Prevalence of Iron Deficiency Using 3 Definitions Among Women in the US and Canada.

Importance: The prevalence of iron deficiency varies widely according to how it is defined. Objective: To compare the prevalence of iron deficiency among women using 3 different definitions. Design, Setting, and Participants: The cross-sectional Hemochromatosis and Iron Overload Screening Study (HEIRS; 2000-2006) evaluated the prevalence, determinants, and outcomes of hemochromatosis and other iron-related disorders. Multiethnic, primary care-based screening (2001-2003) was performed at 5 field centers (4 in the US and 1 in Canada). Volunteer women aged 25 years and older were recruited at primary care venues associated with the field centers. Data were analyzed from June to December 2023. Main Outcomes and Measures: Measures included transferrin saturation, serum ferritin level, and self-reported age, pregnancy, and race and ethnicity. Three iron deficiency definitions were studied: (1) combined transferrin saturation less than 10% and serum ferritin less than 15 ng/mL (HEIRS), (2) serum ferritin less than 15 ng/mL (World Health Organization [WHO]), and (3) serum ferritin less than 25 ng/mL (a threshold for iron-deficient erythropoiesis [IDE]). Results: Among 62 685 women (mean [SD] age, 49.58 [14.27] years), 1957 women (3.12%) had iron deficiency according to the HEIRS definition, 4659 women (7.43%) had iron deficiency according to the WHO definition, and 9611 women (15.33%) had iron deficiency according to the IDE definition. Among 40 381 women aged 25 to 54 years, 1801 women (4.46%) had iron deficiency according to HEIRS, 4267 women (10.57%) had iron deficiency according to WHO, and 8573 women (21.23%) had iron deficiency according to IDE. Prevalence rates of iron deficiency among 2039 women aged 25 to 44 years who reported pregnancy were 5.44% (111 women) according to HEIRS, 18.05% (368 women) according to WHO, and 36.10% (736 women) according to IDE. Iron deficiency prevalence by the 3 respective definitions increased significantly in each racial and ethnic group and was significantly higher among Black and Hispanic participants than Asian and White participants. The relative iron deficiency prevalence among the 62 685 women increased 2.4-fold (95% CI, 2.3-2.5; P < .001) using the WHO definition and increased 4.9-fold (95% CI, 4.7-5.2; P < .001) using the IDE definition. Conclusions and Relevance: Three definitions of iron deficiency were associated with significantly different prevalence of iron deficiency in women, regardless of self-reported age, pregnancy, or race and ethnicity. Using higher serum ferritin thresholds to define iron deficiency could lead to diagnosis and treatment of more women with iron deficiency and greater reduction of related morbidity.

Navigating the complex terrain of motivated behavior: a bibliometric and neuroscientific perspective.

Over several decades, motivated behavior has emerged as a crucial study area within neuroscience. Understanding the neural substrates and mechanisms driving behaviors related to reward, addiction, and other motivation forms is pivotal for novel therapeutic interventions. This review provides a bibliometric analysis of the literature, highlighting the main trends, influential authors, and the potential future direction of the field. Utilizing a dataset comprised by 3,150 publications from the Web of Science and Scopus databases ("motivated behavior as query), we delve into key metrics like publication trends, keyword prevalence, author collaborations, citation impacts, and employed an unsupervised natural language processing technique - Latent Dirichlet Allocation - for topic modeling. From early investigations focusing on basic neural mechanism and behaviors in animal models to more recent studies exploring the complex interplay of neurobiological, psychological, and social factors in humans, the field had undergone a remarkable transformation. The last century has seen a proliferation of research dedicated to uncovering the intricacies of motivation, significantly enriching our understanding of its myriad implications for human behavior and mental health. This bibliometric analysis aims to offer comprehensive insights into this dynamic research area, highlighting the field's key contributions and potential future directions, thereby serving as a valuable resource for researchers, and hopefully give a more thorough understanding of the research area.

An Analysis of Global Surgery Opportunities in American Otolaryngology Residency Programs.

OBJECTIVES: To depict the current state of global surgery opportunities in United States ACGME-approved Otolaryngology residency programs and compare the characteristics of programs with and without these opportunities. METHODS: In this cross-sectional analysis, websites of ACGME-accredited Otolaryngology residency programs were analyzed for information on program size, rank, age, and geographic region as obtained through the Doximity platform in 2023. Additional parameters were obtained for programs listing global surgery opportunities such as funding, faculty oversight, location/region, focus, and relationship to the community served. Data were tabulated and analyzed in Microsoft Excel and Stata. RESULTS: Of the 131 ACGME-accredited Otolaryngology residency programs, 26 (20%) of programs advertised a global surgery opportunity. Nine (35%) of these promoted funding, 15 (58%) offered a clinical focus, one (4%) offered a research focus, and 10 (38%) offered a combined approach. The Midwest region had the most programs with global surgery opportunities (n = 8, 31%). Less than half (42%) of programs had an established partnership with local partners within low and middle-income countries (LMICs). When comparing programs, the average Doximity rank, average program age, and average program size of programs that offered global surgery opportunities was significantly higher than those that did not (37.2 vs. 71.5, 54 vs. 41, 19.5 vs. 13.7; all p < 0.05). CONCLUSIONS: Approximately one-fifth of Otolaryngology training programs have a global surgery opportunity. Programs that offer these opportunities had a higher Doximity ranking, older program age, and a larger trainee cohort. These results highlight potential areas for expanding global surgery opportunities in academic institutions. LEVEL OF EVIDENCE: N/A Laryngoscope, 2024.

The Lawnmower and the Pediatric Lower Extremity: A Catastrophic Combination.

Background: Lower extremity (LE) trauma within the pediatric population may be debilitating and have different implications and etiologies than in adults. Specifically, lawnmower injuries can cause catastrophic sequelae to the lower extremities, often requiring complex reconstruction or resulting in amputation. This study aims to present our experience with pediatric LE lawnmower injuries at one of the busiest level 1 trauma centers in the United States. Methods: An IRB-approved retrospective analysis was performed studying pediatric patients (age <18 years) who experienced LE trauma due to a lawnmower injury over a 5-year period (2012-2017). Patient demographics, perioperative data, and types of reconstruction were reviewed. Univariate analysis of the data was performed to examine trends in exposure and management of pediatric LE lawnmower injuries. Results: Twenty-three patients were identified with pediatric LE lawnmower injuries, of whom 82.6% were male. The patients had a median age of 6 years and a median Injury Severity Score (ISS) of 4. Over one-third (34.8%) of this cohort required immediate amputation. Additionally, 26.1% and 8.7% required local and free flap reconstruction, respectively. In comparison, only 3.6% and 2.3% of all traumatic pediatric LE injuries from the same time frame required local and free flaps, respectively. Conclusions: Lawnmower injuries to the LE can be devastating, causing long-term physical, emotional, and psychosocial consequences for pediatric patients and their families. The data in this study suggest that pediatric LE injuries from lawnmowers more often require complex reconstruction than other traumatic LE injuries. Rapid and effective decision-making by experienced surgeons is necessary to optimize the potential for limb salvage in pediatric LE lawnmower injuries. An algorithm of recommendations on when to transfer these types of injuries to more experienced tertiary centers is provided. Additional resources should be dedicated toward improving public awareness and industrial safety features to help prevent lawnmower injuries in pediatric patients.

Novel insights into the role of translesion synthesis polymerase in DNA incorporation and bypass of 5-fluorouracil in colorectal cancer.

5-Fluorouracil (5-FU) is the first-line chemotherapeutic agent in colorectal cancer, and resistance to 5-FU easily emerges. One of the mechanisms of drug action and resistance of 5-FU is through DNA incorporation. Our quantitative reverse-transcription PCR data showed that one of the translesion synthesis (TLS) DNA polymerases, DNA polymerase η (polη), was upregulated within 72 h upon 5-FU administration at 1 and 10 µM, indicating that polη is one of the first responding polymerases, and the only TLS polymerase, upon the 5-FU treatment to incorporate 5-FU into DNA. Our kinetic studies revealed that 5-fluoro-2'-deoxyuridine triphosphate (5FdUTP) was incorporated across dA 41 and 28 times more efficiently than across dG and across inosine, respectively, by polη indicating that the mutagenicity of 5-FU incorporation is higher in the presence of inosine and that DNA lesions could lead to more mutagenic incorporation of 5-FU. Our polη crystal structures complexed with DNA and 5FdUTP revealed that dA:5FdUTP base pair is like dA:dTTP in the active site of polη, while 5FdUTP adopted 4-enol tautomer in the base pairs with dG and HX increasing the insertion efficiency compared to dG:dTTP for the incorrect insertions. These studies confirm that polη engages in the DNA incorporation and bypass of 5-FU.

The Hidden Risks of Perioperative Transfusions in Traumatic Lower Extremity Free Flap Reconstruction.

BACKGROUND: Blood transfusions have been associated with surgical complications; however, these studies are not specific to lower extremity (LE) reconstruction. We evaluated the effect of perioperative packed red blood cell (PRBC) transfusions on LE free flap outcomes in trauma patients. METHODS: Patients undergoing LE free flap reconstruction following acute injuries from 2016 to 2021 were retrospectively analyzed. The perioperative period for transfusions was defined as ± 3 days from the procedure. Parameters included demographics, perioperative characteristics, and outcomes. Major complications were complications requiring reoperation. Univariate and multivariate analyses were performed to identify associations. RESULTS: Of the 205 patients, 48% received PRBCs perioperatively. There was a trend toward higher major complications rate in the transfusion group (19 vs. 10%, p = 0.09). Wound size, injury severity score (ISS), and intraoperative estimated blood loss were greater in the transfusion group (p < 0.01). Preoperative hemoglobin/hematocrit were lower in the transfusion group (p < 0.001). Units of PRBCs transfused were independently associated with major complications on multivariate analysis (odds ratio [OR] = 1.34, confidence interval [CI]: 1.06-1.70, p = 0.015) and length of hospital stay (LOS; OR = 1.05, CI: 1.02-1.08, p = 0.002). Infection, wound size, ISS, and preoperative hemoglobin/hematocrit were independently associated with increased LOS (p < 0.05) but not with major complications. CONCLUSION: The number of units of PRBCs given perioperatively was the only variable independently associated with major complications on multivariate analysis and was one of many variables associated with increased LOS. These findings suggest the usage of restrictive transfusion protocols in trauma patients requiring LE reconstruction.

Multidimensional Widefield Infrared-Encoded Spontaneous Emission Microscopy: Distinguishing Chromophores by Ultrashort Infrared Pulses.

Photoluminescence (PL) imaging has broad applications in visualizing biological activities, detecting chemical species, and characterizing materials. However, the chemical information encoded in the PL images is often limited by the overlapping emission spectra of chromophores. Here, we report a PL microscopy based on the nonlinear interactions between mid-infrared and visible excitations on matters, which we termed MultiDimensional Widefield Infrared-encoded Spontaneous Emission (MD-WISE) microscopy. MD-WISE microscopy can distinguish chromophores that possess nearly identical emission spectra via conditions in a multidimensional space formed by three independent variables: the temporal delay between the infrared and the visible pulses (t), the wavelength of visible pulses (λvis), and the frequencies of the infrared pulses (ωIR). This method is enabled by two mechanisms: (1) modulating the optical absorption cross sections of molecular dyes by exciting specific vibrational functional groups and (2) reducing the PL quantum yield of semiconductor nanocrystals, which was achieved through strong field ionization of excitons. Importantly, MD-WISE microscopy operates under widefield imaging conditions with a field of view of tens of microns, other than the confocal configuration adopted by most nonlinear optical microscopies, which require focusing the optical beams tightly. By demonstrating the capacity of registering multidimensional information into PL images, MD-WISE microscopy has the potential of expanding the number of species and processes that can be simultaneously tracked in high-speed widefield imaging applications.

Evaluating Adherence to Guideline-based Injury Grading in Pediatric Renal Trauma: How Are Patients Being Worked Up Prior to Transfer to a Level 1 Trauma Center?

OBJECTIVE: To determine whether children with renal trauma who are transferred to a level I trauma center (TC) receive appropriate imaging studies before transfer and whether this impacts care. The American Urologic Association (AUA) Urotrauma guidelines state clinicians should perform IV contrast-enhanced CT with immediate and delayed images when renal trauma is suspected. Adherence to these guidelines in pediatric patients is unknown. METHODS: Children treated for renal trauma at our TC between 2005 and 2019 were identified. Comparisons between patients with initial imaging at a transferring hospital (TH) and patients with initial imaging at our TC were performed using logistic regression. RESULTS: Of the included 293 children, 67% (197/293) were transferred into our TC and 61% (180/293) received initial imaging at the TH. Patients with initial imaging at the TH were more likely to have higher-grade renal injuries (P = .001) and were less likely to have guideline-recommended imaging (31% vs 82%, P < .001). Of patients who were imaged at the TH, 28% (50/180) underwent an additional CT imaging shortly after transfer. When imaging was incomplete at the TH, having an additional scan upon transfer was associated with emergent urologic surgery (P = .004). CONCLUSION: Adherence to the AUA Urotrauma guidelines is low, with most pediatric renal trauma patients not receiving complete staging with delayed-phase imaging before transfer to a TC. Furthermore, patients initially imaged at THs were more likely to receive more CT scans per admission and were exposed to higher amounts of radiation. There is a need to improve imaging protocols for complete staging of renal trauma in children before transfer.

Gym lifestyle factors and male reproductive health: a study into young adult usage and perceptions.

RESEARCH QUESTION: What level of awareness do young adults have regarding the potential impacts of gym lifestyle factors and supplementation on male infertility? DESIGN: Between February and March 2023 a questionnaire (n = 153) was employed to gauge attitudes to and awareness of the effects of male reproductive health and gym lifestyles on male fertility. Two semi-structured focus groups (n = 10 total), stratified by sex assigned at birth, were conducted using a set of discussion topics. RESULTS: The survey revealed a statistically significant difference between male and female awareness of the potential impacts of some forms of high-intensity exercise and protein supplementation on male reproductive health (P = 0.045). Many men do not think about fertility unprompted; the survey revealed that fewer men have thought about their fertility compared with those who are curious about their fertility (P = 4.7 â€¯×  10-5) and those who believe their personal fertility is important to them (P = 8.1 â€¯×  10-6). Men were more likely to make a change in their behaviour if it had a long-term compared with a short-term effect on their fertility (P < 10-5). Five focus group themes surrounding awareness of male reproductive health were extracted. CONCLUSIONS: This work has shown that there is a significant lack of awareness and information surrounding the effects of gym lifestyles on male infertility in a young adult UK population. Crucially, levels of awareness differ significantly between men and women. Men have a potentially alarming lack of concern over their own fertility and how factors such as gym supplements can have negative long-term impacts.

Multimodal Nonlinear Hyperspectral Chemical Imaging Using Line-Scanning Vibrational Sum-Frequency Generation Microscopy.

Vibrational sum-frequency generation (VSFG), a second-order nonlinear optical signal, has traditionally been used to study molecules at interfaces as a spectroscopy technique with a spatial resolution of ~100 µm. However, the spectroscopy is not sensitive to the heterogeneity of a sample. To study mesoscopically heterogeneous samples, we, along with others, pushed the resolution limit of VSFG spectroscopy down to ~1 µm level and constructed the VSFG microscope. This imaging technique not only can resolve sample morphologies through imaging, but also record a broadband VSFG spectrum at every pixel of the images. Being a second-order nonlinear optical technique, its selection rule enables the visualization of non-centrosymmetric or chiral self-assembled structures commonly found in biology, materials science, and bioengineering, among others. In this article, the audience will be guided through an inverted transmission design that allows for imaging unfixed samples. This work also showcases that VSFG microscopy can resolve chemical-specific geometric information of individual self-assembled sheets by combining it with a neural network function solver. Lastly, the images obtained under brightfield, SHG, and VSFG configurations of various samples briefly discuss the unique information revealed by VSFG imaging.

Only the Best of the Bunch-Sperm Preparation Is Not Just about Numbers.

In this Seminar, we present an overview of the current and emerging methods and technologies for optimizing the man and the sperm sample for fertility treatment. We argue that sperms are the secret to success, and that there are many avenues for improving both treatment and basic understanding of their role in outcomes. These outcomes encompass not just whether treatment is successful or not, but the wider intergenerational health of the offspring. We discuss outstanding challenges and opportunities of new technologies such as microfluidics and artificial intelligence, including potential pitfalls and advantages. This article aims to provide a comprehensive overview of the importance of sperm in fertility treatment and suggests future directions for research and innovation.

Quantitative imaging of three-dimensional fiber orientation in the human brain via two illumination angles using polarization-sensitive optical coherence tomography.

The accurate measurement of three-dimensional (3D) fiber orientation in the brain is crucial for reconstructing fiber pathways and studying their involvement in neurological diseases. Optical imaging methods such as polarization-sensitive optical coherence tomography (PS-OCT) provide important tools to directly quantify fiber orientation at micrometer resolution. However, brain imaging based on the optic axis by PS-OCT so far has been limited to two-dimensional in-plane orientation, preventing the comprehensive study of connectivity in 3D. In this work, we present a novel method to obtain the 3D fiber orientation in full angular space with only two illumination angles. We measure the optic axis orientation and the apparent birefringence by PS-OCT from a normal and a 15 deg tilted illumination, and then apply a computational method yielding the 3D optic axis orientation and true birefringence. We verify that our method accurately recovers a large range of through-plane orientations from -85 deg to 85 deg with a high angular precision. We further present 3D fiber orientation maps of entire coronal sections of human cerebrum and brainstem with 10 µm in-plane resolution, revealing unprecedented details of fiber configurations. We envision that further development of our method will open a promising avenue towards large-scale 3D fiber axis mapping in the human brain and other complex fibrous tissues at microscopic level.

Reliability of maximal respiratory nasal pressure tests in healthy young adults.

INTRODUCTION: Sniff nasal inspiratory (SNIP) and expiratory pressure (SNEP) may complement the assessment of respiratory muscle strength. Thus, specifying their reliability is relevant to improving the clinical consistency of both tests. OBJECTIVE: To assess the reliability of SNIP and SNEP in healthy young adults. METHODS: This cross-sectional study included self-reported healthy aged 18 to 29 years. SNIP was performed using a plug to occlude one nostril, while SNEP was conducted using a facemask. Participants performed 20 SNIP and SNEP maneuvers with 30-second intervals in between. The intraclass correlation coefficient (ICC), standard error of measurement (SEM), and minimum detectable change (MDC) assessed the reliability of SNIP and SNEP. Analyses were conducted between the highest peak pressure and the first reproducible maneuver in men and women. RESULTS: The total sample comprised 32 participants: 16 men and 16 women. The ICC, SEM, and MDC for SNIP maneuvers were 0.994 (95%CI 0.988 to 0.997), 1.820 cmH2O, and 5.043 cmH2O, respectively. For SNEP, these parameters were 0.950 (95%CI 0.897 to 0.976), 6.03 cmH2O, and 16.716 cmH2O. The SNIP and SNEP in men showed ICC of 0.992 (95%CI 0.977 to 0.997) and 0.877 (95%CI 0.648 to 0.957), SEM of 2.07 and 7.66 cmH2O, and MDC of 5.74 and 21.23 cmH2O. In women, SNIP and SNEP presented ICC of 0.992 (95%CI 0.977 to 0.997) and 0.957 (95%CI 0.878 to 0.985), SEM of 1.15 and 6.11 cmH2O, and MDC of 3.19 and 16.95 cmH2O. Also, 60% of the highest SNIPs occurred among the 11th and 20th maneuvers in men and women. In men, 55% of the highest SNEPs occurred among the 11th and 20th maneuvers; this value was 50% in women. CONCLUSION: SNIP and SNEP showed excellent reliability. The reliability of SNIP and SNEP in men was good and excellent, respectively, whereas both tests had excellent reliability in women. Also, women reached the highest peak pressure faster than men in both tests.

Easy C. elegans Worm Lifespan Plotting and Statistics with WLSplot.

WLSplot is an R package used to easily analyze lifespan survival data, and display results graphically as a survival curve with useful labels and statistical information auto-generated from the data and added to the graph, within a single function. It is designed primarily with Caenorhabditis elegans lifespan data in mind initially but can easily be used for other types of survival data. The WLSplot GitHub repository provides a blank template spreadsheet to be used for collecting lifespan data, instructions on how to install and run WLSplot, and examples covering RNAi, Genotype, or Drug lifespan experimental set-ups. WLSplot can analyze and plot multiple experiments in bulk while correctly italicizing worm gene names and adding asterisks and p-values to the plot legend when a significantly different lifespan from the designated control lifespan is seen. This is returned as an editable scalable vector graphics (svg) file for each output, and WLSplot can also return the summary of the directly plotted data so that the researcher can do their own further manipulation, in addition to being able to edit the output svg files.

It's Hip to Go Home: An Evaluation of Outpatient Alveolar Bone Grafting in Patients With Cleft Palate.

INTRODUCTION: Secondary alveolar bone grafting (ABG) is a common procedure performed at cleft care centers used to fill the alveolar cleft. The advent of techniques such as minimally invasive trephine drill harvest and placement of continuous-infusion pain pumps at the donor site has made outpatient ABG an increasingly feasible and cost-effective procedure. However, enhanced recovery after surgery protocols to maximize pain control and recovery times for this patient population have not been well established. METHODS: A retrospective single-institution review was conducted of pediatric patients with cleft palate who underwent iliac crest bone graft ABG at a large urban academic children's hospital from 2017 to 2022. Patient age, alveolar cleft repair laterality, pain scores, surgery duration, hospital LOS, readmissions, and re-operations within 30 days were examined. RESULTS: Fifty-four patients met our inclusion criteria. Fifty patients (92.6%) received a pain pump during the operation. The median duration of surgery and LOS in the post-anesthesia care unit were 1.28 and 1.75 hours, respectively. Fifty-two patients (96.3%) were discharged on the same day as their surgery whereas 2 patients (3.7%) stayed in the hospital overnight. The median pain score at the time of discharge was 0 (interquartile range 0, 0). There were 6 (11.1%) minor complications including 5 pain pump malfunctions and 1 recipient site wound breakdown. There was 1 readmission (1.9%) for development of a surgical site infection at the hip and no re-operations within 30 days of surgery. CONCLUSION: The described outpatient ABG protocol demonstrates effective postoperative pain control, short hospital LOS, and few complications requiring hospital readmission or reoperation.

Systematic review of cnidarian microbiomes reveals insights into the structure, specificity, and fidelity of marine associations.

Microorganisms play essential roles in the health and resilience of cnidarians. Understanding the factors influencing cnidarian microbiomes requires cross study comparisons, yet the plethora of protocols used hampers dataset integration. We unify 16S rRNA gene sequences from cnidarian microbiome studies under a single analysis pipeline. We reprocess 12,010 cnidarian microbiome samples from 186 studies, alongside 3,388 poriferan, 370 seawater samples, and 245 cultured Symbiodiniaceae, unifying ~6.5 billion sequence reads. Samples are partitioned by hypervariable region and sequencing platform to reduce sequencing variability. This systematic review uncovers an incredible diversity of 86 archaeal and bacterial phyla associated with Cnidaria, and highlights key bacteria hosted across host sub-phylum, depth, and microhabitat. Shallow (< 30 m) water Alcyonacea and Actinaria are characterized by highly shared and relatively abundant microbial communities, unlike Scleractinia and most deeper cnidarians. Utilizing the V4 region, we find that cnidarian microbial composition, richness, diversity, and structure are primarily influenced by host phylogeny, sampling depth, and ocean body, followed by microhabitat and sampling date. We identify host and geographical generalist and specific Endozoicomonas clades within Cnidaria and Porifera. This systematic review forms a framework for understanding factors governing cnidarian microbiomes and creates a baseline for assessing stress associated dysbiosis.

Promoting rural residents' participation in clinical trials: clinical trials basics programming and training for rural public librarians.

Background: Having diverse representation in clinical trial participation is important. Historically, rural residents have been underrepresented in clinical trial research. Public librarians have an opportunity to promote clinical trial participation among rural residents by offering consumer health information services that help patrons to understand what clinical trials are and how they can find relevant clinical trials. Case Presentation: A consumer health library and a clinical trial center located at a large academic medical center collaborated to provide clinical trial information programming to rural public libraries. The group was awarded a Network of the National Library of Medicine (NNLM) Community Outreach Grant and was able to plan, develop, promote, and implement programs including training workshops, a speaker event, and a book discussion to rural public librarians. Discussion: Marketing the programs to rural public libraries was difficult and many barriers were encountered. Though registration and subsequent participation were low, participants expressed interest and gratitude for the programs. For any future programs targeting this population, further strategies will need to be implemented to ensure increased registrations and attendees.

Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

Axonemal regulation by curvature explains sperm flagellar waveform modulation.

Flagellar motility is critical to natural and many forms of assisted reproduction. Rhythmic beating and wave propagation by the flagellum propels sperm through fluid and enables modulation between penetrative progressive motion, activated side-to-side yaw and hyperactivated motility associated with detachment from epithelial binding. These motility changes occur in response to the properties of the surrounding fluid environment, biochemical activation state, and physiological ligands, however, a parsimonious mechanistic explanation of flagellar beat generation that can explain motility modulation is lacking. In this paper, we present the Axonemal Regulation of Curvature, Hysteretic model, a curvature control-type theory based on switching of active moment by local curvature, embedded within a geometrically nonlinear elastic model of the flagellum exhibiting planar flagellar beats, together with nonlocal viscous fluid dynamics. The biophysical system is parameterized completely by four dimensionless parameter groupings. The effect of parameter variation is explored through computational simulation, revealing beat patterns that are qualitatively representative of penetrative (straight progressive), activated (highly yawing) and hyperactivated (nonprogressive) modes. Analysis of the flagellar limit cycles and associated swimming velocity reveals a cusp catastrophe between progressive and nonprogressive modes, and hysteresis in the response to changes in critical curvature parameter. Quantitative comparison to experimental data on human sperm exhibiting typical penetrative, activated and hyperactivated beats shows a good fit to the time-average absolute curvature profile along the flagellum, providing evidence that the model is capable of providing a framework for quantitative interpretation of imaging data.