bluuebunny/crossref_metadata_2025 huggingface dataset:
Five-year outcomes of biodegradable versus second-generation durable polymer drug-eluting stents used in complex percutaneous coronary intervention
Authors: Xu Na , Jiang Lin , Yao Yi , Xu Jingjing , Liu Ru , Wang Huanhuan , Song Ying , Gao Lijian , Gao Zhan , Zhao Xueyan , Xu Bo , Han Yaling , Yuan Jinqing
Published: February 2023

Background:

There are few data comparing clinical outcomes of complex percutaneous coronary intervention (CPCI) when using biodegradable polymer drug-eluting stents (BP-DES) or second-generation durable polymer drug-eluting stents (DP-DES). The purpose of this study was to investigate the safety and efficacy of BP-DES and compare that with DP-DES in patients with and without CPCI during a 5-year follow-up.

Methods:

Patients who exclusively underwent BP-DES or DP-DES implantation in 2013 at Fuwai hospital were consecutively enrolled and stratified into two categories based on CPCI presence or absence. CPCI included at least one of the following features: unprotected left main lesion, ≥2 lesions treated, ≥2 stents implanted, total stent length >40 mm, moderate-to-severe calcified lesion, chronic total occlusion, or bifurcated target lesion. The primary endpoint was major adverse cardiac events (MACE) including all-cause death, recurrent myocardial infarction, and total coronary revascularization (target lesion revascularization, target vessel revascularization [TVR], and non-TVR) during the 5-year follow-up. The secondary endpoint was total coronary revascularization.

Results:

Among the 7712 patients included, 4882 (63.3%) underwent CPCI. Compared with non-CPCI patients, CPCI patients had higher 2- and 5-year incidences of MACE and total coronary revascularization. Following multivariable adjustment including stent type, CPCI was an independent predictor of MACE (adjusted hazard ratio [aHR]: 1.151; 95% confidence interval [CI]: 1.017–1.303, P = 0.026) and total coronary revascularization (aHR: 1.199; 95% CI: 1.037–1.388, P = 0.014) at 5 years when comparing with non-CPCI patients. The results were consistent at the 2-year endpoints. In patients with CPCI, BP-DES use was associated with significantly higher MACE rates at 5 years (aHR: 1.256; 95% CI: 1.078–1.462, P = 0.003) and total coronary revascularization (aHR: 1.257; 95% CI: 1.052–1.502, P = 0.012) compared with that of DP-DES, but there was a similar risk at 2 years. However, BP-DES had comparable safety and efficacy profiles including MACE and total coronary revascularization compared with DP-DES in patients with non-CPCI at 2 and 5 years.

Conclusions:

Patients underwent CPCI remained at a higher risk of mid- to long-term adverse events regardless of the stent type. The effect of BP-DES compared with DP-DES on outcomes was similar between CPCI and non-CPCI patients at 2 years but had inconsistent effects at the 5-year clinical endpoints.
Effects of coronavirus disease 2019 vaccination on seizures in patients with epilepsy
Authors: Fang Xiqin , Qiao Shan , Zhang Ranran , Yang Tingting , Wang Zhihao , Kong Qingxia , Sun Meihua , Geng Jianhong , Fang Chunyan , Chen Yanxiu , Sun Yanping , Zhang Dongmei , Qu Lixing , Shang Wei , Wang Jianguo , Liu Xuewu
Published: February 2023

Background:

Given that seizures may be triggered by vaccination, this study aimed to evaluate the risk and correlative factors of seizures in patients with epilepsy (PWE) after being vaccinated against coronavirus disease 2019 (COVID-19).

Methods:

This study retrospectively enrolled PWE who were vaccinated against COVID-19 in the epilepsy centers of 11 hospitals in China. We divided the PWE into two groups as follows: (1) patients who developed seizures within 14 days of vaccination were assigned to the SAV (with seizures after vaccination) group; (2) patients who were seizure-free within 14 days of vaccination were assigned to the SFAV (seizure-free after vaccination) group. To identify potential risk factors for seizure reccurence, the binary logistic regression analysis was performed. Besides, 67 PWE who had not been vaccinated were also included for elucidating the effects of vaccination on seizures recurrence, and binary logistic regression analysis was performed to determine whether vaccination would affect the recurrence rate of PWE who had drug reduction or withdrawal.

Results:

The study included a total of 407 patients; of which, 48 (11.8%) developed seizures within 14 days after vaccination (SAV group), whereas 359 (88.2%) remained seizure-free (SFAV group). The binary logistic regression analysis revealed that duration of seizure freedom (P < 0.001) and withdrawal from anti-seizure medications (ASMs) or reduction in their dosage during the peri-vaccination period were significantly associated with the recurrence of seizures (odds ratio = 7.384, 95% confidence interval = 1.732–31.488, P = 0.007). In addition, 32 of 33 patients (97.0%) who were seizure-free three months before vaccination and had a normal electroencephalogram before vaccination did not have any seizures within 14 days of vaccination. A total of 92 (22.6%) patients experienced non-epileptic adverse reactions after vaccination. Binary logistic regression analysis results showed that vaccine did not significantly affect the recurrence rate of PWE who had the behavior of AMS dose reduction or withdrawal (P = 0.143).

Conclusions:

PWE urgently need protection from the COVID-19 vaccine. PWE who are seizure-free for >3 months before vaccination should be vaccinated. Whether the remaining PWE should be vaccinated depends on the local prevalence of COVID-19. Finally, PWE should be prohibited from discontinuing ASMs or reducing their dosage during the peri-vaccination period.
Surgical treatment of cardiac lipoma: 20 years’ experience in a single center
Authors: Li Linlin , Meng Jian , Zhou Xingtong , Liu Chang , Guo Hongwei , Fan Hongguang
Published: February 2023

Background:

Primary cardiac lipoma is very rare, and no consensus has been developed regarding its ideal treatment strategy. This study reviewed the surgical treatment of cardiac lipomas in 20 patients over 20 years.

Methods:

Twenty patients with cardiac lipomas were treated at Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College from January 1, 2002, to January 1, 2022. The patients’ clinical data and pathological reports were retrospectively analyzed, and the follow-up with a range of 1 to 20 years was conducted.

Results:

The cardiac lipomas were located in the right atrium (RA) or superior vena cava (SVC) in seven patients (35%) (atrium in six patiets and SVC in one patient), left ventricle in eight patients (40%) (left ventricular chamber in four patients and left ventricular subepicardium and myocardium in four patients), right ventricle in three patients (15%) (right ventricular chamber in one patient and right ventricular subepicardial layer and myocardium in two patients), subepicardial interventricular groove in one patient (5%), and pericardium in one patient (5%). Complete resection was achieved in 14 patients (70%), including seven patients with lipomas in the RA or SVC. Incomplete resection occurred in six patients (30%) with lipomas in the ventricles. No perioperative deaths occurred. Long-term follow-up was conducted for 19 patients (95%), including two (10%) who died. Both patients who died had lipomas incompletely resected due to ventricles involvement, and preoperative malignant arrhythmias persisted post-operatively.

Conclusions:

The complete resection rate was high, and the long-term prognosis was satisfactory in patients with cardiac lipomas that did not involve the ventricle. The complete resection rate was low in patients with cardiac lipomas in ventricles; and complications, including malignant arrhythmia, were common. Failure of complete resection and post-operative ventricular arrhythmia are correlated with post-operative mortality.
An Update on the Diagnosis and Management of Acute Right Heart Failure
Authors: Ahsan Syed Adeel , Laird Rachel , Dooley Caroline , Akbar Sara , Sweeney James , Ohira Suguru , Kai Masashi , Levine Avi , Gass Alan L. , Frishman William H. , Aronow Wilbert S. , Lanier Gregg M.
Published: February 2023

Right ventricular (RV) dysfunction and resultant acute right heart failure (ARHF) is a rapidly growing field of interest, driven by increasing appreciation of its contribution to heart failure morbidity and mortality. Understanding of ARHF pathophysiology has advanced dramatically over recent years and can be broadly described as RV dysfunction related to acute changes in RV afterload, contractility, preload, or left ventricular dysfunction. There are several diagnostic clinical signs and symptoms as well as imaging and hemodynamic assessments that can provide insight into the degree of RV dysfunction. Medical management is tailored to the different causative pathologies, and in cases of severe or end-stage dysfunction, mechanical circulatory support can be utilized. In this review, we describe the pathophysiology of ARHF, how its diagnosis is established by clinical signs and symptoms and imaging findings, and provide an overview of treatment options, both medical and mechanical.
Safety and Efficacy of Extended Postdischarge Venous Thromboembolism Prophylaxis in Microsurgical Breast Reconstruction
Authors: Hansdorfer Marek A. , Sadowsky Rachel L. , Horen Sydney R. , Becerra Adan Z. , Shenaq Deana S. , Kokosis George
Published: February 2023

Background:

Discharging patients on extended postoperative venous thromboembolism (VTE) prophylaxis is trending in microsurgical breast reconstruction (MBR). This study investigated contemporary bleeding and thromboembolic complications after MBR and reported postdischarge enoxaparin outcomes.

Methods:

The PearlDiver database was queried for MBR patients who did not receive postdischarge VTE prophylaxis (cohort 1) and MBR patients discharged with enoxaparin for at least 14 days (cohort 2), then queried for hematoma, deep venous thrombosis (DVT), and/or pulmonary embolism. Concurrently, a systematic review was undertaken to identify studies investigating VTE with postoperative chemoprophylaxis.

Results:

In total, 13,541 patients in cohort 1 and 786 patients in cohort 2 were identified. The incidence of hematoma, DVT, and pulmonary embolism were 3.51%, 1.01%, 0.55% in cohort 1, and 3.31%, 2.93%, and 1.78% in cohort 2, respectively. There was no significant difference in hematoma between these two cohorts (P = 0.767); however, a significantly lower rate of DVT (P < 0.001) and pulmonary embolism (P < 0.001) occurred in cohort 1. Ten studies met systematic review inclusion. Only three studies reported significantly lower VTE rates with postoperative chemoprophylaxis. Seven studies found no difference in bleeding risk.

Conclusions:

This is the first study utilizing a national database and a systematic review to investigate extended postoperative enoxaparin in MBR. Overall, rates of DVT/PE seem to be declining compared with previous literature. The results of this study suggest that there remains a lack of evidence supporting extended postoperative chemoprophylaxis, although the therapy appears safe in that it does not increase bleeding risk.
A Sublatissimus Dorsi Abscess Due to Pasteurella multocida Caused by a Cat Scratch
Authors: Ando Junji , Miyata Riyo , Harada Masayuki , Yurugi Satoshi , Imai Yuichiro , Kasahara Kei , Kuwahara Masamitsu
Published: February 2023

We encountered a 51-year-old male patient who was not immunocompromised. Thirteen days before his admission, his right forearm was scratched by his pet cat. Swelling, redness, and purulent discharge appeared at the site, but he did not seek medical attention. He developed a high fever and was hospitalized with a diagnosis of septic shock, respiratory failure, and cellulitis on plain computed tomography. After admission, the swelling on his forearm was relieved with empirical antibiotics, but the symptoms spread from his right axilla to his waist. We suspected necrotizing soft tissue infection and made a trial incision in the lateral chest up to the latissimus dorsi, but were unable to prove it. However, an abscess was later found under the muscle layer. Second incisions were made to allow the abscess to drain. The abscess was relatively serous, and no tissue necrosis was observed. The patient’s symptoms improved rapidly. In retrospect, the patient probably already had the axillary abscess on admission. It may have been detected at this point if contrast-enhanced computed tomography had been performed, and early axillary drainage may have accelerated the patient’s recovery, which could also have prevented the formation of the latissimus dorsi muscle abscess. In conclusion, the Pasteurella multocida infection on the patient’s forearm induced a very unusual presentation and caused an abscess to form under the muscle, unlike necrotizing soft tissue infections. Early contrast-enhanced computed tomography may aid earlier and more appropriate diagnosis and treatment in such cases.
Resolution of hepatic fibrosis after ZFN-mediated gene editing in the PiZ mouse model of human α1-antitrypsin deficiency
Authors: Li Yanfeng , Guha Chandan , Asp Patrik , Wang Xia , Tchaikovskya Tatyana L. , Kim Kenneth , Mendel Matthew , Cost Gregory J. , Perlmutter David H. , Roy-Chowdhury Namita , Fox Ira J. , Conway Anthony , Roy-Chowdhury Jayanta
Published: February 2023

Background:

α1-antitrypsin deficiency is most commonly caused by a mutation in exon-7 of SERPINA1 (SA1-ATZ), resulting in hepatocellular accumulation of a misfolded variant (ATZ). Human SA1-ATZ-transgenic (PiZ) mice exhibit hepatocellular ATZ accumulation and liver fibrosis. We hypothesized that disrupting the SA1-ATZ transgene in PiZ mice by in vivo genome editing would confer a proliferative advantage to the genome-edited hepatocytes, enabling them to repopulate the liver.

Methods:

To create a targeted DNA break in exon-7 of the SA1-ATZ transgene, we generated 2 recombinant adeno-associated viruses (rAAV) expressing a zinc-finger nuclease pair (rAAV-ZFN), and another rAAV for gene correction by targeted insertion (rAAV-TI). PiZ mice were injected i.v. with rAAV-TI alone or the rAAV-ZFNs at a low (7.5×1010vg/mouse, LD) or a high dose (1.5×1011vg/mouse, HD), with or without rAAV-TI. Two weeks and 6 months after treatment, livers were harvested for molecular, histological, and biochemical analyses.

Results:

Two weeks after treatment, deep sequencing of the hepatic SA1-ATZ transgene pool showed 6%±3% or 15%±4% nonhomologous end joining in mice receiving LD or HD rAAV-ZFN, respectively, which increased to 36%±12% and 36%±12%, respectively, 6 months after treatment. Two weeks postinjection of rAAV-TI with LD or HD of rAAV-ZFN, repair by targeted insertion occurred in 0.10%±0.09% and 0.25%±0.14% of SA1-ATZ transgenes, respectively, which increased to 5.2%±5.0% and 33%±13%, respectively, 6 months after treatment. Six months after rAAV-ZFN administration, there was a marked clearance of ATZ globules from hepatocytes, and resolution of liver fibrosis, along with reduction of hepatic TAZ/WWTR1, hedgehog ligands, Gli2, a TIMP, and collagen content.

Conclusions:

ZFN-mediated SA1-ATZ transgene disruption provides a proliferative advantage to ATZ-depleted hepatocytes, enabling them to repopulate the liver and reverse hepatic fibrosis.
Assessing Primary Care Clinic Operational Strategies via EMR Data Mining
Authors: Tarpey Richard J.
Published: February 2023

Understanding how operational strategies impact critical performance metrics is critical to the clinic's ability to provide a value-based service to patients. This study investigated the utility of electronic medical record (EMR) audit file data in assessing operational strategies. EMR data were used to assess patient appointment lengths and conclude that shorter scheduled patient visit lengths, which resulted from one operational strategy (physician choice of visit lengths), had a negative impact on a second operational strategy (minimizing patient wait times). Patients with 15-minute appointments had a higher total mean wait time and shorter provider care or contact time.
Validation of the PCL-5, PHQ-9, and GAD-7 in a Sample of First Responders
Authors: Ahmadi Aazi , Galusha Jeanine M. , Ponder Warren N. , Carbajal Jose , Schuman Donna L. , Whitworth James , Yockey R. Andrew
Published: February 2023

Objective

First responders (FRs) commonly present for treatment with complex symptom constellations that frequently include posttraumatic stress disorder, depression, and generalized anxiety. To date, no FR study has validated these measures on a treatment-seeking sample.

Methods

Confirmatory factor analysis was utilized to validate measures that assess these constructs (Posttraumatic Stress Disorder Checklist for DSM-5, Patient Health Questionnaire-9, and Generalized Anxiety Disorder-7) on a treatment-seeking sample of FRs (N = 390).

Results

The seven-factor posttraumatic stress disorder hybrid configuration was the best fit. The best fitting factor model of the depression measure was a two-factor structure, cognitive-affective and somatic depression. Lastly, generalized anxiety was a unidimensional construct.

Limitations

Follow-up studies should validate these measures on each FR subtype.

Conclusion

We position these findings within the FR literature, review clinical implications for providers, and offer recommendations for future research.
Trauma After Cochlear Implantation: The Accuracy of Micro–Computed Tomography and Cone-Beam Fusion Computed Tomography Compared With Histology in Human Temporal Bones
Authors: Iso-Mustajärvi Matti , Silvast Tuomo , Heikka Tuomas , Tervaniemi Jyrki , Calixto Roger , Linder Pia H. , Dietz Aarno
Published: February 2023

Hypothesis

Micro-computed tomography (micro-CT) and cone-beam computed tomography (CBCT), in conjunction with the image fusion technique, may provide similar results for trauma assessment after cochlear implantation, with respect to the trauma evaluation in preclinical cochlear implant (CI) studies, as the histology.

Background

Before clinical use, novel cochlear implant (CI) designs are tested in temporal bone (TB) studies for usability and risk evaluation. The criterion standard for evaluating intracochlear insertion trauma and electrode location has historically been with histological samples. Progress of modern imaging technology has created alternatives to classic histology. This study compares the micro-CT and CBCT fusion images between histological samples in a preclinical CI study.

Methods

Fourteen freshly frozen TBs were inserted with a lateral wall research CI electrode. All TBs were scanned with CBCT preoperatively and postoperatively. After insertion, the TBs were prepared for micro-CT and histology. Twelve TBs underwent first a micro-CT and then the histological process. The CBCTs were used for image fusion, and all three different methods were used for intracochlear trauma evaluation. The results were compared between methods.

Results

There were 4 of 14 translocations detected with the fusion image method and 3 of 12 with the micro-CT and histology. When compared, the trauma grades converged and were not statistically significant.

Conclusion

The trauma grading based on micro-CT is comparable to the histology. The image fusion technique based on CBCT is less accurate because it relies on an empirical assumption of the basal membrane localization, but it is clinically applicable.
Techniques in Facial Fat Grafting: Optimal Results Based on the Science of Facial Aging
Authors: Rodriguez-Unda Nelson A. , Novak Matthew D. , Rohrich Rod J.
Published: February 2023

A thorough understanding of the science of facial aging is imperative to the precise and natural restoration of a youthful appearance and a hallmark of the aging process is fat atrophy. For this reason, fat grafting has become a keystone of the modern facelift. As a result, fat grafting techniques have been refined to achieve optimal results. This is done through the differential use of fractionated and unfractionated fat throughout the face. The following article reviews a single surgeon’s technique for achieving optimal results in facial fat grafting.
The Application of Double-Layer-Vacuum-Assisted Closure Therapy With Flap Repair of Soft Tissue Defects Near the Eyes or EarDL-VAC Therapy
Authors: Tao Zihan , Xu Jianguo , Dai Haiying , Wu Minliang , Liu Lei , Sun Jie , Xue Chunyu , Wang Yuchong
Published: February 2023

Objective:

We aimed to introduce and evaluate the safety of double-layer-vacuum-assisted closure (DL-VAC) therapy with flap repair of the wound near the eyes or ears.

Methods:

This study is case reports of 2 patients who underwent DL-VAC therapy for tissue defects near the eyes or ears. The detailed process of the DL-VAC therapy is carefully described in this study. The postoperative wound healing process was closely observed. The biggest concern was the treatment outcome of DL-VAC therapy on the eyes and ears.

Results:

Two patients underwent DL-VAC therapy due to their soft tissue defects close to the eyes or ears. Both patients achieved primary wound healing and the flaps survived during the follow‐up period, which ranged from 1 to 24 months. Patients did not receive any dressing change until the VAC device was removed on the 5th to 7th postoperative day. No severe complications appeared and the patients were satisfied with both appearance and function.

Conclusions:

Double-layer-vacuum-assisted closure therapy is an effective and safe option for the treatment of wounds near the eyes and ears.
Circulating Tumor DNA as a Prognostic Factor in Patients With Resectable Hepatic Metastases of Uveal Melanoma
Authors: Mariani Pascale , Bidard François-Clément , Rampanou Aurore , Houy Alexandre , Servois Vincent , Ramtohul Toulsie , Pierron Gaelle , Chevrier Marion , Renouf Benjamin , Lantz Olivier , Gardrat Sophie , Vincent-Salomon Anne , Roman-Roman Sergio , Rodrigues Manuel , Piperno-Neumann Sophie , Cassoux Nathalie , Stern Marc-Henri , Renault Shufang
Published: February 2023

Objective:

We report here the results of a prospective study of circulating tumor DNA (ctDNA) detection in patients undergoing uveal melanoma (UM) liver metastases resection (NCT02849145).

Background:

In UM patients, the liver is the most common and often only site of metastases. Local treatments of liver metastases, such as surgical resection, have a likely benefit in selected patients.

Methods:

Upon enrollment, metastatic UM patients eligible for curative liver surgery had plasma samples collected before and after surgery. GNAQ/GNA11 mutations were identified in archived tumor tissue and used to quantify ctDNA by droplet digital polymerase chain reaction which was then associated with the patient’s surgical outcomes.

Results:

Forty-seven patients were included. Liver surgery was associated with a major increase of cell-free circulating DNA levels, with a peak 2 days after surgery (∼20-fold). Among 40 evaluable patients, 14 (35%) had detectable ctDNA before surgery, with a median allelic frequency of 1.1%. These patients experienced statistically shorter relapse-free survival (RFS) versus patients with no detectable ctDNA before surgery (median RFS: 5.5 vs 12.2 months; hazard ratio=2.23, 95% CI: 1.06–4.69, P=0.04), and had a numerically shorter overall survival (OS) (median OS: 27.0 vs 42.3 months). ctDNA positivity at postsurgery time points was also associated with RFS and OS.

Conclusions:

This study is the first to report ctDNA detection rate and prognostic impact in UM patients eligible for surgical resection of their liver metastases. If confirmed by further studies in this setting, this noninvasive biomarker could inform treatment decisions in UM patients with liver metastases.
Non-reciprocity induces resonances in a two-field Cahn–Hilliard model
Authors: Frohoff-Hülsmann Tobias , Thiele Uwe , Pismen Len M.
Published: February 2023

We consider a non-reciprocally coupled two-field Cahn–Hilliard system that has been shown to allow for oscillatory behaviour and suppression of coarsening. After introducing the model, we first review the linear stability of steady uniform states and show that all instability thresholds are identical to the ones for a corresponding two-species reaction–diffusion system. Next, we consider a specific interaction of linear modes—a ‘Hopf–Turing’ resonance—and derive the corresponding amplitude equations using a weakly nonlinear approach. We discuss the weakly nonlinear results and finally compare them with fully nonlinear simulations for a specific conserved amended FitzHugh–Nagumo system. We conclude with a discussion of the limitations of the employed weakly nonlinear approach.

This article is part of the theme issue ‘New trends in pattern formation and nonlinear dynamics of extended systems’.
Antimicrobial Resistance Potential of Microbes Isolated from Fish Ponds in Ikorodu, Lagos State, Nigeria.
Authors: Aina Oladunni Rita , Olaleye Oluremi Nurudee
Published: February 2023

ABSTRACT                                                                                                           
Aquacultures are practised in different water confinements which include plastic ponds, concrete and earthen and are known to harbour pathogens. In aquaculture (fish rearing) the use of antibiotics is on the increase where they are used as disease eradicators and as growth promoters. This study sought to investigate the antibiotic resistance potential of bacteria isolated from fish ponds in Ikorodu, Lagos State. A total number of ten water samples were collected from five different sampling points at depth 1.5m within the ponds, close to the outlets and at the outlets from the cat-fish and tilapia-fish ponds. These were serially diluted and inoculated and the pure isolates were subjected to antibiotics sensitivity testing using Kirby- Bauer’s disc diffusion and minimum inhibitory concentration methods. Pure isolates which were found to show multiple resistances to antibiotics were characterized based on their morphology and biochemical characteristics. The isolates were further identified by molecular analysis using 16SrRNA gene detection and sequencing. The Antibiotic susceptibility test showed that the isolates were resistant to ceftazidime, cefuroxime, nitrofurantoin, ampicillin, amoxycillin, clavulanate. gentamicin, ciprofloxacin and all the isolates were susceptible to Ofloxacin. The molecular analysis revealed that the organisms which showed multiple resistances to antibiotics were Azotobacter chroococcum, Escherichia Coli, Proteus mirabilis and Pseudomonas aeruginosa. In conclusion this study has revealed the need for good management of aquaculture facilities in order to avoid zoonotic diseases; also monitoring of antibiotics usage in fish ponds should be given high priority to avoid resistant genes from being transferred to other bacteria of human clinical significance.
Novel “SMARTer” Clinical Trial Design Improves Odds of Approval and Can Reduce Study Size By 80%: Modeling Use of a ctDNA “Optimizing Diagnostic” for Early Therapy Switching in Immuno-Oncology Trials
Authors: Taub Floyd Elliot , Gao Dexiang
Published: February 2023

Novel pivotal trial designs, that more clearly demonstrate increased benefit over Standard of Care (SOC), especially in oncology and immuno-oncology (IO), are presented. The benefit of therapy is maximized and sample size is dramatically reduced. The novel methodology includes the introduction of a biochemical “Optimizing Diagnostic”, for example a cfDNA test that can detect poor response, when performed early after therapy is begun; this is used to change the therapy of the tested person early in the trial (typically to SOC), before clinical progression. Patients remain in “the new drug first” group, which is compared to SOC. An “Optimizing Diagnostic” is analogous to a “Companion Diagnostic”; both potentially allow approval of drugs that would otherwise fail. A companion diagnostic predicts benefit prior to therapy, the optimizing diagnostic (more accurately) predicts likelihood of benefit after initial therapy. Those patients deemed less likely to respond remain in the novel drug first arm, but are switched to SOC. A Sequential Multiple Assignment Randomized Trial” (SMART) design is proposed to evaluate if switching to SOC or SOC plus continuing the novel therapy is most beneficial. These designs will allow approval of therapy paths including novel agents when the novel agent could not be approved without this design. A good optimizing test may reduce the number of patients needed by 80%, dramatically reducing cost and time; more patients benefit and accrual is easier.

Key Points

A new clinical trial design focused on testing a path that begins with a novel regimen (IO is featured) is presented.

The path includes an “optimizing diagnostic” that determines, early during treatment, if a patient should remain on the new regimen.

Companion diagnostics define the path at a pre-treatment stage, optimizing diagnostics define the path early during treatment. Changes in therapy, typically to the SOC, is made based on the post-test probability of success.

The novel path is significantly more likely to lead to approval than the novel regimen alone.

Use of the novel method can reduce the size of a trial by 80%, and allow approval of the path, when approval of the novel regimen, based on a head-to-head trial vs SOC, would not be possible.
Application of comprehensive evaluation framework to Coronavirus Disease 19 studies: A systematic review of translational aspects of artificial intelligence in health care
Authors: Casey Aaron , Ansari Saba , Nakisa Bahareh , Kelly Blair , Brown Pieta , Cooper Paul , Muhammad Imran , Livingstone Steven , Reddy Sandeep , Makinen Ville-Petteri
Published: February 2023

Background

Despite immense progress in artificial intelligence (AI) models, there has been limited deployment in healthcare environments. The gap between potential and actual AI applications is likely due to the lack of translatability between controlled research environments (where these models are developed) and clinical environments for which the AI tools are ultimately intended.

Objective

We have previously developed the Translational Evaluation of Healthcare AI (TEHAI) framework to assess the translational value of AI models and to support successful transition to healthcare environments. In this study, we apply the TEHAI to COVID-19 literature in order to assess how well translational topics are covered.

Methods

A systematic literature search for COVID-AI studies published between December 2019-2020 resulted in 3,830 records. A subset of 102 papers that passed inclusion criteria were sampled for full review. Nine reviewers assessed the papers for translational value and collected descriptive data (each study was assessed by two reviewers). Evaluation scores and extracted data were compared by a third reviewer for resolution of discrepancies. The review process was conducted on the Covidence software platform.

Results

We observed a significant trend for studies to attain high scores for technical capability but low scores for the areas essential for clinical translatability. Specific questions regarding external model validation, safety, non-maleficence and service adoption received failed scores in most studies.

Conclusions

Using TEHAI, we identified notable gaps in how well translational topics of AI models are covered in the COVID-19 clinical sphere. These gaps in areas crucial for clinical translatability could, and should, be considered already at the model development stage to increase translatability into real COVID-19 healthcare environments.
Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients
Authors: Severson Tesa M. , Zhu Yanyun , Prekovic Stefan , Schuurman Karianne , Nguyen Holly M. , Brown Lisha G. , Hakkola Sini , Kim Yongsoo , Kneppers Jeroen , Linder Simon , Stelloo Suzan , Lieftink Cor , van der Heijden Michiel , Nykter Matti , van der Noort Vincent , Sanders Joyce , Morris Ben , Jenster Guido , van Leenders Geert JLH , Pomerantz Mark , Freedman Matthew L. , Beijersbergen Roderick L. , Urbanucci Alfonso , Wessels Lodewyk , Corey Eva , Zwart Wilbert , Bergman Andries M.
Published: February 2023

Androgen Receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase II clinical trial, we epigenetically profiled enhancer/promoter activities with H3K27ac chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identified a distinct subset of H3K27ac-differentially marked regions that associated with treatment responsiveness. These data were successfully validated in mCRPC patient-derived xenograft models (PDX).In silicoanalyses revealed HDAC3 as a critical factor that can drive resistance to hormonal interventions, which we validatedin vitro. Using cell lines and mCRPC PDX tumorsin vitro, we identified drug-drug synergy between enzalutamide and the pan-HDAC inhibitor vorinostat, providing therapeutic proof-of-concept. These findings demonstrate rationale for new therapeutic strategies using a combination of AR and HDAC inhibitors to improve patient outcome in advanced stages of mCRPC.
A luminal intermediate cell state maintains long-term prostate homeostasis and contributes to tumorigenesis
Authors: Luo Fu , Tshering Lara F. , Tutuska Karis , Szenk Mariola , Rubel Diana , Rail James G. , Russ Savanah , Liu Jingxuan , Nemajerova Alice , Balázsi Gábor , Talos Flaminia
Published: February 2023

Cellular heterogeneity poses tremendous challenges for developing cell-targeted therapies and biomarkers of clinically significant prostate cancer. The origins of this heterogeneity within normal adult and aging tissue remain unknown, leaving cellular states and transcriptional programs that allow expansions of malignant clones unidentified. To define cell states that contribute to early cancer development, we performed clonal analyses and single cell transcriptomics of normal prostate from genetically-engineered mouse models. We uncovered a luminal transcriptional state with a unique “basal-like” Wnt/p63 signaling (luminal intermediate, LumI) which contributes to the maintenance of long-term prostate homeostasis. Moreover, LumI cells greatly expand during early stages of tumorigenesis in several mouse models of prostate cancer. Genetic ablation of p63in vivoin luminal cells reduced the formation of aggressive clones in mouse prostate tumor models. Finally, the LumI cells and Wnt signaling appear to significantly increase in human aging prostate and prostate cancer samples, highlighting the importance of this hybrid cell state for human pathologies with potential translational impact.
Mitochondrial Calcium Uptake Declines during Aging and is Directly Activated by Oleuropein to Boost Energy Metabolism and Skeletal Muscle Performance
Authors: Gherardi Gaia , Weiser Anna , Bermont Flavien , Migliavacca Eugenia , Brinon Benjamin , Jacot Guillaume E. , Hermant Aurélie , Sturlese Mattia , Nogara Leonardo , Barron Denis , Moro Stefano , Blaauw Bert , Rizzuto Rosario , Feige Jerome N. , Mammucari Cristina , Marchi Umberto De
Published: February 2023

Mitochondrial calcium (mtCa2+) uptake via the Mitochondrial Calcium Uniporter (MCU) couples the regulation of calcium homeostasis to energy production. mtCa2+uptake is rate-limiting for mitochondrial activation during muscle contraction, but how MCU is affected during physiopathology and whether it can be stimulated therapeutically remains largely uncharacterized. By profiling human and preclinical aging of skeletal muscle, we discovered a conserved down-regulation of MCUR1 during aging that decreases mtCa2+uptake and drives sarcopenia. Through a screen of 5000 bioactive nutrients, we identify the natural polyphenol Oleuropein as a specific MCU activator that stimulates mitochondrial respiration via binding to MICU1. Oleuropein activates mtCa2+uptake and oxidative energy metabolism to enhance endurance and limit fatigue in vivo both in young and aged. These effects of Oleuropein are mediated by an MCU-dependent mechanism in skeletal muscle as they are lost upon muscle-specific MCU KO. Our work demonstrates that impaired mtCa2+uptake causes mitochondrial dysfunction during aging and establishes Oleuropein as a novel nutrient that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.
Epigenetic modifications mediate cultivar-specific root development and metabolic adaptation to nitrogen availability in wheat
Authors: Zhang Hao , Cui Fa , Zhao Long , Zhang Xiaoyu , Chen Jinchao , Zhang Jing , Li Yongpeng , Niu Yanxiao , Wang Lei , Gao Caixia , Fu Xiangdong , Tong Yiping , Ling Hong-Qing , Li Junming , Xiao Jun
Published: February 2023

The breeding of crops with improved nitrogen use efficiency (NUE) is crucial for sustainable agriculture. However, the role of epigenetic modification in the regulation of cultivar-specific responses to low nitrogen (LN) constraint is not well understood. Here, we analyzed the chromatin landscapes in roots, leaves, and seeds in two wheat cultivars (KN9204 and J411) that differ radically in NUE under normal and nitrogen-limited conditions. Transcriptional regulatory chromatin regions exhibited a clear cultivar-specificity between KN9204 and J411. Cultivar-specific regulation of nitrogen metabolism genes (NMGs) is linked to variation in histone modification levels, rather than differences in DNA sequence. Cultivar-specific histone modification regions were found to contribute to the genetic regulation of NUE-related traits, such as QTL locus of maximum root length of qMRL-7B. Furthermore, LN-induced H3K27ac and H3K27me3 dynamics enhanced root growth more in KN9204, while strengthened the nitrogen uptake system more in J411. Evidence from histone deacetylase inhibitor treatment and transgenic plants with loss-of-function of the H3K27me3 methyltransferase further showed that changes in epigenetic modifications can alter the strategy for root development and nitrogen uptake in response to LN constraint. Taken together, the results of our study highlight the importance of epigenetic regulation in mediating cultivar-specific root development and metabolic adaptation to LN in wheat.
Auto-STEED: A data mining tool for automated extraction of experimental parameters and risk of bias items fromin vivopublications
Authors: Zurrer Wolfgang Emanuel , Cannon Amelia Elaine , Ewing Ewoud , Rosso Marianna , Reich Daniel S. , Ineichen Benjamin V.
Published: February 2023

Background

Systematic reviews, i.e., research summaries that address focused questions in a structured and reproducible manner, are a cornerstone of evidence-based medicine and research. However, certain systematic review steps such as data extraction are labour-intensive which hampers their applicability, not least with the rapidly expanding body of biomedical literature.

Objective

To bridge this gap, we aimed at developing a data mining tool in the R programming environment to automate data extraction from neurosciencein vivopublications. The function was trained on a literature corpus (n=45 publications) of animal motor neuron disease studies and tested in two validation corpora (motor neuron diseases, n=31 publications; multiple sclerosis, n=244 publications).

Results

Our data mining tool Auto-STEED (Automated and STructured Extraction of Experimental Data) was able to extract key experimental parameters such as animal models and species as well as risk of bias items such as randomization or blinding fromin vivostudies. Sensitivity and specificity were over 85 and 80%, respectively, for most items in both validation corpora. Accuracy and F-scores were above 90% and 0.9 for most items in the validation corpora. Time savings were above 99%.

Conclusions

Our developed text mining tool Auto-STEED is able to extract key experimental parameters and risk of bias items from the neurosciencein vivoliterature. With this, the tool can be deployed to probe a field in a research improvement context or to replace one human reader during data extraction resulting in substantial time-savings and contribute towards automation of systematic reviews. The function is available on Github.
Activity-dependent induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation
Authors: Sardar Debosmita , Cheng Yi-Ting , Woo Junsung , Choi Dong-Joo , Lee Zhung-Fu , Kwon Wookbong , Chen Hsiao-Chi , Lozzi Brittney , Cervantes Alexis , Rajendran Kavitha , Huang Teng-Wei , Jain Antrix , Arenkiel Benjamin , Maze Ian , Deneen Benjamin
Published: February 2023

Neuronal activity drives global alterations in gene expression within neurons, yet how it directs transcriptional and epigenomic changes in neighboring astrocytes in functioning circuits is unknown. Here we show that neuronal activity induces widespread transcriptional upregulation and downregulation in astrocytes, highlighted by the identification of a neuromodulator transporter Slc22a3 as an activity-inducible astrocyte gene regulating sensory processing in the olfactory bulb. Loss of astrocytic Slc22a3 reduces serotonin levels in astrocytes, leading to alterations in histone serotonylation. Inhibition of histone serotonylation in astrocytes reduces expression of GABA biosynthetic genes and GABA release, culminating in olfactory deficits. Our study reveals that neuronal activity orchestrates transcriptional and epigenomic responses in astrocytes, while illustrating new mechanisms for how astrocytes process neuromodulatory input to gate neurotransmitter release for sensory processing.
Human APOBEC3B promotes tumor heterogeneityin vivoincluding signature mutations and metastases
Authors: Durfee Cameron , Temiz Nuri Alpay , Levin-Klein Rena , Argyris Prokopios P. , Alsøe Lene , Carracedo Sergio , de la Vega Alicia Alonso , Proehl Joshua , Holzhauer Anna M. , Seeman Zachary J. , Lin Yu-Hsiu T. , Vogel Rachel I. , Sotillo Rocio , Nilsen Hilde , Harris Reuben S.
Published: February 2023

The antiviral DNA cytosine deaminase APOBEC3B has been implicated as a source of mutation in many different cancers. Despite over 10 years of work, a causal relationship has yet to be established between APOBEC3B and any stage of carcinogenesis. Here we report a murine model that expresses tumor-like levels of human APOBEC3B after Cre-mediated recombination. Animals appear to develop normally with full-body expression of APOBEC3B. However, adult males manifest infertility and older animals of both sexes show accelerated rates of tumorigenesis (mostly lymphomas or hepatocellular carcinomas). Interestingly, primary tumors also show overt heterogeneity, and a subset spreads to secondary sites. Both primary and metastatic tumors exhibit increased frequencies of C-to-T mutations in TC dinucleotide motifs consistent with the established biochemical activity of APOBEC3B. Elevated levels of structural variation and insertion-deletion mutations also accumulate in these tumors. Together, these studies provide the first cause-and-effect demonstration that human APOBEC3B is an oncoprotein capable of causing a wide range of genetic changes and driving tumor formationin vivo.
Reduced steroid activation of elephant shark GR and MR after inserting four amino acids from the DNA-binding domain of lamprey corticoid receptor-1
Authors: Katsu Yoshinao , Zhang Jiawen , Baker Michael E.
Published: February 2023

Atlantic sea lamprey contains two corticoid receptors (CRs), CR1 and CR2, that have identical amino acid sequences, except for a four amino acid insert (Thr-Arg-Gln-Gly) in the CR1 DNA-binding domain (DBD). Steroids are stronger transcriptional activators of CR2 than of CR1 suggesting that the insert reduces the transcriptional response of lamprey CR1 to steroids. The DBD in elephant shark mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), which are descended from a CR, lack these four amino acids, suggesting that a CR2 is their common ancestor. To determine if, similar to lamprey CR1, the presence of this insert in elephant shark MR and GR decreases transcriptional activation by corticosteroids, we inserted these four CR1-specific residues into the DBD of elephant shark MR and GR. Compared to steroid activation of wild-type elephant shark MR and GR, cortisol, corticosterone, aldosterone, 11-deoxycorticosterone and 11-deoxycortisol had lower transcriptional activation of these mutant MR and GR receptors, indicating that the absence of this four-residue segment in the DBD in wild-type elephant shark MR and GR increases transcriptional activation by corticosteroids.
Exploring the phytobeneficial and biocontrol capacities of endophytic bacteria isolated from hybrid vanilla pods
Authors: Lalanne-Tisné Guillaume , Barral Bastien , Taibi Ahmed , Coulibaly Zana Kpatolo , Burguet Pierre , Rasoarahona Felah , Quinton Loic , Meile Jean-Christophe , Boubakri Hasna , Kodja Hippolyte
Published: February 2023

Few studies have been conducted on endophytic bacteria of vanilla. In this study, 58 bacterial strains were isolated from two hybrid vanilla plants from Madagascar,Manitra ampotonyandTsy taitra. They were genetically characterised and divided into four distinct phylotypes. A selection of twelve strains corresponding to the identified genetic diversity were testedin vitrofor four phytobeneficial capacities: phosphate solubilisation, free nitrogen fixation, phytohormone and siderophore production. They were also evaluatedin vitrofor their ability to biocontrol the growth of the vanilla pathogenic fungi,Fusarium oxysporum f. sp. radicis vanillaeandCholletotrichum orchidophilum. Bacteria belonging to three different phyla were found to be highly competent in each of the phytobeneficial capacities tested. Bacteria belonging to the phylum related toBacillus siamensisshowed the best capacity to inhibit fungal growth making them good candidates for controlling fungal diseases of vanilla. This competence was highlighted with spectral imaging showing the production of lipopeptides by the bacterial strains confronted with the pathogenic fungi of vanilla.