bluuebunny/crossref_metadata_2025_split huggingface dataset:
No bidirectional association between serum 25-hydroxyvitamin D and erectile dysfunction: Mendelian randomization and genetic association studies
Authors: Liu Xiang , Luo Longhua , Peng Cong , Wang Zixin , Zhou Jiaming , Sun Xiang 
Published: September 2024

Abstract

Background
The causal relationship between the level of serum 25-hydroxyvitamin D [25(OH)D] and the risk of erectile dysfunction (ED) is still unclear.

Aim
We tried to determine the causal relationship between the level of serum 25(OH)D and ED risk.

Methods
In this study, we used genome-wide association study data from the UK Biobank to analyse the relationship between serum 25(OH)D (as the exposure) and ED (as the outcome). Linkage disequilibrium score regression (LDSC) was used to assess the genetic correlation between 2 traits. The CAUSE (Causal Analysis using Summary Effect estimates) method and Mendelian randomization (MR) were employed to evaluate the bidirectional causal relationship. The MRlap method was utilized to assess the impact of sample overlap on the results. To assess potential heterogeneity and horizontal pleiotropy, we utilized methods such as MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier), weighted median, and others.

Outcomes
The primary outcome was defined as self or physician-reported ED, or using oral ED medication, or a history of surgery related to ED.

Results
The LDSC analysis did not reveal a significant genetic correlation between serum 25(OH)D and ED (rg = 0.2787, P = .3536). Additionally, the CAUSE (P value testing that the causal model is a better fit &gt;.05) and MR analyses (odds ratio, 0.8951; 95% confidence interval, 0.7480-1.0710; P = .2260) did not support a causal relationship between 25(OH)D and ED, and our study did not detect any heterogeneity and pleiotropy.

Clinical implications
This study provides evidence on whether vitamin D needs to be ingested to prevent or treat ED.

Strengths and limitations
We used LDSC and MR to avoid bias. However, the population in this study was limited to European ancestry.

Conclusion
No causal relationship was found between 25(OH)D and ED.
A Novel Hybrid Injectable for Soft-tissue Augmentation: Analysis of Data and Practical Experience
Authors: Braz André , de Paula Eduardo Camila Cazerta , Pierce Alexander , Grond Alexandra , Kutikov Artem , Nakab Lauren 
Published: September 2024

Background:
HA/CaHa (HArmonyCa, Allergan Aesthetics, an AbbVie Company) is a hybrid injectable filler developed for aesthetic purposes that contains calcium hydroxyapatite microspheres suspended in a hyaluronic acid gel. This review describes preclinical and clinical data, recommendations for use based on the primary author’s clinical experience, and case studies that illustrate implementation of product use recommendations and patient outcomes.

Methods:
Preclinical data on the lift capacity and tissue integration of the HA/CaHa hybrid injectable and clinical data on its safety, efficacy, and real-world use were extracted from poster presentations, published literature, manufacturer instructions for use, and proprietary data files. Case studies were presented based on clinical experience.

Results:
The HA component of HA/CaHa provides an immediate and noticeable filling and lifting effect, whereas CaHa microspheres result in neocollagenesis. In preclinical studies, HA/CaHa demonstrated higher lift capacity (P < 0.05) and faster tissue integration than a CaHa filler and led to collagen I gene and protein expression. Clinical studies showed clinical safety and effectiveness with high patient satisfaction. The most common adverse event was injection-site response. Clinician recommendations for achieving desired aesthetic results while minimizing or preventing adverse events are reviewed, including patient selection and assessment, treatment approaches based on face shape, injection technique, and postprocedure care.

Conclusion:
The novel hybrid injectable consisting of HA with incorporated CaHa microspheres in a single marketed product may help achieve aesthetic goals by immediately restoring volume and potentially improving skin architecture and soft-tissue quality over time.
Development and internal validation of a clinical risk tool to predict chronic postsurgical pain in adults: a prospective multicentre cohort study
Authors: Papadomanolakis-Pakis Nicholas , Haroutounian Simon , Sørensen Johan Kløvgaard , Runge Charlotte , Brix Lone Dragnes , Christiansen Christian Fynbo , Nikolajsen Lone 
Published: September 2024

Abstract
Chronic postsurgical pain (CPSP) is a highly prevalent condition. To improve CPSP management, we aimed to develop and internally validate generalizable point-of-care risk tools for preoperative and postoperative prediction of CPSP 3 months after surgery. A multicentre, prospective, cohort study in adult patients undergoing elective surgery was conducted between May 2021 and May 2023. Prediction models were developed for the primary outcome according to the International Association for the Study of Pain criteria and a secondary threshold-based CPSP outcome. Models were developed with multivariable logistic regression and backward stepwise selection. Internal validation was conducted using bootstrap resampling, and optimism was corrected by shrinkage of predictor weights. Model performance was assessed by discrimination and calibration. Clinical utility was assessed by decision curve analysis. The final cohort included 960 patients, 16.3% experienced CPSP according to the primary outcome and 33.6% according to the secondary outcome. The primary CPSP model included age and presence of other preoperative pain. Predictors in the threshold-based models associated with an increased risk of CPSP included younger age, female sex, preoperative pain in the surgical area, other preoperative pain, orthopedic surgery, minimally invasive surgery, expected surgery duration, and acute postsurgical pain intensity. Optimism-corrected area-under-the-receiver-operating curves for preoperative and postoperative threshold-based models were 0.748 and 0.747, respectively. These models demonstrated good calibration and clinical utility. The primary CPSP model demonstrated fair predictive performance including 2 significant predictors. Derivation of a generalizable risk tool with point-of-care predictors was possible for the threshold-based CPSP models but requires independent validation.
Pharmacological Management of Acute and Chronic Insomnia: A Cross-Sectional Study
Authors: Valladales-Restrepo Luis Fernando , Sánchez-Ramírez Nicolás , Ospina-Sánchez Santiago , Usma-Valencia Andrés Felipe , Gaviria-Mendoza Andrés , Machado-Duque Manuel , Machado-Alba Jorge Enrique 
Published: September 2024

Objective
Insomnia is a frequent and difficult disease to treat. The objective was to determine the pharmacological management of a group of patients diagnosed with acute and chronic insomnia.

Methods
This is a cross-sectional study that identified patterns of prescription of drugs for outpatient use in patients with insomnia from a population database of 8.5 million individuals in the Health System of Colombia. Sociodemographic and pharmacological variables were considered.

Results
A total of 5825 patients with insomnia were identified. Acute insomnia was the most frequent complaint (85.2%). A total of 76.9% received pharmacological treatment, mainly through off-label drugs (70.7%), such as trazodone (20.2%), quetiapine (12.3%), and clonazepam (11.1%). The approved drugs were used in 9.9% of the patients, especially eszopiclone (4.7%) and zopiclone (3.6%). Benzodiazepines and Z compounds predominated in the elderly and individuals with chronic insomnia.

Conclusions
The pharmacological treatment of insomnia in this group of patients is heterogeneous, and medications not approved for this indication are very frequently used.
Quinoline synergy and reduced use: a study of pharmacodynamic interactions
Authors: Sadouki Zahra , Wey Emmanuel Q. , McHugh Timothy D. , Kloprogge Frank 
Published: September 2024

SynopsisBackgroundMeropenem, gentamicin and ciprofloxacin have been used as empiric broad-spectrum combination therapy in different combinations. Recent restrictions on the use of quinolones jeopardises the rational of administering this combination to increase the spectrum of coverage for this particular case. A mechanistic understanding of pharmacodynamic interaction for these combinations is lacking but can provide insight in the necessity of using the different moieties.ObjectivesTo study pharmacodynamic drug-drug interaction between meropenem, gentamicin and ciprofloxacin againstEscherichia coli.MethodsStatic time kill curve experiments were conducted withEscherichia coli(NCTC® 12241) at 0.25 – 16 × MIC for a duration of 24 hours with samples being collected at 0, 2, 4, 6, 8, and 24 hour. Meropenem, gentamicin and ciprofloxacin were tested alone, in two- and three-way combinations. Bacterial load time series data were enumerated on Meuller Hinton plates and Colony Forming Unit data was modelled using nonlinear mixed-effects models in nlmixr.ResultsMeropenem, gentamicin and ciprofloxacin two- and three-way combinations prevented regrowth, but did not when these moieties were studied alone. Gentamicin and meropenem were synergistic by decreasing ciprofloxacin IC50and the combination effects of meropenem and gentamicin and the addition of meropenem on top of a gentamicin and ciprofloxacin combination were indifferent.ConclusionsOur findings emphasize the added value of a quinolone in the drug combination. In light of the recent move towards reduced use of quinolones, a quinolone free combination still prevented regrowth, it just did not display further synergy on IC50and was indifferent in initial killing.
Polyacrylamide-based Antimicrobial Copolymers to Replace or Rescue Antibiotics
Authors: Williams Shoshana C. , Chosy Madeline B. , Jons Carolyn K. , Dong Changxin , Prossnitz Alexander N. , Liu Xinyu , Herandez Hector Lopez , Cegelski Lynette , Appel Eric A. 
Published: September 2024

ABSTRACTAntibiotics save countless lives each year and have dramatically improved human health outcomes since their introduction in the 20thcentury. Unfortunately, bacteria are now developing resistance to antibiotics at an alarming rate, with many new strains of “superbugs” showing simultaneous resistance to multiple classes of antibiotics. To mitigate the global burden of antimicrobial resistance, we must develop new antibiotics that are broadly effective, safe, and highly stable for the purpose of global access. In this manuscript, we report the development of polyacrylamide-based copolymers as a novel class of broad-spectrum antibiotics with efficacy against several critical pathogens. We demonstrate that these copolymer drugs are selective for bacteria over mammalian cells, indicating a favorable safety profile. We show that they kill bacteria through a membrane disruption mechanism, which allows them to overcome traditional mechanisms of antimicrobial resistance. Finally, we demonstrate their ability to rehabilitate an existing small-molecule antibiotic that is highly subject to resistance development by improving its potency and eliminating the development of resistance in a combination treatment. This work represents a significant step towards combatting antimicrobial resistance.
WEE1 inhibition delays resistance to CDK4/6 inhibitor and antiestrogen treatment in estrogen receptor-positive breast cancer
Authors: He Wei , Demas Diane M. , Kraikivski Pavel , Shajahan-Haq Ayesha N. , Baumann William T. 
Published: September 2024

ABSTRACTAlthough endocrine therapies and Cdk4/6 inhibitors have produced significantly improved outcomes for patients with estrogen receptor positive (ER+) breast cancer, continuous application of these drugs often results in resistance. We hypothesized that cancer cells acquiring drug resistance might increase their dependency on negative regulators of the cell cycle. Therefore, we investigated the effect of inhibiting WEE1 on delaying the development of resistance to palbociclib and fulvestrant. We treated ER+ MCF7 breast cancer cells with palbociclib alternating with a combination of fulvestrant and a WEE1 inhibitor AZD1775 for 12 months. We found that the alternating treatment prevented the development of drug resistance to palbociclib and fulvestrant compared to monotherapies. Furthermore, we developed a mathematical model that can simulate cell proliferation under monotherapy, combination or alternating drug treatments. Finally, we showed that the mathematical model can be used to minimize the number of fulvestrant plus AZD1775 treatment periods while maintaining its efficacy.
Cross-sectional analysis: interpretation of non-statistically significant results in randomised controlled clinical trials in rehabilitation
Authors: Mugnai Caterina , Maistrello Luca Falsiroli , Fiacca Giacomo , Perucchini Michele , Corbetta Noemi , Amateis Federico , Salvioli Stefano 
Published: September 2024

ABSTRACTIntroductionDespite the CONSORT guidelines, which aim to improve the quality of studies, authors often formulate conclusions based on the dichotomous distinction of the p-value, declaring differences between ‘statistically significant’ and ‘non-significant’. This approach confuses the identification of the real efficacy of the studied treatment. To solve this problem, CONSORT guidelines recommend using confidence intervals, which offer a more complete view of possible effects. However, authors’ conclusions often remain based on a binary approach, confusing the absence of evidence with the evidence of absence. This error can influence clinical practice and future research, leading to the identification of ‘negative’ treatments based on ‘statistical insignificance’, which reflects a lack of evidence of absence, not the absence of evidence.ObjectivesTo assess the prevalence of misinterpretation of non-statistically significant results, both in the abstract and in the article, in a sample of all randomised controlled trials (RCTs) with non-statistically significant primary outcomes published in 5 rehabilitation journals with the highest impact factor (IF) published between 2019 and 2023 and to assess whether the primary outcome result is reported according to CONSORT guidelines.MethodsWe will conduct a cross-sectional analysis of all Rcts with non-statistically significant primary outcomes in 5 general rehabilitation journals with the highest IF published between 2019 and 2023. We will determine the prevalence of trials in which non-significance is interpreted as absence of evidence, evidence of absence, or advice to use the intervention in clinical practice in the abstract and article conclusions, and the prevalence of trials that adhered to CONSORT guidelines for reporting the primary outcome.
PiggyBac mediated transgenesis and CRISPR/Cas9 knockout in the greater waxmoth,Galleria mellonella
Authors: Pearce James C. , Campbell Jennie S. , Prior Joann L. , Titball Richard W. , Wakefield James G. 
Published: September 2024

AbstractThe larvae of the greater waxmoth,Galleria mellonella, are gaining prominence as a versatile non-mammalianin vivomodel to study host-pathogen interactions. Their ability to be maintained at 37°C, coupled with a broad susceptibility to human pathogens and a distinct melanisation response that serves as a visual indicator for larval health, positionsGalleriaas a powerful resource for infection research. Despite these advantages, the lack of genetic tools, such as those available for zebrafish and fruit flies, has hindered development of the full potential ofGalleriaas a model organism. In this study, we describe a robust methodology for generating transgenicGalleriausing the PiggyBac transposon system and for precise gene knockouts via CRISPR/Cas9 technology. These advances significantly enhance the utility ofGalleriain molecular research, opening the way to its widespread use as an inexpensive and ethically compatible animal model for infection biology and beyond.
Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi-Goutières Syndrome neuropathology
Authors: Nemec Kelsey M. , Uy Genevieve , Chaluvadi V. Sai , Purnell Freddy S. , Elfayoumi Bilal , O’Brien Carleigh A. , Aisenberg William H. , Lombroso Sonia I. , Guo Xinfeng , Blank Niklas , Oon Chet Huan , Yaqoob Fazeela , Temsamrit Brian , Rawat Priyanka , Thaiss Christoph A. , Wang Qingde , Bennett Mariko L. , Bennett F. Chris 
Published: September 2024

AbstractMicroglia, the brain’s resident macrophages, can be reconstituted by surrogate cells - a process termed “microglia replacement.” To expand the microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized macrophages, a cell model for generation of immune cells from murine bone marrow, as a versatile model for microglia replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary bone marrow-derived (BMD) macrophages in vitro, and, when transplanted into a microglia-free brain, engraft the parenchyma and differentiate into microglia-like cells. Furthermore, ER-Hoxb8 progenitors are readily transducible by virus and easily stored as stable, genetically manipulated cell lines. As a demonstration of this system’s power for studying the effects of disease mutations on microglia in vivo, we created stable,Adar1-mutated ER-Hoxb8 lines using CRISPR-Cas9 to study the intrinsic contribution of macrophages to Aicardi-Goutières Syndrome (AGS), an inherited interferonopathy that primarily affects the brain and immune system. We find thatAdar1knockout elicited interferon secretion and impaired macrophage production in vitro, while preventing brain macrophage engraftment in vivo - phenotypes that can be rescued with concurrent mutation ofIfih1(MDA5) in vitro, but not in vivo. Lastly, we extended these findings by generating ER-Hoxb8 progenitors from mice harboring a patient-specificAdar1mutation (D1113H). We demonstrated the ability of microglia-specific D1113H mutation to drive interferon production in vivo, suggesting microglia drive AGS neuropathology. In sum, we introduce the ER-Hoxb8 approach to model microglia replacement and use it to clarify macrophage contributions to AGS.
Fast-twitch myofibrils grow in proportion to Mylpf dosage in the zebrafish embryo
Authors: Adekeye Tayo E , Teets Emily M , Tomak Emily A , Waterman Sadie L , Sprague Kailee A , White Angelina , Coffin Maddison L , Varga Sabrina M , Easterbrooks Teresa E , Shepherd Sarah J , Austin Jared D , Krivorotko Dmitrii , Hupper Troy E , Kelley Joshua B , Amacher Sharon L , Talbot Jared C 
Published: September 2024

AbstractMuscle cells become stronger by expanding myofibrils, the chains of sarcomeres that produce contraction. Here we investigate how Mylpf (Myosin Light Chain Phosphorylatable Fast) abundance impacts myofibril assembly in fast-twitch muscle. The two zebrafish Mylpf genes (mylpfaandmylpfb) are exclusively expressed in fast-twitch muscle. We show that these cells initially produce six times moremylpfamRNA and protein thanmylpfb. The combined Mylpf protein dosage is necessary for and proportionate to fast-twitch myofibril growth in the embryo. Fast-twitch myofibrils are severely reduced in themylpfa-/-mutant, leading to loss of high-speed movement; however, by persistent slow movement this mutant swims as far through time as its wild-type sibling. Although themylpfb-/-mutant has normal myofibrils, myofibril formation fails entirely in themylpfa-/-;mylpfb-/-double mutant, indicating that the two genes are collectively essential to myofibril formation. Fast-twitch myofibril width is restored in themylpfa-/-mutant by transgenic expression ofmylpfa-GFP, mylpfb-GFP,and by humanMYLPF-GFPto a degree corresponding linearly with GFP brightness. This correlate is inverted by expression ofMYLPFalleles that cause Distal Arthrogryposis, which reduce myofibril size in proportion to protein abundance. These effects indicate that Mylpf dosage controls myofibril growth, impacting embryonic development and lifelong health.
Alpha-synuclein preformed fibril-induced aggregation and dopaminergic cell death in cathepsin D overexpression and ZKSCAN3 knockout mice
Authors: Mueller Toni , Jeffrey Parker , He Yecheng , Ouyang Xiaosen , Westbrook David , Darley-Usmar Victor , Goldberg Matthew S. , Volpicelli-Daley Laura , Zhang Jianhua 
Published: September 2024

Abstractα-synuclein accumulation is recognized as a prominent feature in the majority of Parkinson’s disease cases and also occurs in a broad range of neurodegenerative disorders including Alzheimer’s disease. It has been shown that α-synuclein can spread from a donor cell to neighboring cells and thus propagate cellular damage, antagonizing the effectiveness of therapies such as transplantation of fetal or iPSC derived dopaminergic cells. As we and others previously have shown, insufficient lysosomal function due to genetic mutations or targeted disruption of cathepsin D can cause α-synuclein accumulation. We here investigated whether overexpression of cathepsin D or knockout (KO) of the transcriptional suppressor of lysosomal biogenesis ZKSCAN3 can attenuate propagation of α-synuclein aggregation and cell death. We examined dopaminergic neurodegeneration in the substantia nigra using stereology of tyrosine hydroxylase-immunoreactive cells 4 months and 6 months after intrastriatal injection of α-synuclein preformed fibrils or monomeric α-synuclein control in control, central nervous system (CNS)-cathepsin D overexpressing and CNS-specific ZKSCAN3 KO mice. We also examined pS129-α-synuclein aggregates in the substantia nigra, cortex, amygdala and striatum. The extent of dopaminergic neurodegeneration and pS129-α-synuclein aggregation in the brains of CNS-specific ZKSCAN3 knockout mice and CNS-cathepsin D overexpressing mice was similar to that observed in wild-type mice. Our results indicate that neither enhancing cathepsin D expression nor disrupting ZKSCAN3 in the CNS is sufficient to attenuate pS129-α-synuclein aggregate accumulation or dopaminergic neurodegeneration.
Those unpredictable crossroads
Authors: Marques Joan 
Published: September 2024

Purpose
Providing workforce members with an understandable and workable platform to successfully withstand professional crossroads.

Design/methodology/approach
A reflective, experience-based deliberation on the emotional and action-based steps to be taken when unanticipated crossroads emerge.

Findings
Crossroads are inevitable and can be heart-wrenching, but if addressed mindfully, they can lead to greater fulfillment.

Practical Implications
Providing workforce members a platform to consider when facing the next professional crossroads.

Originality/value
Crossroads happen to all of us, yet, few articles have been written about this all too common process. Given the frequently recurring nature of this predicament, a practical, compassionate notation could bring relief and encouragement to workforce members.