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[This corrects the article DOI: 10.1371/journal.pone.0229623.].

The innovation of iron production is often considered one of the greatest technological advances in human history. A reliable provenancing method for iron is instrumental for the reconstruction of economic, social and geo-political aspects of iron production and use in antiquity. Although the potential of osmium isotopes analysis for this purpose has been previously suggested, here we present for the first time the results of osmium isotope analysis of ores, bloom and metal obtained from a set of systematic, bloomery iron-smelting experiments, utilizing selected ores from the Southern Levant. The results show that the 187Os/188Os ratio is preserved from ore to metal, with no isotopic fractionation. In addition, enrichment/depletion of osmium content was observed in the transition from ore to metal and from ore to slag. This observation has potential significance for our ability to differentiate between the various processes and sheds light on the suitability of various production remains for this method, which emerges as a robust and promising tool for the provenancing of archaeological ferrous metals.

Slag analyses from archaeological iron smelting sites are common. Rigorous analyses of iron and slag from successful experimental smelting, however, are still rare. Furthermore, thorough analyses from a series of smelts, and of the slag produced in different phases of the smelt, are exceedingly rare. The present study investigates the effect of an iron smelter’s decision-making and skills on the products of the smelting process: iron and slag. Four smelting experiments were carried out in a shaft furnace with slag tapping using iron ores from the Southern Levant. Using various analytical techniques, including portable X-ray fluorescence, optical and electron microscopy, metallography, and hardness tests enabled us to correlate the properties of the final products with adjustment of various parameters during the smelting process. The latter include airflow and charging rate, temperature, residence time in the reducing zone, ore-charcoal ratio, and control of the slag characteristics. Results obtained allowed us to empirically demonstrate the direct impact of decisions made by the smelter during the complex technological practice of bloomery smelting. Analysis also highlights the benefits of moderately reducing conditions controlled by the smelter to produce good-quality, low-carbon iron, which is particularly relevant within the geological setting of the Southern Levant.

The Royal City of Meroe, ca. 200 km north of Khartoum in the modern-day Republic of the Sudan, was an ancient capital of the Kingdom of Kush. From the 3rd century b.c. to the 4th century a.d., Kushite rulers controlled significant territory from the banks of the Nile at Meroe, in part through their ability to ensure the production of significant quantities of iron. The extensive archaeological remains of Meroitic iron production have been investigated over decades, and recently a series of experimental iron smelts in a replica Meroitic furnace has shed new light on the archaeometallurgical evidence. The data generated during the smelting campaigns has provided an understanding of the type of iron ore used, the construction and operating parameters of the furnace, and the workshop space created by the ancient iron smelters during the later and post-Meroitic times.

Introduction The desire to reduce patient morbidity has led to de-escalation of axillary surgery after neoadjuvant chemotherapy (NAC) for breast cancer; however, the impact of such de-escalation on oncologic outcomes is unknown. Methods We evaluated the relationship between axillary surgery type (sentinel lymph node [SLN] only vs. axillary lymph node dissection [ALND]) and 5-year outcomes in I-SPY2 trial patients from 2011 to 2022 who completed NAC and surgery. Rates of axillary recurrence (AxR), locoregional recurrence (LRR), distant recurrence-free survival (DRFS), and event-free survival (EFS) were compared. Results Of 1515 patients, SLN-only was performed in 804/1014 (79.3%) ypN0 patients and 127/501 (25.3%) ypN+ patients. Median follow-up time was 3.5 years. Most patients received adjuvant radiation (73.8% of ypN0 patients and 90.8% of ypN+ patients). In ypN0 cases, there was no difference between the SLN-only and ALND groups in 5-year estimated AxR (2.0% vs. 0.8%, p  = 0.57), LRR (4.6% vs. 4.4%, p  = 0.72), or EFS (88.3% vs. 86.4%, p  = 0.09). On multivariable analysis, SLN-only was associated with better DRFS (90.8% vs. 87.9%; hazard ratio [HR] 0.54, p  = 0.04). In ypN+ cases, there was no difference between the SLN-only and ALND groups in 5-year estimated AxR (5.2% vs. 3.6%, p  = 0.81), LRR (7.7% vs. 14%, p  = 0.13), DRFS (70.0% vs. 66.7%, p  = 0.09), or EFS (70.4% vs. 63.2%, p  = 0.07). Conclusions With short-term follow-up, omission of ALND in selected patients was not associated with worse AxR, LRR, DRFS, or EFS in patients with ypN0 or ypN+ disease. While prospective trial results are awaited, these data suggest that ALND may not be necessary for all patients with residual nodal disease after NAC.

Background Internal mammary lymphadenopathy (IML) plays a role in breast cancer stage and prognosis. We aimed to evaluate method of IML detection, how IML impacts response to neoadjuvant chemotherapy (NAC), and oncologic outcomes. Methods We evaluated patients enrolled in the I-SPY-2 clinical trial from 2010 to 2022. We captured the radiographic method of IML detection (magnetic resonance imaging [MRI], positron emission tomography/computed tomography [PET/CT], or both) and compared patients with IML with those without. Rates of locoregional recurrence (LRR), distant recurrence (DR) and event-free survival (EFS) were compared by bivariate analysis. Results Of 2095 patients, 198 (9.5%) had IML reported on pretreatment imaging. The method of IML detection was 154 (77.8%) MRI only, 11 (5.6%) PET/CT only, and 33 (16.7%) both. Factors associated with IML were younger age ( p  = 0.001), larger tumors ( p  < 0.001), and higher tumor grade ( p  = 0.027). Pathologic complete response (pCR) was slightly higher in the IML group (41.4% vs. 34.0%; p  = 0.03). There was no difference in breast or axillary surgery ( p  = 0.41 and p  = 0.16), however IML patients were more likely to undergo radiation (68.2% vs. 54.1%; p  < 0.001). With a median follow up of 3.72 years (range 0.4–10.2), there was no difference between IM+ versus IM− in LRR (5.6% vs. 3.8%; p  = 0.25), DR (9.1% vs. 7.9%; p  = 0.58), or EFS (61.6% vs. 57.2%; p  = 0.48). This was true for patients with and without pCR. Conclusions In this large cohort of patients treated with NAC, outcomes were not negatively impacted by IML. We demonstrated that IML influences treatment selection but is not a poor prognostic indicator when treated with modern NAC and multidisciplinary disease management.

Background Immune-checkpoint inhibitors (ICI) can lead to immune-related adverse events (irAEs) in a significant proportion of patients. The mechanisms underlying irAEs development are mostly unknown and might involve multiple immune effectors, such as T cells, B cells and autoantibodies (AutoAb). Methods We used custom autoantigen (AutoAg) microarrays to profile AutoAb related to irAEs in patients receiving ICI. Plasma was collected before and after ICI from cancer patients participating in two clinical trials (NCT03686202, NCT02644369). A one-time collection was obtained from healthy controls for comparison. Custom arrays with 162 autoAg were used to detect IgG and IgM reactivities. Differences of median fluorescent intensity (MFI) were analyzed with Wilcoxon sign rank test and Kruskal–Wallis test. MFI 500 was used as threshold to define autoAb reactivity. Results A total of 114 patients and 14 healthy controls were included in this study. irAEs of grade (G) ≥ 2 occurred in 37/114 patients (32%). We observed a greater number of IgG and IgM reactivities in pre-ICI collections from patients versus healthy controls (62 vs 32 p  <  0.001 ). Patients experiencing irAEs G ≥ 2 demonstrated pre-ICI IgG reactivity to a greater number of AutoAg than patients who did not develop irAEs (39 vs 33 p  =  0.040) . We observed post-treatment increase of IgM reactivities in subjects experiencing irAEs G ≥ 2 (29 vs 35, p  =  0.021 ) and a decrease of IgG levels after steroids (38 vs 28, p  =  0.009) . Conclusions Overall, these results support the potential role of autoAb in irAEs etiology and evolution. A prospective study is ongoing to validate our findings (NCT04107311).

Maternal systemic inflammation during pregnancy may restrict embryo−fetal growth, but the extent of this effect remains poorly established in undernourished populations. In a cohort of 653 maternal−newborn dyads participating in a multi-armed, micronutrient supplementation trial in southern Nepal, we investigated associations between maternal inflammation, assessed by serum α1-acid glycoprotein and C-reactive protein, in the first and third trimesters of pregnancy, and newborn weight, length and head and chest circumferences. Median (IQR) maternal concentrations in α1-acid glycoprotein and C-reactive protein in the first and third trimesters were 0.65 (0.53–0.76) and 0.40 (0.33–0.50) g/l, and 0.56 (0.25–1.54) and 1.07 (0.43–2.32) mg/l, respectively. α1-acid glycoprotein was inversely associated with birth size: weight, length, head circumference and chest circumference were lower by 116 g (P = 2.3 × 10−6), and 0.45 (P = 3.1 × 10−5), 0.18 (P = 0.0191) and 0.48 (P = 1.7 × 10−7) cm, respectively, per 50% increase in α1-acid glycoprotein averaged across both trimesters. Adjustment for maternal age, parity, gestational age, nutritional and socio-economic status and daily micronutrient supplementation failed to alter any association. Serum C-reactive protein concentration was largely unassociated with newborn size. In rural Nepal, birth size was inversely associated with low-grade, chronic inflammation during pregnancy as indicated by serum α1-acid glycoprotein.

Background For patients with clinically node-positive (cN+) breast cancer undergoing neoadjuvant chemotherapy (NAC), retrieving previously clipped, biopsy-proven positive lymph nodes during sentinel lymph node biopsy [i.e., targeted axillary dissection (TAD)] may reduce false negative rates. However, the overall utilization and impact of clipping positive nodes remains uncertain. Patients and Methods We retrospectively analyzed cN+ ISPY-2 patients (2011–2022) undergoing axillary surgery after NAC. We evaluated trends in node clipping and associations with type of axillary surgery [sentinel lymph node (SLN) only, SLN and axillary lymph node dissection (ALND), or ALND only] and event-free survival (EFS) in patients that were cN+ on a NAC trial. Results Among 801 cN+ patients, 161 (20.1%) had pre-NAC clip placement in the positive node. The proportion of patients that were cN+ undergoing clip placement increased from 2.4 to 36.2% between 2011 and 2021. Multivariable logistic regression showed nodal clipping was independently associated with higher odds of SLN-only surgery [odds ratio (OR) 4.3, 95% confidence interval (CI) 2.8–6.8, p < 0.001]. This was also true among patients with residual pathologically node-positive (pN+) disease. Completion ALND rate did not differ based on clip retrieval success. No significant differences in EFS were observed in those with or without clip placement, both with or without successful clip retrieval [hazard ratio (HR) 0.85, 95% CI 0.4–1.7, p = 0.7; HR 1.8, 95% CI 0.5–6.0, p = 0.3, respectively]. Conclusion Clip placement in the positive lymph node before NAC is increasingly common. The significant association between clip placement and omission of axillary dissection, even among patients with pN+ disease, suggests a paradigm shift toward TAD as a definitive surgical management strategy in patients with pN+ disease after NAC.