Comparing Clinician Estimates versus a Statistical Tool for Predicting Risk of Death within 45 Days of Admission for Cancer Patients.

OBJECTIVES: While clinical practice guidelines recommend that oncologists discuss goals of care with patients who have advanced cancer, it is estimated that less than 20% of individuals admitted to the hospital with high-risk cancers have end-of-life discussions with their providers. While there has been interest in developing models for mortality prediction to trigger such discussions, few studies have compared how such models compare with clinical judgment to determine a patient's mortality risk. METHODS: This study is a prospective analysis of 1,069 solid tumor medical oncology hospital admissions (n = 911 unique patients) from February 7 to June 7, 2022, at Memorial Sloan Kettering Cancer Center. Electronic surveys were sent to hospitalists, advanced practice providers, and medical oncologists the first afternoon following a hospital admission and they were asked to estimate the probability that the patient would die within 45 days. Provider estimates of mortality were compared with those from a predictive model developed using a supervised machine learning methodology, and incorporated routine laboratory, demographic, biometric, and admission data. Area under the receiver operating characteristic curve (AUC), calibration and decision curves were compared between clinician estimates and the model predictions. RESULTS: Within 45 days following hospital admission, 229 (25%) of 911 patients died. The model performed better than the clinician estimates (AUC 0.834 vs. 0.753, p < 0.0001). Integrating clinician predictions with the model's estimates further increased the AUC to 0.853 (p < 0.0001). Clinicians overestimated risk whereas the model was extremely well-calibrated. The model demonstrated net benefit over a wide range of threshold probabilities. CONCLUSION: The inpatient prognosis at admission model is a robust tool to assist clinical providers in evaluating mortality risk, and it has recently been implemented in the electronic medical record at our institution to improve end-of-life care planning for hospitalized cancer patients.

Construction of a Synthetic Colostrum Substitute and Its Protection of Intestinal Cells against Inflammation in an In Vitro Model of Necrotizing Enterocolitis.

Colostrum provides bioactive components that are essential for the colonization of microbiota in the infant gut, while preventing infectious diseases such as necrotizing enterocolitis. As colostrum is not always available from the mother, particularly for premature infants, effective and safe substitutes are keenly sought after by neonatologists. The benefits of bioactive factors in colostrum are recognized; however, there have been no accounts of human colostrum being studied during digestion of the lipid components or their self-assembly in gastrointestinal environments. Due to the weaker bile pool in infants than adults, evaluating the lipid composition of human colostrum and linking it to structural self-assembly behavior is important in these settings and thus enabling the formulation of substitutes for colostrum. This study is aimed at the rational design of an appropriate lipid component for a colostrum substitute and determining the ability of this formulation to reduce inflammation in intestinal cells. Gas chromatography was utilized to map lipid composition. The self-assembly of lipid components occurring during digestion of colostrum was monitored using small-angle X-ray scattering for comparison with substitute mixtures containing pure triglyceride lipids based on their abundance in colostrum. The digestion profiles of human colostrum and the substitute mixtures were similar. Subtle differences in lipid self-assembly were evident, with the substitute mixtures exhibiting additional non-lamellar phases, which were not seen for human colostrum. The difference is attributable to the distribution of free fatty acids released during digestion. The biological markers of necrotizing enterocolitis were modulated in cells that were treated with bifidobacteria cultured on colostrum substitute mixtures, compared to those treated with infant formula. These findings provide an insight into a colostrum substitute mixture that resembles human colostrum in terms of composition and structural behavior during digestion and potentially reduces some of the characteristics associated with necrotizing enterocolitis.

Association Between Remote Monitoring and Acute Care Visits in High-Risk Patients Initiating Intravenous Antineoplastic Therapy.

PURPOSE: Traditional oncology care models have not effectively identified and managed at-risk patients to prevent acute care. A next step is to harness advances in technology to enable patients to report symptoms any time, enabling digital hovering-intensive symptom monitoring and management. Our objective was to evaluate a digital platform that identifies and remotely monitors high-risk patients initiating antineoplastic therapy with the goal of preventing acute care visits. METHODS: This was a single-institution matched cohort quality improvement study conducted at a National Cancer Institute-designated cancer center between January 1, 2019, and March 31, 2020. Eligible patients were those initiating intravenous antineoplastic therapy who were identified as high risk for seeking acute care. Enrolled patients' symptoms were monitored using a digital platform. A dedicated team of clinicians managed reported symptoms. The primary outcomes of emergency department visits and hospitalizations within 6 months of treatment initiation were analyzed using cumulative incidence analyses with a competing risk of death. RESULTS: Eighty-one patients from the intervention arm were matched by stage and disease with contemporaneous high-risk control patients. The matched cohort had similar baseline characteristics. The cumulative incidence of an emergency department visit for the intervention cohort was 0.27 (95% CI, 0.17 to 0.37) at six months compared with 0.47 (95% CI, 0.36 to 0.58) in the control (P = .01) and of an inpatient admission was 0.23 (95% CI, 0.14 to 0.33) in the intervention cohort versus 0.41 (95% CI, 0.30 to 0.51) in the control (P = .02). CONCLUSION: The narrow employment of technology solutions to complex care delivery challenges in oncology can improve outcomes and innovate care. This program was a first step in using a digital platform and a remote team to improve symptom care for high-risk patients.

Natural Language Processing of Computed Tomography Reports to Label Metastatic Phenotypes With Prognostic Significance in Patients With Colorectal Cancer.

PURPOSE: Natural language processing (NLP) applied to radiology reports can help identify clinically relevant M1 subcategories of patients with colorectal cancer (CRC). The primary purpose was to compare the overall survival (OS) of CRC according to American Joint Committee on Cancer TNM staging and explore an alternative classification. The secondary objective was to estimate the frequency of metastasis for each organ. METHODS: Retrospective study of CRC who underwent computed tomography (CT) chest, abdomen, and pelvis between July 1, 2009, and March 26, 2019, at a tertiary cancer center, previously labeled for the presence or absence of metastasis by an NLP prediction model. Patients were classified in M0, M1a, M1b, and M1c (American Joint Committee on Cancer), or an alternative classification on the basis of the metastasis organ number: M1, single; M2, two; M3, three or more organs. Cox regression models were used to estimate hazard ratios; Kaplan-Meier curves were used to visualize survival curves using the two M1 subclassifications. RESULTS: Nine thousand nine hundred twenty-eight patients with a total of 48,408 CT chest, abdomen, and pelvis reports were included. On the basis of NLP prediction, the median OS of M1a, M1b, and M1c was 4.47, 1.72, and 1.52 years, respectively. The median OS of M1, M2, and M3 was 4.24, 2.05, and 1.04 years, respectively. Metastases occurred most often in liver (35.8%), abdominopelvic lymph nodes (32.9%), lungs (29.3%), peritoneum (22.0%), thoracic nodes (19.9%), bones (9.2%), and pelvic organs (7.5%). Spleen and adrenal metastases occurred in < 5%. CONCLUSION: NLP applied to a large radiology report database can identify clinically relevant metastatic phenotypes and be used to investigate new M1 substaging for CRC. Patients with three or more metastatic disease organs have the worst prognosis, with an OS of 1 year.

Analysis of a Remote Monitoring Program for Symptoms Among Adults With Cancer Receiving Antineoplastic Therapy.

IMPORTANCE: Electronic patient-reported outcomes (ePROs) may have the potential to improve cancer care delivery by enhancing patient quality of life, reducing acute care visits, and extending overall survival. However, the optimal cadence of ePRO assessments is unknown. OBJECTIVE: To determine patient response preferences and the clinical value associated with a daily cadence for ePROs for patients receiving antineoplastic treatment. DESIGN, SETTING, AND PARTICIPANTS: This quality improvement study of adult patients undergoing antineoplastic treatment assessed a remote monitoring program using ePROs that was developed to manage cancer therapy-related symptoms. ePRO data submitted between October 16, 2018 to February 29, 2020, from a single regional site within the Memorial Sloan Kettering Cancer Center network were included. Data were analyzed from April 2020 to January 2022. EXPOSURE: While undergoing active treatment, patients received a daily ePRO assessment that, based on patient responses, generated yellow (moderate) or red (severe) symptom alerts that were sent to clinicians. MAIN OUTCOMES AND MEASURES: The main outcomes assessed included patient response rate, symptom alert frequency, and an analysis of the clinical value of daily ePROs. RESULTS: A total of 217 patients (median [range] age, 66 [31-92] years; 103 [47.5%] women and 114 [52.5%] men) initiating antineoplastic therapy at high risk for symptoms were monitored for a median (range) of 91 (2-369) days. Most patients had thoracic (59 patients [27.2%]), head and neck (48 patients [22.1%]), or gastrointestinal (43 patients [19.8%]) malignant neoplasms. Of 14 603 unique symptom assessments completed, 7349 (50.3%) generated red or yellow symptom alerts. Symptoms commonly generating alerts included pain (665 assessments [23.0%]) and functional status (465 assessments [16.1%]). Most assessments (8438 assessments [57.8%]) were completed at home during regular clinic hours (ie, 9 am-5 pm), with higher response rates on weekdays (58.4%; 95% CI, 57.5%-59.5%) than on weekend days (51.3%; 95% CI, 49.5%-53.1%). Importantly, 284 of 630 unique red alerts (45.1%) surfaced without a prior yellow alert for the same symptom within the prior 7 days; symptom severity fluctuated over the course of a week, and symptom assessments generating a red alert were followed by an acute care visit within 7 days 8.7% of the time compared with 2.9% for assessments without a red alert. CONCLUSIONS AND RELEVANCE: These findings suggest that daily ePRO assessments were associated with increased insight into symptom management in patients undergoing antineoplastic treatment and symptom alerts were associated with risk of acute care.

Impact of pasteurization on the self-assembly of human milk lipids during digestion.

Human milk is critical for the survival and development of infants. This source of nutrition contains components that protect against infections while stimulating immune maturation. In cases where the mother's own milk is unavailable, pasteurized donor milk is the preferred option. Although pasteurization has been shown to have minimal impact on the lipid and FA composition before digestion, no correlation has been made between the impact of pasteurization on the FFA composition and the self-assembly of lipids during digestion, which could act as delivery mechanisms for poorly water-soluble components. Pooled nonpasteurized and pasteurized human milk from a single donor was used in this study. The evolving FFA composition during digestion was determined using GC coupled to a flame ionization detector. In vitro digestion coupled to small-angle X-ray scattering was utilized to investigate the influence of different calcium levels, fat content, and the presence of bile salts on the extent of digestion and structural behavior of human milk lipids. Almost complete digestion was achieved when bile salts were added to the systems containing high calcium to milk fat ratio, with similar structural behavior of lipids during digestion of both types of human milk being apparent. In contrast, differences in the colloidal structures were formed during digestion in the absence of bile salt because of a greater amount of FFAs being released from the nonpasteurized than pasteurized milks. This difference in FFAs released from both types of human milk could result in varying nutritional implications for infants.

Natural Language Processing of Large-Scale Structured Radiology Reports to Identify Oncologic Patients With or Without Splenomegaly Over a 10-Year Period.

PURPOSE: To assess the accuracy of a natural language processing (NLP) model in extracting splenomegaly described in patients with cancer in structured computed tomography radiology reports. METHODS: In this retrospective study between July 2009 and April 2019, 3,87,359 consecutive structured radiology reports for computed tomography scans of the chest, abdomen, and pelvis from 91,665 patients spanning 30 types of cancer were included. A randomized sample of 2,022 reports from patients with colorectal cancer, hepatobiliary cancer (HB), leukemia, Hodgkin lymphoma (HL), and non-HL patients was manually annotated as positive or negative for splenomegaly. NLP model training/testing was performed on 1,617/405 reports, and a new validation set of 400 reports from all cancer subtypes was used to test NLP model accuracy, precision, and recall. Overall survival was compared between the patient groups (with and without splenomegaly) using Kaplan-Meier curves. RESULTS: The final cohort included 3,87,359 reports from 91,665 patients (mean age 60.8 years; 51.2% women). In the testing set, the model achieved accuracy of 92.1%, precision of 92.2%, and recall of 92.1% for splenomegaly. In the validation set, accuracy, precision, and recall were 93.8%, 92.9%, and 86.7%, respectively. In the entire cohort, splenomegaly was most frequent in patients with leukemia (32.5%), HB (17.4%), non-HL (9.1%), colorectal cancer (8.5%), and HL (5.6%). A splenomegaly label was associated with an increased risk of mortality in the entire cohort (hazard ratio 2.10; 95% CI, 1.98 to 2.22; P < .001). CONCLUSION: Automated splenomegaly labeling by NLP of radiology report demonstrates good accuracy, precision, and recall. Splenomegaly is most frequently reported in patients with leukemia, followed by patients with HB.

Proteomic Identification and Quantification of Snake Venom Biomarkers in Venom and Plasma Extracellular Vesicles.

The global exploration of snakebites requires the use of quantitative omics approaches to characterize snake venom as it enters into the systemic circulation. These omics approaches give insights into the venom proteome, but a further exploration is warranted to analyze the venom-reactome for the identification of snake venom biomarkers. The recent discovery of extracellular vesicles (EVs), and their critical cellular functions, has presented them as intriguing sources for biomarker discovery and disease diagnosis. Herein, we purified EV's from the snake venom (svEVs) of Crotalus atrox and C. oreganus helleri, and from plasma of BALB/c mice injected with venom from each snake using EVtrap in conjunction with quantitative mass spectrometry for the proteomic identification and quantification of svEVs and plasma biomarkers. Snake venom EVs from C. atrox and C. o. helleri were highly enriched in 5' nucleosidase, L-amino acid oxidase, and metalloproteinases. In mouse plasma EVs, a bioinformatic analysis for revealed upregulated responses involved with cytochrome P450, lipid metabolism, acute phase inflammation immune, and heat shock responses, while downregulated proteins were associated with mitochondrial electron transport, NADH, TCA, cortical cytoskeleton, reticulum stress, and oxidative reduction. Altogether, this analysis will provide direct evidence for svEVs composition and observation of the physiological changes of an envenomated organism.

Patterns of Metastatic Disease in Patients with Cancer Derived from Natural Language Processing of Structured CT Radiology Reports over a 10-year Period.

Background Patterns of metastasis in cancer are increasingly relevant to prognostication and treatment planning but have historically been documented by means of autopsy series. Purpose To show the feasibility of using natural language processing (NLP) to gather accurate data from radiology reports for assessing spatial and temporal patterns of metastatic spread in a large patient cohort. Materials and Methods In this retrospective longitudinal study, consecutive patients who underwent CT from July 2009 to April 2019 and whose CT reports followed a departmental structured template were included. Three radiologists manually curated a sample of 2219 reports for the presence or absence of metastases across 13 organs; these manually curated reports were used to develop three NLP models with an 80%-20% split for training and test sets. A separate random sample of 448 manually curated reports was used for validation. Model performance was measured by accuracy, precision, and recall for each organ. The best-performing NLP model was used to generate a final database of metastatic disease across all patients. For each cancer type, statistical descriptive reports were provided by analyzing the frequencies of metastatic disease at the report and patient levels. Results In 91 665 patients (mean age ± standard deviation, 61 years ± 15; 46 939 women), 387 359 reports were labeled. The best-performing NLP model achieved accuracies from 90% to 99% across all organs. Metastases were most frequently reported in abdominopelvic (23.6% of all reports) and thoracic (17.6%) nodes, followed by lungs (14.7%), liver (13.7%), and bones (9.9%). Metastatic disease tropism is distinct among common cancers, with the most common first site being bones in prostate and breast cancers and liver among pancreatic and colorectal cancers. Conclusion Natural language processing may be applied to cancer patients' CT reports to generate a large database of metastatic phenotypes. Such a database could be combined with genomic studies and used to explore prognostic imaging phenotypes with relevance to treatment planning. © RSNA, 2021 Online supplemental material is available for this article.

Insulin regulates human mammosphere development and function.

Assessing the role of lactogenic hormones in human mammary gland development is limited due to issues accessing tissue samples and so development of a human in vitro three-dimensional mammosphere model with functions similar to secretory alveoli in the mammary gland can aid to overcome this shortfall. In this study, a mammosphere model has been characterised using human mammary epithelial cells grown on either mouse extracellular matrix or agarose and showed insulin is essential for formation of mammospheres. Insulin was shown to up-regulate extracellular matrix genes. Microarray analysis of these mammospheres revealed an up-regulation of differentiation, cell-cell junctions, and cytoskeleton organisation functions, suggesting mammosphere formation may be regulated through ILK signalling. Comparison of insulin and IGF-1 effects on mammosphere signalling showed that although IGF-1 could induce spherical structures, the cells did not polarise correctly as shown by the absence of up-regulation of polarisation genes and did not induce the expression of milk protein genes. This study demonstrated a major role for insulin in mammary acinar development for secretory differentiation and function indicating the potential for reduced lactational efficiency in women with obesity and gestational diabetes.

A Nonproprietary Movement Analysis System (MoJoXlab) Based on Wearable Inertial Measurement Units Applicable to Healthy Participants and Those With Anterior Cruciate Ligament Reconstruction Across a Range of Complex Tasks: Validation Study.

BACKGROUND: Movement analysis in a clinical setting is frequently restricted to observational methods to inform clinical decision making, which has limited accuracy. Fixed-site, optical, expensive movement analysis laboratories provide gold standard kinematic measurements; however, they are rarely accessed for routine clinical use. Wearable inertial measurement units (IMUs) have been demonstrated as comparable, inexpensive, and portable movement analysis toolkits. MoJoXlab has therefore been developed to work with generic wearable IMUs. However, before using MoJoXlab in clinical practice, there is a need to establish its validity in participants with and without knee conditions across a range of tasks with varying complexity. OBJECTIVE: This paper aimed to present the validation of MoJoXlab software for using generic wearable IMUs for calculating hip, knee, and ankle joint angle measurements in the sagittal, frontal, and transverse planes for walking, squatting, and jumping in healthy participants and those with anterior cruciate ligament (ACL) reconstruction. METHODS: Movement data were collected from 27 healthy participants and 20 participants with ACL reconstruction. In each case, the participants wore seven MTw2 IMUs (Xsens Technologies) to monitor their movement in walking, jumping, and squatting tasks. The hip, knee, and ankle joint angles were calculated in the sagittal, frontal, and transverse planes using two different software packages: Xsens' validated proprietary MVN Analyze and MoJoXlab. The results were validated by comparing the generated waveforms, cross-correlation (CC), and normalized root mean square error (NRMSE) values. RESULTS: Across all joints and activities, for data of both healthy and ACL reconstruction participants, the CC and NRMSE values for the sagittal plane are 0.99 (SD 0.01) and 0.042 (SD 0.025); 0.88 (SD 0.048) and 0.18 (SD 0.078) for the frontal plane; and 0.85 (SD 0.027) and 0.23 (SD 0.065) for the transverse plane (hip and knee joints only). On comparing the results from the two different software systems, the sagittal plane was very highly correlated, with frontal and transverse planes showing strong correlation. CONCLUSIONS: This study demonstrates that nonproprietary software such as MoJoXlab can accurately calculate joint angles for movement analysis applications comparable with proprietary software for walking, squatting, and jumping in healthy individuals and those following ACL reconstruction. MoJoXlab can be used with generic wearable IMUs that can provide clinicians accurate objective data when assessing patients' movement, even when changes are too small to be observed visually. The availability of easy-to-setup, nonproprietary software for calibration, data collection, and joint angle calculation has the potential to increase the adoption of wearable IMU sensors in clinical practice, as well as in free living conditions, and may provide wider access to accurate, objective assessment of patients' progress over time.

Remitting seronegative symmetric synovitis with pitting edema (RS3PE) with painful erythematous nodules.

Remitting seronegative symmetric synovitis with pitting edema (RS3PE) is an uncommon syndrome characterised by acute onset severe synovitis of the radiocarpal and small joints of the hands, with associated pitting edema. Discussed here is the case of a 69-year-old man who presented to the emergency department of a tertiary hospital with acute bilateral hand swelling. This was on a background of a recent diagnosis of metastatic adenocarcinoma of the caecum and subsequent hemicolectomy. There was a history of general malaise, fever and lethargy for 5 days prior to the swelling of the hands. On examination, the upper limbs were swollen to the elbow bilaterally. Painful erythematous nodules were noted on the dorsal and palmar aspects of the hands and violaceous periungual discolouration was observed on the right fourth and fifth fingers. Prednisolone was commenced resulting in a dramatic resolution of the articular and cutaneous manifestations within 3 weeks.

Building a Clinically Relevant Risk Model: Predicting Risk of a Potentially Preventable Acute Care Visit for Patients Starting Antineoplastic Treatment.

PURPOSE: To create a risk prediction model that identifies patients at high risk for a potentially preventable acute care visit (PPACV). PATIENTS AND METHODS: We developed a risk model that used electronic medical record data from initial visit to first antineoplastic administration for new patients at Memorial Sloan Kettering Cancer Center from January 2014 to September 2018. The final time-weighted least absolute shrinkage and selection operator model was chosen on the basis of clinical and statistical significance. The model was refined to predict risk on the basis of 270 clinically relevant data features spanning sociodemographics, malignancy and treatment characteristics, laboratory results, medical and social history, medications, and prior acute care encounters. The binary dependent variable was occurrence of a PPACV within the first 6 months of treatment. There were 8,067 observations for new-start antineoplastic therapy in our training set, 1,211 in the validation set, and 1,294 in the testing set. RESULTS: A total of 3,727 patients experienced a PPACV within 6 months of treatment start. Specific features that determined risk were surfaced in a web application, riskExplorer, to enable clinician review of patient-specific risk. The positive predictive value of a PPACV among patients in the top quartile of model risk was 42%. This quartile accounted for 35% of patients with PPACVs and 51% of potentially preventable inpatient bed days. The model C-statistic was 0.65. CONCLUSION: Our clinically relevant model identified the patients responsible for 35% of PPACVs and more than half of the inpatient beds used by the cohort. Additional research is needed to determine whether targeting these high-risk patients with symptom management interventions could improve care delivery by reducing PPACVs.

Comparative analysis of milk microRNA in the therian lineage highlights the evolution of lactation.

Milk is a complex secretion that has an important role in mammalian reproduction. It is only recently that sequencing technologies have allowed the identification and quantification of microRNA (miRNA) in milk of a growing number of mammalian species. This provides a novel window on the study of the evolution and functionality of milk through the comparative analysis of milk miRNA content. Here, milk miRNA sequencing data from five species (one marsupial (tammar wallaby) and four eutherians (human, mouse, cow and pig)) have been retrieved from public depositories and integrated in order to perform a comparison of milk miRNA profiles. The study shows that milk miRNA composition varies widely between species, except for a few miRNAs that are ubiquitously expressed in the milk of all mammals and indicates that milk miRNA secretion has broadly evolved during mammalian evolution. The putative functions of the most abundant milk miRNAs are also discussed.

Guiding Development of the Neonate: Lessons from Mammalia.

Significantly preterm and low-birthweight (LBW) babies have diminished lung and gut development, generally fail to thrive, have increased mortality and higher frequency of mature-onset disease. Mothers often cannot breastfeed, and babies receive either formula or pasteurized donor milk, which may further limit the baby's recovery. New approaches are required to manage the early stages of neonatal development. The tammar wallaby, an Australian marsupial, has a short gestation and a simple placenta, and gives birth to an altricial young equivalent to a final trimester human embryo. The neonate remains in the pouch and attached to the teat for 100 days postpartum. The mother slows growth of the young and progressively changes the composition of the milk to deliver signals for organ development, including the lung and gut. This closely resembles the relationship between the human fetus and delivery of placental and uterine bioactives. Datasets comprised of differentially expressed genes coding for secreted proteins in early lactation in the tammar mammary gland have been compared to databases produced from human placenta, amniotic fluid, colostrum and milk to identify human homologues for the putative signaling molecules for organ development. These data will be used to develop milk fortifiers for treatment of preterm and LBW babies in both the developed and the developing world.

Dermatomyositis as a paraneoplastic phenomenon in oesophageal cancer.

Dermatomyositis is a multisystem disease manifesting as an idiopathic inflammatory myopathy, characterised predominantly by cutaneous and muscular abnormalities. Patients with dermatomyositis display characteristic skin changes in addition to muscle weakness. Many consider dermatomyositis a paraneoplastic syndrome, as up to 32% of patients with dermatomyositis will develop cancer. Discussed here is the case of a 69-year-old man with a new diagnosis of dermatomyositis who was referred to a tertiary institution with an 8-month history of rash, proximal muscle weakness, fatigue and weight loss. In the absence of clinical symptoms, negative cancer markers and a negative CT chest, abdomen and pelvis, positron emission tomography-CT prompted a gastroscopy, which led to the discovery of a stage T1b oesophageal adenocarcinoma. The oesophageal adenocarcinoma was treated with a gastrointestinal endoscopic mucosal resection and subsequent oesophajectomy. The patient's dermatomyositis was treated successfully with oral prednisolone and methotrexate.

Gene expression profiling of postnatal lung development in the marsupial gray short-tailed opossum (Monodelphis domestica) highlights conserved developmental pathways and specific characteristics during lung organogenesis.

BACKGROUND: After a short gestation, marsupials give birth to immature neonates with lungs that are not fully developed and in early life the neonate partially relies on gas exchange through the skin. Therefore, significant lung development occurs after birth in marsupials in contrast to eutherian mammals such as humans and mice where lung development occurs predominantly in the embryo. To explore the mechanisms of marsupial lung development in comparison to eutherians, morphological and gene expression analysis were conducted in the gray short-tailed opossum (Monodelphis domestica). RESULTS: Postnatal lung development of Monodelphis involves three key stages of development: (i) transition from late canalicular to early saccular stages, (ii) saccular and (iii) alveolar stages, similar to developmental stages overlapping the embryonic and perinatal period in eutherians. Differentially expressed genes were identified and correlated with developmental stages. Functional categories included growth factors, extracellular matrix protein (ECMs), transcriptional factors and signalling pathways related to branching morphogenesis, alveologenesis and vascularisation. Comparison with published data on mice highlighted the conserved importance of extracellular matrix remodelling and signalling pathways such as Wnt, Notch, IGF, TGFß, retinoic acid and angiopoietin. The comparison also revealed changes in the mammalian gene expression program associated with the initiation of alveologenesis and birth, pointing to subtle differences between the non-functional embryonic lung of the eutherian mouse and the partially functional developing lung of the marsupial Monodelphis neonates. The data also highlighted a subset of contractile proteins specifically expressed in Monodelphis during and after alveologenesis. CONCLUSION: The results provide insights into marsupial lung development and support the potential of the marsupial model of postnatal development towards better understanding of the evolution of the mammalian bronchioalveolar lung.

Misery Loves Company: Presenting Symptom Clusters to Urgent Care by Patients Receiving Antineoplastic Therapy.

PURPOSE: The Centers for Medicare & Medicaid Services (CMS) identifies suboptimal management of treatment toxicities as a care gap and proposes the measurement of hospital performance on the basis of emergency department visits for 10 common symptoms. Current management strategies do not address symptom co-occurrence. METHODS: We evaluated symptom co-occurrence in three patient cohorts that presented to a cancer hospital urgent care center in 2016. We examined both the CMS-identified symptoms and an expanded clinician-identified set defined as symptoms that could be safely managed in the outpatient setting if identified early and managed proactively. The cohorts included patients who presented with a CMS-defined symptom within 30 days of treatment, patients who presented within 30 days of treatment with a symptom from the expanded set, and patients who presented with a symptom from the expanded set within 30 days of treatment start. Symptom co-occurrence was measured by Jaccard index. A community detection algorithm was used to identify symptom clusters on the basis of a random walk process, and network visualizations were used to illustrate symptom dynamics. RESULTS: There were 6,429 presentations in the CMS symptom-defined cohort. The network analysis identified two distinct symptom clusters centered around pain and fever. In the expanded symptom cohort, there were 5,731 visits and six symptom clusters centered around fever, emesis/nausea, fatigue, deep vein thrombosis, pain, and ascites. For patients who newly initiated treatment, there were 1,154 visits and four symptom clusters centered around fever, nausea/emesis, fatigue, and deep vein thrombosis. CONCLUSION: Uncontrolled symptoms are associated with unplanned acute care. Recognition of the complexity of symptom co-occurrence can drive improved management strategies.

Inertial Measurement Units for Clinical Movement Analysis: Reliability and Concurrent Validity.

The aim of this study was to investigate the reliability and concurrent validity of a commercially available Xsens MVN BIOMECH inertial-sensor-based motion capture system during clinically relevant functional activities. A clinician with no prior experience of motion capture technologies and an experienced clinical movement scientist each assessed 26 healthy participants within each of two sessions using a camera-based motion capture system and the MVN BIOMECH system. Participants performed overground walking, squatting, and jumping. Sessions were separated by 4 ± 3 days. Reliability was evaluated using intraclass correlation coefficient and standard error of measurement, and validity was evaluated using the coefficient of multiple correlation and the linear fit method. Day-to-day reliability was generally fair-to-excellent in all three planes for hip, knee, and ankle joint angles in all three tasks. Within-day (between-rater) reliability was fair-to-excellent in all three planes during walking and squatting, and poor-to-high during jumping. Validity was excellent in the sagittal plane for hip, knee, and ankle joint angles in all three tasks and acceptable in frontal and transverse planes in squat and jump activity across joints. Our results suggest that the MVN BIOMECH system can be used by a clinician to quantify lower-limb joint angles in clinically relevant movements.

Structural characterization of a novel monotreme-specific protein with antimicrobial activity from the milk of the platypus.

Monotreme lactation protein (MLP) is a recently identified protein with antimicrobial activity. It is present in the milk of monotremes and is unique to this lineage. To characterize MLP and to gain insight into the potential role of this protein in the evolution of lactation, the crystal structure of duck-billed platypus (Ornithorhynchus anatinus) MLP was determined at 1.82 Šresolution. This is the first structure to be reported for this novel, mammalian antibacterial protein. MLP was expressed as a FLAG epitope-tagged protein in mammalian cells and crystallized readily, with at least three space groups being observed (P1, C2 and P21). A 1.82 Šresolution native data set was collected from a crystal in space group P1, with unit-cell parameters a = 51.2, b = 59.7, c = 63.1 Å, α = 80.15, ß = 82.98, γ = 89.27°. The structure was solved by SAD phasing using a protein crystal derivatized with mercury in space group C2, with unit-cell parameters a = 92.7, b = 73.2, c = 56.5 Å, ß = 90.28°. MLP comprises a monomer of 12 helices and two short ß-strands, with much of the N-terminus composed of loop regions. The crystal structure of MLP reveals no three-dimensional similarity to any known structures and reveals a heretofore unseen fold, supporting the idea that monotremes may be a rich source for the identification of novel proteins. It is hypothesized that MLP in monotreme milk has evolved to specifically support the unusual lactation strategy of this lineage and may have played a central role in the evolution of these mammals.