Insulin requirement trajectories during COVID-19 versus non-COVID-19 critical illness-A retrospective cohort study.

BACKGROUND: The glycemic response to critical COVID-19 remains uncertain. We aimed to assess the association between COVID-19, insulin requirements, glycemic control, and mortality in intensive care unit (ICU) patients. METHODS: We conducted a retrospective observational study of 350 COVID-19 patients and 1067 non-COVID-19 patients admitted to the ICU. Insulin requirement was defined as the total units of exogenous insulin required to cover one gram of administered carbohydrates (insulin-to-carbohydrate ratio, ICR). We used multivariable generalized linear mixed-model (GLMM) analysis to assess the association of the interaction between COVID-19 and ICU-day with daily ICR, adjusted for fixed and time-dependent covariates. Glycemic control was assessed after stratification on diabetes and COVID-19. We used multivariable logistic regression analysis to assess the association between ICR and 90-day mortality. RESULTS: The mean (95% CI) of the mean daily ICR among patients without diabetes was 0.09 (0.08-0.11) U/g and 0.15 (0.11-0.18) U/g in the non-COVID-19 group and COVID-19 group (p = .01), respectively. In diabetes patients, the corresponding ICRs were 0.52 (0.43-0.62) U/g and 0.59 (0.50-0.68) U/g (p = .32). In multivariable GLMM analysis, the interaction between COVID-19 and ICU-day was independently associated with ICR (risk estimate 1.22, 95% CI 1.15-1.31, p < .001). COVID-19 was associated with higher hypoglycemia prevalence irrespective of diabetes status, higher average glucose levels, more pronounced glucose variability, and a lower proportion of glucose values within target range among patients without diabetes. On multivariable logistic regression analysis, the adjusted odds ratio for 90-day mortality was 1.77 (95% CI 0.94-3.34, p = .076) per one unit increase in mean ICR. CONCLUSION: In our cohort of ICU patients, COVID-19 was associated with higher daily insulin requirements per gram of administered carbohydrates, and worse glycemic control. We found no robust association between ICR and increased odds of death at 90 days.

Non-gastrointestinal symptom burden following colorectal cancer treatment-a systematic review.

BACKGROUND: Colorectal cancer is one of the most common malignancies worldwide. Improvements in screening and treatment have allowed for earlier detection and longer survival. However, treatments, which may involve surgery, radiotherapy and/or chemotherapy, often lead to patients developing both gastrointestinal and non-gastrointestinal symptoms that can persist long term. This systematic review aims to understand better the non-gastrointestinal symptoms that patients develop after colorectal cancer treatment and how these are identified and assessed through the use of questionnaires. METHOD: The review was conducted according to PRISMA guidelines. Scopus, PubMed, Web of Science, PsycINFO and Cochrane Library were searched. Eligible studies evaluated the non-gastrointestinal symptoms that patients had developed and continued to have at 12 months or longer after treatment. Studies that were performed on patients who were within 12 months of treatment, who had a recurrent or a secondary cancer, had stage 4 cancer/were palliative or that looked solely at gastro-intestinal symptoms were excluded. Articles were limited to studies on human subjects written in English published between February 2012 and July 2024. RESULTS: The searches identified 3491 articles. Thirty-seven articles met the inclusion criteria, of which, 33 were quantitative, 2 were qualitative and 2 were mixed methods study designs. Nearly two-thirds (n = 22) were cross-sectional studies, whereas 14 were longitudinal. One study had both a cross-sectional and longitudinal component to it. Most studies were of medium to high quality based on the Newcastle Ottawa Scale (n = 23) and were conducted in 14 countries, the majority of which were performed in the Netherlands (n = 14). The majority of participants in the included studies (n = 30/37) were men. There were also three studies that were performed with only female participants and one study that was performed with male participants only. The age range of research participants across all the studies was 29 to 89 years. Forty-five different validated questionnaires containing 5-125 question items were used to collect information on the side effects and impact of colorectal cancer treatment. Completion rate for questionnaires varied from 30 to 100% (median 63.5%). These determined effects on quality of life, emotional/psychological distress, sexual and urinary dysfunction, neuropathy, fatigue and hip pain. CONCLUSION: This systematic review highlighted a wide range of longer-term non-gastrointestinal symptoms that frequently adversely affect QoL following treatment. These studies included highlighting the importance of nutrition/diet, physical activity, spirituality and communication in managing these long-term side effects.

Essential oils from Cuminum cyminum and Laurus nobilis and their principal constituents: evaluation of antifungal and antimycotoxigenic potential in Aspergillus species.

The antifungal and antimycotoxigenic activities of the essential oils (EO) from Cuminum cyminum and Laurus nobilis, and their respective principal compounds, cuminaldehyde and 1,8-cineole, were evaluated against fungi of the genus Aspergillus: A. carbonarius, A. niger, A. ochraceus, and A. westerdijkiae. The antifungal activity was determined by the contact method and the mycelial growth of the fungi was evaluated. Scanning electron microscopic (SEM) images were obtained to suggest modes of action of the compounds analysed. The antimycotoxigenic activity was determined by high-performance liquid chromatograph. Aspergillus carbonarius was completely inhibited by cumin EO (500 µl l-1), by laurel EO and by cuminaldehyde (5000 µl l-1). The cumin EO (500 µl l-1) completely inhibited the growth of A. niger. All the samples inhibited the mycelial growth of A. ochraceus, especially cumin EO and cuminaldehyde (250 µl l-1). Aspergillus westerdijkiae was completely inhibited by cumin EO and cuminaldehyde (1000 µl l-1), by laurel EO and 1,8-cineole (10 000 µl l-1). A decrease in the production of ochratoxin A (OTA) was observed post-treatment, except in A. ochraceus, only inhibited by laurel EO. SEM images showed morphological changes in fungal structures and spore inhibition post-treatment. The results confirmed the antifungal and antimycotoxigenic effect of EO and their principal constituents on fungi evaluated.

Sequence diversity in the monooxygenases involved in oxime production in plant defense and signaling: a conservative revision in the nomenclature of the highly complex CYP79 family.

Cytochrome P450 monooxygenases of the CYP79 family catalyze conversion of specific amino acids into oximes feeding into a variety of metabolic plant pathways. Here we present an extensive phylogenetic tree of the CYP79 family built on carefully curated sequences collected across the entire plant kingdom. Based on a monophyletic origin of the P450s, a set of evolutionarily distinct branches was identified. Founded on the functionally characterized CYP79 sequences, sequence features of the individual substrate recognition sites (SRSs) were analyzed. Co-evolving amino acid residues were identified using co-evolutionary sequence analysis. SRS4 possesses a specific sequence pattern when tyrosine is a substrate. Except for the CYP79Cs and CYP79Fs, substrate preferences toward specific amino acids could not be assigned to specific subfamilies. The highly diversified CYP79 tree, reflecting recurrent independent evolution of CYP79s, may relate to the different roles of oximes in different plant species. The sequence differences across individual CYP79 subfamilies may facilitate the in vivo orchestration of channeled metabolic pathways based on altered surface charge domains of the CYP79 protein. Alternatively, they may serve to optimize dynamic interactions with oxime metabolizing enzymes to enable optimal ecological interactions. The outlined detailed curation of the CYP79 sequences used for building the phylogenetic tree made it appropriate to make a conservative phylogenetic tree-based revision of the naming of the sequences within this highly complex cytochrome P450 family. The same approach may be used in other complex P450 subfamilies. The detailed phylogeny of the CYP79 family will enable further exploration of the evolution of function in these enzymes.

Antifungal activity of poly(lactic acid) nanofibers containing the essential oil from Corymbia citriodora Hook or the monoterpenes ß-citronellol and citronellal against mycotoxigenic fungi.

Food contamination by mycotoxigenic fungi is one of the principal factors that cause food loss and economic losses in the food industry. The objective of this work was to incorporate the essential oil from Corymbia citriodora Hook and its constituents citronellal and ß-citronellol into poly(lactic acid) nanofibers; to characterize the nanofibers by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy and differential scanning calorimetry; to evaluate the antifungal activity by the fumigation method; to evaluate the antimycotoxigenic activity against Aspergillus carbonarius, Aspergillus ochraceus, Aspergillus westerdijkiae, Aspergillus flavus, and Aspergillus parasiticus; and to evaluate the morphology of these microorganisms. All the nanofibers had a regular, smooth, and continuous morphology. FTIR analyses confirmed that the active ingredients were incorporated into the polymer matrix. All samples exhibited antifungal and ochratoxigenic inhibitory activities of up to 100% and 99%, respectively, with the best results observed for (PLA + 30 wt% ß-citronellol) nanofibers and (PLA + 30 wt% citronellal) nanofibers. However, 100% inhibition of the production of aflatoxin B1 and B2 was not observed. The images obtained by SEM indicated that the nanofibers caused damage to the hyphae, caused a decrease in the production of spores, and caused deformation, rupture, and non-formation of the conid head, might be an alternative for the control of mycotoxigenic fungi.

Cytochromes P450 evolution in the plant terrestrialization context.

Plants started to colonize land around 500 million years ago. It meant dealing with new challenges like absence of buoyancy, water and nutrients shortage, increased light radiation, reproduction on land, and interaction with new microorganisms. This obviously required the acquisition of novel functions and metabolic capacities. Cytochrome P450 (CYP) monooxygenases form the largest superfamily of enzymes and are present to catalyse critical and rate-limiting steps in most plant-specific pathways. The different families of CYP enzymes are typically associated with specific functions. CYP family emergence and evolution in the green lineage thus offer the opportunity to obtain a glimpse into the timing of the evolution of the critical functions that were required (or became dispensable) for the plant transition to land. Based on the analysis of currently available genomic data, this review provides an evolutionary history of plant CYPs in the context of plant terrestrialization and describes the associated functions in the different lineages. Without surprise it highlights the relevance of the biosynthesis of antioxidants and UV screens, biopolymers, and critical signalling pathways. It also points to important unsolved questions that would deserve to be answered to improve our understanding of plant adaptation to challenging environments and the management of agricultural traits. This article is part of the theme issue 'The evolution of plant metabolism'.

Prevalence of complications and co-morbidities in males and females with obesity: Real-world insights from claims data analysis.

AIM: To comprehensively examine the range of co-morbidities among males and females with a diagnosis of obesity. MATERIALS AND METHODS: This cross-sectional retrospective study used US commercial and Medicare claims data from Merative MarketScan Research Databases to identify adults (age ≥ 18 years) with a diagnosis of obesity with continuous insurance coverage from 2018 to 2020. Co-morbidities were tabulated based on coded diagnoses, and prevalences were calculated in males and females across age groups. Age-adjusted odds ratios (ORs) determined differences in co-morbidities between the sexes. RESULTS: Of an eligible sample of 6.9 million, we identified 2 028 273 individuals with at least one obesity-related International Classification of Diseases, 10th Revision, Clinical Modification code. The proportions of males and females with obesity were 43.0% versus 57.0%. The most prevalent co-morbidities among males and females were hypertension (62.8% vs. 52.2%), dyslipidaemia (63.3% vs. 50.3%) and depression and/or anxiety (D/A; 29.7% vs. 48.5%). The prevalence of D/A was high in the younger age group, but steadily decreased with age in both sexes; however, hypertension and dyslipidaemia continued to increase with age. The presence of diagnosis of hypertension and dyslipidaemia was 6-8 years earlier in males than in females. Females had higher odds than males for osteoarthritis (OR 1.33), depression (OR 2.22) or osteoporosis (OR 7.10); all P < .0001. CONCLUSIONS: Males with obesity received a diagnosis of cardiovascular risk factors at an earlier age than females, which may have contributed to the higher prevalence of coronary heart disease. Understanding sex-specific variations in co-morbidities across ages can support early screening and diagnosis of risk clusters for optimal obesity management.

Dominant-negative KAI2d paralogs putatively attenuate strigolactone responses in root parasitic plants.

Many root parasitic plants in the Orobanchaceae use host-derived strigolactones as germination cues. This adaptation facilitates attachment to a host and is particularly important for the success of obligate parasitic weeds that cause substantial crop losses globally. Parasite seeds sense strigolactones through "divergent" KARRIKIN INSENSITIVE2 (KAI2d)/HYPOSENSITIVE TO LIGHT (HTL) α/ß-hydrolases that have undergone substantial duplication and diversification in Orobanchaceae genomes. After germination, chemotropic growth of parasite roots toward a strigolactone source also occurs in some species. We investigated which of the seven KAI2d genes found in a facultative hemiparasite, Phtheirospermum japonicum, may enable chemotropic responses to strigolactones. To do so, we developed a triple mutant Nbd14a,b kai2i line of Nicotiana benthamiana in which strigolactone-induced degradation of SMAX1, an immediate downstream target of KAI2 signaling, is disrupted. In combination with a transiently expressed, ratiometric reporter of SMAX1 protein abundance, this mutant forms a system for the functional analysis of parasite KAI2d proteins in a plant cellular context. Using this system, we unexpectedly found three PjKAI2d proteins that do not trigger SMAX1 degradation in the presence of strigolactones. Instead, these PjKAI2d inhibit the perception of low strigolactone concentrations by strigolactone-responsive PjKAI2d in a dominant-negative manner that depends upon an active catalytic triad. Similar dominant-negative KAI2d paralogs were identified in an obligate hemiparasitic weed, Striga hermonthica. These proteins suggest a mechanism for attenuating strigolactone signaling in parasites, which might be used to enhance the perception of shallow strigolactone gradients during root growth toward a host or to restrict germination responses to specific strigolactones.

Lead Poisoning in Milwaukee: A Medical and Public Health Update.

INTRODUCTION: Every year, children are poisoned with lead with irreversible effects. This exposure most often occurs in older housing built before 1978 with chipping paint from windowsills where children play and ingest the lead particulates. Exposure to lead can cause neurological and psychological dysfunction, among other health issues. OBJECTIVE: This quality improvement study aims to evaluate our knowledge of at-risk children through a public health approach by analyzing the current public health data and possible barriers to lead screening, testing follow-up, and identifying at-risk children. METHODS: We received data on lead-poisoned children and inspected properties from the City of Milwaukee Health Department. We analyzed each child's initial blood lead level, as well as follow-up tests recorded, ZIP code of residence, and family renter versus home ownership. RESULTS: Over 90% of children in the database had recorded follow-up blood lead testing following an initial elevated blood lead level. There was no difference in initial recorded blood lead levels between children with recorded follow-up blood lead levels and children without (21.40, SD = 11.26); t[1.17], P = 0.24). Most affected children were from economically disadvantaged ZIP codes (53206, 53208, 53215), and 94% lived in rented properties. CONCLUSIONS: Over 90% of children in the database had recorded follow-up blood lead testing following an initial elevated blood lead level. There was no difference in initial recorded blood lead levels between children with recorded follow-up blood lead levels and children without (21.40, SD = 11.26); t[1.17], P = 0.24). Most affected children were from economically disadvantaged ZIP codes (53206, 53208, 53215), and 94% lived in rented properties.

Millimeter wave radiation to measure blood flow in healthy human subjects.

Objective.Peripheral Artery Disease (PAD) is a progressive cardiovascular condition affecting 8-10 million adults in the United States. PAD elevates the risk of cardiovascular events, but up to 50% of people with PAD are asymptomatic and undiagnosed. In this study, we tested the ability of a device, REFLO (Rapid Electromagnetic FLOw), to identify low blood flow using electromagnetic radiation and dynamic thermography toward a non-invasive PAD diagnostic.Approach.During REFLO radio frequency (RF) irradiation, the rate of temperature increase is a function of the rate of energy absorption and blood flow to the irradiated tissue. For a given rate of RF energy absorption, a slow rate of temperature increase implies a large blood flow rate to the tissue. This is due to the cooling effect of the blood. Post-irradiation, a slow rate of temperature decrease is associated with a low rate of blood flow to the tissue. Here, we performed two cohorts of controlled flow experiments on human calves during baseline, occluded, and post-occluded conditions. Nonlinear regression was used to fit temperature data and obtain the rate constant, which was used as a metric for blood flow.Main results.In the pilot study, (N= 7) REFLO distinguished between baseline and post-occlusion during the irradiation phase, and between baseline and occlusion in the post-irradiation phase. In the reliability study, (N= 5 with 3 visits each), two-way ANOVA revealed that flow and subject significantly affected skin heating and cooling rates, while visit did not.Significance.Results suggest that MMW irradiation can be used to distinguish between blood flow rates in humans. Utilizing the rate of skin cooling rather than heating is more consistent for distinguishing flow. Future modifications and clinical testing will aim to improve REFLO's ability to distinguish between flow rates and evaluate its ability to accurately identify PAD.

Implementation of universal screening for substance use in pregnancy in a public healthcare system.

Objective: Screening questionnaires are one option for identification of at-risk substance use and substance use disorder (SUD) during pregnancy. We report the experience of a single institution following universal implementation of a brief screening tool for self-reported substance use at the first prenatal encounter. Study Design: This is a prospective implementation study evaluating screening for substance use in pregnancy in a large safety net healthcare system. Universal screening with the National Institute of Drug Abuse (NIDA) Quick Screen V1.0 was integrated into the electronic medical record (EMR) and administered at the first point of contact with the healthcare system. SUD was identified initially with diagnosis within the EMR by a healthcare provider and was confirmed with toxicology (maternal or neonatal) results corroborating a pattern of substance use and maternal and neonatal ICD-10 codes for SUD. Patients identified with SUD were then classified as moderate or severe SUD based on criteria established by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition. We measured rates of NIDA implementation across different healthcare settings, evaluated NIDA concordance with ascertainment of SUD, and compared adverse pregnancy outcomes associated with moderate and severe SUD. Results: From July 28, 2021, through June 25, 2022, 14,634 unique pregnant individuals accessed care at ambulatory and acute care sites. Universal implementation of the NIDA Quick Screen identified at-risk substance use in 2146 (14.7%) of those who accessed our system, or 17.1% of 12,550 screened across the system, with greater screen completion in ambulatory over acute care settings. SUD was identified in 256 (1.7%) of 14,634 individuals and moderate or severe SUD was identified in 184 (1.3%). Among those with moderate or severe SUD, 90 (48.9%) were NIDA positive, 22 (12.0%) NIDA negative, and 72 (39.1%) unscreened. Of 94 individuals with NIDA discordance or who were unscreened 76 (81%) accessed initial care through an acute care setting. Of 96 individuals with opioid use disorder, 68 (70.8%) were treated with medication-assisted therapy, and 56 (58.3%) were screened with the NIDA Quick Screen. Among delivered individuals with available outcomes, those with moderate or severe SUD were less likely to seek prenatal care (71 (76%) vs 9852 (98%), <0.001)) and more likely to deliver before 37 weeks, (18 (20%) vs 909 (9%), RR (95% CI) 2.13 (1.40, 3.24)) compared to individuals without SUD. Neonates exposed to moderate or severe SUD were more likely to have birth weight <10th centile for gestational age (20 (22%) vs 1147 (12%), RR (95% CI) 1.92 (1.29, 2.85)) and require admission to the neonatal intensive care unit (NICU) (19 (21%) vs 964 (10%), RR (95%) 1.95 (1.30, 2.93)). Conclusion: Universal screening was implemented across a large public healthcare system at a high rate, with higher rates of implementation in ambulatory settings. NIDA successfully identified at-risk substance use in 17% of the SUD cohort but failed to identify more than 50% of patients with moderate or severe SUD. Patients with moderate and severe SUD accessed care primarily through the emergency department and experienced higher rates of adverse obstetric and neonatal outcomes. Future efforts to identify, engage, and retain this highest-risk group are needed.

Toward a Public Health Approach to Farmer Suicide Prevention: The Potential Power of Systems Change.

OBJECTIVE: Suicide among farmers has, over the past 20 years, garnered attention from scholars around the world. The purpose of this paper is twofold. First, this paper will present a framework for considering farmer suicide that builds upon the Interpersonal-Psychological Theory of Suicidal Behavior and extends our current explanations of suicide to include a multilevel, multifactorial focus on individual, interpersonal, community and systemic factors at the root of stressors contributing to suicide among farmers. Secondly, a blueprint for farmer suicide prevention, leveraging the Water of Systems Change Model, is proposed. METHOD: In the spirit of conveying multi-layered influence on farmer suicide while highlighting relevant levels for prevention a parsimonious, prevention-based model of farmer suicide is presented. RESULTS: The Water of Systems Change (WSC) model incorporates research to bring attention to the community, organizational, and societal conditions that keep a problem, such as farmer suicide, from being eradicated. CONCLUSION: Suicide is a societal issue that requires a multi-level response. Farmer suicide is a particular concern, as farmers provide for and support all of us. It is incumbent upon public health and the community-at-large to improve our policies, systems, and contexts to create an environment in which farmers are also provided for and supported.

Volumetric Assessment of Traumatic Intracranial Hematomas: Is ABC/2 Reliable?

Accurate measurement of traumatic intracranial hematoma volume is important for assessing disease progression and prognosis, as well as for serving as an important end-point in clinical trials aimed at preventing hematoma expansion. While the ABC/2 formula has traditionally been used for volume estimation in spontaneous intracerebral hemorrhage, its adaptation to traumatic hematomas lacks validation. This study aimed to compare the accuracy of ABC/2 with computer-assisted volumetric analysis (CAVA) in estimating the volumes of traumatic intracranial hematomas. We performed a dual-center observational study that included adult patients with moderate-to-severe traumatic brain injury. Volumes of intracerebral, subdural (SDHs), and epidural hematomas from admission computed tomography scans were measured using ABC/2 and CAVA, and compared using the Wilcoxon signed-rank test, Spearman's rank correlation, Lin's concordance correlation coefficient (CCC), and Bland-Altman plots. Prognostic significance for outcomes was evaluated through logistic and linear regression models. In total, 1,179 patients with 1,543 hematomas were included. Despite a high correlation (Spearman coefficients between 0.95 and 0.98) and excellent concordance (Lin's CCC from 0.89 to 0.96) between ABC/2 and CAVA, ABC/2 overestimated hematoma volumes compared with CAVA, in some instances exceeding 50 ml. Bland-Altman analysis highlighted wide limits of agreement, especially in SDH. While both methods demonstrated comparable accuracy in predicting outcomes, CAVA was slightly better at predicting craniotomies and midline shift. We conclude that while ABC/2 provides a generally reliable volumetric assessment suitable for descriptive purposes and as baseline variables in studies, CAVA should be the gold standard in clinical situations and studies requiring more precise volume estimations, such as those using hematoma expansion as an outcome.

Understanding the impact of distance and disadvantage on lung cancer care and outcomes: a study protocol.

BACKGROUND: Lung cancer is the third most common cancer in the UK and the leading cause of cancer mortality globally. NHS England guidance for optimum lung cancer care recommends management and treatment by a specialist team, with experts concentrated in one place, providing access to specialised diagnostic and treatment facilities. However, the complex and rapidly evolving diagnostic and treatment pathways for lung cancer, together with workforce limitations, make achieving this challenging. This place-based, behavioural science-informed qualitative study aims to explore how person-related characteristics interact with a person's location relative to specialist services to impact their engagement with the optimal lung pathway, and to compare and contrast experiences in rural, coastal, and urban communities. This study also aims to generate translatable evidence to inform the evidence-based design of a patient engagement intervention to improve lung cancer patients' and informal carers' participation in and experience of the lung cancer care pathway. METHODS: A qualitative cross-sectional interview study with people diagnosed with lung cancer < 6 months before recruitment (in receipt of surgery, radical radiotherapy, or living with advanced disease) and their informal carers. Participants will be recruited purposively from Barts Health NHS Trust and United Lincolnshire Hospitals NHS Trusts to ensure a diverse sample across urban and rural settings. Semi-structured interviews will explore factors affecting individuals' capability, opportunity, and motivation to engage with their recommended diagnostic and treatment pathway. A framework approach, informed by the COM-B model, will be used to thematically analyse facilitators and barriers to patient engagement. DISCUSSION: The study aligns with the current policy priority to ensure that people with cancer, no matter where they live, can access the best quality treatments and care. The evidence generated will be used to ensure that lung cancer services are developed to meet the needs of rural, coastal, and urban communities. The findings will inform the development of an intervention to support patient engagement with their recommended lung cancer pathway. PROTOCOL REGISTRATION: The study received NHS Research Ethics Committee (Ref: 23/SC/0255) and NHS Health Research Authority (IRAS ID 328531) approval on 04/08/2023. The study was prospectively registered on Open Science Framework (16/10/2023; https://osf.io/njq48 ).

Adaptive Evolution Signatures in Prochlorococcus: Open Reading Frame (ORF)eome Resources and Insights from Comparative Genomics.

Prochlorococcus, a cyanobacteria genus of the smallest and most abundant oceanic phototrophs, encompasses ecotype strains adapted to high-light (HL) and low-light (LL) niches. To elucidate the adaptive evolution of this genus, we analyzed 40 Prochlorococcus marinus ORFeomes, including two cornerstone strains, MED4 and NATL1A. Employing deep learning with robust statistical methods, we detected new protein family distributions in the strains and identified key genes differentiating the HL and LL strains. The HL strains harbor genes (ABC-2 transporters) related to stress resistance, such as DNA repair and RNA processing, while the LL strains exhibit unique chlorophyll adaptations (ion transport proteins, HEAT repeats). Additionally, we report the finding of variable, depth-dependent endogenous viral elements in the 40 strains. To generate biological resources to experimentally study the HL and LL adaptations, we constructed the ORFeomes of two representative strains, MED4 and NATL1A synthetically, covering 99% of the annotated protein-coding sequences of the two species, totaling 3976 cloned, sequence-verified open reading frames (ORFs). These comparative genomic analyses, paired with MED4 and NATL1A ORFeomes, will facilitate future genotype-to-phenotype mappings and the systems biology exploration of Prochlorococcus ecology.

Modular Synthesis of Azines Bearing a Guanidine Core from N-Heterocyclic Carbene (NHC)-Derived Selenoureas and Diazo Reagents.

N-Heterocyclic carbene (NHC)-derived selenoureas comprise a fundamentally important class of NHC derivatives, with key applications in coordination chemistry and the determination of NHC electronic properties. Considering the broad reactivity of chalcogen-containing compounds, it is surprising to note that the use of NHC-derived selenoureas as organic synthons remains essentially unexplored. The present contribution introduces a novel, straightforward transformation leading to azines bearing a guanidine moiety, through the reaction of a wide range of NHC-derived selenoureas with commercially available diazo compounds, in the presence of triphenylphosphine. This transformation offers a new approach to such products, having biological, materials chemistry, and organic synthesis applications. The guanidine-bearing azines are obtained in excellent yields, with all manipulations taking place in air. A reaction mechanism is proposed, based on both experimental mechanistic findings and density functional theory (DFT) calculations. A one-pot, multicomponent transesterification reaction between selenoureas, α-diazoesters, alcohols, and triphenylphosphine was also developed, providing highly functionalized azines.

Multivariate Analysis of Factors Associated with Feeding Mother's Own Milk at Discharge in Preterm Infants: A Retrospective Cohort Study.

OBJECTIVE: This study aimed to develop a predictive model of feeding mother's own milk (MOM) at discharge using social determinants of health (SDOH), maternal and neonatal factors after deliveries at <33 weeks of gestational age (GA), or birth weight <1,500 g. STUDY DESIGN: Secondary analysis of a retrospective cohort in an inner-city hospital before (Epoch-1, 2018-2019) and after (Epoch-2, 2020-2021) implementing a donor human milk (DHM) program. RESULTS: Among 986 neonates, 495 were born in Epoch-1 (320 Hispanic White, 142 Non-Hispanic Black, and 33 Other) and 491 in Epoch-2 (327, 137, and 27, respectively). Feeding any MOM was less frequent in infants of non-Hispanic Black mothers than in those of Hispanic mothers (p < 0.05) but did not change with epoch (p = 0.46). Among infants who received any MOM, continued feeding MOM to the time of discharge was less frequent in infants of non-Hispanic Black mothers versus those of Hispanic mothers, 94/237 (40%) versus 339/595 (57%; p < 0.05), respectively. In multivariate analysis including SDOH and maternal variables, the odds of feeding MOM at discharge were lower with SDOH including neighborhoods with higher poverty levels, multiparity, substance use disorder, non-Hispanic Black versus Hispanic and young maternal age and increased with GA but did not change after implementing DHM. The predictive model including SDOH, maternal and early neonatal variables had good discrimination (area under the curve 0.85) and calibration and was internally validated. It showed the odds of feeding MOM at discharge were lower in infants of non-Hispanic Black mothers and with feeding DHM, higher need for respiratory support and later initiation of feeding MOM. CONCLUSION: Feeding MOM at discharge was associated with SDOH, and maternal and neonatal factors but did not change after implementing DHM. Disparity in feeding MOM at discharge was explained by less frequent initiation and shorter duration of feeding MOM but not by later initiation of feeding MOM. KEY POINTS: · In this cohort study of preterm infants, factors of feeding MOM at discharge included (1) SDOH; (2) postnatal age at initiation of feeding MOM; and (3) maternal and neonatal factors.. · Feeding MOM at the time of discharge was less frequent in infants of non-Hispanic Black mothers versus those of Hispanic mothers.. · Disparity in feeding MOM at discharge was explained by less frequent initiation and shorter duration of MOM feeding but not by later postnatal age at initiation of feeding MOM..

Periodic orbits, pair nucleation, and unbinding of active nematic defects on cones.

Geometric confinement and topological constraints present promising means of controlling active materials. By combining analytical arguments derived from the Born-Oppenheimer approximation with numerical simulations, we investigate the simultaneous impact of confinement together with curvature singularity by characterizing the dynamics of an active nematic on a cone. Here, the Born-Oppenheimer approximation means that textures can follow defect positions rapidly on the timescales of interest. Upon imposing strong anchoring boundary conditions at the base of a cone, we find a rich phase diagram of multidefect dynamics, including exotic periodic orbits of one or two +1/2 flank defects, depending on activity and nonquantized geometric charge at the cone apex. By characterizing the transitions between these ordered dynamical states, we present detailed understanding of (i) defect unbinding, (ii) defect absorption, and (iii) defect pair nucleation at the apex. Numerical simulations confirm theoretical predictions of not only the nature of the circular orbits but also defect unbinding from the apex.

Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition.

BACKGROUND: Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition. METHODS: We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton's tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS. RESULTS: Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth. CONCLUSIONS: Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.