Advances in samarium-neodymium geochronology: applications to early earth garnet, hydrothermal carbonate, and high temperature metamorphic systems

This study utilizes recent advances in the analysis of neodymium (Nd) and samarium (Sm) by thermal ionization mass spectrometry (TIMS) to constrain timescales of heating and fluid flow within the lithosphere. Garnet grows during metamorphism and can be linked to its pressure and temperature of growth, while carbonate mineralization ages can be linked to hydrothermal fluid flow. The ability to date these common minerals makes it possible to unravel the timing and duration of tectonometamorphic processes. Garnet from the Eoarchean Nuvvuagittuq Supracrustal Belt (NSB) in Québec, Canada yields an age of 2574.66 ± 0.72 Ma. This is the most precise Neoarchean age reported for this terrane and was achieved through a modified partial dissolution procedure designed to remove the effects of much older (up to 3.8 Ga) inherited mineral growth. An accurate age for the most recent metamorphic garnet in the NSB is critical, as the (controversial) Hadean Nd model age calculations for this terrane depend on the time at which the 147Sm/144Nd systematics were last altered. Carbonate mineralization ages are explored for a diverse group of thirty samples using a novel sequential acid extraction procedure. Through this procedure it is possible to constrain carbonate mineralization in a variety of geologic settings (metamorphic fluid flow, hydrothermal and ore-forming systems) to ± 20 Myr. Zoned and bulk garnet geochronology at ten sites within a unusually localized area (~5 km2) of high temperature granulite-facies metamorphism in Bristol, New Hampshire reveals multiple brief (<1 Myr) periods of garnet growth focused between 393 and 386 Ma, at peak temperatures of 730-850°C. Comparison with garnet growth ages and temperatures , in central Massachusetts (364 Ma at 950°C) and Connecticut (341 Ma at 1000°C) reveal a regional trend of pulsed high temperature garnet growth spanning ~60 Myr from north to south, the same time span bracketed by associated igneous rocks dated via zircon geochronology. Ultrahigh metamorphic temperatures were achieved during the Acadian Orogeny in New England in localized, short pulses, likely related to igneous heating and/or associated fluid flow above and beyond the regional heating due to tectonic overthickening

Community-based physical activity interventions for adolescents and adults with complex cerebral palsy : A scoping review

Aim To identify implementation strategies and safety outcomes (adverse events) of community-based physical activity interventions for adolescents and adults with complex cerebral palsy (CP). Method Five electronic databases were systematically searched to April 2022. Data were extracted on the implementation and safety of physical activity interventions for adolescents and adults with CP, classified in Gross Motor Function Classification System (GMFCS) levels IV and V, delivered in a community setting. Results Seventeen studies with 262 participants (160 participants classified in GMFCS levels IV or V) were included. Community settings included schools (n = 4), participants' homes (n = 3), gymnasia (n = 2), swimming pools (n = 2), and other settings (n = 4). Most studies specified medical or safety exclusion criteria. Implementation strategies included pre-exercise screening, use of adapted equipment, familiarization sessions, supervision, physical assistance, and physiological monitoring. Attendance was high and attrition low. Nine studies reported non-serious, expected, and related events. Four studies reported minor soreness and four studies reported minor fatigue post-exercise. Serious adverse events related to exercise were infrequent (reported for 4 of 160 participants [<2%]: three participants withdrew from an exercise programme and one participant ceased exercise for a short period). Most frequently reported was pain, requiring temporary exercise cessation or programme change, or study withdrawal (three participants). Interpretation For most adolescents and adults with CP classified in GMFCS levels IV and V, physical activity interventions can be safely performed in a community setting, without post-exercise pain or fatigue, or serious adverse events

CCR4-bearing T cells participate in autoimmune diabetes.

Chemokine receptor expression is exquisitely regulated on T cell subsets during the course of their migration to inflammatory sites. In the present study we demonstrate that CCR4 expression marks a pathogenic population of autoimmune T cells. CCR4 was found exclusively on memory CD4(+) T cells during the progression of disease in NOD mice. Cells expressing the CCR4 ligand TARC (thymus- and activation-regulated chemokine) were detected within infiltrated islets from prediabetic mice. Interestingly, neutralization of macrophage-derived chemokine (MDC) with Ab caused a significant reduction of CCR4-positive T cells within the pancreatic infiltrates and inhibited the development of insulitis and diabetes. Furthermore, enhanced recruitment of CCR4-bearing cells in NOD mice resulting from transgenic expression of MDC resulted in acceleration of clinical disease. Cumulatively, the results demonstrate that CCR4-bearing T cells participate in the development of such tissue-driven autoimmune reactions

Effect of a MUC5AC Antibody (NPC-1C) Administered With Second-Line Gemcitabine and Nab-Paclitaxel on the Survival of Patients With Advanced Pancreatic Ductal Adenocarcinoma: A Randomized Clinical Trial

Importance: Treatment options are limited for patients with advanced pancreatic ductal adenocarcinoma (PDAC) beyond first-line 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), with such individuals commonly being treated with gemcitabine and nab-paclitaxel. Objective: To determine whether NPC-1C, an antibody directed against MUC5AC, might increase the efficacy of second-line gemcitabine and nab-paclitaxel in patients with advanced PDAC. Design, setting, and participants: This multicenter, randomized phase II clinical trial enrolled patients with advanced PDAC between April 2014 and March 2017 whose disease had progressed on first-line FOLFIRINOX. Eligible patients had tumors with at least 20 MUC5AC staining by centralized immunohistochemistry review. Statistical analysis was performed from April to May 2022. Interventions: Patients were randomly assigned to receive gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) administered intravenously on days 1, 8, and 15 of every 4-week cycle, with or without intravenous NPC-1C 1.5 mg/kg every 2 weeks. Main outcomes and measures: The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. Pretreatment clinical variables were explored with Cox proportional hazards analysis. Results: A total of 78 patients (median [range] age, 62 [36-78] years; 32 [41%] women; 9 [12%] Black; 66 [85%] White) received second-line treatment with gemcitabine plus nab-paclitaxel (n = 40) or gemcitabine plus nab-paclitaxel and NPC-1C (n = 38). Median OS was 6.6 months (95% CI, 4.7-8.4 months) with gemcitabine plus nab-paclitaxel vs 5.0 months (95% CI, 3.3-6.5 months; P = .22) with gemcitabine plus nab-paclitaxel and NPC-1C. Median PFS was 2.7 months (95% CI, 1.9-4.1 months) with gemcitabine plus nab-paclitaxel vs 3.4 months (95% CI, 1.9-5.3 months; P = .80) with gemcitabine plus nab-paclitaxel and NPC-1C. The ORR was 3.1% (95% CI, 0.4%-19.7%) in the gemcitabine plus nab-paclitaxel and NPC-1C group and 2.9% (95% CI, 0.4%-18.7%) in the gemcitabine plus nab-paclitaxel group. No differences in toxicity were observed between groups, except that grade 3 or greater anemia occurred more frequently in patients treated with gemcitabine plus nab-paclitaxel and NPC-1C than gemcitabine plus nab-paclitaxel (39% [15 of 38] vs 10% [4 of 40]; P = .003). The frequency of chemotherapy dose reductions was similar in both groups (65% vs 74%; P = .47). Lower performance status, hypoalbuminemia, PDAC diagnosis less than or equal to 18 months before trial enrollment, lymphocyte-to-monocyte ratio less than 2.8, and CA19-9 greater than 2000 IU/mL were independently associated with poorer survival. Conclusions and relevance: In this randomized clinical trial of advanced PDAC, NPC-1C did not enhance the efficacy of gemcitabine/nab-paclitaxel. These data provide a benchmark for future trials investigating second-line treatment of PDAC. Trial registration: ClinicalTrials.gov Identifier: NCT01834235

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

CCR4-bearing T cells participate in autoimmune diabetes

Chemokine receptor expression is exquisitely regulated on T cell subsets during the course of their migration to inflammatory sites. In the present study we demonstrate that CCR4 expression marks a pathogenic population of autoimmune T cells. CCR4 was found exclusively on memory CD4(+) T cells during the progression of disease in NOD mice. Cells expressing the CCR4 ligand TARC (thymus- and activation-regulated chemokine) were detected within infiltrated islets from prediabetic mice. Interestingly, neutralization of macrophage-derived chemokine (MDC) with Ab caused a significant reduction of CCR4-positive T cells within the pancreatic infiltrates and inhibited the development of insulitis and diabetes. Furthermore, enhanced recruitment of CCR4-bearing cells in NOD mice resulting from transgenic expression of MDC resulted in acceleration of clinical disease. Cumulatively, the results demonstrate that CCR4-bearing T cells participate in the development of such tissue-driven autoimmune reactions