Next generation manufacturing (NGM) has evolved over the past decade to a point where large biopharmaceutical organizations are making large investments in the technology and considering implementation in clinical and commercial processes. There are many well-considered reasons to implement NGM. For the most part, organizations will not fund NGM unless the implementation benefits the funding organization by providing reduced costs, reduced time or additional needed capabilities. Productivity improvements gained from continuous purification are shown in this work, which used a new system that fully integrates and automates several downstream unit operations of a biopharmaceutical process to provide flexibility and easy implementation of NGM. The equipment and automation supporting NGM can be complicated and expensive. Biopharmaceutical Process Development considered two options: (1) design its own NGM system or (2) buy a pre-built system. PAK BioSolutions (Virginia, US), provides a turn-key automated and integrated system that can operate up to four continuous purification stages simultaneously, while maintaining a small footprint in the manufacturing plant. The PAK system provides significant cost benefits (~10x lower) compared to the alternative – integration of many different pieces of equipment through a Distributed Control System (DCS) that would require significant engineering time for design, automation and integration. Integrated and Continuous Biomanufacturing can lead to significant reductions in facility size, reduced manufacturing costs, and enhanced product quality when compared to the traditional batch mode of operation. The PAK system uses new automation strategies that robustly link unit operations. We present the optimized process fit, sterility and bioburden control strategy, and automation features (such as pH feedback control and in-line detergent addition) that enabled continuous operation of a 14 day end-to-end monoclonal antibody purification process at the clinical manufacturing scale.

A document by Sierra Young. Click on the document to view its contents.

Predictive biology is the ability to predict a biological outcome from known inputs (and vice versa). Complex and urgent problems, such as climate change and a growing global population, requires a better grasp of predictive biology approaches. However, predictive biology requires a deep understanding of the genome-to-phenome relationship within an organism. The field of genomics has accelerated rapidly in the last few decades with technological advances that have helped reduced the costs of genomics research and easy-to-use computational tools. Phenomics technologies has not advanced at the same rate. Many phenotyping systems are expensive to own, require special training to use, focus on narrow areas of research, and produce large amounts of data with no standards of storage and documentation. We propose a design philosophy for high-throughput phenotyping systems called the OPEN Series. This philosophy focuses on systems that use off-the-shelf commercial products and open-source software to make high quality phenotyping systems efficiently and for use by general users. In addition, the OPEN Series focuses on integrating cloud-based image processing through the NSF-funded cyberinfrastructure CyVerse, thus allowing users to share and process data remotely. We've worked to integrate this philosophy into our own phenotyping systems, OPEN leaf and OPEN root, to great success. We hope to export our work in creating accessible and affordable phenotyping system to labs across the globe to accelerate our understanding of the genome-to-phenome relationship for predictive biology.

Environmental stressors play a major role in determining plant phenotypic traits over the growing season. Nitrogen, a critical nutrient for plant growth, imposes serious stresses when applied in insufficient or excessive quantities in crop fields, which can directly reduce yield and the grower's profits. Due to significant variations in developmental rates and nitrogen needs across rice genotypes and environments, field phenotyping can become a challenging task. Non-linear manifold learning approaches were evaluated to account for variation in developmental rate using multispectral, multitemporal imagery acquired by an unmanned aerial vehicle (UAV). Imagery (13-16 flyovers per plot) and ground-truth data (including biomass nitrogen content, leaf chlorophyll content, and yield) were collected on 2,345 rice research plots during the 2021 and 2022 growing seasons. To increase the size of the training set, we also evaluated inclusion of similarly sized tiles sampled from commercial row-rice fields imaged between 2019 and 2022. We compared several supervised machine learning approaches with unsupervised strategies based on manifold learning to evaluate the hypothesis that model architectures which account for variation in developmental trajectories improve prediction of yield variation in response to nitrogen addition. This work will contribute to improved nitrogen rate recommendations using UAV-acquired imagery. Optimized nitrogen prescriptions ensure satisfying the plants' nitrogen needs and contribute to reduced environment impacts and production costs.

From preventing scurvy to being part of religious rituals, citrus are intrinsically connected to human health and perception. From tiny mandarins to head-sized pummelos, citrus capability of hybridization provides a vastly diverse array of fruit sizes and shapes, which in turn corresponds to a diversity of flavors and aromas. These sensory qualities are tightly linked to oil glands in the citrus skin. The oil glands are also key to understanding fruit development, and the essential oils contained by them are fundamental in the food and perfume industries. We study the shape of citrus based on 3D X-ray CT scan reconstruction of 163 different citrus samples comprising 58 different species and cultivars, including samples of all fundamental citrus species. First, using the power of X-rays and image processing, we are able to compare and contrast size ratios between different tissues, such as the size of the skin compared to the rind or the flesh. Second, we model the fruit shape as an ellipsoidal surface, and later we study and infer possible oil gland distributions on this surface using principles of directional statistics. We finally compare and contrast these overall fruit shape models along their gland distributions across different citrus species. This morphological modeling will allow us later to link genotype with phenotype, furthering our insight on how the physical shape is genetically specified in DNA.

Stomatal conductance (SC) was utilized to indicate the rate of gas and water exchange through stomata on the leaf surface. When crops are experiencing water stress during the daytime, their stomata will close to prevent water loss. However, the crop will also receive less CO2 for photosynthesis under this condition. Consequently, accurate and efficient SC prediction can improve irrigation efficiency, particularly in the present day when water is scarce. The common way to estimate SC nowadays is to make predictions using other variables that can be measured quickly, such as conventional regression analysis. The limitation of conventional regression analysis is that it does not account for changes in SC when crops are subjected to both prolonged drought and high temperature stress. We intend to use time series prediction techniques, such as Long Short-Term Memory (LSTM), to determine the correlation between variables at different time scales. The objective of this study is to (1) Investigating the relationship between SC and persistent weather patterns. (2) Predict SC based on continuously collected soil moisture, plant canopy temperature and weather information. In this study, we measured the SC of soybean and maize by using a handheld leaf porometer. This was then compared to short-term historical crop SC predictions based on canopy temperature, soil moisture, and weather conditions. Autoregressive Integrated Moving Average (ARIMA) and LSTM based on Recurrent neural network (RNN) are used to predict SC, and the results are compared with the conventional modeling method. More details will be presented at the NAPPN conference.

Trauma is a widespread, harmful and costly public health problem. It occurs as a result of violence, abuse, neglect, loss, disaster, war and other emotionally harmful experiences. Trauma has no boundaries with regard to age, gender, socioeconomic status, race, ethnicity, geography or sexual orientation. It is an almost universal experience of people with mental and substance use disorders. The need to address trauma is increasingly viewed as an important component of effective behavioral health service delivery. Additionally, it has become evident that addressing trauma requires a multi-pronged, multi-agency public health approach inclusive of public education and awareness, prevention and early identification, and effective trauma-specific assessment and treatment The effects of traumatic events place a heavy burden on individuals, families and communities and create challenges for public institutions and service systems. Although many people who experience a traumatic event will go on with their lives without lasting negative effects, others will have more difficulty and experience traumatic stress reactions. Emerging research has documented the relationships among exposure to traumatic events, impaired neurodevelopmental and immune systems responses and subsequent health risk behaviors resulting in chronic physical or behavioral health disorders.

ORCiD: [0000-0002-9614-5436] Keywords: unoccupied aerial vehicles (UAV), maize, plant height, growth rate, genome-wide association study (GWAS), canopy cover, environment, genotype-by-environment interaction Body Text: Plant height is used in many breeding programs for assessing plant health, predicting yield, or monitoring growth rates which can be used in identifying superior hybrids or evaluating abiotic stress factors. This has often been measured at a single time point when plants have reached their terminal height for the season. Collection of plant height using unoccupied aerial vehicles (UAVs) is faster, allowing for measurements throughout the growing season which could facilitate a better understanding of plant-environment interaction and responses. Plant height data was collected weekly for a panel of ~500 diverse lines over four growing seasons. The variation in plant height throughout the season was found to be explained by genotype, year, and genotype by year interactions. However, the relative contributions of these different sources of variation fluctuated throughout development. Genome-wide association studies of plant height and growth rate revealed many significant SNPs associated with plant height and growth rate at different parts of the growing season that would not be identified by terminal height alone. When comparing growth rates from plant height to growth rates estimated from another morphological characteristic, canopy cover, we found that canopy cover appears to be more affected by environment than plant height. This potentially makes canopy cover more useful for understanding environmental modulation of overall plant growth and plant height better for understanding genotypic modulation of overall plant growth.

Inclusion body myositis (IBM) is an acquired myopathy of both inflammatory and degenerative nature. Here we report a case of IBM associated with prolonged use of imatinib not reported in the literature so far. An 81 years old male with a history of gastrointestinal stromal tumor (GIST) operated 8 years ago was evaluated for the progressive loss of weight and muscle strength leading to total immobilization in 6 months. He was under imatinib for 8 years despite the remission of GIST. Physical examination disclosed diffuse loss of muscle strength, most prominently involvement of distal upper and proximal lower extremity in an asymmetrical pattern with normal serum creatinine kinase level (CK). Further investigations including bilateral thigh MRI, electromyography (EMG), and PET/CT suggested myositis and degenerative myopathy and ruled out any malignancy. Quadriceps femoris biopsy proved the diagnosis of IBM and no trigger except for imatinib was displayed. Clinical improvement in terms of wieght loss and muscle weakness was achieved after discontinuation of imatinib. Since imatinib is widely used in different conditions, it is important to be aware of even its rare adverse effects. Poor response of IBM to conventional immunosuppressive agents enhances the value of etiology identification to relieve symptoms in addition to supportive care.

Non-fungible tokens (NFTs) may initially sound like a fancy jargon, but they are actually rather simple to comprehend. Blockchain-based non-fungible tokens (NFTs) are digital items that are often linked to one-of-a-kind digital material, like music or photographs. A multi-billion dollar NFT market has appeared overnight thanks to a recent flurry of public interest. NFT collections are being produced by brands like Coca-Cola, Nike, and conventional artists like Damien Hirst and Grimes, as well as mainstream consumer goods businesses. Individual NFTs may fetch millions or tens of millions of dollars [1].

Objective: This study aimed to evaluate the effectiveness and optimal use of corticosteroids in children with severe coronavirus disease 2019 (COVID-19) pneumonia. Methods: We conducted a retrospective study and included patients (aged<18 years) with severe COVID-19 pneumonia and/or acute respiratory distress syndrome (ARDS) who received standard doses (2–4 mg/kg/day) and high doses (>250 mg/day) of methylprednisolone (MPZ). We adjusted for patients on steroid treatments with a propensity score and patient survival. Results: Fifty-nine patients were included: 61% were male, the median age was 8 (interquartile range [IQR], 2–15) years. The overall survival was 84.4% in patients treated with standard-dose MPZ (n = 45, 76.3%) and 92.2% in patients treated with high-dose MPZ (n = 14, 23.7%; p = 0.67). The demographic, clinical, and laboratory data didn’t differ significantly after propensity score matching, apart from bradycardia, which was a prominent feature of the high-dose group. The clinical and radiological response rates on Day 7 were higher and the need for invasive mechanical ventilation (IMV) was lower in the high-dose group. Conclusion: Pulse MPZ treatment seems to result in better clinical and radiological responses, with less need for IMV, although the mortality rate doesn’t differ between standard and high-dose regimens of MPZ.

α-Farnesene, an acyclic volatile sesquiterpene, plays important roles in aircraft fuel, food flavoring, agriculture, pharmaceutical and chemical industries. Here, we enhanced α-farnesene production through reconstructing the biosynthetic pathways of NADPH and ATP in Pichia pastoris. First, the native oxiPPP was reconstructed by over-expressing the key enzymes in oxiPPP or/and inactivating glucose-6-phosphate isomerase (PGI), indicating that combined over-expression of ZWF1 and SOL3 improves NADPH supply and thus increasing α-farnesene production while inactivation of PGI was not because of the decreased cell growth. Next, different expression level of heterologous cPOS5 were introduced into P. pastoris, and found that low intensity expression of cPOS5 facilitated α-farnesene biosynthesis. Finally, ATP was increased by overexpression of APRT and inactivation of GPD1. The resultant strain P. pastoris X33-38 produced 3.09±0.37 g/L of α-farnesene in shake-flask fermentation, which was 41.7% higher than that of the parent strain. These results provide a new perspective to construct industrial-strength α-farnesene producer by rational modification of NADPH and ATP regeneration pathway in P. pastoris.

: We report a rare case of cortisol secreting extracranial primary neuroectodermal tumor (PNET) originating from adrenal gland in adulthood. PNETs are typically not functional, making this case extremely rare. cortisol secreting PNETS are as of yet, unheard of.

In our recent effort of developing methylation-dependent endonuclease mediated methylation sequencing technology, efficiency and reproducibility were restrained by adapters' self-ligation. In the present study, three strategies to prevent self-ligation of adapters used in enzyme mediated methylation sequencing have been developed. Our data have demonstrated that these strategies can either inhibit or eliminate the adapters' self-ligation. These strategies are crucial in enzyme-mediated methylation sequencing and may be useful in some other genomic sequencing technologies.

The problem of estimating a covariance matrix plays crucial in signal processing and other related fields. This paper proposes a novel bilinear shrinkage estimation by simultaneously regularizing the sample mean and the SCM via the linear shrinkage technique. Through a one-one mapping of the weight parameters, the bilinear shrinkage estimation can be expressed as a generalization version of the well-known linear shrinkage estimation. Available covariance matrix estimators are developed by parametric and nonparametric methods for different target matrices. In our numerical simulations, the bilinear shrinkage estimators can reach lower Frobenius losses compared with the existing linear shrinkage estimators. Moreover, the proposed covariance matrix estimators can work well in application to large array signal processing.

Etoposide combined with platinum drugs is the first-line chemotherapy for small cell lung cancer（SCLC）. Here, we describe the first case with small cell lung cancer, who developed severe rhabdomyolysis after etoposide-nedaplatin chemotherapy. He complained of progressive generalized muscle pain and weakness after first cycle chemotherapy for SCLC, accompanied by elevated creatine kinase (CK), myoglobin (Mb), alanine aminotransferase (ALT), spartate aminotransferase (AST) and lactate dehydrogenase (LDH). Examination and inquiry of medical history were used to exclude the factors of rhabdomyolysis caused by trauma, strenuous activities, infections, hyperthermia and immunity, the patient was diagnosed with severe rhabdomyolysis induced by chemotherapy. After treatment with intravenous fluids and methylprednisolone, the patient’s symptoms were relieved and laboratory tests were significantly improved. An unexpected situation is that the lung CT scan showed that the lung mass was significantly smaller than that before chemotherapy, but the reason is not clear. Rhabdomyolysis induced by anti-cancer drugs, especially chemotherapy drugs, is rarely reported and easily overlooked. Therefore, physicians should be aware of this rare but potentially serious complication when using chemotherapy drugs.

Objective To date, apart from groin and thigh pain, there is a paucity of data regarding the association between transobturator tape (TOT) surgery and lower extremity function. We have aimed to evaluate the association between TOT and various indices of hip joint pain and function. Design Prospective cohort study Settings and Population 37 patients who underwent TOT surgery for the treatments of stress urinary incontinence (SUI). Methods Various tests and questionnaires aimed to assess hip function and surgery outcomes were completed before and after the TOT surgery, at the post-operative clinic. Paired data were compared using the paired sample t-test, after testing for normal distribution. Main Outcome Measures Hip range of motion (ROM), joint function and muscle strength, walking functions, leg length, subjective effect of surgery on patients’ quality of life and the impact of urinary incontinence on daily activities, mental and physical quality of life. Results Decrease in ROM was observed in most cardinal movements of the hip. An increase in leg length following TOT was observed (mean difference in centimeters for both legs 0.87-0.88; p<0.001). An overall trend of decreased strength was noticed, significant for hip adduction. The IIQ-7 and UDI-6 questionnaires demonstrated a significant improvement in urinary function (31.95- and 25.27-point reduction respectively; p<0.05 for both). No significant change was noted in gait function following surgery. Results of the FJS assessment revealed no difference in patient’s awareness of their hip joint. Conclusion Our findings provide support for a yet underestimated association between TOT surgery and hip dysfunction.

Objectives: To improve PPH prediction and to compare machine learning and traditional statistical methods. Design: Cross-sectional Setting: Deliveries across US hospitals Population: Deliveries across 12 US hospitals from the 2002-2008 Consortium for Safe Labor dataset Method: We developed models using the Consortium for Safe Labor dataset. Fifty antepartum and intrapartum characteristics and hospital characteristics were included. Logistic regression, support vector machines, multi-layer perceptron, random forest, and gradient boosting were used to generate prediction models. Receiver operating characteristic area under the curve (ROC-AUC) and precision/recall area under the curve (PR-AUC) were used to compare performance. Main Outcome Measure: The primary outcome was transfusion of blood products or PPH (estimated blood loss ≥1,000mL). The secondary outcome was transfusion of any blood products. Results: Among 228,438 births, 5,760 women (3.1%) had a postpartum hemorrhage, 5,170 women (2.8%) had a transfusion, and 10,344 women (5.6%) met criteria for the transfusion-PPH composite. Models predicting transfusion-PPH composite using antepartum and intrapartum features had the best positive predictive values with the gradient boosting machine learning model performing best overall (ROC-AUC=0.833, 95% CI [0.828-0.838]; PR-AUC=0.210 95% CI [0.201-0.220]). The most predictive features in the gradient boosting model predicting transfusion-PPH composite were mode of delivery, oxytocin incremental dose for labor(mU/min), intrapartum tocolytic use, presence of anesthesia nurse, and hospital type. Conclusion: Machine learning offers higher discrimination than logistic regression in predicting PPH. The CSL dataset may not be optimal for analyzing risk due to strong subgroup effects, which decreases accuracy and limits generalizability.

Introduction: The prognosis of mixed cardiomyopathy (CMP) in patients with implanted cardioverter-defibrillators (ICDs) has not been investigated. We aim to study the demographic, clinical, device therapies and survival characteristics of mixed CMP in a cohort of patients implanted with a defibrillator. Methods: The term mixed CMP was used to categorise patients with impaired left ventricular ejection fraction attributed to documented non-ischemic triggers with concomitant moderate coronary artery disease. This is a single center observational cohort of 526 patients with a mean follow-up 8.7±3.5 years. Results: There were 42.5% patients with ischemic cardiomyopathy (ICM), 26.9% with non-ischemic cardiomyopathy (NICM) and 30.6% with mixed CMP. Mixed CMP, compared to NICM, was associated with higher mean age (69.1±9.6 years), atrial fibrillation (55.3%) and greater incidence of comorbidities. The proportion of patients with mixed CMP receiving device shocks was 23.6% compared to 18.4% in NICM and 27% in ICM. The VT cycle length recorded in mixed CMP (281.6 ± 43.1ms) was comparable with ICM (282.5 ± 44ms; p=0.9) and lesser than NICM (297.7 ± 48.7ms; p=0.1). All-cause mortality in mixed CMP (21.1%) was similar to ICM (20.1%; p=0.8) and higher than NICM (15.6%; p=0.2). Kaplan-Meier curves revealed hazards of 1.57 (95% CI: 0.91, 2.68) for mixed CMP compared to NICM. Conclusion: In a cohort of patients with ICD, the group with mixed CMP represent a phenotype predominantly comprised of elderly with higher incidence of comorbidities. Mixed CMP resembles ICM in terms of number of device shocks and VT cycle length. Long-term prognosis of patients with mixed CMP is worse than NICM and similar to ICM.

Indroduction: Under certain conditions, cardiovascular implantable electronic devices can be directly involved in initiating and sustaining pacemaker-mediated arrhythmias (PMA), of which repetitive reentrant ventriculoatrial synchrony (RRVAS) is the most well-known and common type. RRVAS, also known as pacemaker-mediated tachycardia, was commonly secondary to atrioventricular (AV) dissociation and subsequent ventriculoatrial (VA) conduction. RRVAS in a bi-ventricular system is rare due to its less predisposition to the appearance of AV dissociation and subsequent VA conduction, but urgent in its adverse impact on cardiac resynchronization therapy (CRT), which may predispose to exacerbated heart failure. Methods/Results: We present a rare case of recurrent PMA manifested as a right bundle branch block pattern in a patient with CRT device. Notably, most episodes of PMA were triggered by a premature atrial contraction accompanied by the appearance of VA conduction with no prolongation of AV delay. Conclusion: In this study, we have demonstrated the impact of the appearance of VA conduction due to the loss of capture of right ventricular lead and its potential risk for inducing RRVAS in CRT device.

Medication-induced mood disorders have been rarely reported following epidural steroid injections (ESI). This case series presents three patients who met DSM-V criteria for substance/medication-induced mood disorder after an ESI. In considering a candidacy for ESI, the rare but significant, side effects of psychiatric side effects should be disclosed to patients.

Closed-form algebraic expressions for the pH of ideal weak acid and weak acid buffer solutions (and their titration with a strong base) were obtained and analyzed with the aid of computer algebra systems. These expressions are used to evaluate, without the use of numerical approximations, the precision and accuracy of different approximations commonly employed to calculate the pH. The closed-form expression for the pH of a buffer solution is used to obtain an analytical expression for the pH stability when a strong base is added. Finally, it is shown that the pH expressions for all the systems under study can be obtained from an unique closed-form expression in terms of an effective weak acid constant and an effective acid concentration.

In this retrospective study, we examined the prevalence and spectrum of germline variants in cancer predisposition genes in 38 children and young adults with melanocytic lesions who underwent germline genetic testing at St. Jude Children’s Research Hospital. Diagnoses included malignant melanoma (n=19; 50%), spitzoid melanoma (n=14; 37%), and uveal melanoma (n=5; 13%). Five patients (13%) harbored pathogenic variants: one with bi-allelic PMS2, and one each with heterozygous 17q21.31 deletion, TP53, BRIP1, and ATM pathogenic variants. In this convenience cohort, 13% of children and young adults with melanoma who underwent germline testing harbored an underlying cancer predisposition syndrome.

In this work we propose the construction of discrete-time systems with two time scales in which infectious diseases dynamics are involved. We deal with two general situations. In the first, we consider that individuals affected by the disease move between generalized sites on a faster time scale than the dynamics of the disease itself. The second situation includes the dynamics of the disease acting faster together with another slower general process. Once the models have been built, conditions are established so that the analysis of the asymptotic behavior of their solutions can be carried out through reduced models. This is done using known reduction results for discrete-time systems with two time scales. These results are applied in the analysis of two new models. The first of them illustrates the first proposed situation, being the local dynamics of the SIS-type disease. Conditions are found for the eradication or global endemicity of the disease. In the second model, a case of co-infection with a primary disease and an opportunistic disease is treated, the latter acting faster than the former. Conditions for eradication and endemicity of co-infection are proposed.