2-Azabicyclo[3.2.1]octane scaffold: synthesis and applications.

2-Azabicyclo[3.2.1]octanes are nitrogen containing heterocycles with significant potential in the field of drug discovery. This core has been applied as key synthetic intermediate in several total synthesis, while their unique structure can make them a challenging scaffold to acquire. This Minireview summarizes the synthetic approaches to access this bicyclic architecture and highlights its presence in the total synthesis of several target molecules.

One nodule-one punction-one slide: Optimizing thyroid fine-needle aspiration for a digital workflow.

OBJECTIVE: Interventional pathologists have expanded their expertise by acquiring proficiency in ultrasound-guided thyroid fine-needle aspiration biopsy (FNAB) and are now required to optimize punction procedures due to low resources and digital workflows. The aim of this study is to compare FNAB sample adequacy in two series with one versus two slides available for cytopathological analysis and its influence on diagnosis categorization, time taken to reach a final diagnosis, scanning time and size of the digital files produced. METHODS: Patients were retrospectively selected based on the sampling of thyroid nodules using either two glass slides (two-slide group) or one slide only (one-slide group) and cytological diagnosis was performed using the second edition of the Bethesda system. For each group, the initial 15 cases were sorted to be scanned. RESULTS: From a total of 713 procedures, 328 were sampled into two slides and 385 on one slide only. No significant differences were found regarding nodule size, location or EU-TIRADS classification between the two groups. The one-slide group did not exhibit a higher prevalence of non-diagnostic or atypia of undetermined significance (AUS) categories. As expected, the mean time taken to finalize diagnoses in cases where only one slide was prepared was 1.2 days faster. Scanning time and total file size were also significantly smaller in the one-slide group. CONCLUSIONS: Adopting the 'one nodule-one puncture-one slide' strategy for thyroid FNAB optimization enhances procedural efficiency in digital workflows, leading to cost savings without compromising diagnostic accuracy.

ClotCatcher: a novel natural language model to accurately adjudicate venous thromboembolism from radiology reports.

INTRODUCTION: Accurate identification of venous thromboembolism (VTE) is critical to develop replicable epidemiological studies and rigorous predictions models. Traditionally, VTE studies have relied on international classification of diseases (ICD) codes which are inaccurate - leading to misclassification bias. Here, we developed ClotCatcher, a novel deep learning model that uses natural language processing to detect VTE from radiology reports. METHODS: Radiology reports to detect VTE were obtained from patients admitted to Emory University Hospital (EUH) and Grady Memorial Hospital (GMH). Data augmentation was performed using the Google PEGASUS paraphraser. This data was then used to fine-tune ClotCatcher, a novel deep learning model. ClotCatcher was validated on both the EUH dataset alone and GMH dataset alone. RESULTS: The dataset contained 1358 studies from EUH and 915 studies from GMH (n = 2273). The dataset contained 1506 ultrasound studies with 528 (35.1%) studies positive for VTE, and 767 CT studies with 91 (11.9%) positive for VTE. When validated on the EUH dataset, ClotCatcher performed best (AUC = 0.980) when trained on both EUH and GMH dataset without paraphrasing. When validated on the GMH dataset, ClotCatcher performed best (AUC = 0.995) when trained on both EUH and GMH dataset with paraphrasing. CONCLUSION: ClotCatcher, a novel deep learning model with data augmentation rapidly and accurately adjudicated the presence of VTE from radiology reports. Applying ClotCatcher to large databases would allow for rapid and accurate adjudication of incident VTE. This would reduce misclassification bias and form the foundation for future studies to estimate individual risk for patient to develop incident VTE.

Synovial Fluid Biomarkers for the Diagnosis of Periprosthetic Joint Infection-A Systematic Review and Meta-Analysis of Their Diagnostic Accuracy According to Different Definitions.

BACKGROUND: Different synovial fluid biomarkers have emerged to improve periprosthetic joint infection (PJI) diagnosis. The goals of this paper were (i) to assess their diagnostic accuracy and (ii) to evaluate their performance according to different PJI definitions. METHODS: A systematic review and meta-analysis was performed using studies that reported diagnostic accuracy of synovial fluid biomarkers using validated PJI definitions published from 2010 to March 2022. A database search was performed through PubMed, Ovid MEDLINE, Central, and Embase. The search identified 43 different biomarkers with four being the more commonly studied, with 75 papers overall: alpha-defensin; leukocyte esterase; synovial fluid C-reactive protein; and calprotectin. RESULTS: Overall accuracy was higher for calprotectin, followed by alpha-defensin, leukocyte esterase, and synovial fluid C-reactive protein with sensitivities of 78 to 92% and specificities of 90 to 95%. Their diagnostic performance was different according to which definition was adopted as the reference. Specificity was consistently high across definitions for all four biomarkers. Sensitivity varied the most with lower values for the more sensitive European Bone and Joint Infection Society or Infectious Diseases Society of America definitions with higher values for the Musculoskeletal Infection Society definition. The International Consensus Meeting 2018 definition showed intermediate values. CONCLUSION: All evaluated biomarkers had good specificity and sensitivity, making their use acceptable in the diagnosis of PJI. Biomarkers perform differently according to the selected PJI definitions.

Functionalized Cyclopentenes via the Formal [4+1] Cycloaddition of Photogenerated Siloxycarbenes from Acyl Silanes.

This work describes the first formal cycloaddition reaction of photogenerated nucleophilic carbenes derived from acylsilanes with electrophilic dienes. The resulting transient donor-acceptor cyclopropane rearranges to its stable and highly functionalized cyclopentene isomer in an unprecedented metal-free process. The cyclopropanation-vinyl cyclopropane rearrangement sequence was corroborated by computational calculations. The cyclopropane formation corresponds to a higher energetic barrier, and the vinylcyclopropane-cyclopentene rearrangement proceeds through different mechanisms, although of comparable energies, depending on the stereochemistry of the cyclopropane.

Comparison of short-stem versus conventional stem for hip arthroplasty in patients younger than 60 years: 7-14 years follow-up.

PURPOSE: Short-stem prostheses in hip arthroplasty have emerged as an alternative to conventional stems, especially in younger patients. The purpose of this study was to compare functional and radiological results of a short metaphyseal fitting cementless stem versus a conventional stem implant, in patients younger than 60 years. METHODS: All patients operated from January 2006 to April 2013 were included, obtaining a minimum follow-up of 7 years. Harris Hip Score (HHS) and SF-36 (quality of life) questionnaires were applied and the presence of "thigh pain" was specifically assessed. We also compared complication rate, revision rate and average prosthesis survival. Femoral stress shielding (Gruen scale), stem subsidence, varus-valgus tilt and implant stability (Engh scale) were also compared. RESULTS: A total of 101 short-stem and 74 conventional arthroplasties were included, with an average follow-up of 9.82 (7-14) years. HHS functional score and SF-36 were excellent in both implants and no significant difference between them (p > 0.05) was found. However, "thigh pain" was present in 7 patients with conventional stems and none with short-stems (p < 0.001). The survival rate at 13 years was 99%, for both implants, and no significant differences were found between them (χ2(2) = 0.178; p = 0.673). Conventional stems had stress shielding at the greater trochanter in 72% of the cases and 43% at the calcar, being statistically superior (p < 0.001) to the stress shielding observed in the short stems. CONCLUSION: According to our results, this short-stem seems to allow preservation of bone stock, with decreased stress shielding and also a lower incidence of thigh pain compared to conventional stems. LEVEL OF EVIDENCE: Level III retrospective comparative study.

Nanoaggregate-forming lipid-conjugated AS1411 aptamer as a promising tumor-targeted delivery system of anticancer agents in vitro.

Nanoparticles offer targeted delivery of drugs with minimal toxicity to surrounding healthy tissue and have great potential in the management of human papillomavirus (HPV)-related diseases. We synthesized lipid-modified AS1411 aptamers capable of forming nanoaggregates in solution containing Mg2+. The nanoaggregates presented suitable properties for pharmaceutical applications such as small size (100 nm), negative charge, and drug release. The nanoaggregates were loaded with acridine orange derivative C8 for its specific delivery into cervical cancer cell lines and HPV-positive tissue biopsies. This improved inhibition of HeLa proliferation and cell uptake without significantly affecting healthy cells. Finally, the nanoaggregates were incorporated in a gel formulation with promising tissue retention properties aiming at developing a local delivery strategy of the nanoaggregates in the female genital tract. Collectively, these findings suggest that the nanoformulation protocol has great potential for the delivery of both anticancer and antiviral agents, becoming a novel modality for cervical cancer management.

Synthesis of 6,12-Disubstituted Methanodibenzo[b,f][1,5]dioxocins: Pyrrolidine Catalyzed Self-Condensation of 2'-Hydroxyacetophenones.

The preparation of unprecedented 6,12-disubstituted methanodibenzo[b,f][1,5]dioxocins from pyrrolidine catalyzed self-condensation of 2'-hydroxyacetophenones is herein described. This method provides easy access to this highly bridged complex core, resulting in construction of two C-O and two C-C bonds, a methylene bridge and two quaternary centers in a single step. The intricate methanodibenzo[b,f][1,5]dioxocin compounds were obtained in up to moderate yields after optimization of the reaction conditions concerning solvent, reaction times and the use of additives. Several halide substituted methanodibenzo[b,f][1,5]dioxocins could be prepared from correspondent 2'-hydroxyacetophenones.

Pot-Economy Autooxidative Condensation of 2-Aryl-2-lithio-1,3-dithianes.

The autoxidative condensation of 2-aryl-2-lithio-1,3-dithianes is here reported. Treatment of 2-aryl-1,3-dithianes with n-BuLi in the absence of any electrophile leads to condensation of three molecules of 1,3-dithianes and formation of highly functionalized α-thioether ketones orthothioesters in 51-89% yields upon air exposure. The method was further expanded to benzaldehyde dithioacetals, affording corresponding orthothioesters and α-thioether ketones in 48-97% yields. The experimental results combined with density functional theory studies support a mechanism triggered by the autoxidation of 2-aryl-2-lithio-1,3-dithianes to yield a highly reactive thioester that undergoes condensation with two other molecules of 2-aryl-2-lithio-1,3-dithiane.

Optimizing the management of thyroid specimens to efficiently generate whole slide images for diagnosis.

Transition from optical to digital observation requires an additional procedure in the pathology laboratory, the scanning of glass slides, leading to increased time and digital archive consumption. Thyroid surgical samples often carry the need to collect several tissue fragments that generate many slides to be scanned. This study evaluated the impact of using different inking colours for the surgical margin, section thickness, and glass slide type, in the consumption of time and archive. The series comprehended 40 nodules from 30 patients, including 34 benign nodules in follicular nodular disease, 1 NIFTP, and 5 papillary carcinomas. In 12 nodules, the dominant pattern was microfollicular/solid and in 28 it was macrofollicular. Scanning times/mm2 were longer in red-inked fragments in comparison to green (p = 0.04) and black ones (p = 0.024), and in blue-inked in comparison to green ones (p = 0.043). File sizes/mm2 were larger in red-inked fragments in comparison to green (p = 0.008) and black ones (p = 0.002). The dominant pattern microfollicular/solid was associated with bigger file size/mm2 in comparison with the macrofollicular one (p < 0.001). All scanner outputs increase significantly with the thickness of the section. All scanning outputs increase with the usage of adhesive glass slides in comparison to non-adhesive ones. Small interventions in thyroid sample management that can help optimizing the digital workflow include to prefer black and green inking colours for the surgical margins and 2 µm section in non-adhesive glass slides for increased efficiency.