Genomic co-localization of variation affecting agronomic and human gut microbiome traits in a meta-analysis of diverse sorghum.

Substantial functional metabolic diversity exists within species of cultivated grain crops that directly or indirectly provide more than half of all calories consumed by humans around the globe. While such diversity is the molecular currency used for improving agronomic traits, diversity is poorly characterized for its effects on human nutrition and utilization by gut microbes. Moreover, we know little about agronomic traits' potential trade-offs and pleiotropic effects on human nutritional traits. Here we applied a quantitative genetics approach using a meta-analysis and parallel genome-wide association studies of Sorghum bicolor traits describing changes in the composition and function of human gut microbe communities and any of 200 sorghum seed and agronomic traits across a diverse sorghum population to identify associated genetic variants. A total of fifteen multiple-effect loci (MEL) were initially found where different alleles in the sorghum genome produced changes in seed that affected the abundance of multiple bacterial taxa across two human microbiomes in automated in vitro fermentations. Next, parallel genome-wide studies conducted for seed, biochemical, and agronomic traits in the same population identified significant associations within the boundaries of 13/15 MEL for microbiome traits. In several instances, the co-localization of variation affecting gut microbiome and agronomic traits provided hypotheses for causal mechanisms through which variation could affect both agronomic traits and human gut microbes. This work demonstrates that genetic factors affecting agronomic traits in sorghum seed can also drive significant effects on human gut microbes, particularly bacterial taxa considered beneficial. Understanding these pleiotropic relationships will inform future strategies for crop improvement toward yield, sustainability, and human health.

Comparison of Superior versus Inferior Canaloplasty and Trabeculotomy Using the OMNI Surgical System.

Purpose: To compare outcomes of ab-interno canaloplasty and trabeculotomy of the superior versus inferior angle. Patients and methods: This was a prospective, non-randomized, interventional comparison study done at the Veteran Affairs Hospital in Long Beach, California. All patients underwent cataract surgery with intraocular lens implantation combined with ab-interno canaloplasty and trabeculotomy with the OMNI Surgical System (SightSciences, Menlo Park, CA, USA), either superiorly or inferiorly. Pre- and post-operative intraocular pressure using Goldmann applanation tonometry and best corrected visual acuity were obtained and compared using paired t-tests. Patients were excluded if they had any prior intraocular surgery or prior laser trabeculoplasty procedures. Results: 38 eyes from 29 patients were analyzed. 19 eyes were included in the superior group and 19 eyes in the inferior group. Mean pre-operative IOP in the superior group was 17.6 ± 5.2 mmHg and in the inferior group was 17.6 ± 4.6 mmHg (p > 0.99). At 12 months, mean postoperative IOP for the superior group decreased 24% to 13.3 ± 2.8 mmHg while the inferior group decreased 26% to 13.1 ± 2.2 mmHg (p = 0.92). Mean preoperative medications in the superior group were 2.2 ± 1.3 and in the inferior group was 2.4 ± 1.3 (p = 0.88). At 12 months, this decreased to 1.3 ± 1.5 post-operatively in the superior group and 2.2 ± 1.6 post-operatively in the inferior group (p = 0.64). Conclusion: There was no statistical difference in efficacy between superior versus inferior canaloplasty/trabeculotomy with OMNI. Therefore, surgeons can perform the procedure in the direction that is most comfortable for them without affecting outcomes.

Acute microtubule changes linked to DMD pathology are insufficient to impair contractile function or enhance contraction-induced injury in healthy muscle.

Duchenne muscular dystrophy (DMD) is marked by the genetic deficiency of the dystrophin protein in striated muscle whose consequence is a cascade of cellular changes that predispose the susceptibility to contraction injury central to DMD pathology. Recent evidence identified the proliferation of microtubules enriched in post-translationally modified tubulin as a consequence of dystrophins absence that increases the passive mechanics of the muscle fiber and the excess mechanotransduction elicited reactive oxygen species and calcium signals that promote contraction injury. Motivated by evidence that acutely normalizing the disease microtubule alterations reduced contraction injury in murine DMD muscle (mdx), here we sought the direct impact of these microtubule alterations independent of dystrophins absence and the multitude of other changes consequent to dystrophic disease. To this end we used acute pharmacologic (epithiolone-D, EpoD; 4 hours) or genetic (vashohibin-2 and small vasohibin binding protein overexpression via AAV9; 2 weeks) strategies to effectively model the proliferation of detyrosination enriched microtubules in the mdx muscle. Quantifying in vivo nerve evoked plantarflexor function we find no alteration in peak torque nor contraction kinetics in WT mice modeling these DMD relevant MT alterations. Quantifying the susceptibility to eccentric contraction injury we show EpoD treatment proffered a small but significant protection from contraction injury while VASH/SVBP had no discernable impact. We conclude that the disease dependent MT alterations act in concert with additional cellular changes to predispose contraction injury in DMD.

Ciliated Epibionts Modify the Cardiac Stress Reaction to Perceived Predation in Daphnia.

When animals perceive an acute stressor like a predator, they typically undergo a suite of physiological changes that function to improve survival during the encounter, such as elevation in cardiac output, to supply more energy to muscles. If bodily energy is limited, such as by parasites or infections, these functions could become less efficient and lessen host survival. In the aquatic world of microorganisms, individuals can become colonized by other organisms on their surface (epibionts), which could sap energy from their host from their weight, or even compete with the host for food. Here, we tested if one epibiont (a ciliated protozoan, Vorticella spp.) affects its hosts' ability to mount a physiological stress reaction. We collected wild daphnia (Daphnia ambigua) that had varying burdens of these on their bodies and exposed them to a simulated stressor (crushed daphnia, to simulate nearby predation) under a microscope while monitoring for changes in their heart rates in real time. Out of 121 daphnia, those with no Vorticella epibionts showed no meaningful changes in their heart rate after exposure, but those with light or heavy burdens showed immediate elevations (within 5 min). Moreover, the heart rates of heavily burdened daphnia continued to rise for 1.5 h thereafter, to as much as 17% higher than at baseline. These patterns were unexpected, as they suggest that the ciliated epibionts act to elevate their hosts' physiological reaction, rather than dampen it, perhaps by churning the water column around the host, thereby enhancing the chemical alarm cue. The procedures used in this study may be useful for future investigations into the acute stress reactions of daphnia or other microorganisms.

Can profiles of behaviors occurring within 48 h of a suicide attempt predict future severity of suicidal thoughts and reattempt?: An examination of hospitalized patients 12 Months post-discharge.

Behavioral warning signs (WS) are near-term changes within individuals, which aid in determining imminent risk for suicide attempts. However, those who attempt suicide differ in their engagement of WS, and it is unclear if these differences relate to future risk of suicidal behavior. Using a sample of 132 adults presenting to a hospital following a suicide attempt, the current study sought to determine if differences in engagement in WS for the index attempt prospectively predicted suicide attempt, frequency of ideation, and intensity of suicide ideation 12 months post discharge. Latent class analyses (LCAs) conducted on 6 behaviors (i.e., alcohol use, nightmares, interpersonal negative life events, suicide communication, risky behavior, low sleep, and high sleep) found a 5-class solution optimally fit the data. One identified class, characterized by engagement in risky behaviors the hours before an attempt differed from other identified classes in terms of risk for future suicidal ideation and behaviors. More specifically, participants in "High Risky Behavior" class had higher rates of 12-month suicide reattempt, significantly more frequent suicide ideation, and significantly worse intensity of suicide ideation during the 12 months following their index attempt compared to participants endorsing typical patterns of WS. These results held when adjusting for various traditional baseline covariates (e.g., depressive symptoms). The current study demonstrates that patterns of behavioral WS may be utilized as their own prognostic indicator of future suicidal ideation and behaviors among high-risk individuals reporting a recent suicide attempt, which can inform post-discharge clinical intervention and prevention efforts.

Turning foes to friends: Advanced "in situ nanovaccine" with dual immunoregulation for enhanced immunotherapy of metastatic triple-negative breast cancer.

As a "cold tumor", triple-negative breast cancer (TNBC) exhibits limited responsiveness to current immunotherapy. How to enhance the immunogenicity and reverse the immunosuppressive microenvironment of TNBC remain a formidable challenge. Herein, an "in situ nanovaccine" Au/CuNDs-R848 was designed for imaging-guided photothermal therapy (PTT)/chemodynamic therapy (CDT) synergistic therapy to trigger dual immunoregulatory effects on TNBC. On the one hand, Au/CuNDs-R848 served as a promising photothermal agent and nanozyme, achieving PTT and photothermal-enhanced CDT against the primary tumor of TNBC. Meanwhile, the released antigens and damage-associated molecular patterns (DAMPs) promoted the maturation of dendritic cells (DCs) and facilitated the infiltration of T lymphocytes. Thus, Au/CuNDs-R848 played a role as an "in situ nanovaccine" to enhance the immunogenicity of TNBC by inducing immunogenic cell death (ICD). On the other hand, the nanovaccine suppressed the myeloid-derived suppressor cells (MDSCs), thereby reversing the immunosuppressive microenvironment. Through the dual immunoregulation, "cold tumor" was transformed into a "hot tumor", not only implementing a "turning foes to friends" therapeutic strategy but also enhancing immunotherapy against metastatic TNBC. Furthermore, Au/CuNDs-R848 acted as an excellent nanoprobe, enabling high-resolution near-infrared fluorescence and computed tomography imaging for precise visualization of TNBC. This feature offers potential applications in clinical cancer detection and surgical guidance. Collectively, this work provides an effective strategy for enhancing immune response and offers novel insights into the potential clinical applications for tumor immunotherapy.

Trends in management of patients with new-onset refractory status epilepticus (NORSE) from 2016 to 2023: An interim analysis.

In response to the evolving treatment landscape for new-onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy-seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second-line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second-line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1-1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3-2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second-line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3-8.9)-particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3-21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5-20.1)-than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second-line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes.

Structural characterization of ligand binding and pH-specific enzymatic activity of mouse Acidic Mammalian Chitinase.

Chitin is an abundant biopolymer and pathogen-associated molecular pattern that stimulates a host innate immune response. Mammals express chitin-binding and chitin-degrading proteins to remove chitin from the body. One of these proteins, Acidic Mammalian Chitinase (AMCase), is an enzyme known for its ability to function under acidic conditions in the stomach but is also active in tissues with more neutral pHs, such as the lung. Here, we used a combination of biochemical, structural, and computational modeling approaches to examine how the mouse homolog (mAMCase) can act in both acidic and neutral environments. We measured kinetic properties of mAMCase activity across a broad pH range, quantifying its unusual dual activity optima at pH 2 and 7. We also solved high-resolution crystal structures of mAMCase in complex with oligomeric GlcNAcn, the building block of chitin, where we identified extensive conformational ligand heterogeneity. Leveraging these data, we conducted molecular dynamics simulations that suggest how a key catalytic residue could be protonated via distinct mechanisms in each of the two environmental pH ranges. These results integrate structural, biochemical, and computational approaches to deliver a more complete understanding of the catalytic mechanism governing mAMCase activity at different pH. Engineering proteins with tunable pH optima may provide new opportunities to develop improved enzyme variants, including AMCase, for therapeutic purposes in chitin degradation.

Improving mentalizing deficits in older age with region-specific transcranial direct current stimulation.

Older adults have difficulties to detect the intentions, thoughts, and feelings of others, indicating an age-associated decline of socio-cognitive abilities that are known as "mentalizing". These deficits in mental state recognition are driven by neurofunctional alterations in brain regions that are implicated in mentalizing, such as the right temporo-parietal junction (rTPJ) and the dorso-medial prefrontal cortex (dmPFC). We tested whether focal transcranial current stimulation (tDCS) of the rTPJ and dmPFC has the potential to eliminate mentalizing deficits in older adults. Mentalizing deficits were assessed with a novel mindreading task that required the recognition of mental states in child faces. Older adults (n = 60) performed worse than younger adults (n = 30) on the mindreading task, indicating age-dependent deficits in mental state recognition. These mentalizing deficits were ameliorated in older adults who received sham-controlled andodal tDCS over the rTPJ (n = 30) but remained unchanged in older adults who received sham-controlled andodal tDCS over the dmPFC (n = 30). We, thus, showed for the first time that anodal tDCS over the rTPJ has the potential to remediate age-dependent mentalizing deficits in a region-specific way. This provides a rationale for exploring stimulation-based interventions targeting mentalizing deficits in older age.

Dynamic Drop Penetration of Horizontally Oriented Fiber Arrays.

In this experimental study, we combine drop impact into porous media and onto a single fiber to study drop impact into fiber arrays inspired by mammalian fur coats. In our 3D-printed arrays, we vary the packing density, fiber alignment, strand cross-section, and wettability. Drops impact fibers fixed at both ends, penetrating over short periods of time by momentum and laterally spreading throughout the array. Using image analysis, we measure penetration depth and wetted width into the array. Impact Weber number and intrinsic porosity define penetration, retraction, and rebound regimes. On average, at an impact Weber number of ≈80, staggered fibers reduce penetration by 24% in hydrophilic fibers and 34% in hydrophobic fibers, and the penetration reduction percentage is expected to increase with increasing Weber number. Our results indicate that as density grows toward the density of mammalian pelts, penetration will reach a maximum value independent of drop impact velocity, thereby providing an effective rain barrier. Hydrophilicity at the densities we test, 50-150 strands/cm2, aids fiber array resistance to dynamic penetration by impacting drops through the promotion of lateral drop spreading and inhibition of drop fragmentation. Conversely, hydrophobic fibers best resist low-speed wicking. The fraction of a drop that infiltrates hydrophilic and hydrophobic fibers is nearly identical for a fixed Weber number because lateral spreading restricts the penetration depth into hydrophilic fibers but does not restrict mass infiltration. Above a critical Weber number, the entire drop mass penetrates fiber arrays regardless of strand wettability.

ESR1 and p53 interactome alteration defines mechanisms of tamoxifen response in luminal breast cancer.

The canonical mechanism behind tamoxifen's therapeutic effect on estrogen receptor α/ESR1+ breast cancers is inhibition of ESR1-dependent estrogen signaling. Although ESR1+ tumors expressing wild-type p53 were reported to be more responsive to tamoxifen (Tam) therapy, p53 has not been factored into choice of this therapy and the mechanism underlying the role of p53 in Tam response remains unclear. In a window-of-opportunity trial on patients with newly diagnosed stage I-III ESR1+/HER2/wild-type p53 breast cancer who were randomized to arms with or without Tam prior to surgery, we reveal that the ESR1-p53 interaction in tumors was inhibited by Tam. This resulted in functional reactivation of p53 leading to transcriptional reprogramming that favors tumor-suppressive signaling, as well as downregulation of oncogenic pathways. These findings illustrating the convergence of ESR1 and p53 signaling during Tam therapy enrich mechanistic understanding of the impact of p53 on the response to Tam therapy.

Gene Electrotransfer via Conductivity-Clamped Electric Field Focusing Pivots Sensori-Motor DNA Therapeutics: "A Spoonful of Sugar Helps the Medicine Go Down".

Viral vectors and lipofection-based gene therapies have dispersion-dependent transduction/transfection profiles that thwart precise targeting. The study describes the development of focused close-field gene electrotransfer (GET) technology, refining spatial control of gene expression. Integration of fluidics for precise delivery of "naked" plasmid deoxyribonucleic acid (DNA) in sucrose carrier within the focused electric field enables negative biasing of near-field conductivity ("conductivity-clamping"-CC), increasing the efficiency of plasma membrane molecular translocation. This enables titratable gene delivery with unprecedently low charge transfer. The clinic-ready bionics-derived CC-GET device achieved neurotrophin-encoding miniplasmid DNA delivery to the cochlea to promote auditory nerve regeneration; validated in deafened guinea pig and cat models, leading to improved central auditory tuning with bionics-based hearing. The performance of CC-GET is evaluated in the brain, an organ problematic for pulsed electric field-based plasmid DNA delivery, due to high required currents causing Joule-heating and damaging electroporation. Here CC-GET enables safe precision targeting of gene expression. In the guinea pig, reporter expression is enabled in physiologically critical brainstem regions, and in the striatum (globus pallidus region) delivery of a red-shifted channelrhodopsin and a genetically-encoded Ca2+ sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders.

Natural compound Alternol exerts a broad anti-cancer spectrum and a superior therapeutic safety index in vivo.

Introduction: Alternol is a natural compound isolated from the fermentation of a mutated fungus. We have demonstrated its potent anti-cancer effect via the accumulation of radical oxygen species (ROS) in prostate cancer cells in vitro and in vivo. In this study, we tested its anti-cancer spectrum in multiple platforms. Methods: We first tested its anti-cancer spectrum using the National Cancer Institute-60 (NCI-60) screening, a protein quantitation-based assay. CellTiter-Glo screening was utilized for ovarian cancer cell lines. Cell cycle distribution was analyzed using flow cytometry. Xenograft models in nude mice were used to assess anti-cancer effect. Healthy mice were tested for the acuate systemic toxicity. Results: Our results showed that Alternol exerted a potent anti-cancer effect on 50 (83%) cancer cell lines with a GI50 less than 5 µM and induced a lethal response in 12 (24%) of those 50 responding cell lines at 10 µM concentration. Consistently, Alternol displayed a similar anti-cancer effect on 14 ovarian cancer cell lines in an ATP quantitation-based assay. Most interestingly, Alternol showed an excellent safety profile with a maximum tolerance dose (MTD) at 665 mg/kg bodyweight in mice. Its therapeutic index was calculated as 13.3 based on the effective tumor-suppressing doses from HeLa and PC-3 cell-derived xenograft models. Conclusion: Taken together, Alternol has a broad anti-cancer spectrum with a safe therapeutic index in vivo.

Development of a sterile insect technique as a control strategy for the Asian citrus psyllid: establishing the effect of sterilizing X-rays on fecundity, fertility, and survival.

The Asian citrus psyllid (ACP), Diaphorina citri Kuwayama (Hemiptera: Psyllidae), is a major pest of citrus due to its role as the vector of the bacterium that causes huanglongbing. In commercial citrus, ACP control currently relies on the application of insecticides, which may not be sustainable long-term, nor practical in urban areas. The sterile insect technique (SIT) is an alternative strategy in which large numbers of pests are reared, sterilized using radiation, and then released into the field to compete with wild individuals for matings, suppressing population growth. As a fundamental step toward the development of SIT for ACP, this study sought to identify the optimum radiation dose required to sterilize ACP without affecting their survival and mating capacity. Virgin adult ACP of both sexes were subjected to doses of X-ray irradiation ranging from 40 to 480 Gy, then paired with a nonirradiated mate and allowed to produce offspring. Fecundity was estimated as the number of eggs laid, and fertility as the proportion of those eggs that hatched. Females were more radio-sensitive than males, exhibiting a major drop in fecundity at even the lowest dose and 100% sterility at 80 Gy. In contrast, a fivefold higher dose (400 Gy) did not achieve complete sterility in males, with around 5% offspring survival. However, F1 progeny of males exposed to 320 Gy or higher were subsequently found to be 100% sterile. This confirmation of inherited sterility suggests that balancing the sterilizing effects of radiation against its mortality-inducing effects may warrant further evaluation.

Do Hounsfield Units From Intraoperative CT Scans Correlate With Preoperative Values?

BACKGROUND: There is increasing interest in forecasting postoperative complications using bone density metrics. Vertebral Hounsfield unit measurements obtained from CT scans performed for surgical planning or other purposes, known as opportunistic CTs, have shown promise for their ease of measurement and the ability to target density measurement to a particular region of interest. Concomitant with the rising interest in prognostic bone density measurement use has been the increasing adoption of intraoperative advanced imaging techniques. Despite the interest in both outcome prognostication and intraoperative advanced imaging, there is little information regarding the use of CT-based intraoperative imaging as a means to measure bone density. QUESTIONS/PURPOSES: (1) Can vertebral Hounsfield units be reliably measured by physician reviewers from CT scans obtained intraoperatively? (2) Do Hounsfield units measured from intraoperative studies correlate with values measured from preoperative CT scans? METHODS: To be eligible for this retrospective study, patients had to have been treated with the use of an intraoperative CT scan for instrumented spinal fusion for either degenerative conditions or traumatic injuries between January 2015 and December 2022. Importantly, patients without a preoperative CT scan of the fused levels within 180 days before surgery or who were indicated for surgery because of infection, metastatic disease, or who were having revision surgery after prior instrumentation were excluded from the query. Of the 285 patients meeting these inclusion criteria, 53% (151) were initially excluded for the following reasons: 36% (102) had intraoperative CT scans obtained after placement of instrumentation, 16% (47) had undergone intraoperative CT scans but the studies were not accessible for Hounsfield unit measurement, and 0.7% (2) had prior kyphoplasty wherein the cement prevented Hounsfield unit measurement. Finally, an additional 19% (53) of patients were excluded because the preoperative CT and intraoperative CT were obtained at different peak voltages, which can influence Hounsfield unit measurement. This yielded a final population of 81 patients from whom 276 preoperative and 276 intraoperative vertebral Hounsfield unit measurements were taken. Hounsfield unit data were abstracted from the same vertebra(e) from both preoperative and intraoperative studies by two physician reviewers (one PGY3 and one PGY5 orthopaedic surgery resident, both pursuing spine surgery fellowships). For a small, representative subset of patients, measurements were taken by both reviewers. The feasibility and reliability of Hounsfield unit measurement were then assessed with interrater reliability of values measured from the same vertebra by the two different reviewers. To compare Hounsfield unit values from intraoperative CT scans with preoperative CT studies, an intraclass correlation using a two-way random effects, absolute agreement testing technique was employed. Because the data were formatted as multiple measurements from the same vertebra at different times, a repeated measures correlation was used to assess the relationship between preoperative and intraoperative Hounsfield unit values. Finally, a linear mixed model with patients handled as a random effect was used to control for different patient and clinical factors (age, BMI, use of bone density modifying agents, American Society of Anesthesiologists [ASA] classification, smoking status, and total Charlson comorbidity index [CCI] score). RESULTS: We found that Hounsfield units can be reliably measured from intraoperative CT scans by human raters with good concordance. Hounsfield unit measurements of 31 vertebrae from a representative sample of 10 patients, measured by both reviewers, demonstrated a correlation value of 0.82 (95% CI 0.66 to 0.91), indicating good correlation. With regard to the relationship between preoperative and intraoperative measurements of the same vertebra, repeated measures correlation testing demonstrated no correlation between preoperative and intraoperative measurements (r = 0.01 [95% CI -0.13 to 0.15]; p = 0.84). When controlling for patient and clinical factors, we continued to observe no relationship between preoperative and intraoperative Hounsfield unit measurements. CONCLUSION: As intraoperative CT and measurement of vertebral Hounsfield units both become increasingly popular, it would be a natural extension for spine surgeons to try to extract Hounsfield unit data from intraoperative CTs. However, we found that although it is feasible to measure Hounsfield data from intraoperative CT scans, the obtained values do not have any predictable relationship with values obtained from preoperative studies, and thus, these values should not be used interchangeably. With this knowledge, future studies should explore the prognostic value of intraoperative Hounsfield unit measurements as a distinct entity from preoperative measurements. LEVEL OF EVIDENCE: Level III, diagnostic study.

Effect of Human Head Shape on the Risk of Traumatic Brain Injury: A Gaussian Process Regression-based Machine Learning Approach.

INTRODUCTION: Computational head injury models are promising tools for understanding and predicting traumatic brain injuries. However, most available head injury models are "average" models that employ a single set of head geometry (e.g., 50th-percentile U.S. male) without considering variability in these parameters across the human population. A significant variability of head shapes exists in U.S. Army soldiers, evident from the Anthropometric Survey of U.S. Army Personnel (ANSUR II). The objective of this study is to elucidate the effects of head shape on the predicted risk of traumatic brain injury from computational head injury models. MATERIALS AND METHODS: Magnetic resonance imaging scans of 25 human subjects are collected. These images are registered to the standard MNI152 brain atlas, and the resulting transformation matrix components (called head shape parameters) are used to quantify head shapes of the subjects. A generative machine learning model is used to generate 25 additional head shape parameter datasets to augment our database. Head injury models are developed for these head shapes, and a rapid injurious head rotation event is simulated to obtain several brain injury predictor variables (BIPVs): Peak cumulative maximum principal strain (CMPS), average CMPS, and the volume fraction of brain exceeding an injurious CMPS threshold. A Gaussian process regression model is trained between head shape parameters and BIPVs, which is then used to study the relative sensitivity of the various BIPVs on individual head shape parameters. We distinguish head shape parameters into 2 types: Scaling components ${T_{xx}}$, ${T_{yy}}$, and ${T_{zz}}$ that capture the breadth, length, and height of the head, respectively, and shearing components (${T_{xy}},{T_{xz}},{T_{yx}},{T_{yz}},{T_{zx}}$, and ${T_{zy}}$) that capture the relative skewness of the head shape. RESULTS: An overall positive correlation is evident between scaling components and BIPVs. Notably, a very high, positive correlation is seen between the BIPVs and the head volume. As an example, a 57% increase in peak CMPS was noted between the smallest and the largest investigated head volume parameters. The variation in shearing components ${T_{xy}},{T_{xz}},{T_{yx}},{T_{yz}},{T_{zx}}$, and ${T_{zy}}$ on average does not cause notable changes in the BIPVs. From the Gaussian process regression model, all 3 BIPVs showed an increasing trend with each of the 3 scaling components, but the BIPVs are found to be most sensitive to the height dimension of the head. From the Sobol sensitivity analysis, the ${T_{zz}}$ scaling parameter contributes nearly 60% to the total variance in peak and average CMPS; ${T_{yy}}$ contributes approximately 20%, whereas ${T_{xx}}$ contributes less than 5%. The remaining contribution is from the 6 shearing components. Unlike peak and average CMPS, the VF-CMPS BIPV is associated with relatively evenly distributed Sobol indices across the 3 scaling parameters. Furthermore, the contribution of shearing components on the total variance in this case is negligible. CONCLUSIONS: Head shape has a considerable influence on the injury predictions of computational head injury models. Available "average" head injury models based on a 50th-percentile U.S. male are likely associated with considerable uncertainty. In general, larger head sizes correspond to greater BIPV magnitudes, which point to potentially a greater injury risk under rapid neck rotation for people with larger heads.

A phase I/II study of nintedanib and capecitabine for refractory metastatic colorectal cancer.

BACKGROUND: Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose and efficacy of nintedanib and capecitabine in refractory metastatic colorectal cancer. METHODS: Key eligibility criteria included refractory metastatic colorectal cancer and ECOG performance status of 1 or lower. The primary endpoint was 18-week progression-free survival (PFS). A 1-sided binomial test (at α = .1) compared the observed 18-week PFS with a historic control of .25. RESULTS: Forty-two patients were enrolled, including 39 at the recommended phase II dose. The recommended phase II dose was established to be nintedanib 200 mg by mouth twice daily and capecitabine 1000 mg/m2 by mouth twice daily. The protocol was evaluated for efficacy in 36 patients. The 18-week PFS was 42% (15/36 patients; P = .0209). Median PFS was 3.4 mo. Median overall survival was 8.9 mo. Sixteen (44%) patients experienced a grade 3/4 adverse event, most commonly fatigue (8%), palmoplantar erythrodysesthesia (8%), aspartate aminotransferase elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration (6%). Osteopontin levels at cycle 1, day 1 and cycle 3, day 1 as well as ΔCCL2 levels correlated to disease control at 18 weeks. CONCLUSIONS: The combination of nintedanib and capecitabine is well tolerated. Clinical efficacy appears to be superior to regorafenib or tipiracil hydrochloride monotherapy. Further investigation of similar combinations is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT02393755.

Five key strategies for organizing interdisciplinary scientific events to strengthen careers, collaborations, and creativity.

Science is becoming increasingly interdisciplinary; the widespread emergence of dedicated interdisciplinary journals, conferences, and graduate programs reflects this trend. Interdisciplinary scientific events are extremely valuable in that they offer opportunities for career advancement, especially among early career researchers, for collaboration beyond traditional disciplinary echo chambers, and for the creative generation of innovative solutions to longstanding scientific problems. However, organizing such events can pose unique challenges due to the intentionality required to meaningfully break down the barriers that separate long-independent disciplines. In this paper, we propose five key strategies for organizing and hosting interdisciplinary scientific events. The recommendations offered here apply both to small symposia aiming to contribute an interdisciplinary component to a larger event and to broad interdisciplinary conferences hosting hundreds or thousands of attendees.