bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment of glabellar lines with Botox (onabotulinumtoxinA): Development, insights, and impact
Authors: Carruthers Jean , Carruthers Alastair , Blitzer Andrew , Eadie Nina , Brin Mitchell F. 
Published: July 2023

OnabotulinumtoxinA is an injectable medication that produces muscle relaxation through local chemical denervation at the neuromuscular junction. Discovery of onabotulinumtoxinA’s aesthetic benefits occurred serendipitously in the 1980s at the intersection of several medical disciplines, including ophthalmology, neurology, otolaryngology, and dermatology. Patients receiving onabotulinumtoxinA for blepharospasm, hemifacial spasm, and dystonia noticed their periorbital wrinkles disappearing, particularly frown lines between the eyebrows called glabellar lines (GL).
Aesthetic use of onabotulinumtoxinA necessitated rigorous training programs and vigilant monitoring by Allergan. Approval for the GL indication was based on 2 similarly designed, double-blind, randomized, multicenter clinical studies. Subjects with moderate to severe GL receiving onabotulinumtoxinA achieved significantly greater improvement in GL severity than those receiving placebo. In subsequent studies, more than 80% of subjects were satisfied with onabotulinumtoxinA treatment through day 60, and many reported looking approximately 4 years younger at weeks 4 and 12 than at baseline. OnabotulinumtoxinA has a rapid onset of action, and peak effect occurs between 30 and 60 days. The median duration of response for dynamic GL in the initial studies was 120 days and response progressively improved with subsequent treatments. OnabotulinumtoxinA was well tolerated, and the 2 most common adverse events, headache and blepharoptosis, tended to decrease in frequency with repeat treatment.
The novel use of onabotulinumtoxinA for treating GL was an important step in addressing the clinical need for a noninvasive, straightforward, office-based procedure for facial lines that also left patients extremely satisfied with its treatment effects and represented the beginning of its widespread use for numerous aesthetic indications.
Treatment of crow’s feet lines and forehead lines with Botox (onabotulinumtoxinA): Development, insights, and impact
Authors: Carruthers Alastair , Carruthers Jean , De Boulle Koenraad , Lowe Nicholas , Lee Elisabeth , Brin Mitchell F. 
Published: July 2023

Extrinsic and age-related intrinsic factors contribute to the development of facial lines, including lateral canthal lines (called crow’s feet lines [CFL]) and horizontal forehead lines (FHL).
OnabotulinumtoxinA is a highly effective treatment for facial lines that inhibits acetylcholine release at the neuromuscular junction. This temporary chemical denervation leads to localized muscle relaxation and subsequent wrinkle reduction. Early studies of onabotulinumtoxinA treatment for facial neuronal disorders such as dystonia documented improvements in FHL and CFL. After the neurotoxin was approved for treating frown lines (glabellar lines [GL]), individuals requested treatment for other rhytids, and physicians continued assessing use in new areas. Once onabotulinumtoxinA was in clinical trial development, its efficacy and safety for CFL and FHL were successively evaluated as required by the US Food and Drug Administration and by key global health authorities, including those in the European Union, Japan, and China.
Allergan, collaborating with leading physicians, established clinical programs that included novel safety and efficacy measures to meet regulatory requirements. Global, phase 3, randomized, controlled studies of CFL and FHL met rigorous primary endpoints. Some countries mandated clinical trial data beyond US and European regulations, and Allergan conducted 11 studies in total, fulfilling diverse regulatory and study population data requirements.
Adverse events associated with local spread, including brow and eyelid ptosis, diplopia, headache, and eyelid sensory disorder, were infrequent and well tolerated. Consequently, onabotulinumtoxinA treatment of upper facial lines is now established globally as a highly effective, minimally invasive treatment for patients to achieve a natural appearance and look younger.
The Design of Nested Adaptive Clinical Trials of Multiple Organ Dysfunction Syndrome Children in a Single Study
Authors: VanBuren John M. , Hall Mark , Zuppa Athena F. , Mourani Peter M. , Carcillo Joseph , Dean J. Michael , Watt Kevin , Holubkov Richard 
Published: July 2023

OBJECTIVES:
Describe the statistical design of the Personalized Immunomodulation in Sepsis-induced Multiple Organ Dysfunction Syndrome (MODS) (PRECISE) study.

DESIGN:
Children with sepsis-induced MODS undergo real-time immune testing followed by assignment to an immunophenotype-specific study cohort. Interventional cohorts include the granulocyte macrophage-colony stimulating factor (GM-CSF) for the Reversal of Immunoparalysis in Pediatric Sepsis-induced MODS (GRACE)-2 trial, which uses the drug GM-CSF (or placebo) to reverse immunoparalysis; and the Targeted Reversal of Inflammation in Pediatric Sepsis-induced MODS (TRIPS) trial, which uses the drug anakinra (or placebo) to reverse systemic inflammation. Both trials have adaptive components and use a statistical framework in which frequent data monitoring assesses futility and efficacy, allowing potentially earlier stopping than traditional approaches. Prespecified simulation-based stopping boundaries are customized to each trial to preserve an overall one-sided type I error rate. The TRIPS trial also uses response-adaptive randomization, updating randomization allocation proportions to favor active arms that appear more efficacious based on accumulating data.

SETTING:
Twenty-four U.S. academic PICUs

PATIENTS:
Septic children with specific immunologic derangements during ongoing dysfunction of at least two organs.

INTERVENTIONS:
The GRACE-2 trial compares GM-CSF and placebo in children with immunoparalysis. The TRIPS trial compares four different doses of anakinra to placebo in children with moderate to severe systemic inflammation.

MEASUREMENTS AND MAIN RESULTS:
Both trials assess primary efficacy using the sum of the daily pediatric logistic organ dysfunction-2 score over 28 days. Ranked summed scores, with mortality assigned the worst possible value, are compared between arms using the Wilcoxon Rank Sum test (GRACE-2) and a dose-response curve (TRIPS). We present simulation-based operating characteristics under several scenarios to demonstrate the behavior of the adaptive design.

CONCLUSIONS:
The adaptive design incorporates innovative statistical features that allow for multiple active arms to be compared with placebo based on a child’s personal immunophenotype. The design increases power and provides optimal operating characteristics compared with traditional conservative methods.
Repair of Fingertip Degloving Injuries Using the Extended Reverse Second Dorsal Metacarpal Artery Flap
Authors: Zhang Wenlong , Zhang Xu , Liu Yingnan , Xu Tao , Zhuang Yongqing , Chen Chao 
Published: July 2023

Background:
This study aimed to introduce modified reverse second dorsal metacarpal artery flap (MRSDMAF) transfer for the treatment of fingertip degloving injuries.

Methods:
From January of 2004 to March of 2020, 31 patients with fingertip degloving injuries underwent MRSDMAF transfer. The mean defect and flap size were 4.5 × 1.6 cm and 4.7 × 1.7 cm, respectively. Nerve repair was performed in 18 fingers. Flap sensation, function restoration of the reconstructed fingers, and donor-site morbidity were assessed. For comparison, we reviewed a cohort of 45 patients undergoing modified cross-finger flap (MCFF) transfer.

Results:
Complete flap survival was achieved in 28 fingers, and partial distal flap necrosis was noted in 3 fingers. After a mean of 24 months, the static 2-point discrimination was 8.6 ± 1.0 mm and 7.2 ± 0.8 mm in the MRSDMAF and MCFF groups, with a significant difference (P < 0.0001). Sensory restoration of the MRSDMAF group was inferior to that of the MCFF group. In addition, the MRSDMAF group presented a higher incidence of fingertip pain (P = 0.019) and suboptimal appearance of the reconstructed finger (P = 0.036). On the donor site, the MRSDMAF group presented a lower incidence of scar pain (P = 0.030) and better appearance (P = 0.025).

Conclusion:
MRSDMAF transfer is an alternative treatment for fingertip degloving injuries, especially when MCFF transfer is not feasible.

CLINICAL QUESTION/LEVEL OF EVIDENCE:
Therapeutic, III.
Guidance on conducting methodological studies – an overview
Authors: Khalil Hanan , Munn Zachary 
Published: July 2023

Purpose of review
Methodological studies are defined as studies that are used to develop the validity and reliability of instruments or methods to measure constructs used as variables in research. Other terms used to describe them include methodological review, meta-epidemiological review and research on research. Methodological studies have previously been used to examine the characteristics of certain tools or methods used in research, to examine the adherence of reporting guidelines by researchers, to advance the methodology of certain methods, to examine the heterogeneity and exploring causes of research methodologies and to develop new methodologies.

Recent findings
To date, the guidance to undertake methodological studies is limited. Some studies used either systematic, scoping or mapping approach to undertake them. This narrative review will present a summary of published methodological studies guidance for researchers to consider in the future.

Summary
This article presented a detailed summary of published methodological studies ranging from methods, naming, database searching, data selection and reporting. To date, there is no clear consensus on how to report methodological studies. Further research is warranted in this area to produce robust guidance for undertaking methodological studies.
Univariable and multivariable Mendelian randomization study identified the key role of gut microbiota in immunotherapeutic toxicity
Authors: Liu Baike , Liu Zheran , Jiang Tianxiang , Gu Xiangshuai , Yin Xiaonan , Cai Zhaolun , Zou Xiaoqiao , Dai Lei , Zhang Bo 
Published: July 2023

AbstractBackgroundIn cancer patients receiving immune checkpoint inhibitors (ICIs), there is emerging evidence suggesting a correlation between gut microbiota and immune-related adverse events (irAEs). However, the exact roles of gut microbiota and the causal associations are yet to be clarified.MethodsTo investigate this, we first conducted a univariable bi-directional two-sample Mendelian randomization (MR) analysis. Instrumental variables (IVs) for gut microbiota were retrieved from the MiBioGen consortium (18,340 participants). GWAS summary data for irAEs were gathered from an ICIs-treated cohort with 1,751 cancer patients. Various MR analysis methods, including Inverse variance weighted (IVW), MR PRESSO, maximum likelihood (ML), weighted median, weighted mode, and cML-MA-BIC were used. Furthermore, multivariable MR (MVMR) analysis was performed to account for possible influencing instrumental variables.ResultsOur analysis identified fourteen gut bacterial taxa that were causally associated with irAEs. Notably,Lachnospiraceaewas strongly associated with an increased risk of both high-grade and all-grade irAEs, even after accounting for the effect of BMI in the MVMR analysis.Akkermansia,Verrucomicrobiaceae, andAnaerostipeswere found to exert protective roles in high-grade irAEs. However,Ruminiclostridium6,Coprococcus3,Collinsella, andEubacterium (fissicatena group)were associated with a higher risk of developing high-grade irAEs.RuminococcaceaeUCG004, andDefluviitaleaceaeUCG011were protective against all-grade irAEs, whereasPorphyromonadaceae,Roseburia,Eubacterium (brachy group), andPeptococcuswere associated with an increased risk of all-grade irAEs.ConclusionOur analysis highlights a strong causal association betweenLachnospiraceaeand irAEs, along with some other gut microbial taxa. These findings provide potential modifiable targets for managing irAEs and warrant further investigation.
Heart Rate as a Predictor of Mortality in Heart Failure Patients at the Time of Discharge from the Intensive Care Unit
Authors: Hsiao Chia-Ying , Su Min-I , Chang Yu-Cheng , Lee Ying-Hsiang , Lin Po-Lin , Chiou Wei-Ru 
Published: July 2023

AbstractObjectiveHeart rate serves as a critical prognostic factor in heart failure patients. We hypothesize that elevated heart rate in critically ill heart failure patients upon discharge from the intensive care unit (ICU) could be linked to adverse outcomes.DesignWe implemented a retrospective cohort study using data collected between 2008 and 2019 from the Medical Information Mart for Intensive Care IV (MIMIC-IV version 2.0) database. We examined the association between the last heart rate prior to ICU discharge and in-hospital mortality, total mortality, and ICU readmission.SettingICU at Beth Israel Deaconess Medical CenterPatientsAdult patients admitted to the ICU diagnosed with heart failure.InterventionsNoneMeasurements and Main ResultsFrom the 76,943 ICU stays, we enrolled 2,365 patients in this study. We observed correlations between in-hospital mortality and ICU discharge heart rate of 83.56±15.81 bpm (survivors) vs. 93.84±17.28 bpm (nonsurvivors, p<0.001). Total mortality showed similar trends, with 83.67±15.36 bpm (survivors) vs. 85.23±17.25 bpm (nonsurvivors, p=0.027), as did ICU readmissions at 83.55±15.77 bpm (nonreadmitted) vs. 88.64±17.49 bpm (readmitted, p<0.001). Given multivariate analysis, the ICU discharge heart rate strongly predicted in-hospital mortality (OR 1.035 [95% CI 1.024-1.046], p < 0.001), total mortality (OR 1.007 [95% CI 1.001-1.014], p = 0.027) and ICU readmission (OR 1.015 [95% CI 1.007-1.023], p < 0.001). Patients with an ICU discharge heart rate >90 bpm demonstrated significantly higher in-hospital mortality (OR 2.986 [95% CI 2.066-4.315], p < 0.001), total mortality (OR 1.341 [95% CI 1.083-1.661], p = 0.007), and ICU readmission rates (OR 1.638 [95% CI 1.270-2.114], p < 0.001).ConclusionsThe findings suggest that heart failure patients with an elevated heart rate (>90 bpm) at ICU discharge are more likely to experience increased in-hospital mortality, total mortality, and ICU readmissions, indicating potential negative outcomes.Key PointsQuestion: Does an elevated heart rate at ICU discharge increase in-hospital mortality, total mortality, and ICU readmission?Findings: This retrospective cohort study using the Medical Information Mart for Intensive Care IV database showed that a higher ICU discharge heart rate >90 bpm is a strong predictor of increased in-hospital mortality (OR 2.986, p < 0.001), total mortality (OR 1.341, p = 0.007), and ICU readmission (OR 1.638, p < 0.001).Meaning: Heart failure patients with an elevated heart rate (>90bpm) at ICU discharge are more likely to face increased risks of in-hospital mortality, total mortality, and ICU readmissions.
Monomeric amyloid-β inhibits microglial inflammatory activity in the brain via an APP/heterotrimeric G protein-mediated pathway
Authors: Kwon Hyo Jun , Santhosh Devi , Huang Zhen 
Published: July 2023

SUMMARYMicroglia, the resident immune cell of the brain, play critical roles in brain development, function, and disease. However, how microglial activity is regulated in this process remains to be elucidated. Here we report an amyloid precursor protein (APP) and heterotrimeric G protein-mediated pathway that negatively regulates microglial inflammatory activation during cerebral cortex development. Disruption of this pathway results in dysregulated microglial activity, excessive extracellular matrix proteinase production, cortical basement membrane breach, and laminar assembly disruption. We further show that this pathway is activated by amyloid β (Aβ), the cleavage product of APP that accumulates in large quantities as plaques in the Alzheimer’s disease brain. Specifically, we find Aβ monomers potently suppress inflammatory cytokine transcription and secretion by brain microglia, in an APP and heterotrimeric G protein-dependent manner. These results discover a previously unknown activity of Aβ as a negative regulator of brain microglia as well as a new pathway that mediates the signal transduction. They shed new light on the cell-cell communication mechanisms that regulate brain immune homeostasis and may facilitate further insight into Alzheimer’s disease pathogenesis.
Development of a major histocompatibility complex class II conditional knockout mouse to study cell-specific and time-dependent adaptive immune responses in peripheral nerves
Authors: Ubogu Eroboghene E. , Conner Jeremy A. , Wang Yimin , Yadav Dinesh , Saunders Thomas L. 
Published: July 2023

AbstractIntroductionMajor histocompatibility complex (MHC) class II professional antigen presenting cell-naïve CD4+ T cell interactions via the T-cell receptor complex are necessary for adaptive immunity. MHC class II upregulation in multiple cell types occurs in human autoimmune polyneuropathy patient biopsies, necessitating studies to ascertain cellular signaling pathways required for tissue-specific autoimmunity.MethodsCryopreserved Guillain-Barré syndrome (GBS) patient sural nerve biopsies and sciatic nerves from the severe murine experimental autoimmune neuritis (sm-EAN) GBS model were studied. Cultured conditional ready MHC Class II antigen A-alpha chain (H2-Aa) embryonic stem cells were used to generate H2-Aaflox/+C57BL/6 mice. Mice were backcrossed and intercrossed to the SJL background to generate H2-Aaflox/floxSJL mice, bred with hemizygous Tamoxifen-inducible von Willebrand factor Cre recombinase (vWF-iCre/+) SJL mice to generate H2-Aaflox/flox; vWF-iCre/+ to study microvascular endothelial cell adaptive immune responses. Sm-EAN was induced in adult female SJL Tamoxifen-treated H2-Aaflox/flox; vWF-iCre/+ mice and H2-Aaflox/flox; +/+ littermate controls. Neurobehavioral, electrophysiological and histopathological assessments were performed at predefined time points.ResultsEndoneurial endothelial cell MHC class II expression was observed in normal and inflamed human and mouse peripheral nerves. Adult female Tamoxifen-treated H2-Aaflox/flox; vWF-iCre/+ did not develop sm-EAN despite extensive MHC class II expression in lymphoid and non-lymphoid tissues.DiscussionA conditional MHC class II knockout mouse to study cell- and time-dependent adaptive immune responsesin vivois developed. Initial studies show microvascular endothelial cell MHC class II expression is necessary for peripheral nerve specific autoimmunity, as advocated by humanin vitroadaptive immunity andex vivotransplant rejection studies.
PREVALENCE AND HISTOLOGICAL PATTERNS OF PROSTATE CANCER AMONG PATIENTS PRESENTING WITH OBSTRUCTIVE LOWER URINARY TRACT SYMPTOMS AT MBARARA REGIONAL REFERRAL HOSPITAL
Authors: Kyegombe Willy , Joseph Epodoi , Ronald Okidi , Lagoro Kitara , Eddymond Ekuk , Aniitah Nimusima , Mwesigwa Marvin Mutakooha 
Published: July 2023

ABSTRACTBackgroundProstate cancer is currently the second commonest male cancer in Uganda. Despite this, men are more likely to be tested for prostate cancer only after presenting with obstructive Lower urinary tract symptoms [1] since these are a common presenting complaint among elderly males [2]. However, there is still a lack of published local information on the clinical and biochemical patterns of prostate cancer among patients with lower urinary tract symptoms in Uganda which can negatively affects the equitable distribution of resources for cancer care.AimsTo determine the Patterns of PSA, DRE, histological findings, and prevalence of prostate cancer among patients presenting to Mbarara regional referral hospital with obstructive LUTS.Materials and MethodsA cross-sectional study of 140 patients with obstructive LUTS. Demographics, presenting symptoms were collected using a structured questionnaire and IPSS index, followed by total serum prostate specific antigen level estimation and Digital rectal examination. Patients who had a total serum Prostate Specific Antigen level above 4ng or an abnormal DRE underwent digitally guided transrectal prostate biopsy.ResultsMajority had severe LUTS (n=103,73.57%) with a median tPSA of 14.4 ng/ml and met the criteria for the digitally guided transrectal trucut prostate biopsy(n=99,70.71%). DRE abnormalities were found in 57.14% n=80 of the participants. The commonest abnormalities were prostatic enlargement (n=76,54.29%), hard prostatic consistency (29.2% n=41), loss of the median groove (35.71% n= 50) and nodular prostate (n=60, 42.86%). The prevalence of prostate cancer was high at 52.21% (59/11395% C.I:30.1-46.3), and over 93.3% of the cancer postive patients exhibited abnormalities on DRE.Prostate adenocarcinoma was the only histological type in all biopsies. The mean Gleason score was 8 (±1.148) and the majority had a Gleason score of 8 and above. (77.78%, n=35).ConclusionsThe prevalence of prostate cancer among men presenting to Mbarara Regional referral hospital with obstructive LUTS was high and majority of these had poorly differentiated prostate adenocarcinoma.
Posture analysis in predicting fall-related injuries during French Navy Special Forces selection course using machine learning: A proof of concept study
Authors: Verdonk Charles , Duffaud Anaïs M. , Longin Aurélie , Bertrand Matthieu , Zagnoli Fabien , Trousselard Marion , Canini Frédéric 
Published: July 2023

ABSTRACTIntroductionInjuries induced by falls represent the main cause of failure in the French Navy Special Forces selection course. In the present study we made the assumption that probing the posture might contribute to predicting the risk of fall-related injury at the individual level.MethodsBefore the start of the selection course, the postural signals of 99 male soldiers were recorded using static posturography while they were instructed to maintain balance with their eyes closed. The event to be predicted was a fall-related injury during the selection course that resulted in the definitive termination of participation. Following a machine learning methodology, we designed an artificial neural network model to predict the risk of fall-related injury from the descriptors of postural signal.ResultsThe neural network model successfully predicted with 69.9% accuracy (95% CI=69.3-70.5) the occurrence of a fall-related injury event during the selection course from the selected descriptors of the posture. The area under the curve (AUC) value was 0.731 (95% CI=0.725-0.738), the sensitivity was 56.8% (95% CI=55.2-58.4), and the specificity was 77.7% (95% CI=76.8-0.78.6).ConclusionIf confirmed with a larger sample, these findings suggest that probing the posture using static posturography and machine learning-based analysis might contribute to inform risk assessment of fall-related injury during military training, and could ultimately lead to the development of novel programs for personalized injury prevention in military population.KEY MESSAGESFall-related injuries are a major concern that leads to failure in the French Navy Special Forces selection course.This proof of concept study shows that analyzing the posture with machine learning can predict the risk of fall-related injury at the individual level.The findings may prompt the development of novel programs for personalized injury prevention in military settings.