A potential role for RNA aminoacylation prior to its role in peptide synthesis.

Coded ribosomal peptide synthesis could not have evolved unless its sequence and amino acid-specific aminoacylated tRNA substrates already existed. We therefore wondered whether aminoacylated RNAs might have served some primordial function prior to their role in protein synthesis. Here, we show that specific RNA sequences can be nonenzymatically aminoacylated and ligated to produce amino acid-bridged stem-loop RNAs. We used deep sequencing to identify RNAs that undergo highly efficient glycine aminoacylation followed by loop-closing ligation. The crystal structure of one such glycine-bridged RNA hairpin reveals a compact internally stabilized structure with the same eponymous T-loop architecture that is found in many noncoding RNAs, including the modern tRNA. We demonstrate that the T-loop-assisted amino acid bridging of RNA oligonucleotides enables the rapid template-free assembly of a chimeric version of an aminoacyl-RNA synthetase ribozyme. We suggest that the primordial assembly of amino acid-bridged chimeric ribozymes provides a direct and facile route for the covalent incorporation of amino acids into RNA. A greater functionality of covalently incorporated amino acids could contribute to enhanced ribozyme catalysis, providing a driving force for the evolution of sequence and amino acid-specific aminoacyl-RNA synthetase ribozymes in the RNA World. The synthesis of specifically aminoacylated RNAs, an unlikely prospect for nonenzymatic reactions but a likely one for ribozymes, could have set the stage for the subsequent evolution of coded protein synthesis.

Evaluation of an artificial intelligence-facilitated sperm detection tool in azoospermic samples for use in ICSI.

RESEARCH QUESTION: Can artificial intelligence (AI) improve the efficiency and efficacy of sperm searches in azoospermic samples? DESIGN: This two-phase proof-of-concept study began with a training phase using eight azoospermic patients (>10,000 sperm images) to provide a variety of surgically collected samples for sperm morphology and debris variation to train a convolutional neural network to identify spermatozoa. Second, side-by-side testing was undertaken on two cohorts of non-obstructive azoospermia patient samples: an embryologist versus the AI identifying all the spermatozoa in the still images (cohort 1, n = 4), and a side-by-side test with a simulated clinical deployment of the AI model with an intracytoplasmic sperm injection microscope and the embryologist performing a search with and without the aid of the AI (cohort 2, n = 4). RESULTS: In cohort 1, the AI model showed an improvement in the time taken to identify all the spermatozoa per field of view (0.02 ± 0.30  ×  10-5s versus 36.10 ± 1.18s, P < 0.0001) and improved recall (91.95 ± 0.81% versus 86.52 ± 1.34%, P < 0.001) compared with an embryologist. From a total of 2660 spermatozoa to find in all the samples combined, 1937 were found by an embryologist and 1997 were found by the AI in less than 1000th of the time. In cohort 2, the AI-aided embryologist took significantly less time per droplet (98.90 ± 3.19 s versus 168.7 ± 7.84 s, P < 0.0001) and found 1396 spermatozoa, while 1274 were found without AI, although no significant difference was observed. CONCLUSIONS: AI-powered image analysis has the potential for seamless integration into laboratory workflows, to reduce the time to identify and isolate spermatozoa from surgical sperm samples from hours to minutes, thus increasing success rates from these treatments.

The Influence of Kynurenine Metabolites on Neurodegenerative Pathologies.

As the kynurenine pathway's links to inflammation, the immune system, and neurological disorders became more apparent, it attracted more and more attention. It is the main pathway through which the liver breaks down Tryptophan and the initial step in the creation of nicotinamide adenine dinucleotide (NAD+) in mammals. Immune system activation and the buildup of potentially neurotoxic substances can result from the dysregulation or overactivation of this pathway. Therefore, it is not shocking that kynurenines have been linked to neurological conditions (Depression, Parkinson's, Alzheimer's, Huntington's Disease, Schizophrenia, and cognitive deficits) in relation to inflammation. Nevertheless, preclinical research has demonstrated that kynurenines are essential components of the behavioral analogs of depression and schizophrenia-like cognitive deficits in addition to mediators associated with neurological pathologies due to their neuromodulatory qualities. Neurodegenerative diseases have been extensively associated with neuroactive metabolites of the kynurenine pathway (KP) of tryptophan breakdown. In addition to being a necessary amino acid for protein synthesis, Tryptophan is also transformed into the important neurotransmitters tryptamine and serotonin in higher eukaryotes. In this article, a summary of the KP, its function in neurodegeneration, and the approaches being used currently to target the route therapeutically are discussed.

Breast-Specific Gamma Imaging Versus MRI: Comparing the Diagnostic Performance in Assessing Treatment Response After Neoadjuvant Chemotherapy in Patients With Breast Cancer.

OBJECTIVE: The purpose of this retrospective study was to evaluate the diagnostic performance of breast-specific gamma imaging (BSGI) and breast MRI in assessing for residual tumor after neoadjuvant chemotherapy (NAC) in patients with breast cancer. MATERIALS AND METHODS: A total of 114 patients underwent BSGI and MRI for initial staging as well as after undergoing NAC. Of those, 112 underwent subsequent definitive breast surgery. Thirty of the 114 patients had a complete pathologic response to NAC. RESULTS: BSGI and MRI had comparable sensitivities in detecting residual tumor after NAC (70% vs 83%). BSGI had a higher specificity than MRI in accurately determining complete response after NAC (90% vs 60%). CONCLUSION: BSGI may be a useful adjunctive tool for predicting a complete pathologic response to NAC.

Structure-guided aminoacylation and assembly of chimeric RNAs.

Coded ribosomal peptide synthesis could not have evolved unless its sequence and amino acid specific aminoacylated tRNA substrates already existed. We therefore wondered whether aminoacylated RNAs might have served some primordial function prior to their role in protein synthesis. Here we show that specific RNA sequences can be nonenzymatically aminoacylated and ligated to produce amino acid-bridged stem-loop RNAs. We used deep sequencing to identify RNAs that undergo highly efficient glycine aminoacylation followed by loop-closing ligation. The crystal structure of one such glycine-bridged RNA hairpin reveals a compact internally stabilized structure with the same eponymous T-loop architecture found in modern tRNA. We demonstrate that the T-loop assisted amino acid bridging of RNA oligonucleotides enables the rapid template-free assembly of a chimeric version of an aminoacyl-RNA synthetase ribozyme. We suggest that the primordial assembly of such chimeric ribozymes would have allowed the greater functionality of amino acids to contribute to enhanced ribozyme catalysis, providing a driving force for the evolution of sequence and amino acid specific aminoacyl-RNA synthetase enzymes prior to their role in protein synthesis.

Assessing effects of Cannabis on various neuropathologies: A systematic review.

Natural bioactives possess a wide range of chemical structures that can exert a plethora of pharmacological and toxicological actions, resulting in neuroprotection or neurotoxicity. These pharmacodynamic properties can positively or negatively impact human and animal global healthcare. Remarkably, Ayurvedic botanical Cannabis has been used worldwide by different ethnicities and religions for spiritual, commercial, recreational, nutraceutical, cosmeceutical, and medicinal purposes for centuries. Cannabis-based congeners have been approved by the United States of America's (USA) Food & Drug Administration (FDA) and other global law agencies for various therapeutic purposes. Surprisingly, the strict laws associated with possessing cannabis products have been mitigated in multiple states in the USA and across the globe for recreational use. This has consequently led to a radical escalation of exposure to cannabis-related substances of abuse. However, there is a lacuna in the literature on the acute and chronic effects of Cannabis and its congeners on various neuropathologies. Moreover, in the post-COVID era, there has been a drastic increase in the incidence and prevalence of numerous neuropathologies, leading to increased morbidity and mortality. There is an impending necessity for a safe, economically viable, multipotent, natural bioactive to prevent and treat various neuropathologies. The ayurvedic herb, Cannabis is one of the oldest botanicals known to humans and has been widely used. However, the comprehensive effect of Cannabis on various neuropathologies is not well established. Hence, this review presents effects of Cannabis on various neuropathologies.

Piloting a Transition of Care Curriculum at Two Bi-coastal Medicine-Pediatrics Residency Programs.

BACKGROUND: Lack of consistency in primary care residency training exists in transitions of care (TOC) of adolescents from pediatric to adult medicine, which can lead to conflicting or incomplete training. To fill this gap, we developed a curriculum based on the Got Transition Six Core Elements and piloted it at two bicoastal, academic Medicine-Pediatrics (Med-Peds) residency programs. OBJECTIVES: The goals of this project are to increase resident TOC knowledge, increase transition discussion comfort and skills, and obtain feedback for curriculum improvement. METHODS: Two educational sessions were held at both institutions between 2020-2021. Of 32 potential resident participants, 26 participated in session one and 22 participated in session two. Sessions included a didactic presentation, small group activities, and a guest speaker discussing transitional experience. Electronic pre-session, post-session, and retention surveys evaluated resident knowledge, comfort, and self-reported skills of TOC. A Hybrid Type II design was used with mixed methods to evaluate curriculum effectiveness and implementation. RESULTS: The first and second sessions had 81% and 68% attendance, respectively. Eighty-four percent completed the pre-session survey, 65% completed the post-session survey, and 68% completed the retention survey. TOC knowledge increased by 19% overall (p<0.001). First-year residents gained the most knowledge and implementation skills. Residents participating in alternating medicine and pediatric clinics gained more knowledge than those in a combined Med-Peds clinic (p=0.001). Comfort increased for both initiating and continuing TOC discussions after the first session. Knowledge retention was not statistically significant. CONCLUSION: A standardized TOC curriculum can improve resident knowledge and is easily implemented at multiple institutions. Early-in-training residents and those in alternating medicine and pediatric clinics particularly benefit.

Onco-Testicular Sperm Extraction (oncoTESE): A Contemporary Concept Review and Report of Australian Sperm Retrieval Rates and Fertility Outcomes.

OBJECTIVE: To assess sperm retrieval rates of Onco-Testicular Sperm Extraction (oncoTESE) in men with testicular tumors and coexisting severe spermatogenic impairment. METHODS: Multi-centre Australian wide retrospective review of oncoTESE procedures performed within the last 10 years. Patients were postpubertal adults having a testicular tumor requiring orchidectomy, with severe oligozoospermia or nonobstructive azoospermia. Ipsilateral testicular sperm extraction was performed following radical inguinal orchidectomy. A contralateral micro-testicular sperm extraction was performed if no sperm or insufficient amounts were initially achieved. Surgical sperm retrieval rates, live birth rates and post operative serum testosterone were recorded. RESULTS: Four surgeons compiled a total 13 patients. The mean age was 34.9 years. Seven of 13 were germ cell tumor (GCT), 4 of 13 had non-GCT and 2 of 13 contained benign lesions. Twelve of 13 patients were azoospermic and 1 was severely oligozoospermic. Sperm was found in 6 of 7 GCT patients; 3 of 7 were found in the ipsilateral testis whilst the remaining 4 underwent contralateral micro-testicular sperm extraction; sperm was retrieved in 3 of 4. The respective mean pre and post orchidectomy testosterone was 12.0 vs 14.1nmol/L (GCT cohort). Cryopreserved sperm has been used in assisted reproduction in 2 of 13 patients, with median follow up of 38.7 months. Including use of both cryopreserved and fresh sperm, 6 pregnancies were achieved, including 5 healthy live births and 1 miscarriage. CONCLUSION: OncoTESE appears feasible, with acceptable sperm retrieval and subsequent live birth rates, following assisted reproduction. Despite significant underutilisation in the Australian population, oncoTESE should be considered in the management for TC patients with severe oligozoospermia, or nonobstructive azoospermia.

The Role of Imaging in Health Screening: Screening for Specific Conditions.

There are well-established and emerging screening examinations aimed at identifying malignant and nonmalignant conditions at early, treatable stages. The Radiology Research Alliance's "Role of Imaging in Health Screening" Task Force provides a comprehensive review of specific imaging-based screening examinations. This work reviews and serves as a reference for screening examinations for breast and colon cancer in a healthy population along with screening for lung cancer, hepatocellular carcinoma, and the use of whole body magnetic resonance imaging in at-risk individuals. American College of Radiology scoring systems, along with case-based examples, are included to illustrate the different disease entities. The future of screening is discussed, particularly in the context of artificial intelligence.

The Role of Imaging in Health Screening: Overview, Rationale of Screening, and Screening Economics.

Imaging screening examinations are growing in their indications and volume to identify conditions at an early, treatable stage. The Radiology Research Alliance's 'Role of Imaging in Health Screening' Task Force provides a review of imaging-based screening rationale, economics, and describes established guidelines by various organizations. Various imaging modalities can be employed in screening, and are often chosen based on the specific pathology and patient characteristics. Prevalent disease processes with identifiable progression patterns that benefit from early potentially curative interventions are ideal for screening. Two such examples include colonic precancerous polyp progression to adenocarcinoma in colon cancer formation and atypical ductal hyperplasia progression to ductal carcinoma in situ and invasive ductal carcinoma in breast cancer. Economic factors in imaging-based screening are reviewed, including in the context of value-based reimbursements. Global differences in screening are outlined, along with the role of various organizational guidelines, including the American Cancer Society, the US Preventive Services Task Force, and the American College of Radiology.

Addressing Burnout in Radiologists.

Burnout is a global health problem affecting physicians across all medical specialties. Radiologists, in particular, experience high rates of burn out, and this trend has only continued to worsen. The "Promoting Health and Wellness for Radiologists Task Force of the Association of University Radiologists-Radiology Research Alliance" presents a review of the prevalence, causes, and impact of burnout among radiology faculty and trainees, and a discussion on strategies for overcoming burnout and promoting overall health and well-being among radiologists.

Eight-Year Experience With Botulinum Toxin Type-A Injections for the Treatment of Nonneurogenic Overactive Bladder: Are Repeated Injections Worthwhile?

PURPOSE: To investigate the efficacy and safety of repeated botulinum toxin type-A (BTX-A) injections for patients with drug-refractory nonneurogenic overactive bladder (NNOAB) and explore factors predictive of outcome. METHODS: Data were collected from all patients receiving repeated BTX-A injections for drug-refractory NNOAB between 2004 and 2012. Trigone-sparing injections were administered under sedation with antibiotic prophylaxis. Patient characteristics including age, sex, preoperative urodynamics, injection number, BTX-A dose, complications, and patient global impression of improvement (PGI-I) scores were collected. Correlations between patient factors and outcomes were assessed by using Pearson's chi-square tests. RESULTS: Fifty-two patients with a mean age of 67.4 years (range, 26-93 years) received 140 BTX-A injections in total; 33 (64%), 15 (29%), and 4 patients (7%) received 2, 3 to 4, and 5 to 8 injections, respectively. Mean follow-up time was 49 months (range, 9-101 months). Nine patients developed urinary tract infection; additionally, 3 patients experienced transient urinary retention. Median PGI-I score was 2 out of 7 (interquartile range [IQR], 2). For 46 patients, the PGI-I score remained stable with the administration of each injection. Pearson chi-square tests revealed that male patients or reduced bladder compliance was associated with a higher (worse) PGI-I score. Median PGI-I scores for men and women were 3 (IQR, 1) and 2 (IQR, 1), respectively; additionally, median PGI-I scores for those with normal bladder compliance and those with reduced bladder compliance were 2 (IQR, 2) and 4.5 (IQR, 1), respectively. Median PGI-I scores and complication rates were the same in the older patient (≥70 years) and younger (<70 years) patient cohorts. CONCLUSIONS: Efficacy is maintained with repeated BTX-A injections. Patients including the elderly show a good degree of tolerability with a low complication rate. Male patients or reduced bladder compliance is associated with poorer outcomes.

Damaged right internal jugular venous catheter status after Cox Maze IV procedure.

The Cox-Maze IV (CM-IV) procedure was introduced as a modification of the Cox-Maze III by using a bipolar radiofrequency clamp to replicate the majority of the long linear cut and sew lesions. The CM-IV maintained excellent success rates with low complication, and there are no reports of device-related complication in the literature. In this article, we present a patient who underwent aortic valve replacement with a concomitant CM-IV procedure. There was difficulty removing the right internal jugular catheter during the postoperative course, with evidence of catheter fracture on chest radiograph. Upon catheter removal by Interventional Radiology, the distal segment had sustained a radiofrequency burn strike that had melted the involved segment with significant loss of catheter integrity. Of the several events that have occurred in our high volume Maze program, this resulted in changing the anesthesia protocol by using shorter catheters that will be less likely to become caught in the jaws of the bipolar clamp during the performance of the intercaval line of the CM-IV.

Inhibition of tubulin polymerization by hypochlorous acid and chloramines.

Protein thiol oxidation and modification by nitric oxide and glutathione are emerging as common mechanisms to regulate protein function and to modify protein structure. Also, thiol oxidation is a probable outcome of cellular oxidative stress and is linked to degenerative disease progression. We assessed the effect of the oxidants hypochlorous acid and chloramines on the cytoskeletal protein tubulin. Total cysteine oxidation by the oxidants was monitored by labeling tubulin with the thiol-selective reagent 5-iodoacetamidofluorescein; by reaction with Ellman's reagent, 5,5'-dithiobis(2-nitrobenzoic acid); and by detecting interchain tubulin disulfides by Western blot under nonreducing conditions. Whereas HOCl induced both cysteine and methionine oxidation of tubulin, chloramines were predominantly cysteine oxidants. Cysteine oxidation of tubulin, rather than methionine oxidation, was associated with loss of microtubule polymerization activity, and treatment of oxidized tubulin with disulfide reducing agents restored a considerable portion of the polymerization activity that was lost after oxidation. By comparing the reactivity of hypochlorous acid and chloramines with the previously characterized oxidants, peroxynitrite and the nitroxyl donor Angeli's salt, we have identified tubulin thiol oxidation, not methionine oxidation or tyrosine nitration, as a common outcome responsible for decreased polymerization activity.

Health status, utilization patterns, and outcomes of persons with intellectual disabilities: review of the literature.

A literature review was conducted to analyze existing data on health status, health care utilization, and medical outcomes of persons with intellectual disabilities. We found that barriers exist, but evidence indicates that (a) individuals with intellectual disability and medical needs are living in the community, (b) people with significant medical conditions can be maintained in community settings, and (c) medical supports can and are provided to people with intellectual disabilities and allied medical conditions to enable community living. However, some people had unmet medical needs, and the availability of and access to community-based services were problematic for others. These contradictory findings indicate that it is possible to provide services in the community, but the service delivery system needs improvement.