bluuebunny/crossref_metadata_2025 huggingface dataset:
CRISPR-Cas Controls Cryptic Prophages
Authors: Song Sooyeon , Semenova Ekaterina , Severinov Konstantin , Fernández-García Laura , Benedik Michael J. , Maeda Toshinari , Wood Thomas K.
Published: December 2022

The bacterial archetypal adaptive immune system, CRISPR-Cas, is thought to be repressed in the best-studied bacterium, Escherichia coli K-12. We show here that the E. coli CRISPR-Cas system is active and serves to inhibit its nine defective (i.e., cryptic) prophages. Specifically, compared to the wild-type strain, reducing the amounts of specific interfering RNAs (crRNA) decreases growth by 40%, increases cell death by 700%, and prevents persister cell resuscitation. Similar results were obtained by inactivating CRISPR-Cas by deleting the entire 13 spacer region (CRISPR array); hence, CRISPR-Cas serves to inhibit the remaining deleterious effects of these cryptic prophages, most likely through CRISPR array-derived crRNA binding to cryptic prophage mRNA rather than through cleavage of cryptic prophage DNA, i.e., self-targeting. Consistently, four of the 13 E. coli spacers contain complementary regions to the mRNA sequences of seven cryptic prophages, and inactivation of CRISPR-Cas increases the level of mRNA for lysis protein YdfD of cryptic prophage Qin and lysis protein RzoD of cryptic prophage DLP-12. In addition, lysis is clearly seen via transmission electron microscopy when the whole CRISPR-Cas array is deleted, and eliminating spacer #12, which encodes crRNA with complementary regions for DLP-12 (including rzoD), Rac, Qin (including ydfD), and CP4-57 cryptic prophages, also results in growth inhibition and cell lysis. Therefore, we report the novel results that (i) CRISPR-Cas is active in E. coli and (ii) CRISPR-Cas is used to tame cryptic prophages, likely through RNAi, i.e., unlike with active lysogens, active CRISPR-Cas and cryptic prophages may stably co-exist.
Receptor-Independent Anti-Ferroptotic Activity of TrkB Modulators
Authors: Jakaria Md. , Belaidi Abdel A. , Southon Adam , Dent Krista A. , Lane Darius J. R. , Bush Ashley I. , Ayton Scott
Published: December 2022

Dysregulated brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signalling is implicated in several neurodegenerative diseases, including Alzheimer’s disease. A failure of neurotrophic support may participate in neurodegenerative mechanisms, such as ferroptosis, which has likewise been implicated in this disease class. The current study investigated whether modulators of TrkB signalling affect ferroptosis. Cell viability, C11 BODIPY, and cell-free oxidation assays were used to observe the impact of TrkB modulators, and an immunoblot assay was used to detect TrkB expression. TrkB modulators such as agonist BDNF, antagonist ANA-12, and inhibitor K252a did not affect RSL3-induced ferroptosis sensitivity in primary cortical neurons expressing detectable TrkB receptors. Several other modulators of the TrkB receptor, including agonist 7,8-DHF, activator phenelzine sulphate, and inhibitor GNF-5837, conferred protection against a range of ferroptosis inducers in several immortalised neuronal and non-neuronal cell lines, such as N27 and HT-1080 cells. We found these immortalised cell lines lack detectable TrkB receptor expression, so the anti-ferroptotic activity of these TrkB modulators was most likely due to their inherent radical-trapping antioxidant properties, which should be considered when interpreting their experimental findings. These modulators or their variants could be potential anti-ferroptotic therapeutics for various diseases.
Febrile-Range Hyperthermia Can Prevent Toxic Effects of Neutrophil Extracellular Traps on Mesenchymal Stem Cells
Authors: Linnemann Caren , Nussler Andreas K. , Histing Tina , Ehnert Sabrina
Published: December 2022

Fracture healing is characterized by an inflammatory phase directly after fracture which has a strong impact on the healing outcome. Neutrophils are strong contributors here and can release neutrophil extracellular traps (NETs). NETs are found after trauma, originally thought to capture pathogens. However, they can lead to tissue damage and impede wound healing processes. Their role in fracture healing remains unclear. In this study, the effect of isolated NETs on the function of bone-forming mesenchymal stem cells (SCP-1 cells) was examined. NETs were isolated from stimulated healthy neutrophils and viability, migration, and differentiation of SCP-1 cells were analyzed after the addition of NETs. NETs severely impaired the viability of SCP-1 cells, induced necrosis and already nontoxic concentrations reduced migration significantly. Short-term incubation with NETs had a persistent negative effect on osteogenic differentiation, as measured by AP activity and matrix formation. The addition of DNase or protease inhibitors failed to reverse the negative effect of NETs, whereas a short febrile-range temperature treatment successfully reduced the toxicity and membrane destruction. Thus, the possible modification of the negative effects of NETs in fracture hematomas could be an interesting new target to improve bone healing, particularly in patients with chronic diseases such as diabetes.
An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene
Authors: Jurutka Peter W. , di Martino Orsola , Reshi Sabeeha , Mallick Sanchita , Sausedo Michael A. , Moen Grant A. , Lee Isaac J. , Ivan Dominic J. , Krall Tyler D. , Peoples Samuel J. , Perez Anthony , Tromba Lucas , Le Anh , Khadka Iraj , Petros Ryan , Savage Brianna M. , Salama Eleine , Salama Jakline , Ziller Joseph W. , Noh Youngbin , Lee Ming-Yue , Liu Wei , Welch John S. , Marshall Pamela A. , Wagner Carl E.
Published: December 2022

Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene (1). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC50 as well as IC50 values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than 1. While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to 1.
MicroRNA, Insulin Resistance, and Metabolic Disorders
Authors: Lee Wan
Published: December 2022

Insulin resistance is a significant health problem worldwide that contributes to a number of disorders, including type 2 diabetes and metabolic syndrome [...]
iADRGSE: A Graph-Embedding and Self-Attention Encoding for Identifying Adverse Drug Reaction in the Earlier Phase of Drug Development
Authors: Cheng Xiang , Cheng Meiling , Yu Liyi , Xiao Xuan
Published: December 2022

Adverse drug reactions (ADRs) are a major issue to be addressed by the pharmaceutical industry. Early and accurate detection of potential ADRs contributes to enhancing drug safety and reducing financial expenses. The majority of the approaches that have been employed to identify ADRs are limited to determining whether a drug exhibits an ADR, rather than identifying the exact type of ADR. By introducing the “multi-level feature-fusion deep-learning model”, a new predictor, called iADRGSE, has been developed, which can be used to identify adverse drug reactions at the early stage of drug discovery. iADRGSE integrates a self-attentive module and a graph-network module that can extract one-dimensional sub-structure sequence information and two-dimensional chemical-structure graph information of drug molecules. As a demonstration, cross-validation and independent testing were performed with iADRGSE on a dataset of ADRs classified into 27 categories, based on SOC (system organ classification). In addition, experiments comparing iADRGSE with approaches such as NPF were conducted on the OMOP dataset, using the jackknife test method. Experiments show that iADRGSE was superior to existing state-of-the-art predictors.
Extracellular Vesicles as Biomarkers in Liver Disease
Authors: Muñoz-Hernández Rocío , Rojas Ángela , Gato Sheila , Gallego Javier , Gil-Gómez Antonio , Castro María José , Ampuero Javier , Romero-Gómez Manuel
Published: December 2022

Extracellular vesicles (EVs) are membrane-derived vesicles released by a variety of cell types, including hepatocytes, hepatic stellate cells, and immune cells in normal and pathological conditions. Depending on their biogenesis, there is a complex repertoire of EVs that differ in size and origin. EVs can carry lipids, proteins, coding and non-coding RNAs, and mitochondrial DNA causing alterations to the recipient cells, functioning as intercellular mediators of cell–cell communication (auto-, para-, juxta-, or even endocrine). Nevertheless, many questions remain unanswered in relation to the function of EVs under physiological and pathological conditions. The development and optimization of methods for EV isolation are crucial for characterizing their biological functions, as well as their potential as a treatment option in the clinic. In this manuscript, we will comprehensively review the results from different studies that investigated the role of hepatic EVs during liver diseases, including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, fibrosis, and hepatocellular carcinoma. In general, the identification of patients with early-stage liver disease leads to better therapeutic interventions and optimal management. Although more light needs to be shed on the mechanisms of EVs, their use for early diagnosis, follow-up, and prognosis has come into the focus of research as a high-potential source of ‘liquid biopsies’, since they can be found in almost all biological fluids. The use of EVs as new targets or nanovectors in drug delivery systems for liver disease therapy is also summarized.
Telocytes and Other Interstitial Cells 2.0: From Structure to Function
Authors: Cretoiu Sanda Maria
Published: December 2022

Interstitial cells are often seen as those cells that fill the space between parenchymal cells, responsible for fulfilling the function of an organ [...]
Factors Associated with Annual Influenza Vaccination Uptake in U.S. Older Adults from 2019 to 2020
Authors: Lovier Margaret Anne , Wong Roger
Published: December 2022

Annual influenza vaccination is important for older adults to prevent morbidity and mortality from seasonal influenza. Although the United States has had limited success in increasing influenza vaccination, the rise of the COVID-19 pandemic in 2020 may have changed older adults’ approach to vaccination. The objective of this study is to determine factors associated with influenza vaccination in 2019 and 2020 and compare their degree of associations across the two years. Data from the 2019 and 2020 National Health Interview Survey, a nationally representative cross-sectional interview, were collected for variables relating to annual influenza vaccination and possible associated factors. Data were analyzed using chi-square tests and multiple logistic regression. The results show that never having received a vaccination for pneumonia increased the odds of receiving an influenza vaccination by 6.79–7.80 times. Recent specialist care for eye or oral health significantly increased the odds of receiving an influenza vaccination. Being a smoker, identifying as African American, and considering oneself to have excellent overall health were associated with significantly lower odds of receiving a vaccination. Although self-reported feelings of anxiety were not associated with vaccination in 2019, they increased the odds in 2020. Overall, influenza vaccination in older adults may be tied to reliable healthcare access and perceived susceptibility to infectious respiratory diseases.
Wearable Intelligent Machine Learning Rehabilitation Assessment for Stroke Patients Compared with Clinician Assessment
Authors: Guo Liquan , Zhang Bochao , Wang Jiping , Wu Qunqiang , Li Xinming , Zhou Linfu , Xiong Daxi
Published: December 2022

In order to solve the shortcomings of the current clinical scale assessment for stroke patients, such as excessive time consumption, strong subjectivity, and coarse grading, this study designed an intelligent rehabilitation assessment system based on wearable devices and a machine learning algorithm and explored the effectiveness of the system in assessing patients’ rehabilitation outcomes. The accuracy and effectiveness of the intelligent rehabilitation assessment system were verified by comparing the consistency and time between the designed intelligent rehabilitation assessment system scores and the clinical Fugl–Meyer assessment (FMA) scores. A total of 120 stroke patients from two hospitals participated as volunteers in the trial study, and statistical analyses of the two assessment methods were performed. The results showed that the R2 of the total score regression analysis for both methods was 0.9667, 95% CI 0.92–0.98, p < 0.001, and the mean of the deviation was 0.30, 95% CI 0.57–1.17. The percentages of deviations/relative deviations falling within the mean ± 1.96 SD of deviations/relative deviations were 92.50% and 95.83%, respectively. The mean time for system assessment was 35.00% less than that for clinician assessment, p < 0.05. Therefore, wearable intelligent machine learning rehabilitation assessment has a strong and significant correlation with clinician assessment, and the time spent is significantly reduced, which provides an accurate, objective, and effective solution for clinical rehabilitation assessment and remote rehabilitation without the presence of physicians.
Retinal Macrophage-Like Cells as a Biomarker of Inflammation in Retinal Vein Occlusions
Authors: Maltsev Dmitrii S. , Kulikov Alexei N. , Volkova Yaroslava V. , Burnasheva Maria A. , Vasiliev Alexander S.
Published: December 2022

Aim: To study the macrophage-like cells (MLC) of the inner retinal surface in eyes with retinal vein occlusions (RVO) and the association of MLC with clinical characteristics of RVO. Methods: In this retrospective cross-sectional study, the medical records and multimodal imaging data of treatment-naïve patients with unilateral RVO and no abnormalities of vitreoretinal interface electronic were reviewed and analyzed. To visualize MLC, structural projections of optical coherence tomography (OCT) angiography scans within a slab between two inner limiting membrane segmentation lines (with 0 and −9 µm offset) were evaluated. The density of MLC was calculated and compared between affected and fellow eyes of each patient with regards to OCT and clinical characteristics of RVO. Results: Thirty-six eyes (twenty-eight branch RVO and eight central RVO) of 36 patients (21 males and 15 females, mean age 48.9 ± 9.8 years) were included. The density of MLC in affected eye was statistically significantly higher than that of the fellow eye, 8.5 ± 5.5 and 4.0 ± 3.6 cells/mm2, respectively (p < 0.001). The MLC density in the affected eye had a statistically significantly correlation with that of the fellow eye (r = 0.76, p = 0.0001), but with none of the OCT and clinical characteristics of the affected eye apart from the presence of subfoveal fluid. Eyes with subfoveal fluid had a statistically significantly higher mean number of MLC than that of eyes without subfoveal fluid, 12.6 ± 6.3 and 6.9 ± 4.0 cells/mm2, respectively (p = 0.009). Conclusion: The number of MLC on the inner retinal surface increases in RVO eyes which may reflect the activation of inflammatory pathways.
Advancement in the Treatment of Osteoporosis and the Effects on Bone Healing
Authors: Kushchayeva Yevgeniya , Pestun Iryna , Kushchayev Sergiy , Radzikhovska Nataliia , Lewiecki E. Michael
Published: December 2022

Osteoporosis (OP) is a major global health concern, with aging being one of the most important risk factors. Osteoarthritis (OA) is also an age-related disorder. Patients with OP and/or OA may be treated surgically for fractures or when their quality of life is impaired. Poor bone quality due to OP can seriously complicate the stability of a bone fixation construct and/or surgical fracture treatment. This review summarizes the current knowledge on the pathophysiology of normal and osteoporotic bone healing, the effect of a bone fracture on bone turnover markers, the diagnosis of a low bone mineral density (BMD) before surgical intervention, and the effect of available anti-osteoporosis treatment. Interventions that improve bone health may enhance the probability of favorable surgical outcomes. Fracture healing and the treatment of atypical femoral fractures are also discussed.
The Prevalence and Characteristics of Chronic Ankle Instability in Elite Athletes of Different Sports: A Cross-Sectional Study
Authors: Zhang Congda , Chen Na , Wang Jingsong , Zhang Zhengzheng , Jiang Chuan , Chen Zhong , Fang Jianhui , Peng Juhua , Li Weiping , Song Bin
Published: December 2022

Background: Ankle sprains are one of the most common injuries in athletic populations. Misdiagnosed and untreated ankle sprains will cause chronic ankle instability (CAI), which can significantly affect the performance of athletes. This study aimed to investigate the prevalence and characteristics of CAI in elite athletes of different sports. Method: This cross-sectional study included 198 elite athletes from Guangdong provincial sports teams. All participants answered a questionnaire about ankle sprains and ankle instability. The severity of their ankle instability was evaluated by the Cumberland Ankle Instability Tool (CAIT). Participants further underwent clinical examinations from sports medicine doctors to determine the presence and characteristics of ankle instability. The datasets were analyzed to determine the differences in prevalence between age, gender, sports teams, and sports categories. Results: In 198 athletes, 39.4% (n = 78) had bilateral CAI while 25.3% (n = 50) had unilateral CAI. Female athletes had a higher prevalence of CAI than male athletes in the study (p = 0.01). Prevalence showed differences between sports categories, and were significantly higher in acrobatic athletes than non-contact athletes (p = 0.03). Conclusions: CAI was highly prevalent among elite athletes in this study, with female athletes and athletes in acrobatic sports being associated with a higher risk of developing CAI in their professional careers. Therefore, extra precautions need to be taken into account when applying ankle protections for these athletes.
Understanding the Effect of Multiple Sclerosis on General and Dimensions of Mental Health
Authors: Kang Weixi
Published: December 2022

Objective: The objective of the current study is to investigate how general and dimensions of mental health are affected by multiple sclerosis (MS). Methods: Factor analysis, generalized linear models, and one-sample t-tests were used to analyze data from 78 people with MS with a mean age of 52.19 (S.D. = 12.94) years old and 25.64% males and 38,516 people without MS with a mean age of 49.10 (S.D. = 18.24) years old and 44.27% males from Understanding Society. Results: The current study found that there are three underlying factors of the GHQ-12 labeled as GHQ-12A (social dysfunction and anhedonia; 6 items), GHQ-12B (depression and anxiety; 4 items), and GHQ-12C (loss of confidence; 2 items), and the general mental health, GHQ-12A (social dysfunction and anhedonia), and GHQ-12C (loss of confidence) are associated with MS. Conclusions: Effective mental health management in MS patients is important given mental health in people with MS is linked to the onset of MS and exacerbating disease progression/relapses.
Effects of Physical Exercise Program in Adults with Intellectual and Developmental Disabilities—A Study Protocol
Authors: Ferreira José Pedro , Matos Rui , Campos Maria João , Monteiro Diogo , Antunes Raul , Jacinto Miguel
Published: December 2022

We developed a physical exercise (PE) program for people with Intellectual and Developmental Disabilities (IDD), aiming to determine the effects on physical fitness, health, cognitive ability, and quality of life (QoL). Using experimental methodology, this intervention study recruited 21 adults (18 to 65 years old), institutionalized and with no other associated pathology, who will be allocated to one of the different groups: (i) gym/indoor intervention group (using weight machines), (ii) outdoor intervention group (using low-cost materials), or (iii) control group (without specific intervention, who continue with their normal daily activities). Both intervention groups will engage in 45 min of training per session, twice a week, for 24 weeks. Assessments will be conducted at baseline (initial assessment), 3 months (mid-term assessment), and 6 months (final assessment). Variables assessed include anthropometrics, body composition, functional capacity, muscle strength, general health, cognitive ability, and QoL. The results of this study will assist in the development of more effective strategies, recommendations, and interventions to ensure better and greater adherence to PE by institutionalized individuals with IDD, namely, recommendations for assessment, prescription, and implementation of PE for this population. Additionally, we intend to make available two PE programs, if they are adapted and promote positive effects.
“Orphaned” Stomach—An Infrequent Complication of Gastric Bypass Revision
Authors: Varvoglis Dimitrios N. , Sanchez-Casalongue Manuel , Baron Todd H. , Farrell Timothy M.
Published: December 2022

While generally safe, bariatric operations have a variety of possible complications. We present an uncommon complication after gastric bypass revision, namely the creation of an “orphaned” segment of remnant stomach that was left inadvertently in discontinuity, leading to recurrent intra-abdominal abscesses. Sinogram ultimately proved the diagnosis, and the issue was successfully treated using a combination of surgical and endoscopic methods to control the abscess and to allow internal drainage.
Understanding the Female Physical Examination in Patients with Chronic Pelvic and Perineal Pain
Authors: Pereira Augusto , Fuentes Lucia , Almoguera Belen , Chaves Pilar , Vaquero Gema , Perez-Medina Tirso
Published: December 2022

(1) Background: The objective was to compare the exploration of chronic pelvic pain syndrome (CPPS) patients in different locations and establish the role of physical examination in CPPS patients. (2) Methods: We reviewed clinical data from 107 female patients with CPPS unresponsive to conventional therapies at Puerta de Hierro University Hospital Madrid, Spain, from May 2018 to June 2022. Patients were classified into three groups: (a) pelvic pain; (b) anorectal pain; or (c) vulvar/perineal pain. (3) Results: Although the demographics of patients with CPPS were different, their physical examinations were strikingly similar. Our study observed a comorbidity rate of 36% and 79% of central sensitization of pain. Seventy-one percent of patients had vulvar allodynia/hyperalgesia. Pain on examination was identified in any pelvic floor muscle, in any pelvic girdle structure, and neuropathic pain in 98%, 96%, and 89%, respectively. Patients with vulvar and perineal pain were more different from the other groups; these patients were younger and had fewer comorbidities and less central sensitization, less anorectal pain, more pain during intercourse, and greater nulliparity (p = 0.022; p = 0.040; p = 0.048; p = 0.000; p = 0.006; p = 0.005). (4) Conclusions: The findings of this study are related to the understanding of the pathophysiology of CPPS. The physical examination confirms the central sensitization of female patients with CPPS, helps us to determine the therapeutic management of the patient, and can be considered as a prognostic factor of the disease.
Functional Polymorphism in the ADRB3 Gene, Encoding the Beta-3 Adrenergic Receptor, and Response to Intra-Detrusor Injection of Botulinum Toxin-A in Women with Overactive Bladder
Authors: Ciećwież Sylwester Michał , Lewandowska Klaudyna , Boroń Agnieszka , Brodowski Jacek , Kociszewski Jacek , Clark Jeremy Simon , Ciechanowicz Andrzej
Published: December 2022

Background: There are reports suggesting an association between the rs4994 polymorphism in the ADRB3 gene encoding the beta-3 adrenergic receptor and OAB risk in females. The injection of botulinum toxin-A into the bladder wall is recommended as a possible treatment for OAB patients in whom first-line therapies have failed. The aim of our study was to analyze the possible association between the ADRB3:rs4994 polymorphism and the patient-perceived response to a single intra-detrusor injection of botulinum toxin-A in Polish women with overactive bladder. Methods: The study group consisted of 115 consecutive female patients with OAB. The response to botulinum toxin-A was evaluated at three months after injection, as absolute or relative reductions in OAB symptoms or in scores from questionnaires ICIQ-OAB (parts A and B) and ICIQ-LUTS-QoL (parts A and B). ADRB3:rs4994 variants were identified by the sequencing of genomic DNA extracted from buccal swabs. Results: There were no statistically significant differences between ADRB3:rs4994 [T];[T] homozygotes and [T];[C]+[C];[C] subjects for absolute or relative reductions in symptoms or in scores from all four questionnaire parts at three months after the injection of botulinum toxin-A. Conclusions: Our results do not support the hypothesis that ADRB3:rs4994 polymorphism is associated with the response to the intra-detrusor injection of botulinum toxin-A in Polish females with overactive bladder.
The Effects of Four Weeks of Chiropractic Spinal Adjustments on Blood Biomarkers in Adults with Chronic Stroke: Secondary Outcomes of a Randomized Controlled Trial
Authors: Haavik Heidi , Niazi Imran Khan , Amjad Imran , Kumari Nitika , Rashid Usman , Duehr Jens , Navid Muhammad Samran , Trager Robert J. , Shafique Muhammad , Holt Kelly
Published: December 2022

Certain blood biomarkers are associated with neural protection and neural plasticity in healthy people and individuals with prior brain injury. To date, no studies have evaluated the effects chiropractic care on serum brain-derived neurotrophic factor (BDNF), insulin-like growth factor-II (IGF-II) and glial cell-derived neurotrophic factor (GDNF) in people with stroke. This manuscript reports pre-specified, exploratory, secondary outcomes from a previously completed parallel group randomized controlled trial. We evaluated differences between four weeks of chiropractic spinal adjustments combined with the usual physical therapy (chiro + PT) and sham chiropractic with physical therapy (sham + PT) on resting serum BDNF, IGF-II and GDNF in 63 adults with chronic stroke. Blood samples were assessed at baseline, four weeks (post-intervention), and eight weeks (follow-up). Data were analyzed using a linear multivariate mixed effects model. Within both groups there was a significant decrease in the mean log-concentration of BDNF and IGF-II at each follow-up, and significant increase log-concentration of GDNF at eight-weeks’ follow-up. However, no significant between-group differences in any of the blood biomarkers at each time-point were found. Further research is required to explore which factors influence changes in serum BDNF, IGF-II and GDNF following chiropractic spinal adjustments and physical therapy.
The Clinical and Epidemiological Profile of Paediatric-Onset Multiple Sclerosis in Poland
Authors: Brola Waldemar , Steinborn Barbara , Żak Marek , Mazurkiewicz-Bełdzińska Maria , Jóźwiak Sergiusz , Sobolewski Piotr , Wilski Maciej , Bilska Małgorzata , Siedlarska Magdalena , Puzio-Bochen Iwona , Wencel-Warot Agnieszka , Lemka Małgorzata , Kroczka Sławomir , Czyżyk Elżbieta , Bocheńska Małgorzata , Emich-Widera Ewa , Pietruszewski Jerzy , Boćkowski Leszek , Kapica-Topczewska Katarzyna , Czarnowska Agata , Kułakowska Alina , Ujma-Czapska Barbara , Gruna-Ożarowska Agata , Przysło Łukasz , Połatyńska Katarzyna , Dudzińska Magdalena , Mitosek-Szewczyk Krystyna , Melnyk Aleksandra , Adamczyk-Sowa Monika , Kotulska Katarzyna
Published: December 2022

Background. Paediatric-onset MS (POMS) has a unique clinical profile compared to the more prevalent adult-onset MS. For this study, we aimed to determine the demographic and clinical characteristics of POMS in Poland as well as addressing some of its epidemiological aspects. Methods. A retrospective study was conducted based on the Polish Multiple Sclerosis Registry, considering a population of children and adolescents with MS (age ≤ 18 years). Data were collected by all 13 centres across Poland specializing in diagnosing and treating POMS. The actual course of the disease and its clinical properties were compared between child (≤12 years) and juvenile (>12 years) patients. MS onset and its prevalence were assessed at the end of 2019, stratified by age range. Results. A total of 329 paediatric or juvenile patients (228 girls, 101 boys) with a clinically definite diagnosis of MS, in conformity with the 2017 McDonald Criteria, were enrolled. For 71 children (21.6%), the first symptoms appeared before the age of 12. The female: male ratio increased with age, amounting to 1:1 in the ≤12 years group and to 2.9:1 in the >12 years group. In most cases, the disease had multi-symptomatic onset (31.3%), and its course was mostly of a relapsing–remitting character (95.7%). The initial Expanded Disability Status Score for both groups was 1.63 ± 1.1, whereas the annual relapse rate was 0.84 during the first 2 years. The time between the onset of symptoms and diagnosis was longer in the younger patients (8.2 ± 4.2 vs. 4.6 ± 3.6 months; p < 0.005). On 31 December 2019, the age-adjusted prevalence standardized to the European standard population was 5.19/100,000 (95% CI, 4.64–5.78). Significantly higher prevalence was noted in the 13–18 years group (7.12; 95% CI, 6.64–7.86) than in the 9–12 years group (3.41; 95% CI, 2.98–3.86) and the <9 years group (0.56; 95% CI, 0.46–0.64; p < 0.001). Conclusion. POMS commencing at the age of ≤12 years is rare, differing significantly from the juvenile-onset and adult MS in terms of clinical characteristics, course, and incidence, as stratified by gender.
Association between Psychological Status and Condylar Bony Changes in Adults: A Retrospective Survey-Based Study
Authors: Zhang Chenghao , Ji Ling , Zhao Zhihe , Liao Wen
Published: December 2022

Background: This article studies the association between psychological status and condylar bony changes in adults and assesses psychological questionnaires as an indicator of potential condylar bony changes. It is meaningful because condylar bony changes, a severe subtype of TMD and big concern in orthodontic treatment, would likely be ignored in patients with few TMD symptoms, in which case, even with potential psychological problems (depression, somatization and anxiety) being noticed, orthodontists may underestimate the possibility or severity of condylar bony changes and thus may not perform relevant examinations. Methods: A total of 195 adults (145 female and 50 male) who consulted orthodontists and had clinical records were included in this study. Initial CBCT images taken before orthodontic treatment were used for observing their condylar bony changes, and a comprehensive questionnaire conducted by each adult to evaluate psychological status was collected. Age, sex, TMD symptom history, scores on Patient Health Questionnaire-9 (PHQ-9), PHQ-15 and Generalized Anxiety Disorder-7 (GAD-7), and condylar bony changes of these adults were recorded. Odds ratios (OR) and 95% confidence intervals (CIs) for identifying the independent risk factors associated with condylar bony changes were calculated with univariate and multivariate logistic regression analysis. The kappa statistic was used to assess intraobserver reliability of CBCT analysis. Results: The scores of PHQ-15 (OR: 2.088, 95% CI: 1.061–4.108, p < 0.05) and GAD-7 (OR: 2.133, 95% CI: 1.082–4.204, p < 0.05) were correlated with the condylar bony changes on CBCT. Besides, the probability of having condylar bony changes was positively correlated with the number of psychological problems concomitantly present in an adult (OR: 1.440, 95% CI: 1.10–1.867, p < 0.01). The intraobserver agreement value for CBCT analysis was substantial (κ = 0.732). Conclusions: This study found that positive PHQ-15 (somatization) and GAD-7 (anxiety) scores were associated with condylar bony changes in adults. Moreover, the number of psychological problems concomitantly present in an adult was positively associated with the probability of having condylar bony changes.
Reply to Daitch et al. Comment on “Huang et al. Colistin Monotherapy versus Colistin plus Meropenem Combination Therapy for the Treatment of Multidrug-Resistant Acinetobacter baumannii Infection: A Meta-Analysis. J. Clin. Med. 2022, 11, 3239”
Authors: Huang Chienhsiu , Chen Ihung , Tang Tiju
Published: December 2022

This is an Author Reply to the Letter to the Editor entitled “Colistin Monotherapy versus Colistin plus Meropenem Combination Therapy for the Treatment of Multidrug-Resistant Acinetobacter baumannii Infection: A Meta-Analysis” by Daitch V. et al. [...]
Reliability and Validity of Computerized Adventitious Respiratory Sounds in People with Bronchiectasis
Authors: Herrero-Cortina Beatriz , Francín-Gallego Marina , Sáez-Pérez Juan Antonio , San Miguel-Pagola Marta , Anoro-Abenoza Laura , Gómez-González Cristina , Montero-Marco Jesica , Charlo-Bernardos Marta , Altarribas-Bolsa Elena , Pérez-Trullén Alfonso , Jácome Cristina
Published: December 2022

Background: Computerized adventitious respiratory sounds (ARS), such as crackles and wheezes, have been poorly explored in bronchiectasis, especially their measurement properties. This study aimed to test the reliability and validity of ARS in bronchiectasis. Methods: Respiratory sounds were recorded twice at 4 chest locations on 2 assessment sessions (7 days apart) in people with bronchiectasis and daily sputum expectoration. The total number of crackles, number of wheezes and wheeze occupation rate (%) were the parameters extracted. Results: 28 participants (9 men; 62 ± 12 y) were included. Total number of crackles and wheezes showed moderate within-day (ICC 0.87, 95% CI 0.74–0.94; ICC 0.86, 95% CI 0.71–0.93) and between-day reliability (ICC 0.70, 95% CI 0.43–0.86; ICC 0.78, 95% CI 0.56–0.90) considering all chest locations and both respiratory phases; wheeze occupation rate showed moderate within-day reliability (ICC 0.86, 95% CI 0.71–0.93), but poor between-day reliability (ICC 0.71, 95% CI 0.33–0.87). Bland–Altman plots revealed no systematic bias, but wide limits of agreement, particularly in the between-days analysis. All ARS parameters correlated moderately with the amount of daily sputum expectoration (r > 0.4; p < 0.05). No other significant correlations were observed. Conclusion: ARS presented moderate reliability and were correlated with the daily sputum expectoration in bronchiectasis. The use of sequential measurements may be an option to achieve greater accuracy when ARS are used to monitor or assess the effects of physiotherapy interventions in this population.
Sex-Associated Differences in Short-Term Outcomes in Patients with Deep Sternal Wound Infection after Open-Heart Surgery
Authors: Krasivskyi Ihor , Ivanov Borko , Eghbalzadeh Kaveh , Fehlau Frederike , Gerfer Stephen , Großmann Clara , Elderia Ahmed , Sabashnikov Anton , Rahmanian Parwis Baradaran , Mader Navid , Djordjevic Ilija , Wahlers Thorsten
Published: December 2022

Deep sternal wound infection (DSWI) is a feared complication after cardiac surgery. The impact of sex-related differences on wound infection prevalence is poorly understood. Our aim was to evaluate the effect of sex on short-term outcomes in patients with DSWI after open-heart surgery. The study was a retrospective cohort study. A total of 217 patients with DSWI were identified and retrospectively analyzed using our institutional database. Patients were divided into two groups: males (n = 150) and females (n = 67). This study also includes a propensity score based matching (PSM) analysis (male group (n = 62) and female group (n = 62)) to examine the unequal groups. Mean age (p = 0.088) and mean body mass index (BMI) (p = 0.905) did not significantly differ between both groups. Vacuum assisted closure (VAC) therapy was performed among most patients (82.3% (male group) vs. 83.9% (female group), p = 0.432). The most commonly isolated bacteria from the wounds were Staphylococcus epidermidis and Staphylococcus aureus in both groups. Acute renal failure was significantly higher (p = 0.010) in the male group compared to the female group. However, dialysis rate did not significantly differ (p = 0.491) between male and female groups. Further secondary outcomes showed no major differences between the groups. Likewise, in-hospital mortality rate did not differ significantly (p = 0.680) between both groups. Based on our data, sex has no impact on deep wound infection prevalence after cardiac surgery.
Operative Re-Intervention following Pancreatoduodenectomy: What Has Changed over the Last Decades
Authors: Enderes Jana , Pillny Christiane , Standop Jens , Manekeller Steffen , Kalff Jörg C. , Glowka Tim R.
Published: December 2022

Background: To investigate changes over the last decades in the management of postoperative complications following pancreatoduodenectomy (PD) with special emphasis on reoperations, their indications, and outcomes. Methods: 409 patients who underwent PD between 2008 and 2021 were retrospectively analyzed with respect to their need for reoperations (reoperation, n = 81, 19.8% vs. no reoperation, n = 328, 80.2%). The cohort was then compared to a second cohort comprising patients who underwent PD between 1989 and 2007 (n = 285). Results: 81 patients (19.8%) underwent reoperation. The main cause of reoperation was the dehiscence of pancreatogastrostomy (22.2%). Reoperation was associated with a longer duration of the index operation, more blood loss, and more erythrocyte concentrates being transfused. Patients who underwent reoperation showed more postoperative complications and a higher mortality rate (25% vs. 2%, p < 0.001). Compared to the earlier cohort, the observed increase in reoperations did not lead to increased mortality (5% vs. 6%, p = 353). Conclusions: The main cause for reoperation has changed over the last decades and was the dehiscence of pancreatogastrostomy. Associated with a leakage of pancreatic fluid and clinically relevant PF, it remains the most devastating complication following PD. Strategies for prevention and treatment, e.g., by endoscopic vacuum-assisted-closure therapy are of utmost importance.
Biventricular Arrhythmogenic Cardiomyopathy Associated with a Novel Heterozygous Plakophilin-2 Early Truncating Variant
Authors: Çimen Tolga , Wilzeck Verena C. , Montrasio Giulia , Bonetti Nicole R. , Medeiros-Domingo Argelia , Grebmer Christian , Matter Christian M. , Tanner Felix C. , Manka Robert , Brunckhorst Corinna B. , Duru Firat , Saguner Ardan M.
Published: December 2022

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a hereditary condition that can cause sudden cardiac death in young, frequently athletic individuals under the age of 35 due to malignant arrhythmias. Competitive and endurance exercise may hasten the onset and progression of ARVC, leading to right ventricular dysfunction and potentially fatal ventricular arrhythmias earlier in life. In this article, we present a novel, pathogenic, early truncating heterozygous variant in the PKP2 gene that causes biventricular arrhythmogenic cardiomyopathy and affects a family, of which the only member with the positive phenotype is a competitive endurance athlete.
Hypokalemia Duration in the First Year Associated with Subsequent Peritoneal Dialysis-Associated Peritonitis: A Multicenter Retrospective Cohort Study
Authors: Huo Zhihao , Zhuo Qianqian , Zhong Shaoxin , Wang Fang , Xie Chao , Gong Nirong , Zhong Xiaohong , Yi Zhixiu , Kong Yaozhong , Liu Dehui , Dou Xianrui , Wang Guobao , Ai Jun
Published: December 2022

Background: The association of hypokalemia (LK) with peritoneal dialysis-associated peritonitis (PDAP) risk remains uncertain. Here, we calculated LK duration in the first PD year and evaluated its association with PDAP. Methods: A multicenter, retrospective, incident cohort study of 1633 participants was conducted from January 2008 to October 2020 in China. The duration of LK and severe hypokalemia (SLK) was calculated as the total number of months that a patient’s serum potassium (SK) level was less than 3.5 or 3.0 mEq/L during the first PD year. The study outcome was the risk of subsequent PDAP started in the second year and later. Cox proportional hazards models and competing risk models were used to assess the association. Results: The subsequent PDAP occurred in 420 (25.7%) participants during a median of 28 months of follow-up. Overall, LK duration in the first year was positively associated with a subsequent PDAP risk (per 3-month increments, adjusted HR, 1.13; 95%CI: 1.05–1.23). After categorization, patients with LK duration longer than 6 months had the highest adjusted HR of 1.53 (p = 0.005 vs. those without LK) for subsequent PDAP risk. A similar trend was also found for SLK duration. In a competing risk model, a similar trend was also observed. None of the variables, including demographic and PD characteristics, diabetes history, and several clinical measurements, significantly modified this association. The causative organisms of PDAP were similar to those previously reported. Conclusions: PD patients with longer LK duration in the first year had a higher subsequent PDAP risk.
The Safety of Chemotherapy for Ovarian Malignancy during Pregnancy
Authors: Xing Naidong , Wang Lihui , Sui Xinlei , Zhao Chunru , Huang Yan , Peng Jin
Published: December 2022

Background: Data on epidemiologic features, treatments and outcomes in women diagnosed with ovarian malignancy during pregnancy are very sparse due to its low incidence. The goal of our study was to summarize the epidemiologic characteristics of pregnant women complicated with ovarian malignancy and investigate the safety and efficacy of chemotherapy during pregnancy. Methods: We retrospectively analyzed the clinicopathological data of eight patients suffering from ovarian malignancy during pregnancy in our institution from June 2011 to July 2021. Furthermore, a systematic literature search was conducted in PubMed up to 1 September 2021, which identified 92 cases with ovarian malignancy during pregnancy eligible for the analysis. Therefore, we collected the data of 100 pregnant patients complicated with ovarian malignancy, including clinical demographics, tumor characteristics, treatment interventions and outcomes. Results: In total, 100 pregnant patients complicated with ovarian malignancy were investigated and classified into three groups: 34 cases in the epithelial ovarian cancer (EOC) group, 38 cases in the germ cell tumors (GCTs) group and 28 cases in the sex cord-stromal tumors (SCSTs) group. The onset age of pregnant patients with epithelial ovarian cancer was significantly higher than that of other patients. Pelvic mass and abdominal pain were the common clinical presentations of pregnant patients with ovarian malignancy. For distinguishing epithelial ovarian cancer during pregnancy, the area under the curve (AUC) of CA-125 was 0.718 with an optimal cutoff value of 58.2 U/mL. Moreover, 53 patients underwent surgery during pregnancy, the majority of whom underwent unilateral adnexectomy in the second trimester. Furthermore, 43 patients received chemotherapy during pregnancy, and 28 delivered completely healthy newborns at birth; 13 neonates showed transient abnormalities without further complications; and 2 died during the neonatal period. Conclusions: Our study reveals the safety of chemotherapy for ovarian malignancy during pregnancy. However, large-sample prospective studies are still needed to further explore the safety of chemotherapy in pregnant patients with malignancy to choose the appropriate chemotherapy regimen and achieve the maximum benefit for patients.
Recent and Future Strategies to Overcome Resistance to Targeted Therapies and Immunotherapies in Metastatic Colorectal Cancer
Authors: Dazio Giulia , Epistolio Samantha , Frattini Milo , Saletti Piercarlo
Published: December 2022

Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide, and 20% of patients with CRC present at diagnosis with metastases. The treatment of metastatic CRC is based on a fluoropyrimidine-based chemotherapy plus additional agents such as oxaliplatin and irinotecan. To date, on the basis of the molecular background, targeted therapies (e.g., monoclonal antibodies against epidermal growth factor receptor or inhibiting angiogenesis) are administered to improve the treatment of metastatic CRC. In addition, more recently, immunological agents emerged as effective in patients with a defective mismatch repair system. The administration of targeted therapies and immunotherapy lead to a significant increase in the survival of patients; however these drugs do not always prove effective. In most cases the lack of effectiveness is due to the development of primary resistance, either a resistance-inducing factor is already present before treatment or resistance is acquired when it occurs after treatment initiation. In this review we describe the most relevant targeted therapies and immunotherapies and expand on the reasons for resistance to the different approved or under development targeted drugs. Then we showed the possible mechanisms and drugs that may lead to overcoming the primary or acquired resistance in metastatic CRC.