Relationship Between Absorbed Dose and Response in Neuroendocrine Tumors Treated with [177Lu]Lu-DOTATATE.

Peptide receptor radionuclide therapy presents the possibility of tracing and quantifying the uptake of the drug in the body and performing dosimetry, potentially allowing individualization of treatment schemes. However, the details of how neuroendocrine tumors (NETs) respond to different absorbed doses are insufficiently known. Here, we investigated the relationship between tumor-absorbed dose and tumor response in a cohort of patients with NETs treated with [177Lu]Lu-DOTATATE. Methods: This was a retrospective study based on 69 tumors in 32 patients treated within a clinical trial. Dosimetry was performed at each cycle of [177Lu]Lu-DOTATATE, rendering 366 individual absorbed dose assessments. Hybrid planar-SPECT/CT imaging using [177Lu]Lu-DOTATATE was used, including quantitative SPECT reconstruction, voxel-based absorbed dose rate calculation, semiautomatic image segmentation, and partial-volume correction. Changes in tumor volume were used to determine tumor response. The volume for each tumor was manually delineated on consecutive CT scans, giving a total of 712 individual tumor volume assessments. Tumors were stratified according to grade. The relationship between absorbed dose and response was investigated using mixed-effects models and logistic regression. Tumors smaller than 4 cm3 were excluded. Results: In grade 2 NETs, a clear relationship between absorbed dose and volume reduction was observed. Our observations suggest a 90% probability of partial tumor response for an accumulated tumor-absorbed dose of at least 135 Gy. Conclusion: Our findings are in accordance with previous observations regarding the relationship between tumor shrinkage and absorbed dose. Moreover, our data suggest an absorbed dose threshold for partial response in grade 2 NETs. These observations provide valuable insights for the design of dosimetry-guided peptide receptor radionuclide therapy schemes.

Neural digital twins: reconstructing complex medical environments for spatial planning in virtual reality.

PURPOSE: Specialized robotic and surgical tools are increasing the complexity of operating rooms (ORs), requiring elaborate preparation especially when techniques or devices are to be used for the first time. Spatial planning can improve efficiency and identify procedural obstacles ahead of time, but real ORs offer little availability to optimize space utilization. Methods for creating reconstructions of physical setups, i.e., digital twins, are needed to enable immersive spatial planning of such complex environments in virtual reality. METHODS: We present a neural rendering-based method to create immersive digital twins of complex medical environments and devices from casual video capture that enables spatial planning of surgical scenarios. To evaluate our approach we recreate two operating rooms and ten objects through neural reconstruction, then conduct a user study with 21 graduate students carrying out planning tasks in the resulting virtual environment. We analyze task load, presence, perceived utility, plus exploration and interaction behavior compared to low visual complexity versions of the same environments. RESULTS: Results show significantly increased perceived utility and presence using the neural reconstruction-based environments, combined with higher perceived workload and exploratory behavior. There's no significant difference in interactivity. CONCLUSION: We explore the feasibility of using modern reconstruction techniques to create digital twins of complex medical environments and objects. Without requiring expert knowledge or specialized hardware, users can create, explore and interact with objects in virtual environments. Results indicate benefits like high perceived utility while being technically approachable, which may indicate promise of this approach for spatial planning and beyond.

Maternal Vitamin D Supplementation and Infantile Rickets: Secondary Analysis of a Randomized Trial.

BACKGROUND: The role of maternal vitamin D supplementation in the prevention of infantile rickets is unknown, particularly in low- and middle-income countries without routine infant vitamin D supplementation. Through secondary analysis of a randomized, placebo-controlled trial in Bangladesh, we examined the dose-ranging effects of maternal vitamin D supplementation on the risk of biochemical rickets at 6 to 12 months of age. METHODS: Pregnant women (n = 1300) were randomized into 5 groups: placebo, or vitamin D 4200 IU/week, 16 800 IU/week, or 28 000 IU/week from second trimester to delivery and placebo until 6 months postpartum; or 28 000 IU/week prenatally and until 6 months postpartum. Infants underwent biochemical rickets screening from 6 to 12 months of age (n = 790). Relative risks (RR) and 95% confidence intervals (95% CI) of biochemical rickets were estimated for each group versus placebo. RESULTS: Overall, 39/790 (4.9%) infants had biochemical rickets. Prevalence was highest in the placebo group (7.8%), and the risk was significantly lower among infants whose mothers received combined prenatal and postpartum vitamin D at 28 000 IU/week (1.3%; RR, 0.16; 95% CI, 0.03-0.72). Risks among infants whose mothers received only prenatal supplementation (4200 IU, 16 800 IU, 28 000 IU weekly) were not significantly different from placebo: 3.8% (RR, 0.48; 95% CI, 0.19-1.22), 5.8% (RR, 0.74; 95% CI, 0.33-1.69), and 5.7% (RR, 0.73; 95% CI, 0.32-1.65), respectively. CONCLUSIONS: Maternal vitamin D supplementation (28 000 IU/week) during the third trimester of pregnancy until 6 months postpartum reduced the risk of infantile biochemical rickets. Further research is needed to define optimal postpartum supplementation dosing during lactation.

Prenatal but not continued postpartum vitamin D supplementation reduces maternal bone resorption as measured by C-terminal telopeptide of type 1 collagen without effects on other biomarkers of bone metabolism.

Vitamin D is a key regulator of bone mineral homeostasis and may modulate maternal bone health during pregnancy and postpartum. Using previously-collected data from the Maternal Vitamin D for Infant Growth (MDIG) trial in Dhaka, Bangladesh, we aimed to investigate the effects of prenatal and postpartum vitamin D3 supplementation on circulating biomarkers of bone formation and resorption at delivery and 6 months postpartum. MDIG trial participants were randomized to receive a prenatal;postpartum regimen of placebo or vitamin D3 (IU/week) as either 0;0 (Group A), 4200;0 (B), 16,800;0 (C), 28,000;0 (D) or 28,000;28,000 (E) from 17 to 24 weeks' gestation to 6 months postpartum. As this sub-study was not pre-planned, the study sample included MDIG participants who had data for at least 1 biomarker of interest at delivery or 6 months postpartum, with a corresponding baseline measurement (n = 690; 53 % of 1300 enrolled trial participants). Biomarkers related to bone turnover were measured in maternal venous blood samples collected at enrolment, delivery, and 6 months postpartum: osteoprotegerin (OPG), osteocalcin (OC), receptor activator nuclear factor kappa-B ligand (RANKL), fibroblast growth factor 23 (FGF23), procollagen type 1 N-terminal propeptide, (P1NP) and carboxy terminal telopeptide of type 1 collagen (CTx). Supplementation effects were expressed as percent differences between each vitamin D group and placebo with 95 % confidence intervals (95 % CI). Of 690 participants, 64 % had 25-hydroxyvitamin D concentrations (25OHD) <30 nmol/L and 94 % had 25OHD < 50 nmol/L at trial enrolment. At delivery, mean CTx concentrations were 27 % lower in group E versus placebo (95 % CI: -38, -13; P < 0.001), adjusting for enrolment concentrations. However, at 6 months postpartum, CTx concentrations were not statistically different in group E versus placebo (14 %; 95 % CI: -5.3, 37; P = 0.168), adjusting for delivery CTx concentrations. Effects on other biomarkers at delivery or postpartum were not statistically significant. In conclusion, prenatal high-dose vitamin D supplementation reduced bone resorption during pregnancy, albeit by only one biomarker, and without evidence of a sustained effect in the postpartum period. However, further evidence is needed to substantiate potential maternal bone health benefits of vitamin D in the postpartum period.

Clinical prediction models in children that use repeated measurements with time-varying covariates: a scoping review

BACKGROUND: Emerging evidence suggests that clinical prediction models that use repeated (time-varying) measurements within each patient may have higher predictive accuracy than models that use patient information from a single measurement. OBJECTIVE: To determine the breadth of the published literature reporting the development of clinical prediction models in children that use time-varying predictors. DATA SOURCES: MEDLINE, EMBASE and Cochrane databases. ELIGIBILITY CRITERIA: We included studies reporting the development of a multivariable clinical prediction model in children, with or without validation, to predict a repeatedly measured binary or time-to-event outcome and utilizing at least one repeatedly measured predictor. SYNTHESIS METHODS: We categorized included studies by the method used to model time-varying predictors. RESULTS: Of 99 clinical prediction model studies that had a repeated measurements data structure, only 27 (27%) used methods that incorporated the repeated measurements as time-varying predictors in a single model. Among these 27 time-varying prediction model studies, we grouped model types into nine categories: time-dependent Cox regression, generalized estimating equations, random effects model, landmark model, joint model, neural network, K-nearest neighbor, support vector machine and tree-based algorithms. Where there was comparison of time-varying models to single measurement models, using time-varying predictors improved predictive accuracy. CONCLUSIONS: Various methods have been used to develop time-varying prediction models in children, but there is a paucity of pediatric time-varying models in the literature. Incorporating time-varying covariates in pediatric prediction models may improve predictive accuracy. Future research in pediatric prediction model development should further investigate whether incorporation of time-varying covariates improves predictive accuracy.

A Study on Collaborative Visual Data Analysis in Augmented Reality with Asymmetric Display Types.

Collaboration is a key aspect of immersive visual data analysis. Due to its inherent benefit of seeing co-located collaborators, augmented reality is often useful in such collaborative scenarios. However, to enable the augmentation of the real environment, there are different types of technology available. While there are constant developments in specific devices, each of these device types provide different premises for collaborative visual data analysis. In our work we combine handheld, optical see-through and video see-through displays to explore and understand the impact of these different device types in collaborative immersive analytics. We conducted a mixed-methods collaborative user study where groups of three performed a shared data analysis task in augmented reality with each user working on a different device, to explore differences in collaborative behaviour, user experience and usage patterns. Both quantitative and qualitative data revealed differences in user experience and usage patterns. For collaboration, the different display types influenced how well participants could participate in the collaborative data analysis, nevertheless, there was no measurable effect in verbal communication.

Ocular, Visual, and Anatomical Outcomes in Eyes Requiring Incisional Intraocular Pressure-Lowering Surgery Following the 0.19-mg Fluocinolone Acetonide Intravitreal Implant.

BACKGROUND AND OBJECTIVE: To assess ocular, visual, and anatomical outcomes following the 0.19-mg fluocinolone acetonide (FAc) intravitreal implant (ILUVIEN®) and incisional intraocular pressure (IOP)-lowering surgery in diabetic macular edema. PATIENTS AND METHODS: From a 36-month, phase 4, open-label, observational study (N = 202 eyes, 159 patients), 8 eyes (7 patients) required IOP-lowering surgery post-FAc; eyes were segregated by FAc-induced (n = 5, 2.47%) versus neovascular glaucoma (NVG)-related (n = 3, 1.49%) IOP elevations and assessed for IOP, best corrected visual acuity (BCVA), central subfield thickness (CST), and cup-to-disc ratio (c/d). RESULTS: Changes at 36 months were +5.4 letters BCVA (P > 0.05) and +0.09 c/d (P = 0.0217); IOP and CST were unchanged. FAc-induced-group eyes required fewer IOP-lowering medications than NVG-group eyes (2.0 versus 4.0; P < 0.01) but for longer duration (15.2 versus 2.6 months; P < 0.001). CONCLUSIONS: Post-FAc IOP-lowering surgery, regardless of cause, largely did not affect the outcomes measured; these procedures, then, may not meaningfully threaten positive outcomes. [Ophthalmic Surg Lasers Imaging Retina 2024;55:22-29.].

Feasibility of 177Lu activity quantification using a small portable CZT-based gamma-camera.

BACKGROUND: In image processing for activity quantification, the end goal is to produce a metric that is independent of the measurement geometry. Photon attenuation needs to be accounted for and can be accomplished utilizing spectral information, avoiding the need of additional image acquisitions. The aim of this work is to investigate the feasibility of 177Lu activity quantification with a small CZT-based hand-held gamma-camera, using such an attenuation correction method. METHODS: A previously presented dual photopeak method, based on the differential attenuation for two photon energies, is adapted for the three photopeaks at 55 keV, 113 keV, and 208 keV for 177Lu. The measurement model describes the count rates in each energy window as a function of source depth and activity, accounting for distance-dependent system sensitivity, attenuation, and build-up. Parameter values are estimated from characterizing measurements, and the source depth and activity are obtained by minimizing the difference between measured and modelled count rates. The method is applied and evaluated in phantom measurements, in a clinical setting for superficial lesions in two patients, and in a pre-clinical setting for one human tumour xenograft. Evaluation is made for a LEHR and an MEGP collimator. RESULTS: For phantom measurements at clinically relevant depths, the average (and standard deviation) in activity errors are 17% ± 9.6% (LEHR) and 2.9% ± 3.6% (MEGP). For patient measurements, deviations from activity estimates from planar images from a full-sized gamma-camera are 0% ± 21% (LEHR) and 16% ± 18% (MEGP). For mouse measurements, average deviations of - 16% (LEHR) and - 6% (MEGP) are obtained when compared to a small-animal SPECT/CT system. The MEGP collimator appears to be better suited for activity quantification, yielding a smaller variability in activity estimates, whereas the LEHR results are more severely affected by septal penetration. CONCLUSIONS: Activity quantification for 177Lu using the hand-held camera is found to be feasible. The readily available nature of the hand-held camera may enable more frequent activity quantification in e.g., superficial structures in patients or in the pre-clinical setting.

The 0.19-mg Fluocinolone Acetonide Intravitreal Implant for Diabetic Macular Edema: Intraocular Pressure-Related Effects over 36 Months.

PURPOSE: To evaluate effects of the 0.19-mg fluocinolone acetonide (FAc) intravitreal implant (ILUVIEN) on intraocular pressure (IOP) in patients with diabetic macular edema (DME). DESIGN: Secondary analysis of a 36-month, phase IV, nonrandomized, open-label, observational study. PARTICIPANTS: The study included 202 eyes from 159 patients who received the 0.19-mg FAc implant after a successful prior steroid challenge per the United States label indication. METHODS: Study eyes were assessed for IOP values, incidence of IOP elevations, and best-corrected visual acuity (BCVA) for up to 36 months post-FAc implant. RESULTS: Mean IOP was stable over 36 months post-FAc; IOP change from baseline peaked at 2.12 mmHg at 9 months, then declined to baseline levels. At 36 months, eyes had a 32.5% cumulative probability of an IOP event > 25 mmHg and a 15.6% probability of an IOP event > 30 mmHg (Kaplan-Meier). The probability of requiring IOP-lowering medication at any time by month 36 was 38.3%. A total of 78% of eyes did not have IOP elevations > 25 mmHg if similar values were seen with the previous steroid challenge. Although 7.4% of eyes had an IOP > 30 mmHg during a scheduled study visit, most exceeded this threshold only once (60%). Regardless of IOP status, mean BCVA remained stable. CONCLUSIONS: Over 36 months, the 0.19-mg FAc implant was associated with relatively stable IOPs in patients with DME, and there was no significant impact of IOP elevations identified regarding their effects on long-term visual outcomes. The probability that a prior corticosteroid challenge will not predict an IOP elevation > 25 mmHg over 36 months post-FAc is 22%; therefore, routine IOP monitoring should be scheduled. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Detection and absolute quantification of Lactiplantibacillus plantarum ATCC 202195 by quantitative real-time PCR.

IMPORTANCE: When administered for seven consecutive days shortly after birth, the probiotic bacterium Lactiplantibacillus plantarum ATCC 202195 plus fructooligosaccharide (FOS) was reported to reduce sepsis and lower respiratory tract infection events during early infancy in a randomized trial in India. Since probiotic effects are often strain specific, strain-level detection and quantification by routine molecular methods enables the monitoring of safety outcomes, such as probiotic-associated bacteremia, and allows for the quality of probiotic interventions to be assessed and monitored (i.e., verify strain identity and enumerate). Despite the potential clinical applications of L. plantarum ATCC 202195, an assay to detect and quantify this strain has not previously been described. Herein, we report the design of primer and probe sequences to detect L. plantarum ATCC 202195 and the development and optimization of a real-time PCR assay to detect and quantify the strain with high specificity and high sensitivity.

Mass Spectrometric Detection of Formaldehyde-Crosslinked PBMC Proteins in Cell-Free DNA Blood Collection Tubes.

Streck tubes are commonly used to collect blood samples to preserve cell-free circulating DNA. They contain imidazolidinyl urea as a formaldehyde-releasing agent to stabilize cells. We investigated whether the released formaldehyde leads to crosslinking of intracellular proteins. Therefore, we employed a shotgun proteomics experiment on human peripheral blood mononuclear cells (PBMCs) that were isolated from blood collected in Streck tubes, EDTA tubes, EDTA tubes containing formaldehyde, or EDTA tubes containing allantoin. The identified crosslinks were validated in parallel reaction monitoring LC/MS experiments. In total, we identified and validated 45 formaldehyde crosslinks in PBMCs from Streck tubes, which were also found in PBMCs from formaldehyde-treated blood, but not in EDTA- or allantoin-treated samples. Most were derived from cytoskeletal proteins and histones, indicating the ability of Streck tubes to fix cells. In addition, we confirm a previous observation that formaldehyde crosslinking of proteins induces a +24 Da mass shift more frequently than a +12 Da shift. The crosslinking capacity of Streck tubes needs to be considered when selecting blood-collection tubes for mass-spectrometry-based proteomics or metabolomic experiments.

Associations between human milk oligosaccharides and infant growth in a Bangladeshi mother-infant cohort.

BACKGROUND: We aimed to estimate associations between human milk oligosaccharides (HMOs) and infant growth (length-for-age (LAZ) and weight-for-length (WLZ) z-scores) at 12 months postnatal age. METHODS: In this secondary analysis of data from a maternal vitamin D trial in Dhaka, Bangladesh (N = 192), absolute concentrations of HMOs were measured in 13 ± 1 week(s) postpartum milk samples, infant anthropometric measurements were obtained soon after birth and at 12 months postpartum, and infant feeding was classified during 6 months postpartum. Associations between individual HMOs or HMO groups and LAZ or WLZ were estimated by multivariable linear regression adjusting for infant feeding pattern, maternal secretor status, and other potential confounders. RESULTS: The concentrations of 6'sialyllactose, lacto-N-neotetraose, and the non-fucosylated non-sialylated HMOs were inversely associated with LAZ at 12 months of age, whereas the fucosylated non-sialylated HMO concentration was positively associated with LAZ at 12 months. These associations were robust in analyses restricted to infants who were primarily exclusively/predominantly fed human milk during the first 3 (or 6) months. CONCLUSIONS: Since HMOs are both positively and negatively associated with postnatal growth, there is a need for randomized trials to estimate the causal benefits and risks of exogenously administered HMOs on infant growth and other health outcomes. IMPACT: 6'sialyllactose, lacto-N-neotetraose, and the non-fucosylated non-sialylated human milk oligosaccharides (HMOs) were inversely associated with length-for-age z-scores (LAZ) at 12 months, whereas the fucosylated non-sialylated HMO concentration was positively associated with LAZ at 12 months among Bangladeshi infants. Associations between individual and grouped HMOs with infant length growth at 12 months were as strong or stronger in analyses restricted to infants who were exclusively or predominantly fed human milk up to 3 (or 6) months. Randomized trials are needed to characterize the effects of specific HMOs on infant growth, particularly in countries where postnatal linear growth faltering is common.

Reduced Incidence of Intravitreal Injection-Related Endophthalmitis With Prefilled Syringes.

Purpose: To evaluate the incidence and clinical characteristics of intravitreal injection-related endophthalmitis cases with antivascular endothelial growth factor (anti-VEGF) medications manufactured as prefilled syringes or non-prefilled preparations. Methods: This retrospective chart review comprised eyes that received intravitreal anti-VEGF at a single-specialty retina practice from January 1, 2014, to December 31, 2019. Eyes diagnosed with injection-related endophthalmitis were identified. Demographic and clinical data were abstracted from medical records, including the type of anti-VEGF agent, baseline and follow-up corrected visual acuity (VA), and microbiologic findings. Results: The review identified 88 cases of intravitreal anti-VEGF injection-related endophthalmitis and 325 990 total injections. Total injections included 32 045 (9.8%) bevacizumab (BEV), 93 073 (28.6%) ranibizumab (RAN), 122 947 (37.7%) aflibercept (AFL), and 77 925 (23.9%) ranibizumab prefilled syringe (RANPFS). Ten of the endophthalmitis cases were related to BEV, 21 to RAN, 45 to AFL, and 12 to RANPFS. The endophthalmitis rate was lowest for RANPFS (0.0154%) (BEV, 0.0312%; RAN, 0.0226%; AFL, 0.0366%) (P = .030). Thirty-four (41.5%) of 82 samples were culture positive. RANPFS had a significantly lower rate of culture-proven postinjection endophthalmitis than the other agents (P = .003). The mean VA for endophthalmitis cases related to RANPFS vs non-prefilled agents was similar at presentation (Snellen 20/2092 vs 20/2327) and at the 3-month follow-up (Snellen 20/201 vs 20/272) (both P > .05). Conclusions: Anti-VEGF medications in prefilled syringes may reduce the risk for medication contamination during injection preparation. RANPFS was associated with a lower rate of injection-related endophthalmitis than non-prefilled anti-VEGF medications.

Injured Avatars: The Impact of Embodied Anatomies and Virtual Injuries on Well-Being and Performance.

Human cognition relies on embodiment as a fundamental mechanism. Virtual avatars allow users to experience the adaptation, control, and perceptual illusion of alternative bodies. Although virtual bodies have medical applications in motor rehabilitation and therapeutic interventions, their potential for learning anatomy and medical communication remains underexplored. For learners and patients, anatomy, procedures, and medical imaging can be abstract and difficult to grasp. Experiencing anatomies, injuries, and treatments virtually through one's own body could be a valuable tool for fostering understanding. This work investigates the impact of avatars displaying anatomy and injuries suitable for such medical simulations. We ran a user study utilizing a skeleton avatar and virtual injuries, comparing to a healthy human avatar as a baseline. We evaluate the influence on embodiment, well-being, and presence with self-report questionnaires, as well as motor performance via an arm movement task. Our results show that while both anatomical representation and injuries increase feelings of eeriness, there are no negative effects on embodiment, well-being, presence, or motor performance. These findings suggest that virtual representations of anatomy and injuries are suitable for medical visualizations targeting learning or communication without significantly affecting users' mental state or physical control within the simulation.

Reversible Oxidative Addition of Nonactivated C-H Bonds to Structurally Constrained Phosphenium Ions.

A series of structurally constrained phosphenium ions based on pyridinylmethylamidophenolate scaffolds are shown to undergo P(III)/P(V) oxidative addition with C-H bonds of alkynes, alkenes, and arenes. Nonactivated substrates such as benzene, toluene, and deactivated chlorobenzene are phosphorylated in quantitative yields. Computational and spectroscopic studies suggest a low-barrier isomerization from a bent to a T-shaped isomer that initiates a phosphorus-ligand-cooperative pathway and subsequent ring-chain tautomerism. Remarkably, C-H bond activations occur reversibly, allowing for reductive elimination back to P(III) at elevated temperatures or the exchange with other substrates.

Deep Learning in Surgical Workflow Analysis: A Review of Phase and Step Recognition.

OBJECTIVE: In the last two decades, there has been a growing interest in exploring surgical procedures with statistical models to analyze operations at different semantic levels. This information is necessary for developing context-aware intelligent systems, which can assist the physicians during operations, evaluate procedures afterward or help the management team to effectively utilize the operating room. The objective is to extract reliable patterns from surgical data for the robust estimation of surgical activities performed during operations. The purpose of this article is to review the state-of-the-art deep learning methods that have been published after 2018 for analyzing surgical workflows, with a focus on phase and step recognition. METHODS: Three databases, IEEE Xplore, Scopus, and PubMed were searched, and additional studies are added through a manual search. After the database search, 343 studies were screened and a total of 44 studies are selected for this review. CONCLUSION: The use of temporal information is essential for identifying the next surgical action. Contemporary methods used mainly RNNs, hierarchical CNNs, and Transformers to preserve long-distance temporal relations. The lack of large publicly available datasets for various procedures is a great challenge for the development of new and robust models. As supervised learning strategies are used to show proof-of-concept, self-supervised, semi-supervised, or active learning methods are used to mitigate dependency on annotated data. SIGNIFICANCE: The present study provides a comprehensive review of recent methods in surgical workflow analysis, summarizes commonly used architectures, datasets, and discusses challenges.

METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL.

RNA splicing dysregulation underlies the onset and progression of cancers. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in ∼20% of patients. However, the mechanism for splicing defects in spliceosome-unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover that proteins involved in RNA splicing are posttranscriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing complexes is an independent risk factor for poor prognosis. Moreover, increased splicing factor expression is highly correlated with the abundance of METTL3, an RNA methyltransferase that deposits N6-methyladenosine (m6A) on mRNA. METTL3 is essential for cell growth in vitro and in vivo and controls splicing factor protein expression in a methyltransferase-dependent manner through m6A modification-mediated ribosome recycling and decoding. Our results uncover METTL3-mediated m6A modification as a novel regulatory axis in driving splicing dysregulation and contributing to aggressive CLL. SIGNIFICANCE: METTL3 controls widespread splicing factor abundance via translational control of m6A-modified mRNA, contributes to RNA splicing dysregulation and disease progression in CLL, and serves as a potential therapeutic target in aggressive CLL. See related commentary by Janin and Esteller, p. 176. This article is highlighted in the In This Issue feature, p. 171.

Complementary and alternative metrics for tracking population-level trends in child linear growth.

Stunting prevalence is commonly used to track population-level child nutritional status. However, other metrics derived from anthropometric datasets may be used as alternatives to stunting or provide complementary perspectives on the status of linear growth faltering in low- and middle-income countries (LMICs). Data from 156 Demographic and Health Surveys in 63 LMICs (years 2000 to 2020) were used to generate 2 types of linear growth metrics: (i) measures of location of height distributions (including stunting) for under-5 years (<5y) and 2 to 5 years (2-5y); (ii) model-derived metrics including predicted mean height-for-age z-score (HAZ) at 0, 2, and 5 years; interval slopes of HAZ, height-for-age difference (HAD), and growth delay (GD) from 1 month to 2 years (1mo-2y) and 2-5y; and the SITAR intensity parameter (SITAR-IP) for <5y. Using Spearman's rank correlation coefficient (r), metrics were considered alternatives to stunting if very strongly correlated with stunting (|r|≥0.95) and at least as strongly correlated as stunting with selected population indicators (under 5y mortality, gross domestic product, maternal education). Metrics were considered complementary if less strongly correlated with stunting (|r|<0.95) yet correlated with population indicators. We identified 6 of 15 candidate metrics (stunting 2-5y, mean HAZ <5y and 2-5y, p25 HAZ <5y and 2-5y, predicted HAZ at 2y) as potential alternatives to stunting and 6 as complementary metrics (SITAR-IP, predicted HAZ at 5y, HAZ slope 1m-2y, HAD slope 1m-2y, GD slopes 1m-2y and 2-5y). Three metrics (HAZ slope 2-5y, HAD slope 2-5y years and predicted HAZ at birth) had weak correlations with population indicators (|r| ≤ 0.43). In conclusion, several linear growth metrics could serve as alternatives to stunting prevalence and others may be complementary to stunting in tracking global progress in child health and nutrition. Further research is needed to explore the real-world utility of these alternative and complementary metrics.

Estimation of skeletal muscle mass in 4-year-old children using the D3-creatine dilution method.

BACKGROUND: Given limited experience in applying the creatine-(methyl-D3) (D3Cr) dilution method to measure skeletal muscle mass (SMM) in young children, the feasibility of deployment in a fielding setting and performance of the method was assessed in a cohort of 4-year-old children in Dhaka, Bangladesh. METHODS: Following D3Cr oral dose (10 mg) administration, single fasting urine samples were collected at 2-4 days (n = 100). Twenty-four-hour post-dose collections and serial spot urine samples on days 2, 3 and 4 were obtained in a subset of participants (n = 10). Urinary creatine, creatinine, D3Cr and D3-creatinine enrichment were analyzed by liquid chromatography-tandem mass spectrometry. Appendicular lean mass (ALM) was measured by dual-energy x-ray absorptiometry and grip strength was measured by a hand-held dynamometer. RESULTS: SMM was measured successfully in 91% of participants, and there were no adverse events. Mean ± SD SMM was greater than ALM (4.5 ± 0.4 and 3.2 ± 0.6 kg, respectively). Precision of SMM was low (intraclass correlation = 0.20; 95% CI: 0.02, 0.75; n = 10). Grip strength was not associated with SMM in multivariable analysis (0.004 kg per 100 g of SMM; 95% CI: -0.031, 0.038; n = 91). CONCLUSIONS: The D3Cr dilution method was feasible in a community setting. However, high within-child variability in SMM estimates suggests the need for further optimization of this approach. IMPACT: The D3-creatine (D3Cr) stable isotope dilution method was considered a feasible method for the estimation of skeletal muscle mass (SMM) in young children in a community setting and was well accepted among participants. SMM was weakly associated with both dual-energy x-ray absorptiometry-derived values of appendicular lean mass and grip strength. High within-child variability in estimated values of SMM suggests that further optimization of the D3Cr stable isotope dilution method is required prior to implementation in community research settings.