Whole-genome sequencing for optimized patient management

Whole-genome sequencing of patient DNA can facilitate diagnosis of a disease, but its potential for guiding treatment has been under-realized. We interrogated the complete genome sequences of a 14-year-old fraternal twin pair diagnosed with dopa (3,4-dihydroxyphenylalanine)-responsive dystonia (DRD; Mendelian Inheritance in Man #128230). DRD is a genetically heterogeneous and clinically complex movement disorder that is usually treated with l-dopa, a precursor of the neurotransmitter dopamine. Whole-genome sequencing identified compound heterozygous mutations in the SPR gene encoding sepiapterin reductase. Disruption of SPR causes a decrease in tetrahydrobiopterin, a cofactor required for the hydroxylase enzymes that synthesize the neurotransmitters dopamine and serotonin. Supplementation of l-dopa therapy with 5-hydroxytryptophan, a serotonin precursor, resulted in clinical improvements in both twins.     

Echinacea plants as antioxidant and antibacterial agents: From traditional medicine to biotechnological applications

The genus Echinacea consists of 11 taxa of herbaceous and perennial flowering plants. In particular, Echinacea purpurea (L.) Moench is widely cultivated all over the United States, Canada, and in Europe, exclusively in Germany, for its beauty and reported medicinal properties. Echinacea extracts have been used traditionally as wound healing to improve the immune system and to treat respiratory symptoms caused by bacterial infections. Echinacea extracts have demonstrated antioxidant and antimicrobial activities, and to be safe. This survey aims at reviewing the medicinal properties of Echinacea species, their cultivation, chemical composition, and the potential uses of these plants as antioxidant and antibacterial agents in foods and in a clinical context. Moreover, the factors affecting the chemical composition of Echinacea spp. are also covered.     

Primary Central Nervous System Mucosa-Associated Lymphoid Tissue Lymphoma: Case Report and Literature Review

Primary presentation of intradural non-Hodgkin lymphoma is rare. Recently, B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) have been recognized as an important pathologic subtype. When MALT lymphomas present in the central nervous system (CNS), they are distinguishable from primary high-grade CNS lymphomas. We present the clinicopathologic features of 5 patients with primary CNS MALT lymphoma treated at our institution from 1999 to 2006. Four out of 5 patients were women, and all patients presented with headaches, focal motor deficits, or cranial nerve palsy. Radiologic studies demonstrated ill-defined dural masses in 3 and well-defined masses in 2 patients. Pathology revealed small to medium-sized cells with a moderate amount of cytoplasm and irregular nuclear borders, expressing pan B-cell markers (CD19, CD20, and CD79a) but lacking CD10, CD23, and cyclin D1, confirming low-grade MALT lymphoma. Plasma cells were encountered in all the biopsies with variable reactive T-cell infiltration. δ chain restriction was seen in 3 patients. Therapy consisted of either surgical resection, whole-brain radiation, or systemic or intrathecal chemotherapy. There was no evidence of recurrence or systemic relapse in 4 patients at 4 years of follow-up. One patient died in 2 months, unrelated to CNS lymphoma. This case series illustrates the rare occurrence of low-grade dural B-cell lymphoma and the need to consider this entity in the differential diagnosis of CNS lesions.     

Boerhaave syndrome--unusual cause of chest pain

Spontaneous esophageal rupture (Boerhaave syndrome) is uncommon in children. Delayed or missed diagnosis can lead to poor outcomes in terms of morbidity and mortality. To highlight the importance of early recognition and management of spontaneous esophageal rupture in children, we report a case of a 16-year-old boy who presented in the emergency department with acute chest pain after episodes of vomiting.     

Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor–associated periodic syndrome interacts with wild‐type tumor necrosis factor receptor I and induces ligand‐independent NF‐κB activation

Objective

To investigate the molecular consequences of expressing mutated forms of tumor necrosis factor receptor I (TNFRI) as found in patients with TNFR‐associated periodic syndrome (TRAPS).

Methods

We cloned and expressed full‐length wild‐type (WT) and T50K and P46L variants of TNFRI using a new tightly regulated doxycycline‐dependent expression system. This system enabled the study of molecular interactions between these receptors at both physiologic and pathophysiologic levels of expression.

Results

We used chemical crosslinking on the cell surface to show that WT and mutant forms of TNFRI, derived from TRAPS patients, interact in the absence of TNF ligand. Doxycycline‐controlled up‐regulation of one TNFRI allele, either WT or mutant, caused down‐regulation of the other allele, indicating dynamic control of cell surface assembly. We also demonstrated that increased expression of mutant TNFRI (T50K) was associated with a parallel increase in NF‐κB p65 (RelA) subunit activation, which did not occur with increased expression of WT TNFRI.

Conclusion

The T50K TRAPS‐related variant is capable of sustaining inappropriate NF‐κB activation, resulting in persistent autoinflammation in target organs such as skin, synovial membrane, and the central nervous system. We conclude that some of the inflammatory processes seen in TRAPS do not involve direct interaction of TNF with its receptors, but that other proinflammatory mechanisms capable of up‐regulating TNFRI expression may cause cellular activation through the NF‐κB signaling pathway.

     

Recycled Untreated Rubber Waste for Controlling the Alkali–Silica Reaction in Concrete

Recycled rubber waste (RW) is produced at an alarming rate due to the deposition of 1.5 billion scrap tires annually around the globe, which causes serious threats to the environment due to its open land filling issues. This study investigates the potential application of RW in concrete structures for mitigating the alkali–silica reaction (ASR). Various proportions of RW (5%, 10%, 15%, 20%, and 25%) partially replaced the used aggregates. RW was procured from a local rubber recycling unit. Cubes, prisms, and mortar bar specimens were prepared using a mixture design recommended by ASTM C1260 and tested for evaluating the compressive and flexural strengths and expansion in an ASR conducive environment for specimens incorporating RW. It was observed that the compressive and flexural strength decreased for specimens incorporating RW compared to that of the control specimens without RW. For example, an 18% and an 8% decrease in compressive and flexural strengths, respectively, were observed for specimens with 5% of RW by aggregates volume at 28 days. Mortar bar specimens without RW showed an expansion of 0.23% and 0.28% at 14 and 28 days, respectively, indicating the potential ASR reactivity in accordance with ASTM C1260. A decrease in expansion was observed for mixtures incorporating RW. Specimens incorporating 20% of RW by aggregate volume showed expansions of 0.17% at 28 days, within the limit specified by ASTM C1260. Moreover, specimens incorporating RW showed a lower reduction in compressive and flexural strengths under an ASR conducive environment compared to that of the control specimen without RW. Micro-structural analysis also showed significant micro-cracking for specimens without RW due to ASR. However, no surface cracks were observed for specimens incorporating RW. It can be argued that the use of RW in the construction industry assists in reducing the landfill depositing issues with the additional benefit of limiting the ASR expansion.     

A review on the synthesis of bio-based surfactants using green chemistry principles

ObjectivesWith increasing awareness of the potential adverse impact of conventional surfactants on the environment and human health, there is mounting interest in the development of bio-based surfactants (which are deemed to be safer, more affordable, are in abundance, are biodegradable, biocompatible and possess scalability, mildness and performance in formulation) in personal care products.MethodA comprehensive literature review around alkyl polyglucosides (APGs) and sucrose esters (SEs) as bio-based surfactants, through the lens of the 12 green chemistry principles was conducted. An overview of the use of bio-based surfactants in personal care products was also provided.ResultsBio-based surfactants are derived primarily from natural sources (i.e. both the head and tail molecular group). One of the more common types of bio-based surfactants are those with carbohydrate head groups, where alkyl polyglucosides (APGs) and sucrose esters (SEs) lead this sub-category. As global regulations and user mandate for sustainability and safety increase, evidence to further support these bio-based surfactants as alternatives to their petrochemical counterparts is advantageous. Use of the green chemistry framework is a suitable way to do this. While many of the discussed principles are enforced industrially, others have only yet been applied at a laboratory scale or are not apparent in literature.ConclusionMany of the principles of green chemistry are currently used in the synthesis of APGs and SEs. These and other bio-based surfactants should, therefore, be considered suitable and sustainable alternatives to conventional surfactants. To further encourage the use of these novel surfactants, industry must make an effort to implement and improve the use of the remaining principles at a commercial level.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s40199-022-00450-y.     

Machine Learning Techniques to Explore Clinical Presentations of COVID-19 Severity and to Test the Association With Unhealthy Opioid Use: Retrospective Cross-sectional Cohort Study

BackgroundThe COVID-19 pandemic has exacerbated health inequities in the United States. People with unhealthy opioid use (UOU) may face disproportionate challenges with COVID-19 precautions, and the pandemic has disrupted access to opioids and UOU treatments. UOU impairs the immunological, cardiovascular, pulmonary, renal, and neurological systems and may increase severity of outcomes for COVID-19.ObjectiveWe applied machine learning techniques to explore clinical presentations of hospitalized patients with UOU and COVID-19 and to test the association between UOU and COVID-19 disease severity.MethodsThis retrospective, cross-sectional cohort study was conducted based on data from 4110 electronic health record patient encounters at an academic health center in Chicago between January 1, 2020, and December 31, 2020. The inclusion criterion was an unplanned admission of a patient aged ≥18 years; encounters were counted as COVID-19-positive if there was a positive test for COVID-19 or 2 COVID-19 International Classification of Disease, Tenth Revision codes. Using a predefined cutoff with optimal sensitivity and specificity to identify UOU, we ran a machine learning UOU classifier on the data for patients with COVID-19 to estimate the subcohort of patients with UOU. Topic modeling was used to explore and compare the clinical presentations documented for 2 subgroups: encounters with UOU and COVID-19 and those with no UOU and COVID-19. Mixed effects logistic regression accounted for multiple encounters for some patients and tested the association between UOU and COVID-19 outcome severity. Severity was measured with 3 utilization metrics: low-severity unplanned admission, medium-severity unplanned admission and receiving mechanical ventilation, and high-severity unplanned admission with in-hospital death. All models controlled for age, sex, race/ethnicity, insurance status, and BMI.ResultsTopic modeling yielded 10 topics per subgroup and highlighted unique comorbidities associated with UOU and COVID-19 (eg, HIV) and no UOU and COVID-19 (eg, diabetes). In the regression analysis, each incremental increase in the classifier’s predicted probability of UOU was associated with 1.16 higher odds of COVID-19 outcome severity (odds ratio 1.16, 95% CI 1.04-1.29; P=.009).ConclusionsAmong patients hospitalized with COVID-19, UOU is an independent risk factor associated with greater outcome severity, including in-hospital death. Social determinants of health and opioid-related overdose are unique comorbidities in the clinical presentation of the UOU patient subgroup. Additional research is needed on the role of COVID-19 therapeutics and inpatient management of acute COVID-19 pneumonia for patients with UOU. Further research is needed to test associations between expanded evidence-based harm reduction strategies for UOU and vaccination rates, hospitalizations, and risks for overdose and death among people with UOU and COVID-19. Machine learning techniques may offer more exhaustive means for cohort discovery and a novel mixed methods approach to population health.