bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of non-myeloablative lymphodepleting preconditioning regimens in patients undergoing adoptive T cell therapy
Authors: Nissani Abraham , Lev-Ari Shaked , Meirson Tomer , Jacoby Elad , Asher Nethanel , Ben-Betzalel Guy , Itzhaki Orit , Shapira-Frommer Ronnie , Schachter Jacob , Markel Gal , Besser Michal J. 
Published: May 2021

BackgroundAdoptive cell therapy with T cells genetically engineered to express a chimeric antigen receptor (CAR-T) or tumor-infiltrating T lymphocytes (TIL) demonstrates impressive clinical results in patients with cancer. Lymphodepleting preconditioning prior to cell infusion is an integral part of all adoptive T cell therapies. However, to date, there is no standardization and no data comparing different non-myeloablative (NMA) regimens.MethodsIn this study, we compared NMA therapies with different doses of cyclophosphamide or total body irradiation (TBI) in combination with fludarabine and evaluated bone marrow suppression and recovery, cytokine serum levels, clinical response and adverse events.ResultsWe demonstrate that a cumulative dose of 120 mg/kg cyclophosphamide and 125 mg/m2fludarabine (120Cy/125Flu) and 60Cy/125Flu preconditioning were equally efficient in achieving deep lymphopenia and neutropenia in patients with metastatic melanoma, whereas absolute lymphocyte counts (ALCs) and absolute neutrophil counts were significantly higher following 200 cGyTBI/75Flu-induced NMA. Thrombocytopenia was most profound in 120Cy/125Flu patients. 30Cy/75Flu-induced preconditioning in patients with acute lymphoblastic leukemia resulted in a minor ALC decrease, had no impact on platelet counts and did not yield deep neutropenia. Following cell infusion, 120Cy/125Flu patients with objective tumor response had significantly higher ALC and significant lower inflammatory indexes, such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Receiver-operating characteristics curve analysis 7 days after cell infusion was performed to determine the cut-offs, which distinguish between responding and non-responding patients in the 120Cy/125Flu cohort. NLR≤1.79 and PLR≤32.7 were associated with clinical response and overall survival. Cytokine serum levels did not associate with clinical response in patients with TIL. Patients in the 120Cy/125Flu cohort developed significantly more acute NMA-related adverse events, including thrombocytopenia, febrile neutropenia and cardiotoxicity, and stayed significantly longer in hospital compared with the 60Cy/125Flu and TBI/75Flu cohorts.ConclusionsBone marrow depletion and recovery were equally affected by 120Cy/125Flu and 60Cy/125Flu preconditioning; however, toxicity and consequently duration of hospitalization were significantly lower in the 60Cy/125Flu cohort. Patients in the 30Cy/75Flu and TBI/75Flu groups rarely developed NMA-induced adverse events; however, both regimens were not efficient in achieving deep bone marrow suppression. Among the regimens, 60Cy/125Flu preconditioning seems to achieve maximum effect with minimum toxicity.
Use of historical high-sensitivity cardiac troponin T levels to rule out myocardial infarction
Authors: Roos Andreas , Holzmann Martin J 
Published: May 2021

ObjectiveSeveral high-sensitivity cardiac troponin (hs-cTn)-based strategies exist for rule-out of myocardial infarction (MI). It is unknown whether historical hs-cTnT concentrations can be used. This study aim to evaluate the performance of a rule-out strategy based on the European Society of Cardiology (ESC) 0/1-hour algorithm, using historical hs-cTnT concentrations.MethodsAll visits among patients with chest pain in the emergency department at nine different hospitals in Sweden from 2012 to 2016 were eligible (221 490 visits). We enrolled patients with a 0-hour hs-cTnT of <12 ng/L, a second hs-cTnT measured within 3.5 hours, and ≥1 historical hs-cTnT available. We calculated the risks of MI and all-cause mortality using two rule-out strategies: (1) a delta hs-cTnT of <3 ng/L between the 0-hour hs-cTnT and the second hs-cTnT (modified ESC algorithm) and (2) a historical hs-cTnT <12 ng/L and a delta hs-cTnT of <3 ng/L in relation to the 0-hour hs-cTnT (historical-hs-cTnT algorithm).ResultsA total of 8432 patients were included, of whom 84 (1.0%) had an MI. The modified ESC algorithm triaged 8100 (96%) patients toward ruled-out, for whom 30-day MI risk and negative predictive value (NPV) for MI (95% CI) were 0.4% (0.3% to 0.6%) and 99.6% (99.4% to 99.7%), respectively. The historical-hs-cTnT algorithm ruled out 6700 (80%) patients, with a 30-day MI risk of 0.5% (0.4% to 0.8%) and NPV of 99.5% (99.2% to 99.6%).ConclusionsThe application of algorithm resulted in similar MI risk and NPV to an established algorithm. The usefulness of historical hs-cTnT concentrations should merit further attention.
Hospital safety-net burden is associated with increased inpatient mortality after elective total knee arthroplasty: a retrospective multistate review, 2007–2018
Authors: Kelleher Deirdre Clare , Lippell Ryan , Lui Briana , Ma Xiaoyue , Tedore Tiffany , Weinberg Roniel , White Robert S 
Published: May 2021

BackgroundTotal knee arthroplasty (TKA) is among the most common surgical procedures performed in the USA and comprises an outsized proportion of Medicare expenditures. Previous work-associated higher safety-net burden hospitals with increased morbidity and in-hospital mortality following total hip arthroplasty. Here, we examine the association of safety-net burden on postoperative outcomes after TKA.MethodsWe retrospectively analyzed 1 141 587 patients aged ≥18 years undergoing isolated elective TKA using data from the State Inpatient Databases for Florida, Kentucky, Maryland, New York and Washington from 2007 through 2018. Hospitals were grouped into tertiles by safety-net burden status, defined by the proportion of inpatient cases billed to Medicaid or unpaid (low: 0%–16.83%, medium: 16.84%–30.45%, high: ≥30.45%). Using generalized estimating equation models, we assessed the association of hospital safety-net burden status on in-hospital mortality, patient complications and length of stay (LOS). We also analyzed outcomes by anesthesia type in New York State (NYS), the only state with this data.ResultsMost TKA procedures were performed at medium safety-net burden hospitals (n=6 16 915, 54%), while high-burden hospitals performed the fewest (n=2 04 784, 17.9%). Overall in-patient mortality was low (0.056%), however, patients undergoing TKA at medium-burden hospitals were 40% more likely to die when compared with patients at low-burden hospitals (low: 0.043% vs medium: 0.061%, adjusted OR (aOR): 1.40, 95% CI 1.09 to 1.79, p=0.008). Patients who underwent TKA at medium or high safety-net burden hospitals were more likely to experience intraoperative complications (low: 0.2% vs medium: 0.3%, aOR: 1.94, 95% CI 1.34 to 2.83, p<0.001; low: 0.2% vs high: 0.4%, aOR: 1.91, 95% CI 1.35 to 2.72, p<0.001). There were no statistically significant differences in other postoperative complications or LOS between the different safety-net levels. In NYS, TKA performed at high safety-net burden hospitals was more likely to use general rather than regional anesthesia (low: 26.7% vs high: 59.5%, aOR: 4.04, 95% CI 1.05 to 15.5, p=0.042).ConclusionsPatients undergoing TKA at higher safety-net burden hospitals are associated with higher odds of in-patient mortality than those at low safety-net burden hospitals. The source of this mortality differential is unknown but could be related to the increased risk of intraoperative complications at higher burden centers.
One-year results from a randomized comparative trial of targeted steroid injection via epidural catheter versus standard transforaminal epidural injection for the treatment of unilateral cervical radicular pain
Authors: Conger Aaron , Kendall Richard W , Sperry Beau P , Petersen Russell , Salazar Fabio , Cunningham Shellie , Henrie A Michael , Bisson Erica F , Teramoto Masaru , McCormick Zachary L 
Published: May 2021

Objectives
The objective of this study was to evaluate the long-term effectiveness of catheter-directed cervical interlaminar epidural steroid injection with triamcinolone compared with cervical transforaminal steroid injection with dexamethasone for the treatment of refractory unilateral radicular pain.

Design
Prospective, randomized, comparative trial.

Methods
The primary outcome was the proportion of participants with ≥50% Numeric Rating Scale ‘dominant pain’ (the greater of arm vs neck) reduction from baseline. Secondary outcomes included ≥30% Neck Disability Index reduction and Patient Global Impression of Change response indicating ‘much improved’ or ‘very much improved’.

Results

Data from 117 participants (55.6% women; 52.3±12.5 years of age; body mass index, 28.2±6.5 kg/m
2
) were analyzed. The proportion of participants who experienced ≥50% pain reduction at 1 month, 3 months, and 6 months has been previously reported. At 1 year, 61.2% (95% CI, 46.9% to 73.9%) of the catheter group compared with 51.9% (95% CI, 38.4% to 65.2%) of the transforaminal group reported ≥50% ‘dominant’ pain reduction (p=0.35). The proportion of participants who experienced ≥30% improvement in Neck Disability Index score was 60.4% (95% CI, 45.9% to 73.3%) and 47.1% (95% CI, 33.7% to 60.8%) in the catheter and transforaminal groups (p=0.18). Patient Global Impression of Change improvement was similar in both groups: 60.5% (95% CI, 44.2% to 74.8%) and 57.5% (95% CI, 41.7% to 71.9%) of the catheter and transforaminal groups reported being ‘much improved’ or ‘very much improved’, respectively (p=0.79).

Conclusion
Both cervical catheter-directed interlaminar epidural injection and cervical transforaminal steroid injection were effective in reducing pain and disability in the majority of participants with refractory unilateral cervical radiculopathy for up to 1 year.
Infiltration between the popliteal artery and the capsule of the knee (IPACK) block in knee surgery: a narrative review
Authors: Chan Edmund , Howle Ryan , Onwochei Desire , Desai Neel 
Published: May 2021

Background
The infiltration between the popliteal artery and the capsule of the knee (IPACK) block has been described as an alternative analgesic strategy for knee pain.

Objective
Our aim was to perform a narrative review to examine the place and value that the IPACK block has in comparison to and in conjunction with other regional anesthesia modalities.

Evidence review
Following an extensive search of electronic databases, we included anatomical studies, letters, comparative observational studies, and non-randomized and randomized controlled trials that examined the IPACK block in relation to surgery on the knee under general or neuraxial anesthesia.

Findings
In all, 35 articles were included. Cadaveric studies demonstrated the potential for injected dye to spread to the nerves responsible for the innervation of the posterior as well as anteromedial and anterolateral aspects of the knee. Of the comparative observational studies (n=15) and non-randomized (n=1) and randomized controlled trials (n=13), 2 and 27 were conducted in the context of anterior cruciate ligament reconstruction and knee replacement surgery, respectively. The role of the IPACK block with each different permutation of regional anesthesia techniques was investigated by a small number of studies. Clinical studies, in the setting of knee replacement surgery, revealed variation in the manner in which the IPACK block was performed, and indicated the possible superiority of distal injection at the level of the femoral condyles for the management of posterior knee pain. Evidence suggested the following: the IPACK block in combination with single shot adductor canal block (ACB) may be beneficial for analgesic and functional outcomes; in conjunction with single shot or continuous ACB, the IPACK block might be superior to local infiltration analgesia (LIA); and functional outcomes may be improved with the supplementation of continuous ACB and LIA with the IPACK block. The IPACK block did not commonly result in the occurrence of foot drop. Relative to tibial nerve block (TNB), the IPACK block reduced the occurrence of foot drop and increased the proportion of patients who were able to be discharged on the third postoperative day.

Conclusions
The IPACK block was potentially complementary to the ACB and might be preferable to the TNB as a motor-sparing regional anesthesia technique in knee surgery. Definitive recommendations were not reached in the presence of the heterogeneous and limited evidence base.
Does the addition of iPACK to adductor canal block in the presence or absence of periarticular local anesthetic infiltration improve analgesic and functional outcomes following total knee arthroplasty? A systematic review and meta-analysis
Authors: Hussain Nasir , Brull Richard , Sheehy Brendan , Dasu Michael , Weaver Tristan , Abdallah Faraj W 
Published: May 2021

BackgroundWhen combined with adductor canal block (ACB), local anesthetic infiltration between popliteal artery and capsule of knee (iPACK) is purported to improve pain following total knee arthroplasty (TKA). However, the analgesic benefits of adding iPACK to ACB in the setting of surgeon-administered periarticular local infiltration analgesia (LIA) are unclear.ObjectivesTo evaluate the analgesic benefits of adding iPACK to ACB, compared with ACB alone, in the setting of LIA following TKA.Evidence reviewWe conducted a meta-analysis of randomized trials comparing the effects of adding iPACK block to ACB versus ACB alone on pain severity at 6 hours postoperatively in adult patients undergoing TKA. We a priori planned to stratify analysis for use of LIA. Opioid consumption at 24 hours, functional recovery, and iPACK-related complications were secondary outcomes.FindingsFourteen trials (1044 patients) were analyzed. For the primary outcome comparison in thepresenceof LIA (four trials, 273 patients), adding iPACK to ACB did not improve postoperative pain at 6 hours. However, in theabsenceof LIA (eight trials, 631 patients), adding iPACK to ACB reduced pain by a weighted mean difference (WMD) (95% CI) of −1.33 cm (−1.57 to –1.09) (p<0.00001). For the secondary outcome comparisons in thepresenceof LIA, adding iPACK to ACB did not improve postoperative pain at all other time points, opioid consumption or functional recovery. In contrast, in theabsenceof LIA, adding iPACK to ACB reduced pain at 12 hours, and 24 hours by a WMD (95% CI) of −0.98 (−1.79 to –0.17) (p=0.02) and −0.69 (−1.18 to –0.20) (p=0.006), respectively, when compared with ACB alone, but did not reduce opioid consumption. Functional recovery was also improved by a log(odds ratio) (95% CI) of 1.28 (0.45 to 2.11) (p=0.003). No iPACK-related complications were reported.ConclusionAdding iPACK to ACB in the setting of periarticular LIA does not improve analgesic outcomes following TKA. In the absence of LIA, adding iPACK to ACB reduces pain up to 24 hours and enhances functional recovery. Our findings do not support the addition of iPACK to ACB when LIA is routinely administered.
The articular cartilage preservative effects of genistein in an experimental model of knees osteoarthritis
Authors: Cheng Xiangjun , Xu Peilian 
Published: May 2021

The study aimed to investigate the preservative effects of genistein on articular cartilage in an experimental model of knee osteoarthritis in rats. Thirty male Wistar rats were assigned to 3 equal groups: sham group, osteoarthritis control group (OAG), and genistein-treated osteoarthritis group (GTG). Intra-articular injections of monosodium iodoacetate were used for osteoarthritis induction. After 2 weeks of rest for the induction of the inflammatory process, genistein (30 mg/kg/day) vs. saline gavage was administered for 8 weeks. The expression of matrix metalloproteinase (MMP)-8 and MMP-13, Sox5/Sox6, Indian hedgehog (IHH), and Col2 were evaluated in medial femoral condyle sections by immunohistochemical staining. The number of chondrocytes and cartilage thicknesses were also measured and compared among the groups. No significant change in cartilage thickness was observed in GTG compared with OAG (p = 0.188). Chondrocyte count was significantly higher in the articular cartilage of GTG compared with OAG (p = 0.006). Induction of osteoarthritis significantly increased the expression of MMP-8, MMP-13, and IHH, but decreased Col2, Sox5, and Sox6 expression (p < 0.001); these were partially prevented in the GTG. Our findings support the effectiveness of genistein treatment in the prevention of articular cartilage damage in the experimental model of knee osteoarthritis. The proposed mechanism of action is through the suppression of the MMP, IHH, and Col2 pathways, besides the induction of Sox5 and Sox6 expression. Novelty: Genistein prevents articular cartilage damage in the experimental model of knee osteoarthritis. The osteoprotective effect is manifested by the modulation of expression of MMP, Sox, IHH, and Col2 proteins.
The Phytoclast Group as a tracer of palaeoenvironmental changes in the early Toarcian
Authors: Rodrigues Bruno , Silva Ricardo L. , Mendonça Filho João Graciano , Reolid Matías , Sadki Driss , Comas-Rengifo Maria José , Goy Antonio , Duarte Luís V. 
Published: May 2021

Abstract

In this paper, we present a detailed review of upper Pliensbachian–lower Toarcian kerogen assemblages from the southern areas of the West Tethys shelf (between Morocco and northern Spain) and demonstrate the use of the Phytoclast Group as a tracer of palaeoenvironmental changes in the early Toarcian. The kerogen assemblages in the studied sections from the southern areas of the West Tethys shelf are dominated by the Phytoclast Group and terrestrial palynomorphs, although punctual increases in amorphous organic matter, freshwater (
Botryococcus
) and marine microplankton (dinoflagellate cysts, acritarchs and prasinophyte algae) were observed at specific stratigraphic intervals. The opaque/non-opaque phytoclasts ratio was used to trace changes in palaeoclimate and other palaeoenvironmental parameters and reflect climate gradients associated with water availability during early Toarcian. During the Pliensbachian–Toarcian and Jenkyns events, changes in kerogen assemblages in the southern areas of the West Tethys shelf correlated with changes in the northern Tethys and Panthalassa shelf. The acceleration of the hydrological cycle associated with the aforementioned events was less intense in the northern Gondwana, southern and western Iberian basins, a reflection of the palaeogeographic position of these basins within the semi-arid climate belt when compared with the northern Iberian region and other northern areas of the West Tethys and Panthalassa shelf, inserted in winter-wet and warm temperate climate belts. Amorphous organic matter enrichment associated with the Pliensbachian–Toarcian and Jenkyns events reflects an increase in primary productivity linked with increased continental weathering, fluvial runoff and riverine organic matter, and nutrient input into marine areas, inducing water column stratification and promoting the preservation of organic matter.
Cigarette Smoking and Estrogen-Related Cancer
Authors: Baron John A. , Nichols Hazel B. , Anderson Chelsea , Safe Stephen 
Published: May 2021

AbstractCigarette smoking is a known cause of many cancers, yet epidemiologic studies have found protective associations with the risk of four “estrogen-related” malignancies: endometrial cancer, endometrioid and clear cell ovarian cancers, and thyroid cancer. This review considers epidemiologic and biological aspects of these associations, focusing particularly on estrogen signaling, and contrasts them with those for breast cancer, another estrogen-related malignancy. The observational findings regarding the inverse associations are consistent and remain after adjustment for possible confounding factors. In general, women who smoke do not have lower circulating estrogen levels than nonsmokers, eliminating one possible explanation for reduced risks of these malignancies. For endometrial and endometrioid ovarian cancer, the negative associations could plausibly be explained by interference with signaling through the estrogen receptor α. However, this is unlikely to explain the lower risks of thyroid and clear cell ovarian cancers. For thyroid cancer, an anti-inflammatory effect of nicotine and reduced TSH levels from smoking have been proposed explanations for the inverse association, but both lack convincing evidence. While the overall impact of cigarette smoking is overwhelmingly negative, protective associations such as those discussed here can provide potential clues to disease etiology, treatment, and prevention.
CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory
Authors: Lelliott Emily J. , Kong Isabella Y. , Zethoven Magnus , Ramsbottom Kelly M. , Martelotto Luciano G. , Meyran Deborah , Zhu Joe Jiang , Costacurta Matteo , Kirby Laura , Sandow Jarrod J. , Lim Lydia , Dominguez Pilar M. , Todorovski Izabela , Haynes Nicole M. , Beavis Paul A. , Neeson Paul J. , Hawkins Edwin D. , McArthur Grant A. , Parish Ian A. , Johnstone Ricky W. , Oliaro Jane , Sheppard Karen E. , Kearney Conor J. , Vervoort Stephin J. 
Published: May 2021

Abstract

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor–positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, whereas their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic, and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunologic T-cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous antitumor T-cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor T cells, and induced a retinoblastoma-dependent T-cell phenotype supportive of favorable responses to immune checkpoint blockade in patients with melanoma. Together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost antitumor T-cell immunity.

Significance:
Immunologic memory is critical for sustained antitumor immunity. Our discovery that CDK4/6 inhibitors drive T-cell memory fate commitment sheds new light on their clinical activity, which is essential for the design of clinical trial protocols incorporating these agents, particularly in combination with immunotherapy, for the treatment of cancer.
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Exploring 4D Image Sets of Early Heart Development Using Gesture and
an Immersive, Spatial Operating Environment
Authors: Carpenter John , Lansford Rusty 
Published: May 2021

Abstract
Scientists today can collect more data than they can perceive using traditional visualization methods. New technologies and sensors allow researchers to gather dynamic, complex multidimensional datasets—all of which must be carefully studied to reveal hidden patterns and narratives. The authors used an immersive platform to design a new visualization for real-time, intuitive spatial manipulations of time-based volumetric datasets via a wand-based gestural interface. The resulting work resolves microscopic tissue structures at a human scale in a room-based pixel space, facilitating research, discovery and in-person teaching and collaboration.