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Performance-based engineering for natural hazards facilitates the design and appraisal of structures with rigorous evaluation of their uncertain structural behavior under potentially extreme stochastic loads expressed in terms of failure probabilities against stated criteria. As a result, efficient stochastic simulation schemes are central to computational frameworks that aim to estimate failure probabilities associated with multiple limit states using limited sample sets. In this work, a generalized stratified sampling scheme is proposed in which two phases of sampling are involved: the first is devoted to the generation of strata-wise samples and the estimation of strata probabilities whereas the second aims at the estimation of strata-wise failure probabilities. Phase-I sampling enables the selection of a generalized stratification variable (i.e., not necessarily belonging to the input set of random variables) for which the probability distribution is not known a priori. To improve the efficiency, Markov Chain Monte Carlo Phase-I sampling is proposed when Monte Carlo simulation is deemed infeasible and optimal Phase-II sampling is implemented based on user-specified target coefficients of variation for the limit states of interest. The expressions for these coefficients are derived with due regard to the sample correlations induced by the Markov chains and the uncertainty in the estimated strata probabilities. The proposed stochastic simulation scheme reaps the benefits of near-optimal stratified sampling for a broader choice of stratification variables in high-dimensional reliability problems with a mechanism to approximately control the accuracy of the failure probability estimators. The practicality of the scheme is demonstrated using two examples involving the estimation of failure probabilities associated with highly nonlinear responses induced by wind and seismic excitations., Comment: 45 pages, 12 figures Forthcoming. ASCE Journal of Engineering Mechanics, 2023

Objectives While national medical guidelines recommend genetic testing for all individuals with non-syndromic autism spectrum disorder (ASD), there is underutilization of genetic testing. This study aims to define the perspectives and approaches to initial genetic testing of ASD diagnosticians in order to improve utilization. Methods A prospective cross-sectional study was conducted using an anonymous online survey distributed to 59 staff neurologists, developmental-behavioral pediatricians, psychologists, post-graduate physician fellows, and nurse practitioners from a single academic medical center. Questions explored knowledge, attitudes, and practices of initial genetic testing for ASD among diagnosticians. Results Among the 30 respondents (51% response rate), a lack of comprehensive pre-test genetic counseling was identified and forgetfulness was the most prevalent reason for not recommending genetic testing (n = 7/23, 30%). Insurance prior authorization (PA) for genetic testing was a major barrier for clinicians. More than half of respondents (n = 13/25, 52%) reported being uncomfortable with the PA process. Conclusions Variability in knowledge and practices among ASD diagnosticians regarding genetic testing was identified. Therefore, potential interventions like clinician and administrative staff education, as well as genetic counselor integration into ASD clinics, may be useful to improve genetic testing utilization.

Glioblastoma (GBM) is the most prevalent and aggressive adult brain tumor. Despite multi-modal therapies, GBM recurs, and patients have poor survival (~14 months). Resistance to therapy may originate from a subpopulation of tumor cells identified as glioma-stem cells (GSC), and new treatments are urgently needed to target these. The biology underpinning GBM recurrence was investigated using whole transcriptome profiling of patient-matched initial and recurrent GBM (recGBM). Differential expression analysis identified 147 significant probes. In total, 24 genes were validated using expression data from four public cohorts and the literature. Functional analyses revealed that transcriptional changes to recGBM were dominated by angiogenesis and immune-related processes. The role of MHC class II proteins in antigen presentation and the differentiation, proliferation, and infiltration of immune cells was enriched. These results suggest recGBM would benefit from immunotherapies. The altered gene signature was further analyzed in a connectivity mapping analysis with QUADrATiC software to identify FDA-approved repurposing drugs. Top-ranking target compounds that may be effective against GSC and GBM recurrence were rosiglitazone, nizatidine, pantoprazole, and tolmetin. Our translational bioinformatics pipeline provides an approach to identify target compounds for repurposing that may add clinical benefit in addition to standard therapies against resistant cancers such as GBM.

1AbstractDecades of research have investigated the molecular and cellular mechanisms that control the immune response to malaria. Yet, many studies offer conflicting results on the functional impact of innate immunity for controlling parasite replication early in infection. We conduct a meta-analysis to probe for consensus on the effect of innate immunity on parasite replication, examining three different species of rodent malaria parasite. Screening published studies that span four decades of research we collate, curate and statistically analyse infection dynamics in immune deficient or augmented mice to identify and quantify consensus and identify sources of disagreement among studies. Additionally, we estimate whether host factors or experimental methodology shape the impact of immune perturbations on parasite burden. First, we detected meta-analytic mean effect sizes (absolute Cohen’s h) for the difference in parasite burden between treatment and control groups ranging from 0.1498 to 0.2321 across parasite species. This range is considered a small effect size and translates to a modest change in parasitaemia of roughly 6-12% on average at the peak of infection. Second, we reveal that variation across studies usingP. chabaudiorP. yoeliiis best explained by stochasticity (due to small sample sizes) rather than by host factors or experimental design. Third, we find that forP. bergheithe impact of immune perturbation is increased when young or female mice are used and is greatest when effector molecules (as opposed to upstream signalling molecules) are disrupted (up to an 18% difference in peak parasitaemia). Finally, we find little evidence of publication bias suggesting that our results are robust. The small effects sizes we observe, across three parasite species, following experimental perturbations of the innate immune system may be explained by redundancy in a complex biological system or by incomplete (or inappropriate) data reporting for meta-analysis. Alternatively, our findings might indicate a need to re-evaluate the efficiency with which innate immunity controls parasite replication early in infection. Testing these explanations is necessary to translate understanding from model systems to human malaria infections, manage immunopathology, and facilitate realism in mathematical models.

SUMMARY Air-to-ground coupled seismic arrivals, resulting from infrasound interacting with the ground surface, can be identified on seismometers co-located with microbarometers. Dense networks of co-located sensors provide detailed spatial information about the infrasonic wavefield, allowing investigation of infrasonic propagation and an assessment of the variability in air-to-ground coupling mechanisms. Signals generated by an explosion at Camp Minden, Louisiana, United States, on 2012 October 16 were recorded across the eastern United States on the USArray Transportable Array. 233 infrasound signals were identified at distances of up to 1566 km from the source, with 105 of these sites, at distances of up to 1147 km from the source, recording above-noise air-to-ground coupled seismic arrivals in the 2–4 Hz passband (chosen to maximise seismic arrival signal-to-noise ratios). The spatially dense infrasound recordings allowed a unique investigation of the azimuthal variation in infrasound amplitudes, showing that stratospheric arrival amplitudes increased by a factor greater than 4 between the edge and centre of the stratospheric propagation duct. Air-to-ground coupling coefficients, calculated as the ratios of temporally coincident peak-to-trough seismic and infrasound time-domain amplitudes, span over two orders of magnitude ([9.0 × 10−8, 5.0 × 10−5] ms−1 Pa−1). Sites exhibiting high coupling coefficients are predominantly located on alluvial sediments that support the generation of air-to-ground coupled Rayleigh waves, resulting in poor coherence between the seismic and infrasonic waveforms. In contrast, sites exhibiting low coupling coefficients are predominantly located on chemically weathered bedrock and only support direct coupling, leading to high coherence between air-to-ground coupled seismic and infrasonic recordings. The Camp Minden explosion observations, and a consideration of expected seismic noise and air-to-ground coupled arrival amplitudes, suggest that co-located pairs of seismometers and microbarometers are likely to record signals from small (tens of tons) explosions at distances of over 1000 km under favourable propagation conditions. Co-located deployments may therefore provide a cost-effective method for augmenting current state-of-the-art infrasound array networks, by providing a higher spatial density of recordings; this may assist in correctly associating recorded signals with, and estimating the location of, source events.

Worker hostels or dormitories are common in labour-intensive industries staffed largely by migrant labour, and have long been associated with exploitative practices. More recently, hostels have come under scrutiny because of accusations that they are used to restrict workers’ freedom in ways that are tantamount to modern slavery. Drawing on a qualitative study of a garment hub in South India where such claims have frequently arisen, we explore the conditions of freedom and unfreedom in worker hostels and how suppliers who run such hostels respond to competing expectations about worker freedom. Our findings show that hostels perform three interrelated functions: restriction, protection, and liberation, which together constitute a complex mix of freedom and unfreedom for migrant women workers that we term hybrid (un)freedom. As a result, we problematize the binary understandings of freedom and unfreedom that predominate in the modern slavery literature. We also develop a new way forward for examining freedom in the context of hostels that considers the system of relationships, traditions, and socio-economic arrangements that workers and employers are locked into and that prevent meaningful improvements in the freedom of women workers.

Peer reviewed: True, Funder: University of Glasgow; Id: http://dx.doi.org/10.13039/501100000853, Pancreatic cancer is a deadly and highly metastatic disease, although how metastatic lesions establish is not fully understood. A key feature of pancreatic tumours is extensive fibrosis and deposition of extracellular matrix (ECM). While pancreatic cancer cells are programmed by stimuli derived from a stiff ECM, metastasis requires loss of attachment and adaptation to a softer microenvironment at distant sites. Growing evidence suggests that stiff ECM influences pancreatic cancer cell behaviour. Here, we argue that this influence is reversible and that pancreatic cancer cells can be reprogrammed upon sensing soft substrates. Using engineered polyacrylamide hydrogels with tuneable mechanical properties, we show that collagen VI is specifically upregulated in pancreatic cancer cells on soft substrates, due to a lack of integrin engagement. Furthermore, the expression of collagen VI is inversely correlated with mechanosensing and activity of YAP (also known as YAP1), which might be due to a direct or indirect effect on transcription of genes encoding collagen VI. Collagen VI supports migration in vitro and metastasis formation in vivo. Metastatic nodules formed by pancreatic cancer cells lacking Col6a1 display stromal cell-derived collagen VI deposition, suggesting that collagen VI derived from either cancer cells or the stroma is an essential component of the metastatic niche. This article has an associated First Person interview with Vasileios Papalazarou, joint first author of the paper.

Summary Background Ring fixator techniques can precisely correct complex long bone deformities. In select patients, controlled shortening or intentional fracture deformation with delayed correction can also aid in complex wound coverage and limb salvage. Methods This retrospective cohort study analyzed all patients who underwent acute limb shortening or intentional temporary fracture deformation between 2005 and 2020. Patients were divided into three groups based on reason for acute shortening or intentional deformity: (1) skeletal indications alone, with traditional flap coverage; (2) skeletal and soft tissue indications, to augment traditional reconstructive measures; and (3) skeletal and soft tissue indications, to avoid microsurgery altogether. Comorbidities, orthopedic and reconstructive methods, and functional outcomes were recorded. Results Eighteen patients were identified: six in Group 1, five in Group 2, and seven in Group 3. Fractures were primarily in the distal third of the tibia. On initial assessment, all wounds would have required free tissue transfer. Group 1 patients were reconstructed with free flaps. Among Group 2, closure was accomplished by skin grafting (N = 1), local flaps (N = 1), pedicled muscle flaps (N = 1), and free flaps (N = 2). In Group 3, five wounds were closed primarily and two were skin grafted. All limbs were shortened, averaging 25.1 mm; seven were intentionally deformed, most commonly varus (10–20°). After skeletal correction, residual leg length discrepancy averaged 5.7 mm. No patients required amputation. Conclusions Acute skeletal shortening with or without intentional temporary deformation in select IIIB/IIIC open tibial fractures can facilitate soft tissue coverage and limb salvage in patients who might otherwise require amputation.

OBJECTIVE To compare immediate quality of open reduction of femoral neck fractures by alternative surgical approaches. DESIGN Retrospective cohort study. SETTING Twelve Level 1 North American trauma centers. PATIENTS Eighty adults 18-65 years of age with isolated, displaced, OTA/AO type 31-B2 or -B3 femoral neck fractures treated with internal fixation. INTERVENTION Thirty-two modified Smith-Petersen anterior approaches versus 48 Watson-Jones anterolateral approaches for open reduction performed by fellowship-trained orthopaedic trauma surgeons. MAIN OUTCOME Reduction quality as assessed by 3 senior orthopaedic traumatologists as "acceptable" or "unacceptable" on AP and lateral postoperative radiographs. RESULTS No difference was observed in the rate of acceptable reduction by modified Smith-Petersen (81%) versus Watson-Jones (81%) approach (risk difference null, 95% confidence interval -17.4% to 17.4%, P = 1.00) with 90.4% panel agreement (Fleiss' weighted κ = 0.63, P < 0.01). Stratified analyses did not identify a significant difference in the rate of acceptable reduction between approaches when stratified by Pauwels angle, basicervical or transcervical fracture location, or posterior comminution. The Smith-Petersen approach afforded a better reduction when preoperative skeletal traction was not applied (RR = 1.67 [95% CI 1.10-2.52] vs. RR = 0.87 [95% CI 0.70-1.08], P = 0.006). CONCLUSIONS No difference was observed in the quality of open reduction of displaced femoral neck fractures in young adults when a Watson-Jones anterolateral approach versus a modified Smith-Petersen anterior approach was performed by orthopaedic trauma surgeons. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Pancreatic ductal adenocarcinoma carries a dismal prognosis, with high rates of metastasis and few treatment options. Hyperactivation of KRAS in almost all tumours drives RAC1 activation, conferring enhanced migratory and proliferative capacity as well as macropinocytosis. Macropinocytosis is well understood as a nutrient scavenging mechanism, but little is known about its functions in trafficking of signaling receptors. We find that CYRI-B is highly expressed in pancreatic tumours in a mouse model of KRAS and p53- driven pancreatic cancer. Deletion of CYRI-B accelerates tumourigenesis, leading to enhanced ERK and JNK-induced proliferation in precancerous lesions, indicating a role as a buffer of RAC1 hyperactivation in early stages. However, as disease progresses, loss of CYRI-B inhibits metastasis. CYRI-B depleted tumour cells show reduced chemotactic responses to lysophosphatidic acid, a major driver of tumour spread, due to impaired macropinocytic uptake of LPAR1 receptor. Overall, we implicate CYRI-B as a mediator of growth and signaling in pancreatic cancer, providing new insights into pathways controlling metastasis.

Microbes in aquifers are present suspended in groundwater or attached to the aquifer sediment. Groundwater is often sampled at gasoline ether oxygenate (GEO)-impacted sites to assess the potential biodegradation of organic constituents. However, the distribution of GEO-degrading microorganisms between the groundwater and aquifer sediment must be understood to interpret this potential. In this study, the distribution of ethyl tert-butyl ether (ETBE)-degrading organisms and ETBE biodegradation potential was investigated in laboratory microcosm studies and mixed groundwater-aquifer sediment samples obtained from pumped monitoring wells at ETBE-impacted sites. ETBE biodegradation potential (as determined by quantification of the ethB gene) was detected predominantly in the attached microbial communities and was below detection limit in the groundwater communities. The copy number of ethB genes varied with borehole purge volume at the field sites. Members of the Comamonadaceae and Gammaproteobacteria families were identified as responders for ETBE biodegradation. However, the detection of the ethB gene is a more appropriate function-based indicator of ETBE biodegradation potential than taxonomic analysis of the microbial community. The study shows that a mixed groundwater-aquifer sediment (slurry) sample collected from monitoring wells after minimal purging can be used to assess the aquifer ETBE biodegradation potential at ETBE-release sites using this function-based concept.

INTRODUCTION In the surgical fixation of fractures, proper biomechanical stability is key in preventing clinical complications including poor fracture healing, residual deformity, loss of fixation, or implant failure. Stability is largely influenced by treatment decisions made by the surgeon. The interplay of surgeon-controlled variables and their effect on the three-dimensional (3D) biomechanics of a fracture fixation construct are often not intuitive, and current training methods do not facilitate a deep understanding of these interactions. METHODS A simulation software interface, FracSim, was developed. FracSim is built on a large precomputed library of finite element simulations. The software allows a surgeon to make adjustments to a virtual fracture fixation construct/weight-bearing plan and immediately visualize how these changes affect 3D biomechanics, including implant stress and fracture gap strain, important for clinical success. Twenty-one orthopaedic residents completed an instructor-led educational session with FracSim focused on bridge plating. Subjects completed pretests and posttests of knowledge of biomechanical concepts and a questionnaire. RESULTS Subjects scored a mean of 5.6/10 on the pretest of biomechanical knowledge. Senior residents scored better than junior residents (P = 0.04). After the educational session with FracSim, residents improved their test scores to a mean of 8.0/10, with a significant improvement (P < 0.001). Questionnaire scores indicated that subjects believed that FracSim had realistic implants, constructs, and motions and that training with FracSim was purposeful, desirable, efficient, fun, and useful for enhancing the understanding of fracture fixation biomechanics. DISCUSSION This new type of simulation software enables interactive visualization of 3D fracture fixation biomechanics. Limitations of this study include lack of a control group undergoing traditional education and lack of a delayed posttest to assess retention. FracSim may provide an effective and engaging way to promote a deeper understanding of biomechanical concepts in the orthopaedic learner.

Neuromodulatory therapies for spinal cord injury (SCI) such as electrical epidural stimulation (EES) are increasingly effective at improving patient outcomes. These improvements are thought to be due, at least in part, to plasticity in neuronal circuits. Precisely which circuits are influenced and which afferent classes are most effective in stimulating change remain important open questions. Genetic tools, such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), support targeted and reversible neuromodulation as well as histological characterization of manipulated neurons. We therefore transduced and activated lumbar large diameter peripheral afferents with excitatory (hM3Dq) DREADDs, in a manner analogous to EES, in a rat hemisection model, to begin to trace plasticity and observe concomitant locomotor changes. Chronic DREADDs activation, coupled with thrice weekly treadmill training, was observed to increase afferent fluorescent labeling within motor pools and Clarke's column when compared to control animals. This plasticity may underlie kinematic differences that we observed across stages of recovery, including an increased and less variable hindquarters height in DREADDs animals, shorter step durations, a more flexed ankle joint early in recovery, a less variable ankle joint angle in swing phase, but a more variable hip joint angle. Withdrawal of DREADDs agonist, clozapine-N-oxide (CNO) left these kinematic differences largely unaffected; suggesting that DREADDs activation is not necessary for them later in recovery. However, we observed an intermittent “buckling” phenomenon in DREADDs animals without CNO activation, that did not occur with CNO re-administration. Future studies could use more refined genetic targeted of specific afferent classes, and utilize muscle recordings to find where afferent modulation is most influential in altering motor output.

Kinematic analyses of rodent behavior are frequently used in neuroscience research, and commonly in spinal cord injury (SCI) studies. Unfortunately, skin motion artifact introduces significant errors into these data, because the skin is only loosely coupled to the underlying skeleton by connective tissue. In rats, these errors can be as large as 50-75%,as quantified by past work using x-ray fluoroscopy. Here we show that infrared videography of a subcutaneous tattoo can overcome skin motion artifact in rodent kinematics. The method yields data similar to gold standard x-ray fluoroscopy systems at a fraction of the cost, does not affect the animals’ locomotion, and results in markers that persist for at least 10 weeks. We found that, compared to a gold-standard x-ray fluoroscopy study that directly tracked the skeleton, our method reduced the error in mean hip angle from 17 ± 6.0 to 3.1 ± 2.4 degrees (mean ± SEM), and the root-mean-square (RMS) error across the mean hip angle waveform from 20 to 5.3 degrees (n=4 rats). The knee joint angle waveform derived from infra-red imaging tightly matched the shape of the x-ray waveform after allowing for a constant offset, having RMS error reduced from 8.1 to 1.2 degrees. The method stands to significantly reduce between-animal errors, and hence between laboratory errors, in these ubiquitous model systems, especially important in SCI studies where individuals are assigned to different treatments.

In endemic settings it is known that natural malaria immunity is gradually acquired following repeated exposures. Here we sought to assess whether similar acquisition of blood-stage malaria immunity would occur following repeated parasite exposure by controlled human malaria infection (CHMI). We report the findings of repeat homologous blood-stageClinicalTrials.gov, identifier NCT03906474, NCT02927145.