic linkage between a job listed under duress in France under the Annex to the AJM and the entitlement to exceptional admission. We argue that France’s courts have removed a privilege of Senegalese workers, which has re-politicized France’s migration diplomacy with Senegal. At the same time, retention of the prefectorial discretionary power has levelled the playing field among West and North African countries that have concluded similar bilateral agreements with France. This Article adds to the research on bilateral migration agreements by proposing a multilevel legal analysis, which studies AJMs in the context of France’s common law, EU labor and return directives, and the multilateral of WTO/GATS liberalization.

Dissolved and Particulate Barium Distributions Along the US GEOTRACES North Atlantic and East Pacific Zonal Transects (GA03 and GP16): Global Implications for the Marine Barium Cycle

AbstractProcesses controlling dissolved barium (dBa) were investigated along the GEOTRACES GA03 North Atlantic and GP16 Eastern Tropical Pacific transects, which traversed similar physical and biogeochemical provinces. Dissolved Ba concentrations are lowest in surface waters (∼35–50 nmol kg−1) and increase to 70–80 and 140–150 nmol kg−1 in deep waters of the Atlantic and Pacific transects, respectively. Using water mass mixing models, we estimate conservative mixing that accounts for most of dBa variability in both transects. To examine nonconservative processes, particulate excess Ba (pBaxs) formation and dissolution rates were tracked by normalizing particulate excess 230Th activities. Th‐normalized pBaxs fluxes, with barite as the likely phase, have subsurface maxima in the top 1,000 m (∼100–200 μmol m−2 year−1 average) in both basins. Barite precipitation depletes dBa within oxygen minimum zones from concentrations predicted by water mass mixing, whereas inputs from continental margins, particle dissolution in the water column, and benthic diffusive flux raise dBa above predications. Average pBaxs burial efficiencies along GA03 and GP16 are ∼37% and 17%–100%, respectively, and do not seem to be predicated on barite saturation indices in the overlying water column. Using published values, we reevaluate the global freshwater dBa river input as 6.6 ± 3.9 Gmol year−1. Estuarine mixing processes may add another 3–13 Gmol year−1. Dissolved Ba inputs from broad shallow continental margins, previously unaccounted for in global marine summaries, are substantial (∼17 Gmol year−1), exceeding terrestrial freshwater inputs. Revising river and shelf dBa inputs may help bring the marine Ba isotope budget more into balance.