bluuebunny/crossref_metadata_2025_split huggingface dataset:
Silver isotope and volatile trace element systematics in galena samples from the Iberian Peninsula and the quest for silver sources of Roman coinage
Authors: Milot Jean , Blichert-Toft Janne , Sanz Mariano Ayarzagüena , Malod-Dognin Chloé , Télouk Philippe , Albarède Francis 
Published: December 2021

Abstract
Silver played a key role in the progressive monetization of early Mediterranean civilizations. We combine Pb and Ag isotopes with volatile trace elements (Bi, Sb, and As) to assess whether, during the Roman occupation of Iberia, galena constituted a significant source of silver. We find that the Pb and Ag isotopic compositions of 47 samples of galena from eight different Iberian mining provinces, many of them exploited during Roman times, are uncorrelated. This indicates that their respective isotopic variabilities depend on different petrogenetic processes. Moreover, the range of Ag isotopic abundances is approximately six times wider than that displayed worldwide by silver coins in general and Roman silver coins in particular. Although galena from the Betics provides the best fit for Pb isotopes with Roman coins, their fit with Ag isotopic compositions is at best sporadic. We suggest that, together with Sb, Bi, and As, silver is primarily derived from fluids boiled off from differentiated mantle-derived magmas. These fluids, in turn, reacted with preexisting galena and functioned as a silver trap. Lead sulfides with ε109Ag of ~0 and unusually rich in Ag, Sb, Bi, and As were the most probable sources of ancient silver, whereas samples with ε109Ag departing significantly from ~0 reflect low-temperature isotopic fractionation processes in the upper crust.
Optimal Method for Disulfide Bond Closure in the Synthesis of Atosiban—Antagonist of Oxytocin Receptors
Authors: Avdeev D. V. , Ovchinnikov M. V. , Dudkina Y. S. , Molokoedov A. S. , Azmuko A. A. , Palkeeva M. E. , Sidorova M. V. 
Published: December 2021

Abstract
This work is devoted to the large-scale solid-phase synthesis (SPS) of Atosiban, Mpa1-D-Tyr(OEt)-Ile-Thr-Asn-Cys6-Pro-Orn-Gly-NH2 cyclic 1,6 disulfide, the only clinically used oxytocin receptor antagonist. The conditions have been selected for the closure of the disulfide bond (S–S) in the Atosiban molecule both in the solution and solid phase with the minimal formation of by-products. A comparative assessment of the formation of the S–S bond was carried out under various conditions. The formation of by-products during the closure of the disulfide bond has been studied both in solution and on the polymer support. The developed technique allows for the synthesis of Atosiban on an enlarged scale (10–20 mmol) involving the cyclization of a protected intermediate with the formation of the S–S bond during solid-phase synthesis with the minimal formation of by-products.
Knee extensor muscle weakness is a risk factor for the development of knee osteoarthritis: an updated systematic review and meta-analysis including 46 819 men and women
Authors: Øiestad Britt Elin , Juhl Carsten B , Culvenor Adam G , Berg Bjørnar , Thorlund Jonas Bloch 
Published: December 2021

ObjectiveTo update a systematic review on the association between knee extensor muscle weakness and the risk of incident knee osteoarthritis in women and men.DesignSystematic review and meta-analysis.Data sourcesSystematic searches in PubMed, EMBASE, SPORTDiscus, CINAHL, AMED and CENTRAL in May 2021.Eligible criteria for selecting studiesLongitudinal studies with at least 2 years follow-up including baseline measure of knee extensor muscle strength, and follow-up measure of symptomatic or radiographic knee osteoarthritis. Studies including participants with known knee osteoarthritis at baseline were excluded. Risk of bias assessment was conducted using six criteria for study validity and bias. Grading of Recommendations Assessments, Development and Evaluation assessed overall quality of evidence. Meta-analysis estimated the OR for the association between knee extensor muscle weakness and incident knee osteoarthritis.ResultsWe included 11 studies with 46 819 participants. Low quality evidence indicated that knee extensor muscle weakness increased the odds of symptomatic knee osteoarthritis in women (OR 1.85, 95% CI 1.29 to 2.64) and in adult men (OR 1.43, 95% CI 1.14 to 1.78), and for radiographic knee osteoarthritis in women: OR 1.43 (95% CI 1.19 to 1.71) and in men: OR 1.39 (95% CI 1.07 to 1.82). No associations were identified for knee injured populations except for radiographic osteoarthritis in men.DiscussionThere is low quality evidence that knee extensor muscle weakness is associated with incident symptomatic and radiographic knee osteoarthritis in women and men. Optimising knee extensor muscle strength may help to prevent knee osteoarthritis.PROSPERO registration numberCRD42020214976.
Single-centre study surveying neurology trainees’ and faculty’s perceptions of the impact of the COVID-19 pandemic on residents’ medical education
Authors: Alhajala Hisham , Ramadan Ahmad Riad , Suneja Aarushi , Schultz Lonni , Zaman Iram F 
Published: December 2021

ObjectiveTo assess perceptions of our neurology residents and faculty regarding training experience and medical education during the early COVID-19 pandemic.MethodsWe distributed two online, voluntary and anonymous surveys to trainees and teaching faculty of our Neurology Department at Henry Ford Hospital. Surveys inquired about trainees’ stress, well-being, clinical experience and satisfaction with medical education and available support resources during the first wave of the COVID-19 pandemic in Michigan (mid-March to June 2020).ResultsA total of 17/31 trainees and 25/42 faculty responded to the surveys. Eight (47%) trainees reported high stress levels. Nine (57%) were redeployed to cover COVID-19 units. Compared with non-redeployed trainees, redeployed residents reported augmented medical knowledge (89% vs 38%, p=0.05). There was no difference in the two groups regarding overall satisfaction with residency experience, stress levels and didactics attendance. Twenty-one (84%) faculty felt that the redeployment interfered with trainees education but was appropriate, while 10 (59%) trainees described a positive experience overall. Both trainees and faculty believed the pandemic positively impacted trainees’ experience by increasing maturity level, teamwork, empathy, and medical knowledge, while both agreed that increased stress and anxiety levels were negative outcomes of the pandemic. Twelve (70%) trainees and 13 (52%) faculty were interested in pursuing more virtual didactics in the future.ConclusionOur findings provide an objective assessment of residents' experience during the COVID-19 pandemic and can guide teaching programmes in their medical education response in the face of future global crises.
Mediating effects of early health on the relationship between early poverty and long-term health outcomes of children: a birth cohort study
Authors: Chiang Wan-Lin , Chiang Tung-liang 
Published: December 2021

ObjectiveThis study analyses the mediating effects of early health prior to age 3 on the association between early poverty and the health outcomes of children at age 12.DesignPopulation-based longitudinal birth cohort study.SettingTaiwan Birth Cohort Study (TBCS), 2005–2017.Participants16 847 TBCS children born in 2005 and followed up at 18 months, 3, 5, 8 and 12 years with available data on poverty and health status.Main outcome measuresChild’s general health, measured by the mothers’ ratings of their child’s health, and hospitalisation experience at 12 years of age.ResultsAmong the TBCS children, the prevalence of fair/poor health and hospitalisation was 20.8% and 2.5% at age 12. The ORs of experiencing fair/poor health and hospitalisation at age 12 were 1.33 (95% CI 1.21 to 1.45) and 1.35 (1.07 to 1.69) for early poverty, respectively. When early poor health was added in the multiple logistic regression models, the effects of early poverty were attenuated on poor general health and no longer significant on hospitalisation for children aged 12 years. Mediation analysis showed that 50%–87% of the total effect of early poverty on health at age 12 was mediated by early health status before age 3.ConclusionsOur findings suggest that poor health in early life plays as a significant mediator in the relationship between early poverty and the long-term health outcomes of children. Universal health coverage thus should be achieved to prevent the adverse health effects of poverty throughout the life course, as one of the most important strategies for children growing up in poverty.
Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma
Authors: Makkouk Amani , Yang Xue (Cher) , Barca Taylor , Lucas Anthony , Turkoz Mustafa , Wong Jonathan T S , Nishimoto Kevin P , Brodey Mary M , Tabrizizad Maryam , Gundurao Smitha R Y , Bai Lu , Bhat Arun , An Zili , Abbot Stewart , Satpayev Daulet , Aftab Blake T , Herrman Marissa 
Published: December 2021

BackgroundGlypican-3 (GPC-3) is an oncofetal protein that is highly expressed in various solid tumors, but rarely expressed in healthy adult tissues and represents a rational target of particular relevance in hepatocellular carcinoma (HCC). Autologous chimeric antigen receptor (CAR) αβ T cell therapies have established significant clinical benefit in hematologic malignancies, although efficacy in solid tumors has been limited due to several challenges including T cell homing, target antigen heterogeneity, and immunosuppressive tumor microenvironments. Gamma delta (γδ) T cells are highly cytolytic effectors that can recognize and kill tumor cells through major histocompatibility complex (MHC)-independent antigens upregulated under stress. The Vδ1 subset is preferentially localized in peripheral tissue and engineering with CARs to further enhance intrinsic antitumor activity represents an attractive approach to overcome challenges for conventional T cell therapies in solid tumors. Allogeneic Vδ1 CAR T cell therapy may also overcome other hurdles faced by allogeneic αβ T cell therapy, including graft-versus-host disease (GvHD).MethodsWe developed the first example of allogeneic CAR Vδ1 T cells that have been expanded from peripheral blood mononuclear cells (PBMCs) and genetically modified to express a 4-1BB/CD3z CAR against GPC-3. The CAR construct (GPC-3.CAR/secreted interleukin-15 (sIL)-15) additionally encodes a constitutively-secreted form of IL-15, which we hypothesized could sustain proliferation and antitumor activity of intratumoral Vδ1 T cells expressing GPC-3.CAR.ResultsGPC-3.CAR/sIL-15 Vδ1 T cells expanded from PBMCs on average 20,000-fold and routinely reached >80% purity. Expanded Vδ1 T cells showed a primarily naïve-like memory phenotype with limited exhaustion marker expression and displayed robust in vitro proliferation, cytokine production, and cytotoxic activity against HCC cell lines expressing low (PLC/PRF/5) and high (HepG2) GPC-3 levels. In a subcutaneous HepG2 mouse model in immunodeficient NSG mice, GPC-3.CAR/sIL-15 Vδ1 T cells primarily accumulated and proliferated in the tumor, and a single dose efficiently controlled tumor growth without evidence of xenogeneic GvHD. Importantly, compared with GPC-3.CAR Vδ1 T cells lacking sIL-15, GPC-3.CAR/sIL-15 Vδ1 T cells displayed greater proliferation and resulted in enhanced therapeutic activity.ConclusionsExpanded Vδ1 T cells engineered with a GPC-3 CAR and sIL-15 represent a promising platform warranting further clinical evaluation as an off-the-shelf treatment of HCC and potentially other GPC-3-expressing solid tumors.
Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency
Authors: Verheyen Sarah , Blatterer Jasmin , Speicher Michael R , Bhavani Gandham SriLakshmi , Boons Geert-Jan , Ilse Mai-Britt , Andrae Dominik , Sproß Jens , Vaz Frédéric Maxime , Kircher Susanne G , Posch-Pertl Laura , Baumgartner Daniela , Lübke Torben , Shah Hitesh , Al Kaissi Ali , Girisha Katta M , Plecko Barbara 
Published: December 2021

BackgroundMucopolysaccharidoses (MPS) are monogenic metabolic disorders that significantly affect the skeleton. Eleven enzyme defects in the lysosomal degradation of glycosaminoglycans (GAGs) have been assigned to the known MPS subtypes (I–IX). Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-O-sulfate group from 2-sulfoglucuronate. Knockout of Arsk in mice was consistent with mild storage pathology, but no human phenotype has yet been described.MethodsIn this study, we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Functional consequences of the two ARSK variants were assessed by mutation-specific ARSK constructs derived by site-directed mutagenesis, which were ectopically expressed in HT1080 cells. Urinary GAG excretion was analysed by dimethylene blue and electrophoresis, as well as liquid chromatography/mass spectrometry (LC-MS)/MS analysis.ResultsThe phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex. Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities. Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS. Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK-specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by C18-reversed-phase chromatography followed by MS.ConclusionOur work provides a detailed clinical and molecular characterisation of a novel subtype of mucopolysaccharidosis, which we suggest to designate subtype X.
New tobacco and nicotine products in Latin America and the Caribbean: assessing the market and regulatory environment
Authors: Crosbie Eric , Severini Gianella , Beem Alexandra , Tran Brian , Sebrie Ernesto Marcelo 
Published: December 2021

ObjectiveTo document the regulatory environment of new tobacco and nicotine products (NTNPs), including electronic nicotine delivery systems (ENDS) and heated tobacco products (HTPs), in Latin America and the Caribbean (LAC).MethodsReview of market research reports and databases, regulatory websites, Campaign for Tobacco-Free Kids, relevant published literature and the 2021 WHO Report on the Global Tobacco Epidemic.ResultsENDS entered the LAC market in the 2010s and are now available in most LAC countries. A majority of LAC countries (n=18) have either banned the commercialisation of ENDS (n=7) or regulated ENDS as tobacco products (n=7), medicinal products (n=1) or consumer products (n=3). The remaining LAC countries (n=15) do not regulate ENDS. HTPs were first introduced in 2017 and have been officially launched in five countries (Colombia, Guatemala, Dominican Republic, Mexico and Costa Rica). Few countries have banned HTP commercialisation (n=3) or regulated commercialisation and use (n=7), while the majority of countries have existing legislation that applies to HTPs (n=19). A few countries (n=4) have no tobacco control legislation and therefore do not regulate HTPs.ConclusionNTNPs are emerging products in the LAC region. Governments should follow WHO guidance and the decisions of the Conference of Parties to the WHO Framework Convention on Tobacco Control and ban or regulate NTNPs as tobacco products; otherwise NTNPs could create a new generation of tobacco and nicotine users.
QCD sum rules analysis of weak decays of doubly heavy baryons: the $$b\rightarrow c$$ processes
Authors: Xing Zhi-Peng , Zhao Zhen-Xing 
Published: December 2021

AbstractA comprehensive study of $$b\rightarrow c$$

b
→
c

weak decays of doubly heavy baryons is presented in this paper. The transition form factors as well as the pole residues of the initial and final states are respectively obtained by investigating the three-point and two-point correlation functions in QCD sum rules. Contributions from up to dimension-6 operators are respectively considered for the two-point and three-point correlation functions. The obtained form factors are then applied to a phenomenological analysis of semi-leptonic decays.
FDA Approval Summary: Margetuximab plus Chemotherapy for Advanced or Metastatic HER2-Positive Breast Cancer
Authors: Royce Melanie , Osgood Christy L. , Amatya Anup K. , Fiero Mallorie H. , Chang C.J. George , Ricks Tiffany K. , Shetty Krithika A. , Kraft Jeffrey , Qiu Junshan , Song Pengfei , Charlab Rosane , Yu Jingyu , King Kathryn E. , Rastogi Anshu , Janelsins Brian , Weinberg Wendy C. , Clouse Kathleen , Borders-Hemphill Vicky , Brown Lindsey , Gomez-Broughton Candace , Li Zhong , Nguyen Thuy Thanh , Qiu Zhihao , Ly Anh-Thy , Chang Suyoung , Gao Tingting , Tu Chi-Ming , King-Kallimanis Bellinda , Pierce William F. , Chiang Kelly , Lee Clara , Goldberg Kirsten B. , Leighton John K. , Tang Shenghui , Pazdur Richard , Beaver Julia A. , Amiri-Kordestani Laleh 
Published: December 2021

Abstract
On December 16, 2020, the FDA granted regular approval to margetuximab-cmkb (MARGENZA), in combination with chemotherapy, for the treatment of adult patients with HER2-positive (HER2+) metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Approval was based on data from SOPHIA, a multicenter, randomized, open-label, active controlled study comparing margetuximab with trastuzumab, in combination with chemotherapy. The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review. SOPHIA demonstrated a 0.9-month difference in median PFS between the two treatment arms [5.8 vs. 4.9 months, respectively; stratified HR, 0.76 (95% confidence interval: 0.59–0.98; P = 0.0334)]. Overall survival (OS) was immature at the data cut-off date of September 10, 2019. Infusion-related reactions (IRR) are an important safety signal associated with margetuximab plus chemotherapy. In SOPHIA, 13% of patients treated with margetuximab plus chemotherapy reported IRRs, of which 1.5% were grade 3. The most commonly reported adverse drug reactions (&gt;10%) with margetuximab in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, IRR, palmar-plantar erythrodysesthesia, and extremity pain. Overall, the favorable risk-benefit profile for margetuximab when added to chemotherapy supported its approval for the intended indication.
Associations Between Time After Stroke and Exercise Training Outcomes: A Meta‐Regression Analysis
Authors: Marzolini Susan , Wu Che‐Yuan , Hussein Rowaida , Xiong Lisa Y. , Kangatharan Suban , Peni Ardit , Cooper Christopher R. , Lau Kylie S.K. , Nzodjou Mahdoum Ghislaine , Pakosh Maureen , Zaban Stephanie A. , Nguyen Michelle M. , Banihashemi Mohammad Amin , Swardfager Walter 
Published: December 2021

Background
Knowledge gaps exist regarding the effect of time elapsed after stroke on the effectiveness of exercise training interventions, offering incomplete guidance to clinicians.

Methods and Results
To determine the associations between time after stroke and 6‐minute walk distance, 10‐meter walk time, cardiorespiratory fitness and balance (Berg Balance Scale score [BBS]) in exercise training interventions, relevant studies in post‐stroke populations were identified by systematic review. Time after stroke as continuous or dichotomized (≤3 months versus >3 months, and ≤6 months versus >6 months) variables and weighted mean differences in postintervention outcomes were examined in meta‐regression analyses adjusted for study baseline mean values (pre‐post comparisons) or baseline mean values and baseline control‐intervention differences (controlled comparisons). Secondary models were adjusted additionally for mean age, sex, and aerobic exercise intensity, dose, and modality. We included 148 studies. Earlier exercise training initiation was associated with larger pre‐post differences in mobility; studies initiated ≤3 months versus >3 months after stroke were associated with larger differences (weighted mean differences [95% confidence interval]) in 6‐minute walk distance (36.3 meters; 95% CI, 14.2–58.5), comfortable 10‐meter walk time (0.13 m/s; 95% CI, 0.06–0.19) and fast 10‐meter walk time (0.16 m/s; 95% CI, 0.03–0.3), in fully adjusted models. Initiation ≤3 months versus >3 months was not associated with cardiorespiratory fitness but was associated with a higher but not clinically important Berg Balance Scale score difference (2.9 points; 95% CI, 0.41–5.5). In exercise training versus control studies, initiation ≤3 months was associated with a greater difference in only postintervention 6‐minute walk distance (baseline‐adjusted 27.3 meters; 95% CI, 6.1–48.5; fully adjusted, 24.9 meters; 95% CI, 0.82–49.1; a similar association was seen for ≤6 months versus >6 months after stroke (fully adjusted, 26.6 meters; 95% CI, 2.6–50.6).

Conclusions
There may be a clinically meaningful benefit to mobility outcomes when exercise is initiated within 3 months and up to 6 months after stroke.
Beyond Overcoming: A Woman Writer’s Articulation of Pain in Socialist China
Authors: Licandro Daniela 
Published: December 2021

Abstract
Feminist inquiries into the status of women in Mao-era China have shed light on the challenges women experienced in their double role as producers and reproducers in the nascent socialist state. Less is known about how women lived up to expectations of (re)productivity while struggling with illness. Drawing on gender studies, literary studies, history, and the history of medicine, this article examines articulations of pain in the diaries that writer Yang Mo (1914-95) kept between 1945 and 1982, and published in 1985, to explore intersections among normative configurations of pain, gender politics, and identity construction in socialist China. Yang’s diaries show that the narrative of pain is fundamentally shaped by cultural and political discourses of “overcoming” physical and ideological shortcomings – discourses that the party-state upheld to transform the Chinese people into physically-fit, ideologically-correct socialist citizens. Within this context, this study focuses on Yang’s embodied experience to reveal both the empowering potential of these discourses and their inherent limits.