bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and pharmacokinetics of a highly bioavailable resveratrol preparation (JOTROL TM)
Authors: Kemper Christopher , Behnam Dariush , Brothers Shaun , Wahlestedt Claes , Volmar Claude-Henry , Bennett Daniel , Hayward Marshall 
Published: June 2022

AbstractResveratrol exhibits a wide range of biological properties, including anti-glycation, antioxidant, anti-inflammation, neuroprotective (including against advanced dementia and Alzheimer’s disease), anti-cancer, and anti-aging activity in experimental models (Galiniak et al., Acta Biochim Pol 66:13-21, 2019). Unfortunately, this compound exhibits low bioavailability and solubility (Galiniak et al., Acta Biochim Pol 66:13-21, 2019), requiring large doses that can cause nausea and GI distress. JOTROLTM is a micellar 10% resveratrol solubilization formulation that is thought to increase bioavailability of resveratrol via lymphatic system absorption. Jupiter Neurosciences (formerly Jupiter Orphan Therapeutics; “Jupiter”) is pursuing the use of resveratrol in mucopolysaccharidosis type 1 (MPS 1), Friedreich’s ataxia, and Alzheimer’s disease/mild cognitive impairment. This paper describes a first in human study (FIH) to evaluate the bioavailability of resveratrol after ascending, single oral doses up to 700 mg resveratrol as JOTROLTM. After a single 500 mg dose of JOTROLTM, a Cmax of 455 ng/mL was observed, vs. 85 ng/mL Cmax after a 1 g encapsulated dose (Turner et al., Neurology 85:1383-91, 2015) and 1942 ng/mL after a 2.5 g micronized dose (Howells et al., Cancer Prev Res (Phila) 4:1419-1425, 2011). In this study, resveratrol exposures (AUCs and Cmax) increased with increasing doses. This increase appears to be higher than dose-proportional for AUC0-t and Cmax. Resveratrol and its three major conjugates accounted for 40 to 55% of the dose in urine, consistent with a high extent of absorption, but < 1% of drug-related material was intact relative to key metabolites in plasma and urine. Studies in Alzheimer’s patients and in MPS 1 are currently in development to test the effect this improved bioavailability has on those patient populations (Clintrials.gov, NCT04668274, 12/16/2020, https://clinicaltrials.gov/ct2/show/NCT04668274).
Association between non-alcoholic fatty liver disease and epicardial adipose tissue volume with cardiometabolic risk in coronary heart disease
Authors: Rasmy Hany Samir , Hamed Ahmed Shaaban , Demerdash Salah El , Zeidan Hanan Hafez , Amin Sameh Attia 
Published: June 2022

Abstract
Background
Regional adiposity has a significant impact on the formation of adverse metabolic and cardiovascular risk profiles. While much of the attention was directed to the importance of intra-abdominal adipose tissue, there were several new investigations about mediastinal and epicardial regions’ visceral adiposity. Our study aimed to determine the association between non-alcoholic fatty liver and increased epicardial adipose tissue mass with coronary artery disease severity.

Methods
This study was conducted on sixty patients who presented with symptoms of coronary artery disease and attended elective coronary angiography to rule out coronary artery disease. All patients have been subjected to full hepatic profile, noninvasive scoring system such as Fibrosis-4 and non-alcoholic fatty liver disease fibrosis score and abdominal ultrasound for diagnosis of non-alcoholic fatty liver disease and trans-thoracic echocardiography for measurement of average epicardial adipose tissue thickness. Student T test, analysis of variance test, chi-square test, and Fisher’s exact test were used for statistical analysis.

Results
According to the severity of coronary artery disease, patients with significant coronary stenosis had statistically significant higher degree of hepatic steatosis in abdominal ultrasound (P value < 0.001) while regarding the non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 for non-alcoholic fatty liver disease diagnosis, there was no significance between both groups. Also, the epicardial adipose tissue mean thickness was found to be statistically significantly higher among those with significant coronary stenosis than those without [7.859 ± 0.691 mm versus 5.600 ± 0.386 mm]. Moreover, statistically significant higher epicardial adipose tissue thickness values were found among grade 3 hepatic steatosis than in grades 2, 1, or 0 (P value < 0.001). At a cutoff > 6.1 mm, epicardial adipose tissue thickness was a valuable tool in discrimination between significant and non-significant coronary artery disease with specificity and sensitivity of 100%.

Conclusion
High epicardial adipose tissue thickness may represent a marker of severity of non-alcoholic fatty liver disease as well as an independent predictor of coronary artery disease risk.
Clinical Characteristics and Outcomes of Acute Lymphoblastic Leukemia in Adolescents and Young Adults in Malawi
Authors: Kasonkanji Edwards , Kimani Stephen , Skiver Brent , Ellis Grace , Seguin Ryan , Kaimila Bongani , Tomoka Tamiwe , Mulenga Maurice , Montgomery Nathan , Fedoriw Yuri , Gopal Satish , Westmorland Katherine D. , Painschab Matthew S. 
Published: June 2022

PURPOSE There are limited data on treatment and outcomes for acute lymphoblastic leukemia (ALL) among adolescents and young adults in sub-Saharan Africa. We describe a prospective observational cohort in Malawi. METHODS Patients age 15-39 years with newly diagnosed ALL at Kamuzu Central Hospital, Malawi, were enrolled from 2013 to 2019; follow-up was censored on December 2020. ALL diagnosis was confirmed on-site using immunohistochemistry and telepathology consultation involving pathologists in Malawi and the United States. All but four patients were treated with a modified pediatric-inspired regimen (Cancer and Leukemia Group B 10403 protocol). Key modifications included omission of asparaginase and no dose escalation for methotrexate. RESULTS Of 19 participants, the median age was 22 (range 15-36) years. Of the 15 patients who initiated treatment, 11 (73%) achieved remission after induction, one (7%) died during induction, two (13%) had refractory disease, and one (7%) absconded. No patients were lost to follow-up. Eventually, 10 of 11 patients (91%) with confirmed remission relapsed. The median duration of first remission was 10 (range 3-22) months. Twelve of 15 treated patients (80%) had died at the time of censoring. Among treated patients, the 12- and 24-month overall survival was 50% (95% CI, 23 to 72) and 17% (95% CI, 3 to 42), respectively. CNS involvement was associated with worse survival. CONCLUSION It is possible to treat adolescents and young adults with ALL in low-resource settings using a low-cost, pediatric-inspired regimen; however, outcomes are poor. Both cost and limitations in supportive care infrastructure limit intensive cytotoxic approaches such as asparaginase. Patient-reported outcomes are needed to understand the quality of life and cost-effectiveness. Critically, innovative, leap-frog therapies, such as monoclonal or bispecific antibodies, and feasible economic models for resource-limited settings are urgently needed.
Incidence of Cardiovascular Events in Patients Treated With Immune Checkpoint Inhibitors
Authors: Laenens Dorien , Yu Yuling , Santens Béatrice , Jacobs Johanna , Beuselinck Benoit , Bechter Oliver , Wauters Els , Staessen Jan , Janssens Stefan , Van Aelst Lucas 
Published: June 2022

PURPOSE In rare cases, immune checkpoint inhibitors (ICIs) cause immune-mediated myocarditis. However, true incidence of other major adverse cardiovascular events (MACEs) after ICI treatment remains unknown, mainly because late occurring side effects are rarely reported in prospective clinical trials. The aims of this study were (1) to identify incidence and risk factors of MACE in a real-life ICI-treated cancer cohort and (2) to compare incidence rates with patients with cancer who are not treated with ICIs and population controls. METHODS In total, 672 patients treated with ICIs were included. The primary end point was MACE, a composite of acute coronary syndrome, heart failure (HF), stroke, and transient ischemic attack. Secondary outcomes were acute coronary syndrome and HF separately. Incidence rates were compared between groups after matching according to age, sex, cardiovascular history, and cancer type. RESULTS The incidence of MACE was 10.3% during a median follow-up of 13 (interquartile range, 6-22) months. In multivariable analysis, a history of HF (hazard ratio 2.27; 95% CI, 1.03 to 5.04; P = .043) and valvular heart disease (hazard ratio 3.01; 95% CI, 1.05 to 8.66; P = .041) remained significantly associated with MACE. Cumulative incidence rates were significantly higher in the ICI group compared with the cancer cohort not exposed to ICI and the population controls, mainly driven by a higher risk of HF events. CONCLUSION Cardiovascular events during and after ICI treatment are more common than currently appreciated. Patients at risk are those with a history of cardiovascular disease. Compared with matched cancer and population controls, MACE incidence rates are significantly higher, suggesting a potential harmful effect of ICI treatment besides the underlying risk.
Oxaliplatin (3 months v 6 months) With 6 Months of Fluoropyrimidine as Adjuvant Therapy in Patients With Stage II/III Colon Cancer: KCSG CO09-07
Authors: Kim Seung Tae , Kim Sun Young , Lee Jeeyun , Yun Seong Hyeon , Kim Hee Cheol , Lee Woo Yong , Kim Tae Won , Hong Yong Sang , Lim Seok-Byung , Baek Ji Yeon , Oh Jae Hwan , Ahn Joong Bae , Shin Sang Joon , Han Sae-Won , Kim Seong Geun , Kang Seok Yun , Sym Sun Jin , Zang Dae Young , Kim Yeul Hong , Choi In Sil , Kang Jung Hun , Kim Min-Ji , Park Young Suk 
Published: June 2022

PURPOSE The combination of oxaliplatin and fluoropyrimidine for 6 months is one of the standard options for adjuvant therapy for high-risk stage II and III colorectal cancers (CRCs). The optimal duration of oxaliplatin to diminish neurotoxicity without compromising efficacy needs to be clarified. PATIENTS AND METHODS This open-label, randomized, phase III, noninferiority trial randomly assigned patients with high-risk stage II and III CRC to 3 and 6 months of oxaliplatin with 6 months of fluoropyrimidine groups (3- and 6-month arms, respectively). The primary end point was disease-free survival (DFS), and the noninferiority margin was a hazard ratio (HR) of 1.25. RESULTS In total, 1,788 patients were randomly assigned to the 6-month (n = 895) and 3-month (n = 893) arms, and 83.6% in the 6-month arm and 85.7% in the 3-month arm completed the treatment. The neuropathy rates with any grade were higher in the 6-month arm than in the 3-month arm (69.5% v 58.3%; P < .0001). The 3-year DFS rates were 83.7% and 84.7% in the 6-month and 3-month arms, respectively, with an HR of 0.953 (95% CI, 0.769 to 1.180; test for noninferiority, P = .0065) within the noninferiority margin. Among patients with stage III CRC treated by capecitabine plus oxaliplatin, the 3-year DFS of the 3-month arm was noninferior as compared with that of the 6-month arm with an HR of 0.713 (95% CI, 0.530 to 0.959; P = .0009). However, among patients with high-risk stage II and stage III CRC treated by infusional fluorouracil, leucovorin, and oxaliplatin, the noninferiority of the 3-month arm compared with the 6-month arm was not proven. CONCLUSION This study suggests that adding 3 months of oxaliplatin to 6 months of capecitabine could be considered an alternative adjuvant treatment for stage III CRC (ClinicalTrials.gov identifier: NCT01092481 ).
PARP Inhibitor Insensitivity to BRCA1/2 Monoallelic Mutations in Microsatellite Instability-High Cancers
Authors: Sokol Ethan S. , Jin Dexter X. , Fine Alexander , Trabucco Sally E. , Maund Sophia , Frampton Garrett , Molinero Luciana , Antonarakis Emmanuel S. 
Published: June 2022

PURPOSE To examine the overlap of homologous recombination deficiency (HRD) and microsatellite instability high (MSI-H) status, and to dissect driver versus bystander status of BRCA1/2 mutations ( BRCAm) in this context. METHODS A pan-cancer comprehensive genomic profiling cohort (n = 213,199) was examined for overlap between BRCAm and MSI-H status. BRCA1/2 variant zygosity was examined and correlated with MSI-H status, tumor mutational burden, and genome-wide loss of heterozygosity (gLOH). Clinical histories of two patients with prostate cancer with co-occurring BRCAm and MSI-H are described. RESULTS HRD and MSI-H phenotypes were generally mutually exclusive events ( P < .001). BRCAm that co-occurred together with high tumor mutational burden or MSI-H were predominantly monoallelic bystander alterations. In breast, ovarian, and pancreatic cancers, very few BRCAm occurred in the context of MSI-H; however, in prostate cancer, 12.8% of BRCA1 and 3.4% of BRCA2 alterations co-occurred with MSI-H. In these BRCA-associated cancers, co-occurring BRCAm were generally monoallelic and were not associated with elevated gLOH. Two patients with prostate cancer with co-occurring BRCAm and MSI-H showed resistance to poly (ADP-ribose) polymerase inhibition but sensitivity to subsequent anti–programmed cell death protein 1 therapy. CONCLUSION MSI-H status and HRD are generally mutually exclusive phenomena across cancer types, but may rarely co-occur, especially in prostate cancer. Although MSI-H samples had a higher BRCAm prevalence relative to microsatellite-stable tumors, these BRCA1/2 mutations were generally monoallelic and were not associated with elevated gLOH. Our findings suggest that most BRCAm coexisting with microsatellite instability are likely bystander events that may not result in sensitivity to poly (ADP-ribose) polymerase inhibitors.
Tumor Mutational Burden Is a Potential Predictive Biomarker for Response to Immune Checkpoint Inhibitors in Patients With Advanced Biliary Tract Cancer
Authors: Liddell Savannah S. , Chakrabarti Sakti , Wintheiser Grant A. , Zemla Tyler J. , Shi Qian , Tella Sri Harsha , Jin Zhaohui , Wookey Vanessa B. , Hassan Hind , Tran Nguyen H. , Borad Mitesh J. , Mahipal Amit 
Published: June 2022

PURPOSEPatients with advanced biliary tract cancers (BTCs) have a dismal prognosis. This multisite, single-institution study analyzed the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with advanced BTC.MATERIALS AND METHODSThe prospectively maintained institutional database was searched for patients with advanced BTC. Electronic medical records of the patients with advanced BTC treated with an ICI that included programmed death-1 or programmed death-ligand 1 blockers were retrospectively reviewed to obtain data on patient characteristics, tumor characteristics including molecular biomarkers, detailed treatment, response characteristics, survival, and toxicities. The analysis included overall response rate, survival, and correlation between survival and molecular biomarkers.RESULTSThe institutional database query identified 47 patients with advanced BTC who received at least one dose of an ICI; 11 (24%) patients in the first-line setting and the rest of the patients had refractory disease. The median age of the cohort was 62 years, and 51% were female. The overall response rate was 10.6%, with a disease control rate of 53.2%. The median progression-free survival (PFS) and overall survival were 3.6 months and 6.9 months, respectively. Biomarker analysis revealed improved PFS in patients with tumor mutational burden > 5 mutations per megabase (median PFS: 6.4 v 2.2 months; P = .0027). No unexpected adverse events were observed.CONCLUSIONICIs are well tolerated and have modest antitumor activity in patients with advanced BTC. The study result supports the exploration of tumor mutational burden as a potential predictive biomarker for response to ICIs in patients with advanced BTC.
Diagnosis and Management of Central Diabetes Insipidus in Adults
Authors: Tomkins Maria , Lawless Sarah , Martin-Grace Julie , Sherlock Mark , Thompson Chris J 
Published: June 2022

AbstractCentral diabetes insipidus (CDI) is a clinical syndrome which results from loss or impaired function of vasopressinergic neurons in the hypothalamus/posterior pituitary, resulting in impaired synthesis and/or secretion of arginine vasopressin (AVP). AVP deficiency leads to the inability to concentrate urine and excessive renal water losses, resulting in a clinical syndrome of hypotonic polyuria with compensatory thirst. CDI is caused by diverse etiologies, although it typically develops due to neoplastic, traumatic, or autoimmune destruction of AVP-synthesizing/secreting neurons. This review focuses on the diagnosis and management of CDI, providing insights into the physiological disturbances underpinning the syndrome. Recent developments in diagnostic techniques, particularly the development of the copeptin assay, have improved accuracy and acceptability of the diagnostic approach to the hypotonic polyuria syndrome. We discuss the management of CDI with particular emphasis on management of fluid intake and pharmacological replacement of AVP. Specific clinical syndromes such as adipsic diabetes insipidus and diabetes insipidus in pregnancy as well as management of the perioperative patient with diabetes insipidus are also discussed.
Absence of a robust mitotic timer mechanism in early preimplantation mouse embryos leads to chromosome instability
Authors: Allais Adélaïde , FitzHarris Greg 
Published: June 2022

ABSTRACT
Preimplantation embryos often consist of a combination of euploid and aneuploid cells, suggesting that safeguards preventing the generation and propagation of aneuploid cells in somatic cells might be deficient in embryos. In somatic cells, a mitotic timer mechanism has been described, in which even a small increase in the duration of M phase can cause a cell cycle arrest in the subsequent interphase, preventing further propagation of cells that have undergone a potentially hazardously long M phase. Here, we report that cell divisions in the mouse embryo and embryonic development continue even after a mitotic prolongation of several hours. However, similar M-phase extensions caused cohesion fatigue, resulting in prematurely separated sister chromatids and the production of micronuclei. Only extreme prolongation of M phase caused a subsequent interphase arrest, through a mechanism involving DNA damage. Our data suggest that the simultaneous absence of a robust mitotic timer and susceptibility of the embryo to cohesion fatigue could contribute to chromosome instability in mammalian embryos.
This article has an associated ‘The people behind the papers’ interview.
Exposure to e-cigarette vapor extract induces vocal fold epithelial injury and triggers intense mucosal remodeling
Authors: Lungova Vlasta , Wendt Kristy , Thibeault Susan L. 
Published: June 2022

ABSTRACT
Vaping has been reported to cause acute epiglottitis, a life-threatening airway obstruction induced by direct epithelial injury and subsequent inflammatory reaction. Here, we show that we were able to recapitulate this phenomenon in vitro. Exposure of human engineered vocal fold (VF) mucosae to 0.5% and 5% electronic cigarette (e-cigarette) vapor extract (ECVE) for 1 week induced cellular damage of luminal cells, disrupting homeostasis and innate immune responses. Epithelial erosion was likely caused by accumulation of solvents and lipid particles in the cytosol and intercellular spaces, which altered lipid metabolism and plasma membrane properties. Next, we investigated how the mucosal cells responded to the epithelial damage. We withdrew the ECVE from the experimental system and allowed VF mucosae to regenerate for 1, 3 and 7 days, which triggered intense epithelial remodeling. The epithelial changes included expansion of P63 (TP63)-positive basal cells and cytokeratin 14 (KRT14) and laminin subunit α-5 (LAMA5) deposition, which might lead to local basal cell hyperplasia, hyperkeratinization and basement membrane thickening. In summary, vaping presents a threat to VF mucosal health and airway protection, thereby raising further concerns over the safety of e-cigarette use.
This article has an associated First Person interview with the first author of the paper.
Radiographic patterns on Chest X-ray as a supporting imaging tool in triaging of suspected Corona Virus Disease (COVID) patients
Authors: NISHTAR TAHIRA , ULLAH NADEEM , AHMAD FATIMA SULTAN , RAHIM SOHANA 
Published: June 2022

Objective: To evaluate the radiographic patterns on Chest X-Ray (CXR) in accordance with Modified Brixia Scoring as supporting imaging tool in triaging of Corona Virus Disease (COVID-19) pneumonia.
Methods: In this cross-sectional study, chest radiographs of suspected COVID patients at emergency triage, Lady Reading Hospital (LRH) from April 18th to July 22nd 2020 were evaluated for patterns of COVID pneumonia and scored in accordance with modified Brixia score. Each zone was categorized as score of “one” for interstitial pattern, “two” for mixed interstitial /alveolar pattern and “three” for alveolar pattern. Radiographic patterns consistent with COVID pneumonia or patients having strong clinical suspicion were advised Polymerase Chain Reaction (PCR) tests.
Results: Total of 2,225 individuals were screened for patterns of COVID-19 pneumonia on chest radiograph. Out of these 1465(65.8%) had normal chest radiograph and 760(34.2%) had abnormal findings. Out of the total, 648 suspected COVID patients were selected for PCR. The radiographic patterns ranged from mixed interstitial/alveolar pattern in 261(40.3%) patients, alveolar pattern in 231(35.6%), interstitial pattern in 87(13.4%), pleural effusion in 12(1.9%), other findings in 5(0.8%) while 52(8%) suspected Covid patients had normal radiographs. The PCR was positive in 326(50.3%), negative in 100(15.4%) and inconclusive in 60(9.3%) while 162(25%) were lost to follow up. Amongst the 52 suspected Covid patients having normal chest radiographs, 10 were positive on PCR, 21 negative, seven suspected and two inconclusive, while 12 were lost to follow up.
Conclusion: Chest radiograph is used for triaging of suspected COVID pneumonia patients in emergency settings. It assesses the severity of disease according to modified Brixia scoring for treatment plan.
doi: https://doi.org/10.12669/pjms.38.6.5279
How to cite this:Nishtar T, Nadeem Ullah, Ahmad FS, Rahim S. Radiographic patterns on Chest X-ray as a supporting imaging tool in triaging of suspected Corona Virus Disease (COVID) patients. Pak J Med Sci. 2022;38(6):---------. doi: https://doi.org/10.12669/pjms.38.6.5279
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.