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In patients with midgut neuroendocrine tumors that progressed during octreotide analogue therapy, the addition of 177 Lu-Dotatate to octreotide resulted in an 18% response rate and a significantly higher rate of progression-free survival at 20 months than high-dose octreotide alone. Neuroendocrine tumors of the midgut (which is defined as the jejunoileum and the proximal colon) commonly metastasize to the mesentery, peritoneum, and liver and are frequently associated with the carcinoid syndrome. 1 , 2 Neuroendocrine tumors of the midgut represent the most common type of malignant gastrointestinal neuroendocrine tumors and are associated with 5-year survival rates of less than 50% among persons with metastatic disease. 3 , 4 First-line systemic therapy usually consists of a somatostatin analogue for control of both hormonal secretion and tumor growth. 5 – 7 With the exception of everolimus for the treatment of nonfunctional neuroendocrine tumors, 8 no standard second-line systemic treatment . . .

Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 ( Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) ( Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Treatment with Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).

The chemical behavior of water under extreme pressures and temperatures lies at the heart of processes shaping planetary interiors, influences the deep carbon cycle, and underpins innovative high-temperature, high-pressure synthesis of materials. Recent experiments reveal that hydrocarbons immersed in ionized water under extreme conditions transform into heavy hydrocarbons and nanodiamonds. However, the chemistry of water at extreme conditions and its role in hydrocarbon condensation remains poorly understood. Here, using ab initio molecular dynamics simulations with enhanced sampling techniques and machine-learning interatomic potentials, we show that increasing pressure at high temperature induces water ionization, creating a superacid-like environment that favors the protonation of hydrocarbons into transient pentacoordinated carbonium ions like CH\\(_5^+\\). These elusive intermediates release molecular hydrogen and yield highly reactive carbocations, driving hydrocarbon chain growth toward nanodiamonds. We demonstrate how the combination of water ionization and pressure-induced methane polarization leads to superacid-driven hydrocarbon chemistry, famously known at far milder conditions. Our findings reveal, for the first time, a superacid aqueous regime and establish the existence of superacid chemistry under extreme conditions. Moreover, they provide a unifying reaction network that explains chemical transformations in environments such as planetary interiors and high pressure, high temperature experiments.

In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in male rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggers clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes. β-cell dysfunction in type 2 diabetes is associated with pathological aggregates of IAPP that accumulate in pancreatic islets. Here, the authors describe a novel antibody cloned from healthy elderly donors that selectively targets IAPP oligomers and protects from IAPP toxicity.

Combustion related particulate matter air pollution (PM) is associated with an increased risk of respiratory infections in adults. The exact mechanism underlying this association has not been determined. We hypothesized that increased concentrations of combustion related PM would result in dysregulation of the innate immune system. This epidemiological study includes 111 adult patients hospitalized with respiratory infections who underwent transcriptional analysis of their peripheral blood. We examined the association between gene expression at the time of hospitalization and ambient measurements of particulate air pollutants in the 28 days prior to hospitalization. For each pollutant and time lag, gene-specific linear models adjusting for infection type were fit using LIMMA (Linear Models For Microarray Data), and pathway/gene set analyses were performed using the CAMERA (Correlation Adjusted Mean Rank) program. Comparing patients with viral and/or bacterial infection, the expression patterns associated with air pollution exposure differed. Adjusting for the type of infection, increased concentrations of Delta-C (a marker of biomass smoke) and other PM were associated with upregulation of iron homeostasis and protein folding. Increased concentrations of black carbon (BC) were associated with upregulation of viral related gene pathways and downregulation of pathways related to antigen presentation. The pollutant/pathway associations differed by lag time and by type of infection. This study suggests that the effect of air pollution on the pathogenesis of respiratory infection may be pollutant, timing, and infection specific.

Copy number variations are genomic structural variants that are frequently associated with human diseases. Among these copy number variations, duplications of DNA segments are often assumed to lead to dosage effects by increasing the copy number of either genes or their regulatory elements. We produced a series of large targeted duplications within a conserved gene desert upstream of the murine HoxD locus. This DNA region, syntenic to human 2q31-32, contains a range of regulatory elements required for Hoxd gene transcription, and it is often disrupted and/or reorganized in human genetic conditions collectively known as the 2q31 syndrome. Unexpectedly, one such duplication led to a transcriptional down-regulation in developing digits by impairing physical interactions between the target genes and their upstream regulatory elements, thus phenocopying the effect obtained when these enhancer sequences are deleted. These results illustrate the detrimental consequences of interrupting highly conserved regulatory landscapes and reveal a mechanism where genomic duplications lead to partial loss of function of nearby located genes.

The rate of respiratory viral infection (RVI) associated with acute air pollution exposure is well established, but whether bacterial and viral infections respond similarly to traffic related air pollution (TRAP) exposure is less well understood. Using a novel seasonal time-stratified case-crossover design and conditional logistic regression, we separately estimated the rate of hospitalization for 465 patients with RVI, respiratory bacterial infection (RBI), or combined respiratory viral and bacterial infection (RVBI) associated with increased ambient particulate matter ≤2.5 µm (PM 2.5 ), black carbon (BC), nitrogen dioxide (NO 2 ) and carbon monoxide (CO) concentrations in the previous 1, 2, and 3 weeks (lag days 0–6, 7–13, 14–20). In a novel approach, a four-physician panel adjudicated each case of infection to accurately classify the type of infection present and only patients with the highest diagnostic certainty were enrolled in this study. Associations were strongest between TRAP and RVI at the 0–6 lag period, with fewer, less precise associations at later lag times for RVBI and RBI. Each 2.6 µg/m 3 increase in PM 2.5 on lag days 0–6 was associated with a 22.1% increased rate of RVI hospitalization (95% CI: 1.6%, 46.7%). Each 0.1 µg/m 3 increase in BC was associated with a 30.0% increase (95% CI: 5.0%, 61.1%) in the rate of hospitalization for RVI. Rates of hospitalization for RVI associated with increased PM 2.5 were generally largest for lag days 0–6 and 7–13. The RVI/BC rate ratio was larger for females than males for days 0–13, but not for PM 2.5 and NO 2 . Short term increases in PM 2.5 , BC, NO 2 , and CO concentrations (markers of traffic pollution) were associated with an increased rate of RVI hospitalization, while sex-specific associations were observed between BC and RVI for females. Further study of the mechanism underlying the effect of TRAP on RVI is needed.

INTRODUCTION The “I‐Learn Cognition and Behavior” program, integrating e‐learning and simulation, aims to equip long‐term care facility staff with non‐pharmacological approaches for managing agitation in residents with neurocognitive disorders. This study evaluated the program's effectiveness. METHOD In this multicenter cluster‐randomized trial, long‐term care facilities served as the randomization units for a population of residents with neurocognitive disorders and agitation who underwent blinded assessments at baseline, 3, 6, and 10 months. Assessments included the Cohen–Mansfield Agitation Inventory (CMAI) as the primary outcome, the Neuropsychiatric Inventory‐Nursing Home (NPI‐NH), the Quality of Life in Alzheimer's Disease questionnaire, the Maslach Burnout Inventory (MBI), psychotropic use, and hospitalizations. Mixed‐effects models analyzed changes in outcomes. RESULTS Twelve long‐term care facilities were randomized to receive the I‐Learn program (intervention) or usual care (control). One hundred sixty‐nine residents were enrolled. There were no significant differences in total CMAI score changes between groups. The intervention group demonstrated significant reduced CMAI non‐aggressive verbal agitation, MBI depersonalization, and psychotropic medication use (higher withdrawal rates and lower dosage increases) compared to the control group. NPI‐NH scores decreased less in the intervention group. DISCUSSION The I‐Learn program demonstrated potential for improving specific aspects of agitation in residents and well‐being in caregivers while significantly reducing psychotropic medication use. “I‐Learn Cognition and Behavior” is an easily accessible program with the potential for widespread distribution, contributing to improved well‐being and quality of care in long‐term care facilities for managing agitation in residents with neurocognitive disorders. Highlights We investigated whether the I‐Learn staff training program, which integrates e‐learning and simulation, improves agitation, well‐being, psychotropic medication use, and hospitalizations among nursing home residents with neurocognitive disorders and agitation. The most significant achievements of implementing the I‐Learn program in nursing homes were the improved well‐being of long‐term care facility staff and the substantial reduction in psychotropic medication use. As a strategy for managing agitation, the I‐Learn program holds the potential to elevate the quality of care for residents with neurocognitive disorders, with a particular benefit in decreasing the reliance on psychotropic agents.

Thermal manikins are valuable tools used in advancing our understanding of thermal comfort. This study examines the effect of varying clothing insulation on the predicted degree of thermal comfort using a thermal manikin named MONICA (MONitoring Indoor Comfort and Air quality). The experiments were conducted in a controlled climate chamber with the room temperature maintained at 24 °C. Three different clothing configurations were tested: naked, summer clothes (0.2 clo), and winter office clothes (0.7 clo). The equivalent temperature was measured for each configuration and compared to the Predicted Mean Vote (PMV) values obtained simultaneously. Additionally, the study utilized the Background Oriented Schlieren (BOS) technique to visualize the thermally driven airflow around the manikin. The findings from this study confirm the effectiveness of the thermal manikin in simulating human thermal responses and provide valuable insights into the role of clothing insulation in thermal comfort assessments. The obtained results will be useful for choosing the right clothing insulation for future thermal comfort assessments with the manikin.

Human islet transplantation is a viable treatment option for type 1 diabetes mellitus (T1DM). However, pancreatic islet inflammation after transplantation induced by innate immune responses is likely to hinder graft function. This is mediated by incompatibility between islets and the blood interface, known as instant blood-mediated inflammatory reaction (IBMIR). Herein we hypothesized that portal venous administration of islet cells with human recombinant antithrombin (ATryn ® ), a serine protease inhibitor (serpin), which plays a central role in the physiological regulation of coagulation and exerts indirect anti-inflammatory activities, may offset coagulation abnormalities such as disseminated intravascular coagulation (DIC) and IBMIR. The current prospective, randomized experiment was conducted using an established preclinical pig model. Three groups were constituted for digested pancreatic tissue transplantation (0.15 ml/kg): control, NaCl 0.9% (n = 7); gold standard, heparin (25 UI/kg) (n = 7); and human recombinant ATryn® (500 UI/kg) (n = 7). Blood samples were collected over time (T0 to 24 h), and biochemical, coagulation, and inflammatory parameters were evaluated. In both the control and heparin groups, one animal died after a portal thrombosis, while no deaths occurred in the ATryn®-treated group. As expected, islet transplantation was associated with an increase in plasma IL-6 or TNF-α levels in all three groups. However, DIC was only observed in the control group, an effect that was suppressed after ATryn® administration. ATryn® administration increased antithrombin activity by 800%, which remained at 200% for the remaining period of the study, without any hemorrhagic complications. These studies suggest that coadministration of ATryn® and pancreatic islets via intraportal transplantation may be a valuable therapeutic approach for DIC without risk for islets and subjects.