bluuebunny/crossref_metadata_2025_split huggingface dataset:
Continuation of Pembrolizumab with Additional Chemotherapy after Progression with PD-1/PD-L1 Inhibitor Monotherapy in Patients with Advanced NSCLC: A Randomized, Placebo-Controlled Phase II Study
Authors: Jung Hyun Ae , Park Sehhoon , Choi Yoon-La , Lee Se-Hoon , Ahn Jin Seok , Ahn Myung-Ju , Sun Jong-Mu 
Published: January 2022

Abstract

Purpose:
Although programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors have shown survival benefits in patients with non–small cell lung cancer (NSCLC), most patients progress. This study evaluated whether continuing pembrolizumab with additional chemotherapy after failure of prior PD-1/PD-L1 inhibitor extends survival.

Patients and Methods:
This placebo-controlled, double-blind, randomized phase II study enrolled patients with NSCLC who received one or two cytotoxic chemotherapy, including at least one platinum-doublet regimen, and progressed on second- or third-line PD-1/PD-L1 inhibitor monotherapy as the last systemic therapy. Patients were randomized (1:1) to pembrolizumab or placebo plus chemotherapy, stratified by histology and clinical outcomes to prior PD-1/PD-L1 inhibitor. The primary endpoint was progression-free survival (PFS).

Results:
A total of 98 patients were randomized to the pembrolizumab-chemotherapy (N = 47) and placebo-chemotherapy arm (N = 51). At the median follow-up duration of 10.5 months, there was no statistical difference in PFS [median 4.1 months vs. 5.9 months; HR = 1.06; 95% confidence interval (CI), 0.69–1.62; P = 0.78) and overall survival (median 11.5 months vs. 12.0 months; HR = 1.09; 95% CI, 0.66–1.83; P = 0.73) between the pembrolizumab-chemotherapy and placebo-chemotherapy arms. In a subgroup with PD-L1 expression in ≥50% of tumor cells and favorable clinical outcomes to prior PD-1/PD-L1 inhibitor (partial response or 6 months or longer of stable disease), the pembrolizumab-chemotherapy arm showed a higher 24-month survival rate than the placebo-chemotherapy arm (74% vs. 38%; HR = 0.52; 95% CI, 0.13–2.1; P = 0.34).

Conclusions:
This study did not show a survival benefit with the continuation of pembrolizumab with chemotherapy in patients whose NSCLC progressed on second- or third-line PD-1/PD-L1 inhibitors.
See related commentary by Tseng and Gainor, p. 2206
Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3
Authors: Gao Peng , You Mei , Li Li , Zhang Qin , Fang Xia , Wei Xiao , Zhou Qing , Zhang Hexuan , Wang Miao , Lu Zongshi , Wang Lijuan , Sun Fang , Liu Daoyan , Zheng Hongting , Yan Zhencheng , Yang Gangyi , Zhu Zhiming 
Published: January 2022

Background:
High salt intake is the leading dietary risk factor for cardiovascular diseases. Although clinical evidence suggests that high salt intake is associated with nonalcoholic fatty liver disease, which is an independent risk factor for cardiovascular diseases, it remains elusive whether salt-induced hepatic damage leads to the development of cardiovascular diseases.

Methods:
Mice were fed with normal or high-salt diet for 8 weeks to determine the effect of salt loading on liver histological changes and blood pressure, and salt withdrawal and metformin treatment were also conducted on some high-salt diet–fed mice. Adeno-associated virus 8, global knockout, or tissue-specific knockout mice were used to manipulate the expression of some target genes in vivo, including SIRT3 (sirtuin 3), NRF2 (NF-E2-related factor 2), and AMPK (AMP-activated protein kinase).

Results:
Mice fed with a high-salt diet displayed obvious hepatic steatosis and inflammation, accompanied with hypertension and cardiac dysfunction. All these pathological changes persisted after salt withdrawal, displaying a memory phenomenon. Gene expression analysis and phenotypes of SIRT3 knockout mice revealed that reduced expression of SIRT3 was a chief culprit responsible for the persistent inflammation in the liver, and recovering SIRT3 expression in the liver effectively inhibits the sustained hepatic inflammation and cardiovascular damage. Mechanistical studies reveal that high salt increases acetylated histone 3 lysine 27 (H3K27ac) on SIRT3 promoter in hepatocytes, thus inhibiting the binding of NRF2, and results in the sustained inhibition of SIRT3 expression. Treatment with metformin activated AMPK, which inhibited salt-induced hepatic inflammatory memory and cardiovascular damage by lowering the H3K27ac level on SIRT3 promoter, and increased NRF2 binding ability to activate SIRT3 expression.

Conclusions:
This study demonstrates that SIRT3 inhibition caused by histone modification is the key factor for the persistent hepatic steatosis and inflammation that contributes to cardiovascular damage under high salt loading. Avoidance of excessive salt intake and active intervention of epigenetic modification may help to stave off the persistent inflammatory status that underlies high-salt–induced cardiovascular damage in clinical practice.
Heterogenising the Indian Hindu Diaspora in Thailand
Authors: Panyamanee Pittikorn 
Published: January 2022

Abstract
The Indian diaspora is a diverse community of migrants who live dispersed around the globe. This includes the situation of Indian emigration to Thailand, which has been ongoing for hundreds of years. Several scholars in Indian Diaspora Studies have previously contributed to an understanding of the different social groups of the heterogenous Indian diaspora in terms of ethnicities, religions, periods of migration, and social and political consciousness. However, Indian Diaspora Studies in Thailand undertaken by Thai scholars over the past decade have only focused on the Siamese Brahmin and the Thai-Indian Sikh and Muslim diaspora in Thailand, and have tended to view Hindu immigrants to Thailand as a homogeneous group. Their contribution is constrained by considering migrants only through the lens of ethnicity, and dualistically conceptualising ethnic boundaries between Indianness and Thainess as a result. This paper, in conversation with previous scholarship, applies the notion of heterogeneity to understand the complexity of the Indian Hindu diaspora in contemporary Thai societies. This article, based on case studies in the Chiang Mai province, asserts that the Thai-Indian Hindu diaspora consists of heterogeneous groups that utilise multi-ethnic-religious identities as cultural strategies to establish their self-identification. Therefore, the Indian Hindu diaspora in Thai society is associated with the (re)formation and recombination of traditional and modern diasporic types of consciousness, reflecting the complexity of the Indian Hindu diaspora in Thailand today.
Conservation of Dry Air, Water, and Energy in CAM and Its Potential Impact on Tropical Rainfall
Authors: Harrop Bryce E. , Pritchard Michael S. , Parishani Hossein , Gettelman Andrew , Hagos Samson , Lauritzen Peter H. , Leung L. Ruby , Lu Jian , Pressel Kyle G. , Sakaguchi Koichi 
Published: January 2022

AbstractFor the Community Atmosphere Model version 6 (CAM6), an adjustment is needed to conserve dry air mass. This adjustment exposes an inconsistency in how CAM6’s energy budget incorporates water—in CAM6 water in the vapor phase has energy, but condensed phases of water do not. When water vapor condenses, only its latent energy is retained in the model, while its remaining internal, potential, and kinetic energy are lost. A global fixer is used in the default CAM6 model to maintain global energy conservation, but locally the energy tendency associated with water changing phase violates the divergence theorem. This error in energy tendency is intrinsically tied to the water vapor tendency, and reaches its highest values in regions of heavy rainfall, where the error can be as high as 40 W m−2annually averaged. Several possible changes are outlined within this manuscript that would allow CAM6 to satisfy the divergence theorem locally. These fall into one of two categories: 1) modifying the surface flux to balance the local atmospheric energy tendency and 2) modifying the local atmospheric tendency to balance the surface plus top-of-atmosphere energy fluxes. To gauge which aspects of the simulated climate are most sensitive to this error, the simplest possible change—where condensed water still does not carry energy and a local energy fixer is used in place of the global one—is implemented within CAM6. Comparing this experiment with the default configuration of CAM6 reveals precipitation, particularly its variability, to be highly sensitive to the energy budget formulation.Significance StatementThis study examines and explains spurious regional sources and sinks of energy in a widely used climate model. These energy errors result from not tracking energy associated with water after it transitions from the vapor phase to either liquid or ice. Instead, the model used a global fixer to offset the energy tendency related to the energy sources and sinks associated with condensed water species. We replace this global fixer with a local one to examine the model sensitivity to the regional energy error and find a large sensitivity in the simulated hydrologic cycle. This work suggests that the underlying thermodynamic assumptions in the model should be revisited to build confidence in the model-simulated regional-scale water and energy cycles.
Risk Factors for Level-VII Lymph Node Metastases of Thyroid Neoplasms: A Meta-Analysis
Authors: Ruo Wang Zhi , Xiao Sun Han , Ming Feng Zhe , Yue Zhu Chun , Wen Meng Zhi , Hua Zhang Feng 
Published: January 2022

Objective The present study conducted a meta-analysis to forecast the risk factors associated with level-VII lymph node metastases in case of thyroid neoplasms, intending to assist in determining the requirement for level-VII lymph node lymphadenectomy during the surgery. Methods Electronic databases, PubMed, Embase, the Cochrane Library, CNKI, Wanfang Data, VIP, and CBM electronic databases were searched for studies focused on level-VII lymph node metastases in thyroid neoplasms, published up to April 2021. Stata 13.1 software was used for analyses. Results The literature search identified a total of 997 studies. Among these, 8 studies, involving 1813 patients, were included in the present case. All these studies were case-control studies. Results for meta‐analysis showed that male (OR = 1.340, 95% CI: 1.018-1.764, P = .037), age < 45 years (OR = 4.178, 95% CI: 1.601–10.908, P = .003), tumor size ≥ 2.0 cm (OR = 1.960, 95% CI: 1.079-3.562, P = .027), extrathyroidal extension (OR = 2.037, 95% CI: 1.578-2.630, P < .001), distant metastasis (OR = 2.775, 95% CI: 2.005-3.840, P < .001), central lymph node metastasis (OR = 3.500, 95% CI: 1.127-10.874, P = .03), contralateral cervicolateral metastasis (OR = 2.119, 95% CI: 1.514-2.965, P < .001), and bilateral nodal metastasis (OR = 4.651, 95% CI: 2.697-8.020, P < .001) acted as risk factors for level-VII lymph node metastases. In addition to this, sensitivity analyses and bias test showed that the results of meta‐analysis were reliable and stable and involved no publication bias. Conclusion In the present study, male gender, age < 45 years, tumor size ≥ 2.0 cm, extrathyroidal extension, distant metastasis, central lymph node metastasis, contralateral cervicolateral metastasis, and bilateral nodal metastasis were identified as risk factors for level-VII lymph node metastases in case of thyroid neoplasms.
Sphenomaxillary Plate: Landmine or Landmark?
Authors: Gotlib Tomasz , Kuźmińska Magdalena , Bobecka-Wesołowska Konstancja 
Published: January 2022

Objectives Sphenomaxillary plate (SMP) is an inconstant bony septum separating the maxillary and sphenoid sinuses. Neglecting the SMP during endoscopic sinus surgery may lead to mistaking the sphenoid sinus for the posterior ethmoid cell with potentially dangerous consequences. However, its proper identification may allow planned sphenoidotomy through the posterior wall of the maxillary sinus or to enlarge transnasal or transethmoidal sphenoidotomy. The aim of this study was to evaluate (1) the incidence and morphology of the SMP and (2) possibility and safety of trans-SMP sphenoidotomy. Methods In the radioanatomical part of the study multiplanar reconstruction analysis of 117 consecutive paranasal sinus CT scans was conducted. In the clinical part of the research, trans-SMP sphenoidotomy was performed in consecutive patients operated on for chronic rhinosinusitis. Results The SMP was found in 25% of sides (34% of patients). It was constantly located superolateral to the posterior insertion of the middle turbinate. The SMP formed the prominence on the posterior wall of the maxillary sinus that could be identified using volume rendering in 11% of sides (19% of patients). 30 trans-SMP sphenoidotomies were performed in 18 patients. The SMP prominence was identified in 15 sides. In absence of SMP prominence, identification of the SMP was still possible using other anatomical landmarks. Conclusions The SMP is present in over 30% Caucasian subjects at least on one side. Sphenoidotomy through the SMP is feasible and safe.
Impact of postoperative acute kidney injury on short-term outcomes of patients with Bentall surgery for any reason
Authors: Merkle-Storms Julia , Djordjevic Ilija , Gaisendrees Christopher , Ivanov Borko , Weber Carolyn , Krasivskyi Ihor , Avgeridou Soi , Mihaylova Mariya , Mader Navid , Kuhn-Régnier Ferdinand , Sabashnikov Anton , Wahlers Thorsten 
Published: January 2022

Background Acute kidney injury (AKI) after cardiac surgery is a well-known risk factor for increased postoperative mortality and morbidity. The effect of postoperative developed AKI on postoperative outcomes in patients after Bentall procedure has been incompletely investigated. The present study was dedicated to assessing the impact of postoperative AKI on morbidity and 30-day mortality in this specific cohort. Methods In a retrospective observational study, we investigated 249 patients undergoing Bentall procedure from January 2014 to March 2018 at the University Hospital of Cologne, Germany. After excluding patients with preoperative renal impairment, patients were divided into an AKI group ( n = 88) and a non-AKI group ( n = 97). Postoperative outcomes and 30-day mortality were analyzed using univariate regression analysis. AKI was defined by AKIN criteria. Results Mortality during ICU and hospital stay, as well as 30-day mortality, was significantly higher in the AKI group (all p < 0.001). Patients with postoperative developed AKI revealed 9.3-fold higher odds for ICU mortality and 6.7-fold higher odds for 30-day mortality in comparison to non-AKI group (all p < 0.004) as well as 4.5-fold higher odds for stroke. Coronary artery bypass time, as well as cross-clamp time, were similarly distributed between groups, whereas incidences of postoperative bleeding, myocardial infarction, and need for rethoracotomy occurred significantly more often in patients with postoperatively developed AKI (all p < 0.04). Conclusion Patients undergoing Bentall surgery who postoperatively developed AKI showed significantly higher morbidity and mortality. AKI points out to be an early predictor for poor outcomes. Thus, as a consequence, patients with postoperatively developed AKI should be highly monitored for immediate intervention.
Mesenchymal Stem Cell Exosomes Promote Functional Osteochondral Repair in a Clinically Relevant Porcine Model
Authors: Zhang Shipin , Wong Keng Lin , Ren Xiafei , Teo Kristeen Ye Wen , Afizah Hassan , Choo Andre Boon Hwa , Lai Ruenn Chai , Lim Sai Kiang , Hui James Hoi Po , Toh Wei Seong 
Published: January 2022

Background: Previous studies have reported the efficacy of human mesenchymal stem cell (MSC) exosomes for the repair of osteochondral defects in rats and rabbits. However, the safety and efficacy of MSC exosomes remain to be validated in a clinically relevant large animal model. Purpose: To validate the safety and efficacy of human MSC exosomes for osteochondral repair in a clinically relevant micropig model. Study Design: Controlled laboratory study. Methods: Bilateral osteochondral defects (6-mm diameter and 1-mm depth) were surgically created in the medial femoral condyles in knees of 12 micropigs. The pigs then received 2-mL intra-articular injections of MSC exosomes and hyaluronic acid (HA) (Exosome+HA) or HA alone after surgery and thereafter at 8 and 15 days. Osteochondral repair was assessed by magnetic resonance imaging (MRI) at 15 days and at 2 and 4 months after surgery as well as by macroscopic, histological, biomechanical, and micro—computed tomography (micro-CT) analyses at 4 months after surgery. Results: Exosome+HA–treated defects demonstrated significantly better MRI scores than HA-treated defects at 15 days and at 2 and 4 months. Additionally, Exosome+HA–treated defects demonstrated functional cartilage and subchondral bone repair, with significantly better macroscopic and histological scores and biomechanical properties (Young modulus and stiffness) than HA-treated defects at 4 months. Micro-CT further showed significantly higher bone volume and trabecular thickness in the subchondral bone of Exosome+HA–treated defects than that of HA-treated defects. Importantly, no adverse response or major systemic alteration was observed in any of the animals. Conclusion: This study shows that the combination of MSC exosomes and HA administered at a clinically acceptable frequency of 3 weekly intra-articular injections can promote functional cartilage and subchondral bone repair, with significantly improved morphological, histological, and biomechanical outcomes in a clinically relevant porcine model. Clinical Relevance: Our findings provide a robust scientific rationale to support a phase 1/2 clinical trial to test MSC exosomes in patients with osteochondral lesions.
Acromioclavicular Disk as a Potential Source of Pain in AC Joint Injuries
Authors: Ostermann Roman C. , Moen Todd C. , Siegert Paul , Bukowsky Claus , Lang Susanna , Heuberer Philipp R. , Pauzenberger Leo 
Published: January 2022

Background: Injuries of the acromioclavicular joint (ACJ) are common shoulder injuries that often lead to pain and dysfunction of the affected shoulder. Regardless of operative or nonoperative treatment, a relatively large number of patients remain symptomatic and experience pain. However, the specific source of persistent pain in the ACJ remains ambiguous. Purpose: To investigate the presence of sensory nerve fibers or pain-generating neurotransmitters within the intra-articular disk of the ACJ to determine its potential role as an independent pain generator in ACJ disorders. Study Design: Descriptive laboratory study. Methods: Twelve paired ACJs from 6 fresh human cadavers (mean age, 56 years; range, 41-82 years) were harvested and freed from surrounding soft tissues, leaving only the ACJ capsule intact. The specimens were placed in 4.5% formaldehyde fixative for a minimum of 48 hours. Coronal plane sections were obtained and demineralized in EDTA for a week, embedded in paraffin for 12 hours, and dehydrated overnight. With a rotation microtome, 2-μm sections were cut and stained with hematoxylin and eosin to investigate tissue architecture and confirm the presence of a fibrocartilaginous intra-articular disk. The sections were immunohistochemically stained with antisera against S100, neuropeptide Y (NPY), and substance P (SP) to detect for neural tissue. Additionally, a nerve fiber count per 10 high-power fields representing an area of 0.2 mm2 was conducted for S100 stains. All sections were examined for the presence of positive immunoreactivity to S100, NPY, and SP. Results: The presence of a fibrocartilaginous intra-articular disk could be observed in all 12 examined ACJs. In all specimens, an immunoreactivity to S100, NPY, and SP could be observed within the superior peripheral region of the intra-articular disk. High-power field nerve counts of the S100 stains revealed a mean ± SD of 7.9 ± 2.28 nerves per 10 high-power fields (range, 4-12). Conclusion: The documented immunoreactivity to S100, NPY, and SP indicates the presence of somatic and autonomic nerve fibers within the intra-articular disk of the ACJ. Clinical Relevance: Confirming the presence of nerve fibers within the intra-articular disk of the ACJ suggests that the disk itself could be an independent source of pain after injury and thus a possible explanation for recalcitrant pain after treatment.
Systemic inflammatory response during cardiopulmonary bypass: Axial flow versus radial flow oxygenators
Authors: Yildirim Funda , Amanvermez Senarslan Dilsad , Yersel Seyhmus , Bayram Barıs , Taneli Fatma , Tetik Omer 
Published: January 2022

Background: The objective of this study was to investigate the inflammatory effects of different oxygenator flow pattern types in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Methods: We designed this randomized, single-blind, prospective study of patients with coronary artery disease. We compared the systemic inflammatory effects of oxygenators with two types of flow: axial flow and radial flow. Therefore, we divided the patients into two groups: 24 patients in the axial group and 28 patients in the radial group. IL-1, IL-6, IL-10, and TNF-α were examined for cytokine activation leading to a systemic inflammatory reaction. The samples were collected at three different time intervals: T1, T2, and T3 (T1 was taken before cardiopulmonary bypass, T2 just 1 h after CPB onset, and T3 was taken 24 h after the surgery). Results: There were no significant differences in demographic characteristics between the two groups. We observed that there were notably lower levels of humoral inflammatory response parameters (IL-1, IL-6, and TNF-α) in the radial flow oxygenator group than in the axial flow group at the specific sampling times. For IL-10, there was no significant difference for any time period. Conclusion: It might be advantageous to use a radial-flow-patterned oxygenator to limit the inflammatory response triggered by the oxygenators in cardiopulmonary bypass.
Simulation model for analysis and evaluation of selected measures of the helicopter’s readiness
Authors: Ziółkowski Jarosław , Małachowski Jerzy , Oszczypała Mateusz , Szkutnik-Rogoż Joanna , Konwerski Jakub 
Published: January 2022

A methodology of analysis and evaluation of the selected indices of the helicopter readiness used in the Polish Navy is presented in this paper. These objects are the multi-purpose helicopters of the Polish and Russian production, performing mainly the rescue tasks. A mathematical model was based on the source databases covering a period of 2 years, which were developed in the form of the multi-format MS Excel spreadsheets. While considering the operating environment and a specificity of the performed tasks, an event-based model of the operation process was proposed in this paper, which enables to evaluate selected indices of readiness. Due to the specificity of the individual types of renovations and repairs, the calculated measures of the readiness were enabled in a multi-faceted manner, that is, they were referred to three separate operating periods covering the current operating period, the entire (i.e. two-year) studying period including extended renovations and the entire studying period including extended renovations and repairs. A broader approach enabled to calculate the functional and technical indices of the readiness of the helicopter.