bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Evaluation of a Community Surveillance Method for Estimating Deaths Due to Injuries in Rural Nepal
Authors: Bhatta Santosh , Mytton Julie , Joshi Elisha , Bhatta Sumiksha , Adhikari Dhruba , Manandhar Sunil Raja , Joshi Sunil Kumar
Published: August 2021

Almost 10% of global deaths are secondary to injuries, yet in the absence of routine injury surveillance and with few studies of injury mortality, the number and cause of injury deaths in many countries are not well understood. This study aimed to develop and evaluate the feasibility of a method to identify injury deaths in rural Nepal. Working with local government authorities, health post staff and female community health volunteers (FCHVs), we developed a two-stage community fatal injury surveillance approach. In stage one, all deaths from any cause were identified. In stage two, an interview with a relative or friend gathered information about the deceased and the injury event. The feasibility of the method was evaluated prospectively between February 2019 and January 2020 in two rural communities in Makwanpur district. The data collection tools were developed and evaluated with 108 FCHVs, 23 health post staff and two data collectors. Of 457 deaths notified over one year, 67 (14.7%) fatal injury events were identified, and interviews completed. Our method suggests that it is feasible to collect data on trauma-related deaths from rural areas in Nepal. These data may allow the development of injury prevention interventions and policy.
The Relationship between Diabetes Family Conflict and Parental Conflict on Problem Recognition in Illness Self-Management among Individuals with Type 1 Diabetes Mellitus
Authors: Cho Mi-Kyoung , Kim Mi Young
Published: August 2021

We investigated the relationship between diabetes family conflict and parental conflict on problem recognition in illness self-management (PRISM) among individuals with type 1 diabetes mellitus (T1DM). We employed a descriptive research design. Participants were 243 individuals with T1DM who completed online questionnaires. Data were analyzed with descriptive statistics, correlations, and multiple regression analyses. Results revealed that barriers were felt in all areas (understanding and organizing care, regimen pain and bother, healthcare team interaction, family interaction, and peer interaction), especially peer interaction. The significant influencing factors in the regression model for the total PRISM score of individuals with T1DM were conflict behavior toward mothers (t = 4.44, p < 0.001), diabetes family conflict (t = 5.77, p < 0.001), conflict behavior toward fathers (t = 2.58, p = 0.011), women (t = 2.67, p = 0.008), non-religious (t = −2.33, p = 0.020), and diabetic complications (t = 2.17, p = 0.031). The explanatory power of the constructed regression model for PRISM was 42.0% (F = 30.12, p < 0.001). To promote self-management among individuals with T1DM, the development of interventions that promote improved peer interactions, a family-centered approach, and a program that can minimize conflicts between families and parents are required.
The Influence of Sociodemographic Heterogeneity on the Perceptions of COVID-19: A Countrywide Survey Study in the USA
Authors: Mondal Pritish , Sinharoy Ankita , Sankoorikal Binu-John , Siddaiah Roopa , Mazur Lauren , Graff Gavin
Published: August 2021

Background: Sociodemographic factors such as age, race, education, family income, and sex have been reported to influence COVID-related perceptions, reflected by knowledge, stress, and preventive behavior. We conducted a US-based survey to estimate the difference in COVID-related perceptions among diverse sociodemographic groups and the influence of sociodemographic heterogeneity on COVID-related perceptions. Methods: The survey enquired about sociodemographic parameters and relevant information to measure knowledge, stress, and preventive behavior. COVID-perception scores among sociodemographic subgroups were compared with ANOVA (Bonferroni). The general linear model (GLM) was used to estimate the association among sociodemographic factors and COVID-related perceptions. Results: Females (75%) and White participants (78%) were the predominant (N = 3734). Females, White participants, wealthy, and educated participants demonstrated better knowledge, while participants of minority races, younger ages, low incomes, and females experienced high stress. Females, African-Americans, and educated participants better adopted preventive behaviors. Race, family income, and sex were the highest contributors to the predictive model. Sociodemographic determinants had statistically significant associations with knowledge (F-score = 7.72, p < 0.001; foremost predictor: race), stress (F-score = 16.46, p < 0.001; foremost predictor: income), and preventive behavior (GLM: F-score = 7.72, p < 0.001, foremost predictor: sex). Conclusion: Sociodemographic heterogeneity significantly influenced COVID-related perceptions, while race, family income, and sex were the strongest determinants of COVID-related perceptions.
Cellular Defensive Mechanisms of Tea Polyphenols: Structure-Activity Relationship
Authors: Truong Van-Long , Jeong Woo-Sik
Published: August 2021

Tea is particularly rich in polyphenols, including catechins and theaflavins, thearubigins, flavonols, and phenolic acids, which are believed to contribute to the health benefits of tea. The health-promoting effects of tea polyphenols are believed to be related to their cellular defensive properties. This review is intended to briefly summarize the relationship between the chemical structures of tea polyphenols and their biological activities. Tea polyphenols appear as direct antioxidants by scavenging reactive oxygen/nitrogen species; chelating transition metals; and inhibiting lipid, protein, and DNA oxidations. They also act directly by suppressing “pro-oxidant” enzymes, inducing endogenous antioxidants, and cooperating with vitamins. Moreover, tea polyphenols regulate cellular signaling transduction pathways, importantly contributing to the prevention of chronic diseases and the promotion of physiological functions. Apparently, the features in the chemical structures of tea polyphenols are closely associated with their antioxidant potentials.
Hypofractionated Radiotherapy Upregulates Several Immune Checkpoint Molecules in Head and Neck Squamous Cell Carcinoma Cells Independently of the HPV Status While ICOS-L Is Upregulated Only on HPV-Positive Cells
Authors: Wimmer Sebastian , Deloch Lisa , Hader Michael , Derer Anja , Grottker Fridolin , Weissmann Thomas , Hecht Markus , Gostian Antoniu-Oreste , Fietkau Rainer , Frey Benjamin , Gaipl Udo S.
Published: August 2021

While the treatment of squamous cell carcinoma of the head and neck (HNSCC) with radiotherapy (RT) is complemented more and more by immunotherapy in clinical trials, little is known about the impact of the human papillomavirus (HPV) status or the applied RT scheme on the immune phenotype of the tumor cells. Therefore, we aimed to examine the impact of the HPV status of four human HNSCC cell lines on cell death and the expression of immune checkpoint molecules (ICMs) after RT with either hypofractionation irradiation (5x3.0Gy) or a high single dose (1x19.3Gy) via multicolor flow cytometry and quantitative PCR at an early time point after therapy. In our study, 5x3.0Gy RT induced high numbers of early and late apoptotic cells independent of the HPV status, but necrosis was only increased in the HPV-positive UM-Scc-47 cells. Generally, the immune stimulatory ICMs (CD70, CD137-L, ICOS-L) were less affected by RT compared to the immune suppressive ones (PD-L1, PD-L2, and the herpesvirus entry mediator (HVEM)). A significant higher surface expression of the analyzed ICMs was found after hypofractionated RT compared to a single high dose; however, regardless of the HPV status, with the exception of ICOS-L. Here, HPV-positive HNSCC tumor cells showed a stronger response to 5x3.0Gy than HPV-negative ones. On the RNA level, only minor alterations of ICMs were observed following RT, with the exception of the HPV negative cell line CAL33 treated with 5x3.0Gy, where PD-L2, HVEM and CD70 were significantly increased. We conclude that the HPV status may not distinctly predict immunological responses following RT, and thus cannot be used as a single predictive marker for therapy responses in HNSCC. In contrast, the patient-specific individual expression of ICMs following RT is preferable for the targeted patient selection for immune therapy directed against distinct ICM.
GhTBL34 Is Associated with Verticillium Wilt Resistance in Cotton
Authors: Zhao Yunlei , Jing Huijuan , Zhao Pei , Chen Wei , Li Xuelin , Sang Xiaohui , Lu Jianhua , Wang Hongmei
Published: August 2021

Verticillium wilt (VW) is a typical fungal disease affecting the yield and quality of cotton. The Trichome Birefringence-Like protein (TBL) is an acetyltransferase involved in the acetylation process of cell wall polysaccharides. Up to now, there are no reports on whether the TBL gene is related to disease resistance in cotton. In this study, we cloned a cotton TBL34 gene located in the confidence interval of a major VW resistance quantitative trait loci and demonstrated its relationship with VW resistance in cotton. Analyzing the sequence variations in resistant and susceptible accessions detected two elite alleles GhTBL34-2 and GhTBL34-3, mainly presented in resistant cotton lines whose disease index was significantly lower than that of susceptible lines carrying the allele GhTBL34-1. Comparing the TBL34 protein sequences showed that two amino acid differences in the TBL (PMR5N) domain changed the susceptible allele GhTBL34-1 into the resistant allele GhTBL34-2 (GhTBL34-3). Expression analysis showed that the TBL34 was obviously up-regulated by infection of Verticillium dahliae and exogenous treatment of ethylene (ET), and salicylic acid (SA) and jasmonate (JA) in cotton. VIGS experiments demonstrated that silencing of TBL34 reduced VW resistance in cotton. We deduced that the TBL34 gene mediating acetylation of cell wall polysaccharides might be involved in the regulation of resistance to VW in cotton.
Nature versus Number: Monocytes in Cardiovascular Disease
Authors: Williams Helen , Mack Corinne D. , Li Stephen C. H. , Fletcher John P. , Medbury Heather J.
Published: August 2021

Monocytes play a key role in cardiovascular disease (CVD) as their influx into the vessel wall is necessary for the development of an atherosclerotic plaque. Monocytes are, however, heterogeneous differentiating from classical monocytes through the intermediate subset to the nonclassical subset. While it is recognized that the percentage of intermediate and nonclassical monocytes are higher in individuals with CVD, accompanying changes in inflammatory markers suggest a functional impact on disease development that goes beyond the increased proportion of these ‘inflammatory’ monocyte subsets. Furthermore, emerging evidence indicates that changes in monocyte proportion and function arise in dyslipidemia, with lipid lowering medication having some effect on reversing these changes. This review explores the nature and number of monocyte subsets in CVD addressing what they are, when they arise, the effect of lipid lowering treatment, and the possible implications for plaque development. Understanding these associations will deepen our understanding of the clinical significance of monocytes in CVD.
Coordination of Di-Acetylated Histone Ligands by the ATAD2 Bromodomain
Authors: Evans Chiara M. , Phillips Margaret , Malone Kiera L. , Tonelli Marco , Cornilescu Gabriel , Cornilescu Claudia , Holton Simon J. , Gorjánácz Mátyás , Wang Liping , Carlson Samuel , Gay Jamie C. , Nix Jay C. , Demeler Borries , Markley John L. , Glass Karen C.
Published: August 2021

The ATPase Family, AAA domain-containing protein 2 (ATAD2) bromodomain (BRD) has a canonical bromodomain structure consisting of four α-helices. ATAD2 functions as a co-activator of the androgen and estrogen receptors as well as the MYC and E2F transcription factors. ATAD2 also functions during DNA replication, recognizing newly synthesized histones. In addition, ATAD2 is shown to be up-regulated in multiple forms of cancer including breast, lung, gastric, endometrial, renal, and prostate. Furthermore, up-regulation of ATAD2 is strongly correlated with poor prognosis in many types of cancer, making the ATAD2 bromodomain an innovative target for cancer therapeutics. In this study, we describe the recognition of histone acetyllysine modifications by the ATAD2 bromodomain. Residue-specific information on the complex formed between the histone tail and the ATAD2 bromodomain, obtained through nuclear magnetic resonance spectroscopy (NMR) and X-ray crystallography, illustrates key residues lining the binding pocket, which are involved in coordination of di-acetylated histone tails. Analytical ultracentrifugation, NMR relaxation data, and isothermal titration calorimetry further confirm the monomeric state of the functionally active ATAD2 bromodomain in complex with di-acetylated histone ligands. Overall, we describe histone tail recognition by ATAD2 BRD and illustrate that one acetyllysine group is primarily engaged by the conserved asparagine (N1064), the “RVF” shelf residues, and the flexible ZA loop. Coordination of a second acetyllysine group also occurs within the same binding pocket but is essentially governed by unique hydrophobic and electrostatic interactions making the di-acetyllysine histone coordination more specific than previously presumed.
Optimization of Blood Handling and Peripheral Blood Mononuclear Cell Cryopreservation of Low Cell Number Samples
Authors: Hope Christopher M. , Huynh Dao , Wong Ying Ying , Oakey Helena , Perkins Griffith Boord , Nguyen Trung , Binkowski Sabrina , Bui Minh , Choo Ace Y. L. , Gibson Emily , Huang Dexing , Kim Ki Wook , Ngui Katrina , Rawlinson William D. , Sadlon Timothy , Couper Jennifer J. , Penno Megan A. S. , Barry Simon C. ,   on behalf of the ENDIA Study Group
Published: August 2021

Background: Rural/remote blood collection can cause delays in processing, reducing PBMC number, viability, cell composition and function. To mitigate these impacts, blood was stored at 4 °C prior to processing. Viable cell number, viability, immune phenotype, and Interferon-γ (IFN-γ) release were measured. Furthermore, the lowest protective volume of cryopreservation media and cell concentration was investigated. Methods: Blood from 10 individuals was stored for up to 10 days. Flow cytometry and IFN-γ ELISPOT were used to measure immune phenotype and function on thawed PBMC. Additionally, PBMC were cryopreserved in volumes ranging from 500 µL to 25 µL and concentration from 10 × 106 cells/mL to 1.67 × 106 cells/mL. Results: PBMC viability and viable cell number significantly reduced over time compared with samples processed immediately, except when stored for 24 h at RT. Monocytes and NK cells significantly reduced over time regardless of storage temperature. Samples with >24 h of RT storage had an increased proportion in Low-Density Neutrophils and T cells compared with samples stored at 4 °C. IFN-γ release was reduced after 24 h of storage, however not in samples stored at 4 °C for >24 h. The lowest protective volume identified was 150 µL with the lowest density of 6.67 × 106 cells/mL. Conclusion: A sample delay of 24 h at RT does not impact the viability and total viable cell numbers. When long-term delays exist (>4 d) total viable cell number and cell viability losses are reduced in samples stored at 4 °C. Immune phenotype and function are slightly altered after 24 h of storage, further impacts of storage are reduced in samples stored at 4 °C.
In Vitro and In Silico Evaluation of New 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone as Promising Cyclooxygenase Inhibitors
Authors: Peregrym Krzysztof , Szczukowski Łukasz , Wiatrak Benita , Potyrak Katarzyna , Czyżnikowska Żaneta , Świątek Piotr
Published: August 2021

Since long-term use of classic NSAIDs can cause severe side effects related mainly to the gastroduodenal tract, discovery of novel cyclooxygenase inhibitors with a safe gastric profile still remains a crucial challenge. Based on the most recent literature data and previous own studies, we decided to modify the structure of already reported 1,3,4-oxadiazole based derivatives of pyrrolo[3,4-d]pyridazinone in order to obtain effective COX inhibitors. Herein we present the synthesis, biological evaluation and molecular docking studies of 12 novel compounds with disubstituted arylpiperazine pharmacophore linked in a different way with 1,3,4-oxadiazole ring. None of the obtained molecules show cytotoxicity on NHDF and THP-1 cell lines and, therefore, all were qualified for further investigation. In vitro cyclooxygenase inhibition assay revealed almost equal activity of new derivatives towards both COX-1 and COX-2 isoenzymes. Moreover, all compounds inhibit COX-2 isoform better than Meloxicam which was used as reference. Anti-inflammatory activity was confirmed in biological assays according to which title molecules are able to reduce induced inflammation within cells. Molecular docking studies were performed to describe the binding mode of new structures to cyclooxygenase. Investigated derivatives take place in the active site of COX, very similar to Meloxicam. For some compounds, promising druglikeness was calculated using in silico predictions.
Possible Link between Higher Transmissibility of Alpha, Kappa and Delta Variants of SARS-CoV-2 and Increased Structural Stability of Its Spike Protein and hACE2 Affinity
Authors: Kumar Vipul , Singh Jasdeep , Hasnain Seyed E. , Sundar Durai
Published: August 2021

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak in December 2019 has caused a global pandemic. The rapid mutation rate in the virus has created alarming situations worldwide and is being attributed to the false negativity in RT-PCR tests. It has also increased the chances of reinfection and immune escape. Recently various lineages namely, B.1.1.7 (Alpha), B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.617.3 have caused rapid infection around the globe. To understand the biophysical perspective, we have performed molecular dynamic simulations of four different spikes (receptor binding domain)-hACE2 complexes, namely wildtype (WT), Alpha variant (N501Y spike mutant), Kappa (L452R, E484Q) and Delta (L452R, T478K), and compared their dynamics, binding energy and molecular interactions. Our results show that mutation has caused significant increase in the binding energy between the spike and hACE2 in Alpha and Kappa variants. In the case of Kappa and Delta variants, the mutations at L452R, T478K and E484Q increased the stability and intra-chain interactions in the spike protein, which may change the interaction ability of neutralizing antibodies to these spike variants. Further, we found that the Alpha variant had increased hydrogen interaction with Lys353 of hACE2 and more binding affinity in comparison to WT. The current study provides the biophysical basis for understanding the molecular mechanism and rationale behind the increase in the transmissivity and infectivity of the mutants compared to wild-type SARS-CoV-2.
Loose Morphology and High Dynamism of OSER Structures Induced by the Membrane Domain of HMG-CoA Reductase
Authors: Grados-Torrez Ricardo Enrique , López-Iglesias Carmen , Ferrer Joan Carles , Campos Narciso
Published: August 2021

The membrane domain of eukaryotic HMG-CoA reductase (HMGR) has the conserved capacity to induce endoplasmic reticulum (ER) proliferation and membrane association into Organized Smooth Endoplasmic Reticulum (OSER) structures. These formations develop in response to overexpression of particular proteins, but also occur naturally in cells of the three eukaryotic kingdoms. Here, we characterize OSER structures induced by the membrane domain of Arabidopsis HMGR (1S domain). Immunochemical confocal and electron microscopy studies demonstrate that the 1S:GFP chimera co-localizes with high levels of endogenous HMGR in several ER compartments, such as the ER network, the nuclear envelope, the outer and internal membranes of HMGR vesicles and the OSER structures, which we name ER-HMGR domains. After high-pressure freezing, ER-HMGR domains show typical crystalloid, whorled and lamellar ultrastructural patterns, but with wide heterogeneous luminal spaces, indicating that the native OSER is looser and more flexible than previously reported. The formation of ER-HMGR domains is reversible. OSER structures grow by incorporation of ER membranes on their periphery and progressive compaction to the inside. The ER-HMGR domains are highly dynamic in their formation versus their disassembly, their variable spherical-ovoid shape, their fluctuating borders and their rapid intracellular movement, indicating that they are not mere ER membrane aggregates, but active components of the eukaryotic cell.
MicroRNA-29a in Osteoblasts Represses High-Fat Diet-Mediated Osteoporosis and Body Adiposis through Targeting Leptin
Authors: Lian Wei-Shiung , Wu Re-Wen , Chen Yu-Shan , Ko Jih-Yang , Wang Shao-Yu , Jahr Holger , Wang Feng-Sheng
Published: August 2021

Skeletal tissue involves systemic adipose tissue metabolism and energy expenditure. MicroRNA signaling controls high-fat diet (HFD)-induced bone and fat homeostasis dysregulation remains uncertain. This study revealed that transgenic overexpression of miR-29a under control of osteocalcin promoter in osteoblasts (miR-29aTg) attenuated HFD-mediated body overweight, hyperglycemia, and hypercholesterolemia. HFD-fed miR-29aTg mice showed less bone mass loss, fatty marrow, and visceral fat mass together with increased subscapular brown fat mass than HFD-fed wild-type mice. HFD-induced O2 underconsumption, respiratory quotient repression, and heat underproduction were attenuated in miR-29aTg mice. In vitro, miR-29a overexpression repressed transcriptomic landscapes of the adipocytokine signaling pathway, fatty acid metabolism, and lipid transport, etc., of bone marrow mesenchymal progenitor cells. Forced miR-29a expression promoted osteogenic differentiation but inhibited adipocyte formation. miR-29a signaling promoted brown/beige adipocyte markers Ucp-1, Pgc-1α, P2rx5, and Pat2 expression and inhibited white adipocyte markers Tcf21 and Hoxc9 expression. The microRNA also reduced peroxisome formation and leptin expression during adipocyte formation and downregulated HFD-induced leptin expression in bone tissue. Taken together, miR-29a controlled leptin signaling and brown/beige adipocyte formation of osteogenic progenitor cells to preserve bone anabolism, which reversed HFD-induced energy underutilization and visceral fat overproduction. This study sheds light on a new molecular mechanism by which bone integrity counteracts HFD-induced whole-body fat overproduction.
Drug Delivery Systems for the Treatment of Knee Osteoarthritis: A Systematic Review of In Vivo Studies
Authors: Gambaro Francesco Manlio , Ummarino Aldo , Torres Andón Fernando , Ronzoni Flavio , Di Matteo Berardo , Kon Elizaveta
Published: August 2021

Many efforts have been made in the field of nanotechnology to improve the local and sustained release of drugs, which may be helpful to overcome the present limitations in the treatment of knee OA. Nano-/microparticles and/or hydrogels can be now engineered to improve the administration and intra-articular delivery of specific drugs, targeting molecular pathways and pathogenic mechanisms involved in OA progression and remission. In order to summarize the current state of this field, a systematic review of the literature was performed and 45 relevant studies were identified involving both animal models and humans. We found that polymeric nanoparticles loaded with anti-inflammatory drugs (i.e., dexamethasone or celecoxib) are the most frequently investigated drug delivery systems, followed by microparticles and hydrogels. In particular, the nanosystem most frequently used in preclinical research consists of PLGA-nanoparticles loaded with corticosteroids and non-steroidal anti-inflammatory drugs. Overall, improvement in histological features, reduction in joint inflammation, and improvement in clinical scores in patients were observed. The last advances in the field of nanotechnology could offer new opportunities to treat patients affected by knee OA, including those with previous meniscectomy. New smart drug delivery approaches, based on nanoparticles, microparticles, and hydrogels, may enhance the therapeutic potential of intra-articular agents by increasing the permanence of selected drugs inside the joint and better targeting specific receptors and tissues.
Nocturnal Oxygen Saturation Parameters as Independent Risk Factors for Type 2 Diabetes Mellitus among Obstructive Sleep Apnea Patients
Authors: Gabryelska Agata , Chrzanowski Jędrzej , Sochal Marcin , Kaczmarski Piotr , Turkiewicz Szymon , Ditmer Marta , Karuga Filip Franciszek , Czupryniak Leszek , Białasiewicz Piotr
Published: August 2021

Obstructive sleep apnea (OSA) is a recognized independent risk factor for metabolic disorders, type 2 diabetes mellites (DM2) in particular. Therefore, the study aimed to assess the influence of nocturnal oxygen saturation parameters on the onset of DM2 among OSA patients. The study consisted of 549 participants, who underwent polysomnography examination. Based on apnea hypopnea index (AHI), 465 patients were diagnosed with OSA. One hundred and seven individuals had comorbid DM2. Cox regression models were used to assess the effect of oxygen saturation parameters on the onset of DM2. Classification and regression trees (CART) analysis was used to assess the onset of the DM2 in the study group in context of oxygen saturation variables. One-way Cox regression showed higher risk of earlier DM2 for increased values of BMI, AHI, decreased basal O2 and O2 nadir value, while lowered mean O2 desaturation has not shown statistical significance. In the CART analysis, the following cut-off points 92.2%, 81.7%, 87.1% were determined for basal O2, O2 nadir and mean O2 desaturation, respectively, with the first two parameters being statistically significant. Therefore, basal O2 is independent from AHI, BMI and age is a risk factor of DM2 among OSA patients.
Evaluation of Frailty Syndrome and Adherence to Recommendations in Elderly Patients with Hypertension
Authors: Pobrotyn Piotr , Pasieczna Aleksandra , Diakowska Dorota , Uchmanowicz Bartosz , Mazur Grzegorz , Banasik Mirosław , Kołtuniuk Aleksandra
Published: August 2021

Frailty syndrome (FS) often coexists with many diseases of the elderly, including arterial hypertension, and may affect the disease course and adherence to therapeutic recommendations. This study aimed to evaluate the relationship between frailty and adherence to therapeutic recommendations in elderly hypertensive patients. The study included 259 patients hospitalized between January 2019 and November 2020 due to exacerbation of hypertension symptoms. Medical records were used to obtain basic sociodemographic and clinical data. The study was based on the Tilburg Frailty Indicator (TFI) and the Hill–Bone Scale (HBCS). The obtained data were analyzed within a cross-sectional design. The mean frailty score indicated by the TFI questionnaire was 7.09 ± 3.73. The most prominent FS component was associated with the physical domain (4.24 ± 2.54). The mean overall adherence measured with the HBCS was 20.51 ± 3.72. The linear regression model testing the Hill–Bone “reduced sodium intake” score against the TFI domains showed no relationships between the variables. Another regression model for the Hill–Bone “appointment-keeping” subscale indicated significant predictors for physical and social TFI domains (p = 0.002 and p < 0.0001, respectively). For the Hill–Bone “taking antihypertensive drugs” variable, the regression model found significant relationships with all TFI domains: physical (p < 0.0001), psychological (p = 0.003) and social (p < 0.0001). Our study suggests that frailty in patients with arterial hypertension can negatively impact their adherence to therapeutic recommendations.
Comparison of 6.0 mm versus 6.5 mm Optical Zone on Visual Outcomes after LASIK
Authors: Moshirfar Majid , Huynh Rachel , Bundogji Nour , Tukan Alyson N. , Sant Thomas M. , McCabe Shannon E. , West William B. , Drennan Kirk , Ronquillo Yasmyne C. , Hoopes Phillip C.
Published: August 2021

Previous studies have demonstrated safety and efficacy using 6.0 and 6.5 mm optical zones in the WaveLight EX500 Excimer Laser System but have not evaluated if differing optical zone sizes influence refractive outcomes. This study examines visual outcomes between two study populations undergoing LASIK with either a 6.0 mm (1332 patients) or 6.5 mm (1332 patients) optical zone. Outcomes were further stratified by severity of myopia (low, moderate, and high) and astigmatism (low and high). Patients were matched by age and preoperative manifest sphere and cylinder. Postoperative measurements were then compared. The 6.5 mm group demonstrated better postoperative manifest refractive spherical equivalent (MRSE), manifest sphere, and absolute value of the difference in actual and target spherical equivalent refraction (|∆ SEQ|), within the total population, moderate myopia, and low astigmatism groups, but this did not lead to improved postoperative uncorrected distance visual acuity (UDVA) or best corrected distance visual acuity (CDVA). Though astigmatic correction and postoperative angle of error were similar between optical zone sizes, they were significantly worse with high myopia. Overall, this study demonstrates differences in visual outcomes between the 6.0 and 6.5 mm optical zone sizes that may warrant consideration; however, essentially, the results are comparable between them.
Computed Tomography in Limb Salvage and Deformity Correction—3D Assessment, Indications, Radiation Exposure, and Safety Considerations
Authors: Zak Lukas , Tiefenboeck Thomas M. , Wozasek Gerald E.
Published: August 2021

Computed tomography (CT) is an essential tool in orthopedic surgery but is known to be a method with that entails radiation exposure. CT increases the risk of developing fatal cancer, which should not be underestimated. However, patients with bone defects and/or deformities must frequently undergo numerous investigations during their treatment. CT is used for surgical planning, evaluating callus maturation, alignment measurement, length measurement, torsion measurement, and angiography. This study explores the indications in CT scans for limb lengthening and deformity correction and estimates the effective radiation dose. These results should help avoid unnecessary radiation exposure by narrowing the examination field and by providing explicit scanning indications. For this study, 19 posttraumatic patients were included after the bone reconstruction of 21 lower limbs. All patients underwent CT examinations during or after treatment with an external ring fixator. The mean effective dose was 3.27 mSv, with a mean cancer risk of 1:117,014. The effective dose depended on the location and indication of measurement, with a mean dose of 0.04 mSv at the ankle up to 6.8 mSv (or higher) for vascular depictions. CT evaluation, with or without 3D reconstruction, is a crucial tool in complex bone reconstruction and deformity treatments. Therefore, strict indications are necessary to reduce radiation exposure—especially in young patients—without compromising the management of their patients.
Long COVID: Distinction between Organ Damage and Deconditioning
Authors: Kersten Johannes , Baumhardt Michael , Hartveg Paul , Hoyo Luis , Hüll Elina , Imhof Armin , Kropf-Sanchen Cornelia , Nita Nicoleta , Mörike Johannes , Rattka Manuel , Andreß Stefanie , Scharnbeck Dominik , Schmidtke-Schrezenmeier Gerlinde , Tadic Marijana , Wolf Alexander , Rottbauer Wolfgang , Buckert Dominik
Published: August 2021

(1) Background: Long COVID syndrome refers to long-term sequelae of the novel viral disease, which occur even in patients with initially mild disease courses. However, there is still little evidence of the actual organic consequences and their frequency, and there is no standardized workup to diagnose long COVID syndrome yet. In this study, we aim to determine the efficiency of a stepwise diagnostic approach for reconvalescent COVID-19 patients with cardiopulmonary symptoms. (2) Methods: The diagnostic workup for long COVID syndrome included three steps. In the first step, the focus was on broad applicability (e.g., blood tests and body plethysmography). In the second step, cardiopulmonary exercise testing (CPET) and cardiac MRI (CMR) were used. The third step was tailored to the individual needs of each patient. The observation period lasted from 22 February to 14 May 2021. (3) Results: We examined 231 patients in our long COVID unit (mean [SD] age, 47.8 [14.9], 132 [57.1%] women). Acute illness occurred a mean (SD) of 121 (77) days previously. Suspicious findings in the first visit were seen in 80 (34.6%) patients, prompting further diagnostics. Thirty-six patients were further examined with CPET and CMR. Of those, 16 (44.4%) had pathological findings. The rest had functional complaints without organ damage (“functional long COVID”). Cardiopulmonary sequelae were found in asymptomatic as well as severe courses of the initial COVID-19 disease. (4) Conclusions: A structured diagnostic pathway for the diagnosis of long COVID syndrome is practicable and rational in terms of resource allocation. With this approach, manifest organ damage can be accurately and comprehensively diagnosed and distinguished from functional complaints.
Effects of Roux-en-Y Gastric Bypass and Sleeve Gastrectomy on Non-Alcoholic Fatty Liver Disease: A 12-Month Follow-Up Study with Paired Liver Biopsies
Authors: Pedersen Julie Steen , Rygg Marte Opseth , Serizawa Reza Rafiolsadat , Kristiansen Viggo Bjerregaard , Albrechtsen Nicolai J. Wewer , Gluud Lise Lotte , Madsbad Sten , Bendtsen Flemming
Published: August 2021

Roux-en-Y gastric bypass (RYGB) improves, and can sometimes resolve, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) but data based on histological assessment for the efficacy of sleeve gastrectomy (SG) in resolving NAFLD are sparse. Consequently, we aimed to compare the efficacy of RYGB vs. SG on NAFLD 12 months after surgery. In a prospective cohort study, 40 patients with obesity underwent bariatric surgery (16 RYGB and 24 SG). During surgery, a liver biopsy was taken and repeated 12 months later. NAFLD severity was evaluated using the NAFLD Activity Score (NAS) and Kleiner Fibrosis score. RYGB and SG patients were comparable at baseline. Mean (standard deviation, SD) NAS was 3.3 (0.9) in RYGB and 3.1 (1.4) in SG (p = 0.560) with similar degrees of steatosis, inflammation, and ballooning. Two RYGB patients, and six SG patients, had NASH (p = 0.439). Twelve months after surgery, NAS was significantly and comparably (p = 0.241) reduced in both RYGB (−3.00 (95% CI −3.79–−2.21), p < 0.001) and SG (−2.25 (95% CI −2.92–−1.59), p < 0.001) patients. RYGB patients had significantly more reduced (p = 0.007) liver steatosis (−0.91 (95% CI −1.47–−1.2) than SG patients (−0.33 (95% CI −0.54–−0.13) and greater improvement in the plasma lipid profile. Fibrosis declined non-significantly. NASH was resolved in seven of eight patients without a worsening of their fibrosis. RYGB and SG have similar beneficial effects on NAS and NASH without the worsening of fibrosis. RYGB is associated with a more pronounced reduction in liver steatosis.
Obstructive Sleep Apnea and Cardiac Arrhythmias: A Contemporary Review
Authors: Laczay Balint , Faulx Michael D.
Published: August 2021

Obstructive sleep apnea (OSA) is a highly prevalent disorder with a growing incidence worldwide that closely mirrors the global obesity epidemic. OSA is associated with enormous healthcare costs in addition to significant morbidity and mortality. Much of the morbidity and mortality related to OSA can be attributed to an increased burden of cardiovascular disease, including cardiac rhythm disorders. Awareness of the relationship between OSA and rhythm disorders is variable among physicians, a fact that can influence patient care, since the presence of OSA can influence the incidence, prevalence, and successful treatment of multiple rhythm disorders. Herein, we provide a review of this topic that is intentionally broad in scope, covering the relationship between OSA and rhythm disorders from epidemiology and pathophysiology to diagnosis and management, with a particular focus on the recognition of undiagnosed OSA in the general clinical population and the intimate relationship between OSA and atrial fibrillation.
Competing Risks Model for Prediction of Small for Gestational Age Neonates and the Role of Second Trimester Soluble Fms-like Tyrosine Kinase-1
Authors: Nowacka Urszula , Papastefanou Ioannis , Bouariu Alexandra , Syngelaki Argyro , Nicolaides Kypros H.
Published: August 2021

Small for gestational age (SGA) fetuses/neonates are characterized by the increased risk for adverse outcomes that can be reduced if the condition is identified antenatally. We have recently developed a new approach in SGA prediction that considers SGA a spectrum condition that is reflected in two dimensions: gestational age at delivery and Z score in birth weight for gestational age. The new method has a better predictive ability than the traditionally used risk-scoring systems and logistic regression models. In this prospective study in 40241 singleton pregnancies, at 19–24 weeks’ gestation, we examined the potential value of the antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and the ratio of sFlt-1 to the angiogenic placental growth factor (PlGF) in the prediction of SGA. We found that first, sFlt-1 did not improve the performance of screening by maternal risk factors, and second, the ratio of sFlt-1/PlGF had a worse performance than PlGF alone in the prediction of SGA. Consequently, second trimester sFlt-1 and sFlt-1/PlGF are not useful in screening for SGA.
The Role of Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Leukemia
Authors: Algeri Mattia , Merli Pietro , Locatelli Franco , Pagliara Daria
Published: August 2021

Allogeneic hematopoietic stem cell transplantation (HSCT) offers potentially curative treatment for many children with high-risk or relapsed acute leukemia (AL), thanks to the combination of intense preparative radio/chemotherapy and the graft-versus-leukemia (GvL) effect. Over the years, progress in high-resolution donor typing, choice of conditioning regimen, graft-versus-host disease (GvHD) prophylaxis and supportive care measures have continuously improved overall transplant outcome, and recent successes using alternative donors have extended the potential application of allotransplantation to most patients. In addition, the importance of minimal residual disease (MRD) before and after transplantation is being increasingly clarified and MRD-directed interventions may be employed to further ameliorate leukemia-free survival after allogeneic HSCT. These advances have occurred in parallel with continuous refinements in chemotherapy protocols and the development of targeted therapies, which may redefine the indications for HSCT in the coming years. This review discusses the role of HSCT in childhood AL by analysing transplant indications in both acute lymphoblastic and acute myeloid leukemia, together with current and most promising strategies to further improve transplant outcome, including optimization of conditioning regimen and MRD-directed interventions.
The Risk of Bladder Cancer in Type 2 Diabetes Mellitus with Combination Therapy of SGLT-2 Inhibitors and Pioglitazone
Authors: Li Yan-Rong , Liu Chi-Hung , Sun Wei-Chiao , Fan Pei-Yi , Liu Feng-Hsuan , Chen Tien-Hsing , Wu Victor Chien-Chia , Lin Chihung , Hsiao Ching-Chung
Published: August 2021

Background: Either sodium-glucose cotransporter-2 (SGLT-2) inhibitors or pioglitazone (Pio) has doubtful issues of bladder cancer, especially for the combination therapy with these two drugs. Our study aimed to investigate the risk of bladder cancer under combination therapy of SGLT-2 inhibitors and Pio. Materials and Methods: We included 97,024 patients with type 2 diabetes mellitus (T2DM) in the Chang Gung Research Database in Taiwan from 1 January 2016 to 31 December 2019. The primary outcome was newly diagnosed bladder cancer after combination therapy with SGLT-2 inhibitors and Pio. Group 1 received both study drugs, group 2 received SGLT-2 inhibitors, group 3 received Pio, and group 4 received non-study drugs (the reference group). The secondary outcome in each group was all-cause mortality. Results: In group 1, no newly diagnosed bladder cancer was detected after a mean 2.8-year follow-up and all-cause mortality decreased significantly (adjusted hazard ratio (AHR), 0.70; 95% confidence interval (CI), 0.54–0.92) in comparison to the reference group (group 4). In group 2 and group 3, no trend of increased bladder cancer was observed (group 2: AHR 0.49, 95% CI 0.05–4.94; group 3: AHR 0.48, 95% CI 0.15–1.58) and it still reduced all-cause mortality (group 2: AHR 0.83, 95% CI 0.70–0.99; group 3: AHR 0.90, 95% CI 0.83–0.99). Conclusions: In T2DM patients without previous or active bladder cancer, the combination therapy of SGLT-2 inhibitors and Pio was not associated with newly diagnosed bladder cancer and had lower all-cause mortality.
Prevalence and Significance of Pyuria in Chronic Kidney Disease Patients in Saudi Arabia
Authors: Almaiman Lina , Allemailem Khaled S. , El-Kady Asmaa M. , Alrasheed Mishaal , Almatroudi Ahmad , Alekezem Fahad S. , Elrasheedy Abdelrahman , Al-Megrin Wafa Abdullah , Alobaid Hussah M. , Elshabrawy Hatem A.
Published: August 2021

Chronic kidney disease (CKD) is considered a major health problem, which poses a burden for health care systems worldwide. It has been estimated that 10% of the population worldwide have CKD; however, most of the cases are undiagnosed. If left untreated, CKD could lead to kidney failure, which highlights the importance of early diagnosis and treatment. Pyuria has been reported in CKD patients, and could be the result of several comorbidities, such as diabetes, or urinary tract infections (UTIs). A few studies have shown that pyuria is associated with the late stages of CKD. However, there are limited data on the prevalence of non-UTI (sterile) and UTI–pyuria in different CKD patient populations, and its association with the decline in kidney function and progression of CKD. In this retrospective study, we report the prevalence of pyuria (sterile and UTI) in 754 CKD patients of King Fahd Specialist Hospital, Buraydah, Saudi Arabia. Our data showed that 164/754 CKD patients (21.8%) had pyuria, whereas 590 patients (78.2%) presented with no pyuria. There was a significantly higher percentage of late-stage (stage 4) CKD patients in the pyuric group compared to the non-pyuric group (36.6% vs. 11.9%). In line with the previous data, proteinuria was detected in a significantly higher percentage of pyuric patients, in addition to significantly higher levels of serum creatinine and urea, compared to non-pyuric patients. Furthermore, 13.4% of the pyuric CKD patients had UTI, whereas 86.6% presented with sterile pyuria. E. coli was indicated as the causative agent in 45.5% of UTI patients. Our patient data analysis showed that a significantly higher percentage of UTI–pyuric CKD patients, than sterile pyuric patients (63.6% vs. 19.7%), had higher numbers of urinary white blood cells (>50/HPF, WBCs). The data also showed that a higher percentage of UTI–pyuric patients were late-stage CKD patients, compared to sterile pyuric patients (50% vs. 34.5%). Our findings indicate that a high level of pyuria could be considered as a marker for late-stage CKD, and that UTI is an important risk factor for the decline in kidney function and the progression to late-stage CKD. We believe that further studies are needed to correlate pyuria to kidney function, which could be helpful in monitoring the progression of CKD. Moreover, the management of comorbidities, such as diabetes and UTIs, which are risk factors for CKD and associated pyuria, could help to control the progression of CKD to the late stages.
Measuring Overtourism: A Necessary Tool for Landscape Planning
Authors: Buitrago Eva M. , Yñiguez Rocío
Published: August 2021

The tourism debate prior to the COVID-19 pandemic was dominated by the problems inherent in overtourism, reflecting an inadequate land management. Although publications on overtourism have grown exponentially in recent years, its scientific study still has major shortcomings, particularly with regard to measurement. With the aim of overcoming this insufficiency, we have carried out a review of the literature (using the mapping review method) and, based on its conclusions, we have drawn up a proposal to systematise the measurement of overtourism by combining several tools: indicators, surveys, interviews, and other tools linked to the Internet and social networks. The results of the research make a contribution to the expansion of the literature on the topic and may have important practical implications in formulating effective land-use policies by guiding policy makers in the management of overtourism. They could be of use in both the early detection of overtourism and the design of policies that prevent and/or detect situations of risk and that correct existing problems. This is especially relevant in the current international context to implement the effective transition to a responsible tourism model post-COVID-19.
The Legal Principles of Bethlehem & Operation Timber Sycamore: The “Islamist Winter” Pre-Emptively Targets “Arab Life” by Hiring “Arab Barbarians”
Authors: Al-Kassimi Khaled
Published: August 2021

The following legal-historical research is critical of “Islamist” narratives and their desacralized reverberations claiming that Arab-Muslim receptivity to terror is axiomatic to “cultural experiences” figuring subjects conforming to Arab-Islamic philosophical theology. The critique is founded on deconstructing—while adopting a Third World Approach to International Law (TWAIL)—the (im)moral consequences resulting from such rhetoric interpreting the Arab uprising of 2011 from the early days as certainly metamorphosing into an “Islamist Winter”. This secular-humanist hypostasis reminded critics that International Law and International Relations continues to assert that Latin-European philosophical theology furnishes the exclusive temporal coordinates required to attain “modernity” as telos of history and “civil society” as ethos of governance. In addition, the research highlights that such culturalist assertation—separating between law and morality—tolerates secular logic decriminalizing acts patently violating International Law since essentializing Arab-Muslims as temporally positioned “outside law” provides liberal-secular modernity ontological security. Put differently, “culture talk” affirms that since a secular-humanist imaginary of historical evolution stipulates that it is “inevitable” and “natural” that any “non-secular” Arab protests will unavoidably lead to lawlessness, it therefore becomes imperative to suspiciously approach the “Islamist” narrative of 2011 thus deconstructing the formulation of juridical doctrines (i.e., Bethlehem Legal Principles) decriminalizing acts arising from a principle of pre-emption “moralizing” demographic and geographic alterations (i.e., Operation Timber Sycamore) across Arabia. The research concludes that jus gentium continues to be characterized by a temporal inclusive exclusion with its redemptive ramifications—authorized by sovereign power—catalyzing “epistemic violence” resulting in en-masse exodus and slayed bodies across Arabia.