bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biotissue stent for supraciliary outflow in open-angle glaucoma patients: surgical procedure and first clinical results of an aqueous drainage biostent
Authors: Ianchulev Tsontcho , Weinreb Robert N , Kamthan Gautam , Calvo Ernesto , Pamnani Ravinder , Ahmed Iqbal K 
Published: January 2023

Background/aimsTo report a first-in-human trial in open-angle glaucoma (OAG) subjects treated with a new microinterventional biostent-reinforced cyclodialysis technique to enhance supraciliary aqueous drainage.MethodsSubjects (N=10; 74.1±7.9 years old) with OAG and cataracts underwent combined phacoemulsification cataract surgery with implantation of a permanent endoscleral supraciliary biostent to reinforce a controlled cyclodialysis cleft. The biostent comprised decellularised scleral allograft tissue microtrephined into a polymer tubular implant intraoperative/postoperative safety, intraocular pressure (IOP) and glaucoma medications were tracked through 12 months postimplantation.ResultsBaseline medicated IOP averaged 24.2±6.9 mm Hg with subjects using 1.3±0.8 IOP-lowering medications. Successful biostent implantation was achieved in all individuals without significant complications. Immediate IOP lowering was sustained through 1 year. Twelve-month mean IOP was reduced 40% from baseline to 14.6±3.2 mm Hg (p=0.004; paired two-tailed t-test), and 80% of patients achieved >20% IOP reduction. Biostenting reduced glaucoma medication use 62%, from a baseline mean of 1.3 required medications to 0.5 medications (p=0.037) at postoperative 12 months. The biotissue implant was well tolerated and demonstrated good endothelial safety with only 11% endothelial cell loss at 12 months after combined phaco-biostenting surgery, similar to that expected after phacoemulsification alone. Mean BCVA increased from baseline 20/130 Snellen to 20/36 at postoperative 12 months (p=0.001).ConclusionSupraciliary biostenting in OAG patients is well tolerated, has a good safety profile and produces long-term IOP-lowering while reducing glaucoma medication requirements.
Comparative efficacy of exercise therapy and oral non-steroidal anti-inflammatory drugs and paracetamol for knee or hip osteoarthritis: a network meta-analysis of randomised controlled trials
Authors: Weng Qianlin , Goh Siew-Li , Wu Jing , Persson Monica S M , Wei Jie , Sarmanova Aliya , Li Xiaoxiao , Hall Michelle , Doherty Michael , Jiang Ting , Zeng Chao , Lei Guanghua , Zhang Weiya 
Published: January 2023

ObjectiveClinical guidelines recommend exercise as a core treatment for knee or hip osteoarthritis (OA). However, how its analgesic effect compares to analgesics, for example, oral non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol—the most commonly used analgesics for OA, remains unknown.DesignNetwork meta-analysis.Data sourcesPubMed, Embase, Scopus, Cochrane Library and Web of Science from database inception to January 2022.Eligibility criteria for selecting studiesRandomised controlled trials (RCTs) comparing exercise therapy with oral NSAIDs and paracetamol directly or indirectly in knee or hip OA.ResultsA total of n=152 RCTs (17 431 participants) were included. For pain relief, there was no difference between exercise and oral NSAIDs and paracetamol at or nearest to 4 (standardised mean difference (SMD)=−0.12, 95% credibility interval (CrI) −1.74 to 1.50; n=47 RCTs), 8 (SMD=0.22, 95% CrI −0.05 to 0.49; n=2 RCTs) and 24 weeks (SMD=0.17, 95% CrI −0.77 to 1.12; n=9 RCTs). Similarly, there was no difference between exercise and oral NSAIDs and paracetamol in functional improvement at or nearest to 4 (SMD=0.09, 95% CrI −1.69 to 1.85; n=40 RCTs), 8 (SMD=0.06, 95% CrI −0.20 to 0.33; n=2 RCTs) and 24 weeks (SMD=0.05, 95% CrI −1.15 to 1.24; n=9 RCTs).ConclusionsExercise has similar effects on pain and function to that of oral NSAIDs and paracetamol. Given its excellent safety profile, exercise should be given more prominence in clinical care, especially in older people with comorbidity or at higher risk of adverse events related to NSAIDs and paracetamol.CRD42019135166
Modulation of myeloid and T cells in vivo by Bruton’s tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma
Authors: Sinha Meenal , Betts Courtney , Zhang Li , Griffith Madeline J , Solman Isabelle , Chen Brandon , Liu Eric , Tamaki Whitney , Stultz Jacob , Marquez Jaqueline , Sivagnanam Shamilene , Cheung Alexander , Pener Denise , Fahlman Anne , Taber Erin , Lerner Kimberly , Crocker Matthew , Todd Kendra , Rajagopalan Brindha , Ware Clarisha , Bridge Mark , Vo Johnson , Dragomanovich Hannah , Sudduth-Klinger Julie , Vaccaro Gina , Lopez Charles D , Tempero Margaret , Coussens Lisa M , Fong Lawrence 
Published: January 2023

BackgroundIn preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC.MethodsPreviously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality.ResultsIn the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator+(ICOS+) CD4+T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10+B-cell frequency. Monotherapy also led to a trend in increased mature CD208+dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1–) eomesodermin (EOMES+)) CD8+T-cell frequency, with a concomitantly decreased dysfunctional (PD-1+EOMES+) CD8+T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation.ConclusionIbrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors.Trial registration numberNCT02562898.
Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer
Authors: Nasca Vincenzo , Barretta Francesco , Corti Francesca , Lonardi Sara , Niger Monica , Elez Maria Elena , Fakih Marwan , Jayachandran Priya , Shah Aakash Tushar , Salati Massimiliano , Fenocchio Elisabetta , Salvatore Lisa , Cremolini Chiara , Ros Javier , Ambrosini Margherita , Mazzoli Giacomo , Intini Rossana , Overman Michael J , Miceli Rosalba , Pietrantonio Filippo 
Published: January 2023

BackgroundImmune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs.MethodsWe conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a ‘burden score’ constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models.ResultsAmong 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two’s effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, ‘aggregated’ burden scores were developed to distinguish ‘protective’ (endocrine and musculoskeletal) and ‘harmful’ (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS.ConclusionsOur results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response.
Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy
Authors: Dai Jie , Bai Xue , Gao Xuan , Tang Lirui , Chen Yu , Sun Linzi , Wei Xiaoting , Li Caili , Qi Zhonghui , Kong Yan , Cui Chuanliang , Chi Zhihong , Sheng Xinan , Xu Zelong , Lian Bin , Li Siming , Yan Xieqiao , Tang Bixia , Zhou Li , Wang Xuan , Xia Xuefeng , Guo Jun , Mao Lili , Si Lu 
Published: January 2023

BackgroundAccumulating data suggest that mucosal melanoma, well known for its poor response to immune checkpoint blockade (ICB) and abysmal prognosis, is a heterogeneous subtype of melanoma with distinct genomic and clinical characteristics between different anatomic locations of the primary lesions. Primary malignant melanoma of the esophagus (PMME) is a rare, highly aggressive disease with a poorer prognosis compared with that of non-esophageal mucosal melanoma (NEMM). In this study, we retrospectively analyzed the efficacy of anti-programmed death (PD)-1 in patients with PMME and explored its molecular basis.MethodsThe response and survival of patients with PMME and NEMM under anti-PD-1 monotherapy were retrospectively analyzed. To explore the molecular mechanisms of the difference in therapeutic efficacy between PMME and NEMM, we performed genomic analysis, bulk RNA sequencing, and multiplex immunohistochemistry staining.ResultsWe found that PMME (n=28) responded better to anti-PD-1 treatment than NEMM (n=64), with a significantly higher objective response rate (33.3% (95% CI 14.3% to 52.3%) vs 6.6% (95% CI 0.2% to 12.9%)) and disease control rate (74.1% (95% CI 56.4% to 91.7%) vs 37.7% (95% CI 25.2% to 50.2%)). Genomic sequencing analysis revealed that the genomic aberration landscape of PMME predominated in classical cancer driver genes, with approximately half of PMME cases harboring mutations inBRAF,N/KRAS, andNF1. In contrast, most NEMM cases were triple wild-type. Transcriptome analysis revealed that, compared with NEMM, PMME displayed more significant proliferation and inflammatory features with higher expression of genes related to antigen presentation and differentiation, and a less immunosuppressive signature with lower expression of inhibitory immune checkpoints and dedifferentiation-related genes. The multiplex immunohistochemical analysis also demonstrated higher CD8+T-cell infiltration in PMME than in NEMM.ConclusionsPMME is an outlier of mucosal melanoma showing a malicious phenotype but a particularly high response rate to ICB because of its distinct molecular characteristics. Patient stratification based on anatomic origin can facilitate clinical decision-making in patients with mucosal melanoma following the verification of our results in future prospective studies.
Transcript capture and ultradeep long-read RNA sequencing (CAPLRseq) to diagnose HNPCC/Lynch syndrome
Authors: Schwenk Vincent , Leal Silva Rafaela Magalhaes , Scharf Florentine , Knaust Katharina , Wendlandt Martin , Häusser Tanja , Pickl Julia M A , Steinke-Lange Verena , Laner Andreas , Morak Monika , Holinski-Feder Elke , Wolf Dieter A 
Published: January 2023

PurposeWhereas most human genes encode multiple mRNA isoforms with distinct function, clinical workflows for assessing this heterogeneity are not readily available. This is a substantial shortcoming, considering that up to 25% of disease-causing gene variants are suspected of disrupting mRNA splicing or mRNA abundance. Long-read sequencing can readily portray mRNA isoform diversity, but its sensitivity is relatively low due to insufficient transcriptome penetration.MethodsWe developed and applied capture-based target enrichment from patient RNA samples combined with Oxford Nanopore long-read sequencing for the analysis of 123 hereditary cancer transcripts (capture and ultradeep long-read RNA sequencing (CAPLRseq)).ResultsValidating CAPLRseq, we confirmed 17 cases of hereditary non-polyposis colorectal cancer/Lynch syndrome based on the demonstration of splicing defects and loss of allele expression of mismatch repair genesMLH1,PMS2,MSH2andMSH6. Using CAPLRseq, we reclassified two variants of uncertain significance inMSH6andPMS2as either likely pathogenic or benign.ConclusionOur data show that CAPLRseq is an automatable and adaptable workflow for effective transcriptome-based identification of disease variants in a clinical diagnostic setting.
Middle column Stent-screw Assisted Internal Fixation (SAIF): a modified minimally-invasive approach to rescue vertebral middle column re-fractures
Authors: Di Caterino Fortunato , Koetsier Eva , Hirsch Joshua A , Isalberti Maurizio , San Millan Diego , Marchi Francesco , La Barbera Luigi , Pileggi Marco , Cianfoni Alessandro 
Published: January 2023

BackgroundThere is limited literature regarding the re-fracture of a previously augmented vertebral compression fracture (VCF). These re-fractures may present as an asymptomatic remodeling of the vertebral body around the cement cast while in other cases they involve the middle column, at the transition zone between the cement-augmented and non-augmented vertebral body. In the latter, a posterior wall retropulsion is possible and, if left untreated, might progress to vertebral body splitting, central canal stenosis, and kyphotic deformity. There is no consensus regarding the best treatment for these re-fractures. There are cases in which a repeated augmentation relieves the pain, but this is considered an undertreatment in cases with middle column involvement, posterior wall retropulsion, and kyphosis.MethodsWe report four cases of re-fracture with middle column collapse of a previously augmented VCF, treated with the stent-screw assisted internal fixation (SAIF) technique. A modified more postero-medial deployment of the anterior metallic implants was applied, to target the middle column fracture. This modified SAIF allowed the reduction and stabilization of the middle column collapse as well as the partial correction of the posterior wall retropulsion and kyphosis.ResultsComplete relief of back pain with stable clinical and radiographic findings at follow-up was obtained in all cases.ConclusionsIn selected cases, the middle column SAIF technique is safe and effective for the treatment of the re-fracture with middle column collapse of a previously cement-augmented VCF. This technique requires precision in trocar placement and could represent a useful addition to the technical armamentarium for VCF treatment.
Dose–response effects of two nicotine salt formulations on electronic cigarette appeal and sensory attributes
Authors: Han Dae-Hee , Wong Melissa , Peraza Natalia , Vogel Erin A , Cahn Rael , Mason Tyler B , Kirkpatrick Matthew , Tackett Alayna P , Leventhal Adam M 
Published: January 2023

Objectives
Various organic acids are used to create nicotine salt formulations, which may improve the appeal and sensory experience of vaping electronic cigarettes (e-cigarettes). This clinical experiment examined the effects of partially and highly protonated forms of two nicotine salt formulations (nicotine lactate and benzoate) versus free-base (no acid additive) on the appeal and sensory attributes of e-cigarettes.

Methods
Current adult tobacco product users (n=116) participated in an online remote double-blind within-subject randomised experiment involving standardised self-administration of e-cigarette solutions varying in nicotine formulation (free-base, 50% nicotine lactate –1:2 lactic acid to nicotine molar ratio, 100% nicotine lactate – 1:1 ratio, 50% nicotine benzoate and 100% nicotine benzoate). Each formulation had equivalent nicotine concentrations (27.0–33.0 mg/mL) and was administered in four flavours in a pod-style device. After each administration, participants rated appeal (liking, disliking and willingness to use again) and sensory attributes (0–100 scale).

Results
Compared with free-base nicotine, 50% and 100% nicotine lactate and benzoate yielded higher appeal, smoothness and sweetness and lower harshness and bitterness. Dose–response analyses found 100% vs 50% nicotine salt improved appeal, smoothness, bitterness and harshness for nicotine lactate and sweetness, smoothness and harshness for nicotine benzoate. Solutions with higher pH were associated with worse appeal and sensory attributes across nicotine formulations. Nicotine formulation effects did not differ by tobacco use status and flavours.

Conclusion
Restricting benzoic acid or lactic acid additives or setting minimal pHs in e-cigarettes merits consideration in regulations designed to reduce vaping among populations deterred from using e-cigarettes with aversive sensory properties.

Trial registration number

This study was registered under ClinicalTrials.gov Identifier:
NCT03742817
under the title ‘Effects of e-Cigarettes on Perceptions and Behavior’.
ІСТОРИЧНИЙ АНАЛІЗ РОЗВИТКУ ТА СТАНОВЛЕННЯ НАЛЕЖНОЇ КЛІНІЧНОЇ ПРАКТИКИ
Authors: Hala L. O. 
Published: January 2023

Мета роботи. Визначити ключові етапи розвитку й становлення сучасної концепції Належної клінічної практики (Good Clinical Practice – GCP) в історичному аспекті.
Матеріали і методи. У дослідженні було використано результати аналізу наукової та спеціальної літератури з питань історичного розвитку й посилення вимог до проведення клінічних випробувань, а також такі методи дослідження як історичний, системний, аналітико-порівняльний, логічний аналіз та узагальнення.
Результати й обговорення. На підставі вивчення історичної хронології розвитку GCP визначено п’ять етапів цього процесу:
І. VI ст. до н. е. – ХІ ст. – приділення уваги підтримці етичних принципів у відношенні лікаря до пацієнта, використання контрольної групи в харчовому експерименті та поява перших правил проведення випробування ліків;
ІІ. ХVI ст. – ХІХ ст. – проведення перших експериментів за участі людей, які є підґрунтям формування сучасних підходів до проведення клінічних досліджень;
ІІІ. початок ХХ ст. – 40-ві рр. ХХ ст. – поступове формування та посилення вимог до ЛЗ, продуктів харчування та косметики стосовно маркування, складу, безпечності для використання та інформаційного супроводу;

IV. 40-ві рр. ХХ ст. – 80-ті рр. ХХ ст. – численні спроби нормативного врегулювання вимог до проведення клінічних випробувань (Нюрнберзький кодекс, Загальна декларація прав людини, Міжнародний пакт про громадянські та політичні права, Міжнародний пакт про економічні, соціальні та культурні права, Гельсінкська декларація та інші);
V. 80-ті рр. ХХ ст. – до нашого часу – прийняття ВООЗ і Радою міжнародних організацій медичних наук єдиного міжнародного документу щодо проведення біомедичних досліджень із залученням людей. Уведення в дію у 1997 році Керівництва з GCP та подальше внесення змін і доповнень.

Висновки. Аналіз становлення вимог GCP свідчить, що відповідні історичні події та їхні наслідки призвели до розуміння необхідності контролю та регулювання процесу проведення клінічних досліджень. В основу керівних принципів GCP покладено ключові положення Гельсінської декларації та Нюрнберзького кодексу, тому вимоги GCP повною мірою стоять на захисті здоров’я та безпеки суб’єктів дослідження.
СИМУЛЯЦІЙНЕ НАВЧАННЯ ЯК ЗАСІБ ОВОЛОДІННЯ ФАХОВИМИ КОМПЕТЕНТНОСТЯМИ З ЦИКЛУ «ТОРАКАЛЬНА ХІРУРГІЯ» СТУДЕНТАМИ 5 КУРСУ
Authors: Війтович Л. Є. 
Published: January 2023

Основна мета підготовки студентів-медиків – це вдосконалення практичних умінь, необхідних для роботи лікаря. В сучасних умовах активно розвивається симуляційне навчання як один із шляхів набуття необхідних фахових компетентностей, покращення результатів навчання та підготовки конкурентоспроможних фахівців інноваційного типу.
Метою статті було ознайомлення з методикою проведення заняття з циклу «Торакальна хірургія» на п’ятому курсі на тему «Хірургічна патологія дихальної системи. Робота в симуляційному центрі. Пункція плевральної порожнини. Дренування плевральної порожнини» з використанням принципів симуляційної освіти як засобу оволодіння фаховими компетентностями.
Використання методики симуляційного навчання при підготовці студентів-медиків забезпечує краще засвоєння навичок комунікації, складних практичних та когнітивних навичок, покращує формування компетентностей, та програмних результатів навчання, передбачених освітньо-професійною програмою.