Family ideals in an era of low fertility.

Taking stock of individuals' perceived family ideals is particularly important in the current moment given unprecedented fertility declines and the diversification of households in advanced industrial societies. Study participants in urban China, Japan, South Korea, Singapore, the United States, Italy, Spain, and Norway were asked to evaluate vignettes describing families whose characteristics vary on ten dimensions. In contrast to previous studies that focused on a single dimension, such as fertility ideals or gender roles, this holistic vignette approach identifies the relative importance of each dimension. Multilevel regression analysis reveals both expected and unexpected findings. Parenthood remains a positive ideal, but the number of children does not matter once other family dimensions are considered, a potentially important finding in light of conventional wisdom regarding the two-children ideal. When evaluating families with at least one child, respondents tend to positively evaluate more traditional arrangements, including valuing marriage relative to cohabitation and, particularly, divorce. Also, in addition to financial resources, good communication between immediate and extended family members, as well as maintaining respect in the larger community, are highly salient attributes of an ideal family. Notwithstanding some important cross-national differences, egalitarian gender roles and avoiding work-family conflict are also valued positively. Overall, even as the study reveals some notable variations between societies, respondents across countries identify similar components of an ideal family.

NCCN Guidelines® Insights: Bladder Cancer, Version 3.2024.

Bladder cancer, the sixth most common cancer in the United States, is most commonly of the urothelial carcinoma histologic subtype. The clinical spectrum of bladder cancer is divided into 3 categories that differ in prognosis, management, and therapeutic aims: (1) non-muscle-invasive bladder cancer (NMIBC); (2) muscle invasive, nonmetastatic disease; and (3) metastatic bladder cancer. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Bladder Cancer, including changes in the fifth edition of the WHO Classification of Tumours: Urinary and Male Genital Tumours and how the NCCN Guidelines aligned with these updates; new and emerging treatment options for bacillus Calmette-Guérin (BCG)-unresponsive NMIBC; and updates to systemic therapy recommendations for advanced or metastatic disease.

Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy.

Mitochondria form a complex, interconnected reticulum that is maintained through coordination among biogenesis, dynamic fission, and fusion and mitophagy, which are initiated in response to various cues to maintain energetic homeostasis. These cellular events, which make up mitochondrial quality control, act with remarkable spatial precision, but what governs such spatial specificity is poorly understood. Herein, we demonstrate that specific isoforms of the cellular bioenergetic sensor, 5' AMP-activated protein kinase (AMPKα1/α2/ß2/γ1), are localized on the outer mitochondrial membrane, referred to as mitoAMPK, in various tissues in mice and humans. Activation of mitoAMPK varies across the reticulum in response to energetic stress, and inhibition of mitoAMPK activity attenuates exercise-induced mitophagy in skeletal muscle in vivo. Discovery of a mitochondrial pool of AMPK and its local importance for mitochondrial quality control underscores the complexity of sensing cellular energetics in vivo that has implications for targeting mitochondrial energetics for disease treatment.

RNA Regulation by Poly(ADP-Ribose) Polymerases.

Posttranscriptional regulation of RNA facilitates the fine-tuning of gene expression. It occurs through multiple pathways that include the nuclear processing of mRNA and its precursors, mRNA silencing, regulation of mRNA decay, and regulation of translation. Poly(ADP-ribose) polymerases (PARPs), enzymes that modify target proteins with ADP-ribose, play important roles in many of the RNA regulatory pathways through multiple mechanisms. For example, RNA-binding PARPs can target specific transcripts for regulation; ADP-ribosylation of RNA-regulatory proteins can alter their localization, activity, or RNA binding; and noncovalent interactions of RNA-binding proteins with poly(ADP-ribose) can affect their function. In addition to regulating RNA during non-stress conditions, PARPs regulate RNA function during cellular stress conditions that are critical for the proper execution of a stress response. In this review, we summarize the current knowledge regarding PARP-dependent regulation of RNAs, and describe how by modulating RNA processing, translation, and decay PARPs impact multiple processes in the cell.

National Canadian Survey on the Management of Noneuploid Embryos.

OBJECTIVE: To comprehensively describe current preimplantation genetic testing for aneuploidy (PGT-A) practices and management of non-euploid embryos in Canada. METHODS: This was a cross-sectional study utilizing an online survey distributed by email to all medical directors of fertility clinics with independent in vitro fertilization (IVF) embryology laboratories. The survey was designed to determine practice patterns regarding PGT-A usage; PGT-A reference laboratory, platform, and thresholds for classifying embryos; and management of embryos classified as mosaic, inconclusive, or aneuploid. RESULTS: Twenty-five medical directors (69%) participated in the survey. The majority of clinics (91%) offered PGT-A screening, with 45% of clinics offering PGT-A as routine screening. The majority of clinics (90%) that offered PGT-A received mosaicism data; 61% of these clinics had transferred mosaic embryos, and 94% would transfer mosaic embryos. Clinics that performed ≥1000 IVF cycles annually were more likely to have transferred mosaic embryos (100% vs. 45.5%; P = 0.043). The mean percentage of IVF cycles using PGT-A was lower in clinics that had transferred mosaic embryos (12.3% vs. 30.4%; P = 0.033). Only 1 clinic had transferred an aneuploid embryo, but 2 other clinics would consider this option. The majority of clinics (61%) that receive mosaicism data would recommend noninvasive prenatal testing (NIPT) following mosaic embryo transfer, with 22% of clinics indicating that this would be the only genetic test offered. CONCLUSION: We report significant practice variation in PGT-A and management of non-euploid embryos across Canada and highlight areas where consensus should be encouraged.

Preimplantation genetic testing for aneuploidy in patients with low embryo numbers: benefit or harm?

PURPOSE: We sought to explore the utility of preimplantation genetic testing for aneuploidy (PGT-A) in a poor prognosis group of women with few embryos available for transfer. METHODS: This was a retrospective matched cohort study examining records for first or second-cycle IVF patients with 1 to 3 blastocysts. The study group comprised 130 patients who underwent PGT-A on all embryos. The control group included 130 patients matched by age, BMI, and blastocyst number and quality who did not undergo PGT-A during the same time period. RESULTS: The live birth rate (LBR) per embryo transfer (ET) were similar in the PGT-A and control groups, and the spontaneous abortion (SAB) rate was the same (23%). However, we found a significantly higher LBR per oocyte retrieval in the control group vs the PGT-A group (43% vs 20%, respectively) likely due to the many no-euploid cycles in the PGT-A group. In a subgroup analysis for age, the similar LBR per ET persisted in women < 38. However, in older women, there was a trend to a higher LBR per ET in the PGT-A group (43%) vs the control group (22%) but a higher LBR per oocyte retrieval in the control group (31%) vs the PGT-A group (13%). CONCLUSIONS: Overall, we observed a significant increase in LBR per oocyte retrieval in women in the control group compared to women undergoing PGT-A, and no difference in SAB rate. Our data suggests that PGT-A has no benefit in a subpopulation of women with few embryos and may cause harm.

Intraoperative OK-432 pleurodesis for preventing recurrence of primary spontaneous pneumothorax in children and adolescents: a single-center experience.

BACKGROUND: Primary spontaneous pneumothorax (PSP) commonly occurs in lean, tall, male children and adolescents. To reduce recurrence rates of PSP, chemical pleurodesis could be helpful for patients undergoing video-assisted thoracoscopic surgery (VATS) wedge bullectomy. The efficacy and safety of intraoperative OK-432 (Picibanil) pleurodesis on preventing the recurrence of PSP in pediatric patients remain unclear. METHODS: It is a retrospective observational study in a single center, between 2014 and 2020, enrolled 48 (8 females) pediatric PSP patients with persistent air leakage at the mean age of 16.3 ± 1.1 years to receive VATS wedge bullectomy and pleural abrasion. Twenty patients received additional intraoperative OK-432 pleurodesis. The clinical characteristics of patients, surgical outcomes, and recurrence rates were analyzed. RESULTS: The OK-432 group had longer operation time (118.6 ± 35.6 vs. 96.5 ± 23.3 min; p < 0.05) and higher proportion of postoperative fever (75.0% vs. 28.5%; p = 0.015) than the standard group. No serious adverse events were noted and other surgical outcomes in the two groups were comparable. After a mean follow-up period of 18.1 ± 19.1 months, the OK-432 group had a lower recurrence rate compared with the standard group (5% vs. 28.6%; p < 0.05, odds ratio 0.13, 95% confidence interval: 0.01-1.15), but it had no significant difference in statistics on the Kaplan-Meier curves (log-rank p = 0.105). CONCLUSION: It was the first study that focused on the addition of intraoperative OK-432 pleurodesis for PSP with persistent air leakage in children and adolescents receiving VATS. It demonstrated the efficacy with a low recurrence rate and short-term safety as a single-center experience. LEVEL OF EVIDENCE: Retrospective review, therapeutic study, Level III.

Single-site laparoscopic burnia for inguinal hernias in girls: comparison with open repair.

BACKGROUND: Burnia is a suturless repair for inguinal hernias in girls. It is performed under laparoscopy by grabbing the sac, inverting it into the peritoneal cavity, and cauterizing. The aim of this study is to report our experience with single-site laparoscopic burnia (BURNIA) and compare them with open repair (OPEN). METHODS: With IRB approval, pediatric female patients younger than 18 years of age who underwent inguinal hernia repair between January 2015 and December 2017 were enrolled. Medical records were retrospectively reviewed. The patients were divided into two groups, BURNIA and OPEN. RESULTS: 198 patients were included. In BURNIA, 49 patients underwent bilateral repairs, and 50 patients underwent 51 unilateral repairs (one patient had metachronous contralateral hernia). In OPEN, 27 patients underwent bilateral repairs, and 72 patients underwent 77 unilateral repairs (five patients had metachronous contralateral hernias). The mean age of BURNIA was similar to OPEN for bilateral repairs (49.1 ± 36.6 vs. 43.7 ± 26.4 months, p = 0.46), but significantly older for unilateral repairs (54.6 ± 29.8 vs. 29.0 ± 31.4, p < 0.01). The mean operation time of BUNIA was similar to OPEN for bilateral repairs (24.2 ± 7.6 vs. 22.4 ± 8.6 min, p = 0.35), but significantly longer for unilateral repairs (19.2 ± 7.0 vs, 13.6 ± 8.8 min, p < 0.01). The mean follow-up duration of BURNIA was significantly shorter than OPEN for bilateral and unilateral repairs, respectively (32.5 ± 8.8 vs. 45.4 ± 4.8 months, p < 0.01) (30.2 ± 8.8 vs. 39.1 ± 9.6 months, p < 0.01). No conversion was required in BURNIA. There were no complications and no recurrence in all patients. CONCLUSIONS: Single-site laparoscopic burnia is technically feasible, and as safe and effective as open inguinal hernia repair.

Ten kHz spinal cord stimulation for the treatment of chronic peripheral polyneuropathy: 12-Month results from prospective open-label pilot study.

BACKGROUND: The goal of this study was to demonstrate that the paresthesia-independent 10 kHz spinal cord stimulation (SCS) can provide long-term pain relief in patients with peripheral polyneuropathy (PPN). Clinically diagnosed subjects with PPN refractory to conventional medical management were enrolled in this prospective, multicenter study between November 2015 and August 2016, after institutional review board approval and patient informed consent were obtained. METHODS: Subjects underwent trial stimulation utilizing 2 epidural leads, and if successful, were implanted with a permanent 10 kHz SCS system and followed up for 12 months post-implant. Outcome measures included adverse events, pain, neurological assessments, disability, function, quality of life, pain interference, sleep, satisfaction, and global impression of change. Data are presented as descriptive statistics. Permanent implant population results are reported as mean ± standard error. RESULTS: Twenty-one of the 26 trialed subjects had a successful trial and 18 received a permanent implant. All subjects had the leads placed anatomically without the need for paresthesia. Subjects experienced significant and sustained pain relief (at least 65% at all timepoints) whereas physicians noted improvements in neurological function. Significant improvements in disability, function, sleep, sensory, and affective dimensions of pain were reported at all timepoints. All adverse events were resolved without sequelae. CONCLUSION: Findings from this study suggest that 10 kHz SCS may provide sustained pain relief and disability improvements in patients suffering from PPN.

Divergent effects of canonical and non-canonical TGF-ß signalling on mixed contractile-synthetic smooth muscle cell phenotype in human Marfan syndrome aortic root aneurysms.

Aortic root aneurysm formation is a cardinal feature of Marfan syndrome (MFS) and likely TGF-ß driven via Smad (canonical) and ERK (non-canonical) signalling. The current study assesses human MFS vascular smooth muscle cell (SMC) phenotype, focusing on individual contributions by Smad and ERK, with Notch3 signalling identified as a novel compensatory mechanism against TGF-ß-driven pathology. Although significant ERK activation and mixed contractile gene expression patterns were observed by traditional analysis, this did not directly correlate with the anatomic site of the aneurysm. Smooth muscle cell phenotypic changes were TGF-ß-dependent and opposed by ERK in vitro, implicating the canonical Smad pathway. Bulk SMC RNA sequencing after ERK inhibition showed that ERK modulates cell proliferation, apoptosis, inflammation, and Notch signalling via Notch3 in MFS. Reversing Notch3 overexpression with siRNA demonstrated that Notch3 promotes several protective remodelling pathways, including increased SMC proliferation, decreased apoptosis and reduced matrix metalloproteinase activity, in vitro. In conclusion, in human MFS aortic SMCs: (a) ERK activation is enhanced but not specific to the site of aneurysm formation; (b) ERK opposes TGF-ß-dependent negative effects on SMC phenotype; (c) multiple distinct SMC subtypes contribute to a 'mixed' contractile-synthetic phenotype in MFS aortic aneurysm; and (d) ERK drives Notch3 overexpression, a potential pathway for tissue remodelling in response to aneurysm formation.

Insights into the biogenesis, function, and regulation of ADP-ribosylation.

ADP-ribosylation-the transfer of ADP-ribose (ADPr) from NAD+ onto target molecules-is catalyzed by members of the ADP-ribosyltransferase (ART) superfamily of proteins, found in all kingdoms of life. Modification of amino acids in protein targets by ADPr regulates critical cellular pathways in eukaryotes and underlies the pathogenicity of certain bacteria. Several members of the ART superfamily are highly relevant for disease; these include the poly(ADP-ribose) polymerases (PARPs), recently shown to be important cancer targets, and the bacterial toxins diphtheria toxin and cholera toxin, long known to be responsible for the symptoms of diphtheria and cholera that result in morbidity. In this Review, we discuss the functions of amino acid ADPr modifications and the ART proteins that make them, the nature of the chemical linkage between ADPr and its targets and how this impacts function and stability, and the way that ARTs select specific amino acids in targets to modify.

Low Utility of Screening Hematologic Testing for Image-Guided Biopsies in Patients Without Bleeding Risks.

OBJECTIVE. This study evaluates the prevalence of an abnormal international normalized ratio (INR) and platelet count before image-guided percutaneous needle biopsies over a 10-year period, comparing data from patients with and those without known conditions predisposing to coagulopathy. MATERIALS AND METHODS. A review of electronic medical records identified patients who were scheduled for a biopsy in a single institution's radiology department for the period of 2007-2016. The following information was recorded: demographic data, patient history of conditions that predispose to bleeding (e.g., liver disease, anticoagulant therapy, history of coagulopathy), and INR and platelet values within 30 days before biopsy. Data were stratified by biopsies that were performed versus those that were cancelled. RESULTS. Over 10 years, 3864 percutaneous biopsies were performed, and 6371 were cancelled. Approximately half of the biopsies (48.2%) were performed in patients without a predisposing condition; of those patients, 0.8% and 0.1% had an INR greater than 1.5 and greater than 1.8, respectively, and 0.4% had a platelet count of 50,000/µL or less (≤ 50 × 109/L). In patients with no known predisposing condition, 0.6% and 0.0% of biopsies cancelled were in patients who had an INR greater than 1.5 and greater than 1.8, respectively, and 0.1% of biopsies cancelled were in patients who had a platelet count of 50,000/µL or less. Ordering prebiopsy testing of patients with no predisposing conditions for the 1864 percutaneous biopsies performed over the 10-year study period resulted in more than $850,000 in laboratory-related health care costs. Our results suggest that the cost of identifying one abnormal INR is nearly $700,000. CONCLUSION. For patients without any known bleeding risks who are scheduled to undergo image-guided percutaneous biopsies, identifying an abnormal INR or abnormal platelet count is rare. Eliminating this testing in patients without predisposing conditions has the potential to create savings in costs and time for both physicians and patients.

Lung Base Findings of Coronavirus Disease (COVID-19) on Abdominal CT in Patients With Predominant Gastrointestinal Symptoms.

OBJECTIVE. This series of patients presented to the emergency department (ED) with abdominal pain, without the respiratory symptoms typical of coronavirus disease (COVID-19), and the abdominal radiologist was the first to suggest COVID-19 infection because of findings in the lung bases on CT of the abdomen. CONCLUSION. COVID-19 infection can present primarily with abdominal symptoms, and the abdominal radiologist must suggest the diagnosis when evaluating the lung bases for typical findings.

Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm.

Poly(ADP-ribose) is a major regulatory macromolecule in the nucleus, where it regulates transcription, chromosome structure, and DNA damage repair. Functions in the interphase cytoplasm are less understood. Here, we identify a requirement for poly(ADP-ribose) in the assembly of cytoplasmic stress granules, which accumulate RNA-binding proteins that regulate the translation and stability of mRNAs upon stress. We show that poly(ADP-ribose), six specific poly(ADP-ribose) polymerases, and two poly(ADP-ribose) glycohydrolase isoforms are stress granule components. A subset of stress granule proteins, including microRNA-binding Argonaute family members Ago1-4, are modified by poly(ADP-ribose), and such modification increases upon stress, a condition when both microRNA-mediated translational repression and microRNA-directed mRNA cleavage are relieved. Similar relief of repression is also observed upon overexpression of specific poly(ADP-ribose) polymerases or, conversely, upon knockdown of glycohydrolase. We conclude that poly(ADP-ribose) is a key regulator of posttranscriptional gene expression in the cytoplasm.

Automatic Normalization of Anatomical Phrases in Radiology Reports Using Unsupervised Learning.

In today's radiology workflow, free-text reporting is established as the most common medium to capture, store, and communicate clinical information. Radiologists routinely refer to prior radiology reports of a patient to recall critical information for new diagnosis, which is quite tedious, time consuming, and prone to human error. Automatic structuring of report content is desired to facilitate such inquiry of information. In this work, we propose an unsupervised machine learning approach to automatically structure radiology reports by detecting and normalizing anatomical phrases based on the Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) ontology. The proposed approach combines word embedding-based semantic learning with ontology-based concept mapping to derive the desired concept normalization. The word embedding model was trained using a large corpus of unlabeled radiology reports. Fifty-six anatomical labels were extracted from SNOMED CT as class labels of the whole human anatomy. The proposed framework was compared against a number of state-of-the-art supervised and unsupervised approaches. Radiology reports from three different clinical sites were manually labeled for testing. The proposed approach outperformed other techniques yielding an average precision of 82.6%. The proposed framework boosts the coverage and performance of conventional approaches for concept normalization, by applying word embedding techniques in semantic learning, while avoiding the challenge of having access to a large amount of annotated data, which is typically required for training classifiers.

Alterations at Arg76 of human connexin 46, a residue associated with cataract formation, cause loss of gap junction formation but preserve hemichannel function.

The connexins are members of a family of integral membrane proteins that form gap junction channels between apposed cells and/or hemichannels across the plasma membranes. The importance of the arginine at position 76 (Arg76) in the structure and/or function of connexin 46 (Cx46) is highlighted by its conservation across the entire connexin family and the occurrence of pathogenic mutations at this (or the corresponding homologous) residue in a number of human diseases. Two mutations at Arg76 in Cx46 are associated with cataracts in humans, highlighting the importance of this residue. We examined the expression levels and macroscopic and single-channel properties of human Cx46 and compared them with those for two pathogenic mutants, namely R76H and R76G. To gain further insight into the role of charge at this position, we generated two additional nonnaturally occurring mutants, R76K (charge conserving) and R76E (charge inverting). We found that, when expressed exogenously in Neuro2a cells, all four mutants formed membrane hemichannels, inducing membrane permeability at levels comparable to those recorded in cells expressing the wild-type Cx46. In contrast, the number of gap-junction plaques and the magnitude of junctional coupling were reduced by all four mutations. To gain further insight into the role of Arg76 in the function of Cx46, we performed homology modeling of Cx46 and in silico mutagenesis of Arg76 to Gly, His, or Glu. Our studies suggest that the loss of interprotomeric interactions has a significant effect on the extracellular domain conformation and dynamics, thus affecting the hemichannel docking required for formation of cell-cell channels.

High and ultra-high resolution metabolite mapping of the human brain using 1H FID MRSI at 9.4T.

Magnetic resonance spectroscopic imaging (MRSI) is a promising technique for mapping the spatial distribution of multiple metabolites in the human brain. These metabolite maps can be used as a diagnostic tool to gain insight into several biochemical processes and diseases in the brain. In comparison to lower field strengths, MRSI at ultra-high field strengths benefits from a higher signal to noise ratio (SNR) as well as higher chemical shift dispersion, and hence spectral resolution. This study combines the benefits of an ultra-high field magnet with the advantages of an ultra-short TE and TR single-slice FID-MRSI sequence (such as negligible J-evolution and loss of SNR due to T2 relaxation effects) and presents the first metabolite maps acquired at 9.4T in the healthy human brain at both high (voxel size of 97.6µL) and ultra-high (voxel size of 24.4µL) spatial resolutions in a scan time of 11 and 46min respectively. In comparison to lower field strengths, more anatomically-detailed maps with higher SNR from a larger number of metabolites are shown. A total of 12 metabolites including glutamate (Glu), glutamine (Gln), N-acetyl-aspartyl-glutamate (NAAG), Gamma-aminobutyric acid (GABA) and glutathione (GSH) are reliably mapped. Comprehensive description of the methodology behind these maps is provided.

MultiNet PyGRAPPA: Multiple neural networks for reconstructing variable density GRAPPA (a 1H FID MRSI study).

Magnetic resonance spectroscopic imaging (MRSI) is a powerful tool for mapping metabolite levels across the brain, however, it generally suffers from long scan times. This severely hinders its application in clinical settings. Additionally, the presence of nuisance signals (e.g. the subcutaneous lipid signals close to the skull region in brain metabolite mapping) makes it challenging to apply conventional acceleration techniques to shorten the scan times. The goal of this work is, therefore, to increase the overall applicability of high resolution metabolite mapping using 1H MRSI by introducing a novel GRAPPA acceleration acquisition/reconstruction technique. An improved reconstruction method (MultiNet) is introduced that uses machine learning, specifically neural networks, to reconstruct accelerated data. The method is further modified to use more neural networks with nonlinear hidden layers and is then combined with a variable density undersampling scheme (MultiNet PyGRAPPA) to enable higher in-plane acceleration factors of R = 5.6 and R = 7 for a non-lipid suppressed ultra-short TR and TE 1H FID MRSI sequence. The proposed method is evaluated for high resolution metabolite mapping of the human brain at 9.4T. The results show that the proposed method is superior to conventional GRAPPA: there is no significant residual lipid aliasing artifact in the images when the proposed MultiNet method is used. Furthermore, the MultiNet PyGRAPPA acquisition/reconstruction method with R = 5.6 results in reproducible high resolution metabolite maps (with an in-plane matrix size of 64 × 64) that can be acquired in 2.8 min on 9.4T. In conclusion, using multiple neural networks to predict the missing points in GRAPPA reconstruction results in a more reliable data recovery while keeping the noise levels under control. Combining this high fidelity reconstruction with variable density undersampling (MultiNet PyGRAPPA) enables higher in-plane acceleration factors even for non-lipid suppressed 1H FID MRSI, without introducing any structured aliasing artifact in the image.