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Background: Prior studies in breast cancer (BC) have demonstrated variability in the immune microenvironment of BCs across subtypes, with higher levels of immune infiltration observed in triple-negative (TN) BC. Clinical trials of immunotherapy in BC have largely targeted patients with TNBC, however many of these patients do not respond to treatment, suggesting heterogeneity across TN tumors. Further, immune infiltrated hormone receptor–positive, HER2-negative (HR+/HER2-) tumors have been observed. Patients with these tumors may benefit from immune checkpoint blockade (ICB). Identification of patients with immunogenic tumors would be valuable for future patient selection and stratification in clinical trials. In this study, we conducted comprehensive molecular profiling of a set of commercially procured BC samples to characterize the tumor microenvironment (TME) of HR+/HER2- and TN tumors and to identify patient or tumor features associated with immune infiltration. Methods: 163 surgically resected BC samples were used for this study (93 HR+/HER2-, 70 TN). Clinically validated immunohistochemistry (IHC) assays were used to evaluate the expression of two immune checkpoint (IC) molecules, PD-L1 (by VENTANA PD-L1 (SP142) Assay and Agilent PD-L1 IHC 28-8 pharmDx) and LAG3 (antibody clone 17B4). The presence of CD8+ cells was measured by IHC (Dako/Agilent clone C8/144B) and used to derive the spatial location and density (topology) of CD8+ cells within the TME. RNA sequencing (RNA-seq) was used to construct gene expression signatures representative of immune cell types. Furthermore, RNAseq data was used to identify expressed somatic mutations and to calculate the total expressed tumor mutational burden (‘eTMB’). Results: As previously reported, the prevalence of PD-L1 + tumors was higher in TN vs HR+/HER2− BC, however close to half (44.1% SP142 IC> 1%) of HR+/HER2- tumors showed some degree of PD-L1 expression. Similar patterns were observed for LAG3 IHC expression (32.3% and 64.7% of HR+ and TN tumors respectively with >1% expression). Concordant expression of the two markers (SP142 IC> 1% and LAG3 >=1% or < 1% and < 1%) was observed in approximately 80% of tumors in both subtypes. Less than 10% of tumors in both subtypes had high LAG3 (>1%) and low PD-L1(< 1%) expression. Most (82.4%) HR+/HER2- tumors in the dataset were deficient in CD8+ cells in both stroma and tumor parenchyma, however a subset (12.9%) were identified as having an ‘excluded’ CD8 pattern, and four (4.7%) were classified as ‘inflamed’. The frequency of both the excluded and inflamed states was slightly higher among the TN tumors (20.6% and 15.9% respectively). Expression of PD-L1+ occurred more frequently among tumors with higher CD8 expression. Among both TN and HR+ tumors, most ‘inflamed’ tumors were grade 3. We also examined a range of gene expression signatures representative of various immune cell subpopulations, their distribution within each subtype, and relationships with other molecular data. For example, expression of a CXCL13+ T cell signature, a cell type that has been shown to be predictive of response to anti-PD-L1 + chemo combo therapy in TNBC, was significantly higher in TN vs HR+ tumors, however, a large subset of HR+ tumors had levels of expression of the signature above the median observed in TN tumors. In addition, we noted that eTMB, while low overall, was positively correlated with certain immune-related expression signatures across HR+/HER2− samples, including signatures previously associated with improved response to ICB, as well as PD-L1 positivity. Conclusions: We observed heterogeneity in the immune profile of the real-world HR+ and TN tumors in this cohort. A subset of tumors in both subtypes expressed markers or signatures previously reported to be associated with response to ICB. (1) Cancer Cell. 2021 Dec 13;39(12):1578-1593.e8. Citation Format: Aparna Chhibber, Lloye M. Dillon, John B. Wojcik, Vishantie Dostal, George Lee, Fayaz Seifuddin, Scott Ely, Mark D. Stern, Charlie Benson-Garnett, Mustimbo Roberts, Jenny Wu. Characterization of Immune Contexture in HR+/HER2- and Triple Negative Breast Cancer in a Real-world Cohort [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-09-07.

Somites are transient structures derived from the pre-somitic mesoderm (PSM), involving mesenchyme-to-epithelial transition (MET) where the cells change their shape and polarize. Using Scanning electron microscopy (SEM), immunocytochemistry and confocal microscopy, we study the progression of these events along the tail-to-head axis of the embryo, which mirrors the progression of somitogenesis (younger cells located more caudally). SEM revealed that PSM epithelialization is a gradual process, which begins much earlier than previously thought, starting with the dorsalmost cells, then the medial ones, and then, simultaneously, the ventral and lateral cells, before a somite fully separates from the PSM. The core (internal) cells of the PSM and somites never epithelialize, which suggests that the core cells could be 'trapped' within the somitocoele after cells at the surfaces of the PSM undergo MET. Three-dimensional imaging of the distribution of the cell polarity markers PKCζ, PAR3, ZO1, the Golgi marker GM130 and the apical marker N-cadherin reveal that the pattern of polarization is distinctive for each marker and for each surface of the PSM, but the order of these events is not the same as the progression of cell elongation. These observations challenge some assumptions underlying existing models of somite formation.

During primitive streak formation in the chick embryo, cells undergo mesendoderm specification and convergent extension at the same time and in the same cells. Previous work has implicated cVG1 (GDF3) as a key factor for induction of primitive streak identity and positioning the primitive streak, whereas FGF signalling was implicated in regulating cell intercalation via regulation of components of the WNT-planar cell polarity (PCP) pathway. FGF has also been reported to be able to induce a primitive streak (but lacking the most axial derivatives such as notochord/prechordal mesendoderm). These signals emanate from different cell populations in the embryo, so how do they interact to ensure that the same cells undergo both cell intercalation and acquire primitive streak identity? Here we begin to address this question by examining in more detail the ability of the two classes of signals in regulating the two developmental events. Using misexpression of inducers and/or exposure to inhibitors and in situ hybridisation, we study how these two signals regulate expression of Brachyury (TBXT) and PRICKLE1 as markers for the primitive streak and the PCP, respectively. We find that both signals can induce both properties, but while FGF seems to be required for induction of the streak by cVG1, it is not necessary for induction of PRICKLE1. The results are consistent with cVG1 being a common regulator for both primitive streak identity and the initiation of convergent extension that leads to streak elongation.

During preimplantation development, contractile forces generated at the apical cortex segregate cells into inner and outer positions of the embryo, establishing the inner cell mass (ICM) and trophectoderm. To which extent these forces influence ICM-trophectoderm fate remains unresolved. Here, we found that the nuclear lamina is coupled to the cortex via an F-actin meshwork in mouse and human embryos. Actomyosin contractility increases during development, upregulating Lamin-A levels, but upon internalization cells lose their apical cortex and downregulate Lamin-A. Low Lamin-A shifts the localization of actin nucleators from nucleus to cytoplasm increasing cytoplasmic F-actin abundance. This results in stabilization of Amot, Yap phosphorylation and acquisition of ICM over trophectoderm fate. By contrast, in outer cells, Lamin-A levels increase with contractility. This prevents Yap phosphorylation enabling Cdx2 to specify the trophectoderm. Thus, forces transmitted to the nuclear lamina control actin organization to differentially regulate the factors specifying lineage identity.

Background Cardiovascular magnetic resonance (CMR) is increasingly used in newborns with congenital heart disease. However, reporting on ventricular volumes and mass is hindered by an absence of normative data in this population. Design/methods Healthy term (37–41 weeks gestation) newborns underwent non-sedated, free-breathing CMR within the first week of life using the ‘feed and wrap’ technique. End-diastolic volume (EDV), end-systolic volume (ESV) stroke volume (SV) and ejection fraction (EF) were calculated for both left ventricle (LV) and right ventricle (RV). Papillary muscles were separately contoured and included in the myocardial volume. Myocardial mass was calculated by multiplying myocardial volume by 1.05 g/ml. All data were indexed to weight and body surface area (BSA). Inter-observer variability (IOV) was performed on data from 10 randomly chosen infants. Results Twenty healthy newborns (65% male) with a mean (SD) birth weight of 3.54 (0.46) kg and BSA of 0.23 (0.02) m2 were included. Normative LV parameters were indexed EDV 39.0 (4.1) ml/m2, ESV 14.5 (2.5) ml/m2 and ejection fraction (EF) 63.2 (3.4)%. Normative RV indexed EDV, ESV and EF were 47.4 (4.5) ml/m2, 22.6 (2.9) ml/m2 and 52.5 (3.3)% respectively. Mean LV and RV indexed mass were 26.4 (2.8) g/m2 and 12.5 (2.0) g/m2, respectively. There was no difference in ventricular volumes by gender. IOV was excellent with an intra-class coefficient > 0.95 except for RV mass (0.94). Conclusion This study provides normative data on LV and RV parameters in healthy newborns, providing a novel resource for comparison with newborns with structural and functional heart disease.

During early vertebrate development, signals from a special region of the embryo, the organizer, can redirect the fate of non-neural ectoderm cells to form a complete, patterned nervous system. This is called neural induction and has generally been imagined as a single signalling event, causing a switch of fate. Here, we undertake a comprehensive analysis, in very fine time course, of the events following exposure of competent ectoderm of the chick to the organizer (the tip of the primitive streak, Hensen’s node). Using transcriptomics and epigenomics we generate a gene regulatory network comprising 175 transcriptional regulators and 5614 predicted interactions between them, with fine temporal dynamics from initial exposure to the signals to expression of mature neural plate markers. Using in situ hybridization, single-cell RNA-sequencing, and reporter assays, we show that the gene regulatory hierarchy of responses to a grafted organizer closely resembles the events of normal neural plate development. The study is accompanied by an extensive resource, including information about conservation of the predicted enhancers in other vertebrates.

Rehabilitation professionals prescribe exercise regularly with the goals of decreasing pain, increasing function, and returning athletes to competition. To maximize the effect of an exercise intervention, the program must be individualized and in context for the athlete considering biopsychosocial aspects of care. Current models of exercise prescription may not be ideal considering that less than 50% of injured athletes return to their pre-injury level. Advice on exercise prescription has been offered in the past, but the paradigms are either not user friendly or user friendly but linear, based on phases of recovery. As such, there is a need for a more flexible exercise prescription paradigm that should improve the individuality of exercise prescription. In this Current Opinion, we offer a user-friendly construct-oriented paradigm designed to facilitate the creation of individualized exercise programs for athletes.

Digital Health Technologies (DHTs) such as connected sensors offer particular promise for improving data collection and patient empowerment in neurology research and care. This study analyzed the recent evolution of the use of DHTs in trials registered on ClinicalTrials.gov for four chronic neurological disorders: epilepsy, multiple sclerosis, Alzheimer’s, and Parkinson’s disease. We document growth in the collection of both more established digital measures (e.g., motor function) and more novel digital measures (e.g., speech) over recent years, highlighting contexts of use and key trends.

Stress fractures likely have a 1-2% incidence in athletes in general. In runners, a more vulnerable population, incidence rates likely range between 3.2 and 21% with female runners having greater susceptibility. The incidence of femoral shaft stress fractures is less well known. New basic and translational science research may impact the way clinicians diagnose and treat femoral stress fractures. By using a fictitious case study, this paper applies bone science to suggest new approaches to evaluating and treating femoral shaft stress fractures in the running population.

The current dogma about the heartbeat origin is based on “the pacemaker cell,” a specialized cell residing in the sinoatrial node (SAN) that exhibits spontaneous diastolic depolarization triggering rhythmic action potentials (APs). Recent high-resolution imaging, however, demonstrated that Ca signals and APs in the SAN are heterogeneous, with many cells generating APs of different rates and rhythms or even remaining non-firing (dormant cells), i.e., generating only subthreshold signals. Here we numerically tested a hypothesis that a community of dormant cells can generate normal automaticity, i.e., “the pacemaker cell” is not required to initiate rhythmic cardiac impulses. Our model includes 1) non-excitable cells generating oscillatory local Ca releases and 2) an excitable cell lacking automaticity. While each cell in isolation was not “the pacemaker cell”, the cell system generated rhythmic APs: The subthreshold signals of non-excitable cells were transformed into respective membrane potential oscillations via electrogenic Na/Ca exchange and further transferred and integrated (computed) by the excitable cells to reach its AP threshold, generating rhythmic pacemaking. Cardiac impulse is an emergent property of the SAN cellular network and can be initiated by cells lacking intrinsic automaticity. Cell heterogeneity, weak coupling, subthreshold signals, and their summation are critical properties of the new pacemaker mechanism, i.e., cardiac pacemaker can operate via a signaling process basically similar to that of “temporal summation” happening in a neuron with input from multiple presynaptic cells. The new mechanism, however, does not refute the classical pacemaker cell-based mechanism: both mechanisms can co-exist and interact within SAN tissue.

Purpose/Objective(s) Preoperative (pre-op) SRS has been demonstrated to be a feasible alternative to postoperative (post-op) SRS primarily based on single institution studies with potential benefits in adverse radiation effect (ARE) and leptomeningeal disease (LMD) compared to post-op SRS. This study (Preoperative Radiosurgery for Brain Metastases – PROPS-BM) reports pre-op SRS treatment details and outcomes from a large multicenter cohort. Materials/Methods Patients (pts) with brain metastases (BM) from solid cancers, of which at least 1 lesion was treated with pre-op SRS and underwent planned resection were included from 5 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included classically radiosensitive or non-solid cancers, prior or planned whole brain radiotherapy (WBRT), and Results The cohort included 242 pts with 253 pre-op treated index lesions. The majority of pts (62.4%) had a single BM, 93.7% underwent gross total resection (GTR), and 98.8% were treated with a single fraction to a median dose of 15 Gy to a median gross tumor volume (GTV) of 9.9 cc. Median interval between pre-op SRS and surgery was 1 day. Most pts had non-small cell lung (43.4%), breast (20.2%), or melanoma (12.8%) cancer. The table below details 1 and 2-year outcomes. Extent of resection was a strong independent predictor of cavity local recurrence (LR) with LR occurring in 7 of 16 cavities (43.8%) status post subtotal resection (STR) compared with 32 of 237 (13.5%) cavities status post GTR (P = 0.005). The majority of LMD was cLMD type (13 of 19 pts with LMD, 68.4%). Ten of 242 pts (4.1%) experienced grade ≥3 post-op surgical complications. Conclusion This multicenter cohort study represents the largest population of pts treated with pre-op SRS to our knowledge. Approximately half of the pts included are from previously unpublished cohorts. The favorable oncologic outcomes, especially the notably low rates of LMD and ARE, previously demonstrated in single institution studies are confirmed in this expanded multicenter analysis without evidence of excessive post-op surgical complications. STR, though infrequent, is associated with significantly worse cavity LR in this setting. A randomized trial between pre-op and post-op SRS is warranted and is currently being designed.

Framework materials constitute a broad family of solids that range from zeolites and metal-organic frameworks (MOFs) to coordination polymers. The synthesis of such network structures typically rely on precursor molecular building blocks. As an example, the UiO-66 MOF series is constructed of hexanuclear [Zr6O4(OH)4(CO2)12] cluster nodes and linear carboxylate linkers. Unfortunately, these Zr MOF cluster nodes cannot currently be manufactured in a sustainable way, motivating a search for "green" alternative synthesis methods. Stabilizing the hexanuclear Zr(IV) cluster (i.e., the hexamer, {Zr612+}) without the use of organic ligation would enable the use of environmentally friendly solvents such as water. The Zr(IV) tetranuclear cluster (i.e., the tetramer, {Zr48+}) can be stabilized in solution with or without organic ligands, yet the hexamer has yet to be synthesized without supporting ligands. The reasons why certain zirconium clusters are favored in aqueous solution over others are not well understood. This study reports the relative thermodynamic instability of the hypothetical hexamer {Zr612+} compared to the ubiquitous {Zr48+} tetramer. Density functional theory calculations were performed to obtain the hydrolysis Gibbs free energy of these species and used to construct Zr Pourbaix diagrams that illustrate the effects of electrochemical potential, pH, and Zr(IV) concentration. It was found that the aqueous {Zr612+} hexamer is ∼17.8 kcal/mol less stable than the aqueous {Zr48+} tetramer at pH = 0, V = 0, and [Zr(IV)] = 1 M, which is an energy difference on the order of counterion interactions. Electronic structure analyses were used to explore trends in the highest occupied molecular orbital-lowest unoccupied molecular orbital gap, frontier molecular orbitals, and electrostatic potential distribution of these clusters. The evidence suggests that the aqueous {Zr612+} hexamer may be promoted with more strategic syntheses incorporating minimal ligands and counterions.

Ruth Bellairs passed away on 30 December 2021 at the age of 95. Ruth was a legendary figure in chick embryology; she pioneered many new techniques and made some important discoveries, and we were both extremely fortunate to benefit from her extraordinary mentorship, C.W. as final honours project undergraduate in her lab and then as her PhD student (1967-70), and C.D.S. as her postdoc (1978-1984).

During early avian development, only a narrow band of cells (the edge cells, also called ‘margin of overgrowth’) at the rim of the embryo is responsible for blastoderm expansion by crawling over the vitelline membrane (VM) to cover the whole egg yolk in just 4 days (a process called epiboly). Surprisingly, this has not yet been studied in detail. Here we explore the edge cells of the chick embryo using in situ hybridization, immunohistochemistry and live imaging. Morphological and molecular properties reveal that the edge has a distinctive structure, being subdivided into sub-regions, including at least four distinct zones (which we name as leading, trailing, deep and stalk zones). This allows us to study reorganization of the edge region that accompanies reattachment of an explanted blastoderm to the VM. Immunohistochemistry uncovers distinct polarized cellular features resembling the process of collective cell migration described in other systems. Live imaging reveals dynamic lamellipodial and filopodial activity at the leading edge of the outermost cells. Our data provide evidence that edge cells are a distinct tissue. We propose that edge cells may be a useful model system for the study of wound healing and other closure events in epithelial cell sheets.

We study the relation between obscuration and supermassive black hole (SMBH) accretion using a large sample of hard X-ray selected active galactic nuclei (AGNs). We find a strong decrease in the fraction of obscured sources above the Eddington limit for dusty gas (log lambda(Edd) >= -2) confirming earlier results, and consistent with the radiation-regulated unification model. This also explains the difference in the Eddington ratio distribution functions (ERDFs) of type 1 and type 2 AGNs obtained by a recent study. The break in the ERDF of nearby AGNs is at log lambda*(Edd) = -1.34 +/- 0.07. This corresponds to the lambda(Edd) where AGNs transition from having most of their sky covered by obscuring material to being mostly devoid of absorbing material. A similar trend is observed for the luminosity function, which implies that most of the SMBH growth in the local universe happens when the AGN is covered by a large reservoir of gas and dust. These results could be explained with a radiation-regulated growth model, in which AGNs move in the N-H-lambda(Edd) plane during their life cycle. The growth episode starts with the AGN mostly unobscured and accreting at low lambda(Edd). As the SMBH is further fueled, lambda(Edd), N-H and the covering factor increase, leading the AGN to be preferentially observed as obscured. Once lambda(Edd) reaches the Eddington limit for dusty gas, the covering factor and N-H rapidly decrease, leading the AGN to be typically observed as unobscured. As the remaining fuel is depleted, the SMBH goes back into a quiescent phase., The Astrophysical Journal, 938 (1), ISSN:0004-637X, ISSN:2041-8213

Rapid innovation and proliferation of software as a medical device have accelerated the clinical use of digital technologies across a wide array of medical conditions. Current regulatory pathways were developed for traditional (hardware) medical devices and offer a useful structure, but the evolution of digital devices requires concomitant innovation in regulatory approaches to maximize the potential benefits of these emerging technologies. A number of specific adaptations could strengthen current regulatory oversight while promoting ongoing innovation.

NGC 5033 is an intriguing Seyfert galaxy because its subclassification may change with time, and because optical and submillimeter observations find that the massive black hole does not sit at the dynamical center of the galaxy, pointing to a past merger. We obtained a new optical spectrum of NGC 5033 using the 200″ Hale telescope at Palomar that clearly reveals a broad Hβ line (FWHM = 5400 ± 300 km s−1). This signals a clear view of the optical broad line region and requires Seyfert-1.5 designation. Some spectra obtained in the past suggest a Seyfert-1.9 classification, potentially signaling a variable or “changing-look” geometry. Our analysis of a 2019 Chandra spectrum of the massive black hole reveals very little obscuration, also suggesting a clean view of the central engine. However, the narrow Fe Kα emission line is measured to have an equivalent width of EW = 460 − 90 + 100 eV. This value is extremely high compared to typical values in unobscured active galactic nuclei . Indeed, the line is persistently strong in NGC 5033: the line equivalent width in a 2002 XMM-Newton snapshot is EW = 250 − 40 + 40 eV, similar to the EW = 290 − 100 + 100 eV equivalent width measured using ASCA in 1999. These results can likely be explained through a combination of an unusually high covering factor for reflection, and fluxes that are seen out of phase owing to light travel times. We examine the possibility that NGC 5033 may strengthen evidence for the X-ray Baldwin effect.

Murine models are employed to probe various aspects of peritoneal dialysis (PD), such as peritoneal inflammation and fibrosis. These events drive peritoneal membrane failure in humans, which remains an area of intense investigation due to its profound clinical implications in managing patients with end-stage kidney disease (ESKD). Despite the clinical importance of PD and its related complications, current experimental murine models suffer from key technical challenges that compromise the models' performance. These include PD catheter migration and kinking and usually warrant earlier catheter removal. These limitations also drive the need for a greater number of animals to complete a study. Addressing these drawbacks, this study introduces technical improvements and surgical nuances to prevent commonly observed PD catheter complications in a murine model. Moreover, this modified model is validated by inducing peritoneal inflammation and fibrosis using lipopolysaccharide injections. In essence, this paper describes an improved method to create an experimental model of PD.

Introduction: Fetal arterial duct aneurysm, saccular, or fusiform enlargement of the arterial duct affect > 8% of pregnancies. It is uncommonly associated with serious sequelae postnatally, including thromboembolic events such as stroke and left pulmonary artery obstruction, rupture with demise, and vocal cord compression. Risk factors include maternal diabetes, late maternal age, maternal blood type A, large size for gestational age, and connective tissue disorders. The clinical importance remains unknown, making it difficult to determine how to monitor this finding postnatally. Methods: This is a retrospective echocardiogram study assessing the outcomes of fetally diagnosed arterial duct aneurysm. Images and records were reviewed to confirm the diagnosis and assess risk factors and outcomes. Descriptive statistics were performed. Results: Fifty-three affected fetuses were identified. The median gestational age at diagnosis was 34.9 weeks (IQR 32.6, 36.6). The median maternal age was 31 years (IQR 27.3–34.1). Eight (15%) had maternal diabetes. The most common blood type was type O. The median maximal dimension of the aneurysm was 7.6 mm (IQR 6.1, 8.7). The aortic end was the maximal dimension in 67.9%. Median postnatal follow-up period was 76 days (IQR 7.5, 368). No patients sustained postnatal demise related to the duct, rupture of the ductal aneurysm, cerebral infarction, or other sequelae. No newborn had associated connective tissue disorders. No patients underwent ductal intervention. Conclusion: In our experience, no adverse outcomes related to the ductal aneurysm were identified. This should be considered when counselling families about the need for postnatal follow-up.

Classical studies have established that the marginal zone, a ring of extra-embryonic epiblast immediately surrounding the embryonic epiblast (area pellucida) of the chick embryo, is important in setting embryonic polarity by positioning the primitive streak, the site of gastrulation. The more external extra-embryonic region (area opaca) was thought to have only nutritive and support functions. Using experimental embryology approaches, this study reveals three separable functions for this outer region. First, juxtaposition of the area opaca directly onto the area pellucida induces a new marginal zone from the latter; this induced domain is entirely posterior in character. Second, ablation and grafting experiments using an isolated anterior half of the blastoderm and pieces of area opaca suggest that the area opaca can influence the polarity of the adjacent marginal zone. Finally, we show that the loss of the ability of such isolated anterior half-embryos to regulate (re-establish polarity spontaneously) at the early primitive streak stage can be rescued by replacing the area opaca by one from a younger stage. These results uncover new roles of chick extra-embryonic tissues in early development.

The sports medicine literature is filled with associations between injury and causal factors. However, those results have been inconsistent. We’re left wondering which of our athletes might need more attention and where our efforts might be best spent. Resistance to injury is the result of interaction between many variables. These variables are interdependent with dynamic relationships which can be sometimes correlated, at times anti-correlated and from time to time show no relationship with injury risk. Relationships we may have seen yesterday do not necessarily hold true for today and we should not use those to infer what will happen. This perspective piece builds on prior works and describes how the complex interaction between injury determinants presents in other systems, why determinants are not stable and instead vary over time due to internal and external forcing and why our prediction ability remains limited even when determinants are identified. Patterns built from frequent time series data in conjunction with nonlinear dynamical methods can offer us a new approach to thinking about injury prediction.

For more than 20 years, AO VUKhIN has developed design documentation for coke, petroleum, and chemical production in Russia and elsewhere. VUKhIN has established itself as an experienced design organization.