Pump-driven clinical infusions: laboratory comparison of pump types, fluid composition and flow rates on model drug delivery applying a new quantitative tool, the pharmacokinetic coefficient of short-term variation (PK-CV).

Critically ill or anesthetized patients commonly receive pump-driven intravenous infusions of potent, fast-acting, short half-life medications for managing hemodynamics. Stepwise dosing, e.g. over 3-5 min, adjusts physiologic responses. Flow rates range from < 0.1 to > 30 ml/h, depending on pump type (large volume, syringe) and drug concentration. Most drugs are formulated in aqueous solutions. Hydrophobic drugs are formulated as lipid emulsions. Do the physical and chemical properties of emulsions impact delivery compared to aqueous solutions? Does stepwise dose titration by the pump correlate with predicted plasma concentrations? Precise, gravimetric, flow rate measurement compared delivery of a 20% lipid emulsion (LE) and 0.9% saline (NS) using different pump types and flow rates. We measured stepwise delivery and then computed predicted plasma concentrations following stepwise dose titration. We measured the pharmacokinetic coefficient of short-term variation, (PK-CV), to assess pump performance. LE and NS had similar mean flow rates in stepwise rate increments and decrements between 0.5 and 32 ml/h and continuous flows 0.5 and 5 ml/h. Pharmacokinetic computation predictions suggest delayed achievement of intended plasma levels following dose titrations. Syringe pumps exhibited smaller variations in PK-CV than large volume pumps. Pump-driven deliveries of lipid emulsion and aqueous solution behave similarly. At low flow rates we observed large flow rate variability differences between pump types showing they may not be interchangeable. PK-CV analysis provides a quantitative tool to assess infusion pump performance. Drug plasma concentrations may lag behind intent of pump dose titration.

CD8α Structural Domains Enhance GUCY2C CAR-T Cell Efficacy.

Despite success in treating some hematological malignancies, CAR-T cells have not yet produced similar outcomes in solid tumors due, in part, to the tumor microenvironment, poor persistence, and a paucity of suitable target antigens. Importantly, the impact of the CAR components on these challenges remains focused on the intracellular signaling and antigen-binding domains. In contrast, the flexible hinge and transmembrane domains have been commoditized and are the least studied components of the CAR. Here, we compared the hinge and transmembrane domains derived from either the CD8ɑ or CD28 molecule in identical GUCY2C-targeted third-generation designs for colorectal cancer. While these structural domains do not contribute to differences in antigen-independent contexts, such as CAR expression and differentiation and exhaustion phenotypes, the CD8ɑ structural domain CAR has a greater affinity for GUCY2C. This results in increased production of inflammatory cytokines and granzyme B, improved cytolytic effector function with low antigen-expressing tumor cells, and robust anti-tumor efficacy in vivo compared with the CD28 structural domain CAR. This suggests that CD8α structural domains should be considered in the design of all CARs for the generation of high-affinity CARs and optimally effective CAR-T cells in solid tumor immunotherapy.

CELEBRIMBOR: core and accessory genes from metagenomes.

MOTIVATION: Metagenome-Assembled Genomes (MAGs) or Single-cell Amplified Genomes (SAGs) are often incomplete, with sequences missing due to errors in assembly or low coverage. This presents a particular challenge for the identification of true gene frequencies within a microbial population, as core genes missing in only a few assemblies will be mischaracterized by current pangenome approaches. RESULTS: Here, we present CELEBRIMBOR, a Snakemake pangenome analysis pipeline which uses a measure of genome completeness to automatically adjust the frequency threshold at which core genes are identified, enabling accurate core gene identification in MAGs and SAGs. AVAILABILITY AND IMPLEMENTATION: CELEBRIMBOR is published under open source Apache 2.0 licence at https://github.com/bacpop/CELEBRIMBOR and is available as a Docker container from this repository. Supplementary material is available in the online version of the article.

The relationship between chronotype and treatment time of day on post-treatment depression symptom severity for depressed patients receiving cognitive behavioural therapy.

BACKGROUND: Major depressive disorder (MDD) represents a serious public health problem that affects a quarter billion individuals worldwide. Consequently, there is a need to identify modifiable factors of services that support treatment success. The relationship between circadian preferences (i.e., chronotype), treatment time of day, and outcomes is an understudied research area. Executing optimal treatment timing based on these factors could lead to substantial returns on a modifiable variable. METHOD: The present study evaluated the associations between chronotype and treatment time of day on post-treatment depression symptom severity. In a tertiary setting, outpatients with MDD (n = 227) received 14 sessions of cognitive behavioural therapy in a group format, at one of three time of days: morning, afternoon, or evening. Participants completed measures of depression and chronotype at baseline and post-treatment. RESULT: Statistically significant increases in morningness were found for the afternoon and evening groups, but not the morning group. There was no significant interaction effect between pre-treatment morningness-eveningness scores and treatment time of day on post-treatment depression scores nor treatment response. However, there was a significant interaction effect of change in morningness-eveningness scores and post-treatment depression severity in the afternoon group. LIMITATIONS: The lack of a control group limits conclusions drawn. CONCLUSION: The results suggest that individual circadian phase may impact treatment outcomes in relation to time of day. Further intentionally designed research is warranted to improve understanding of predictors, moderators, and mediators of patient outcomes based on treatment time of day and circadian phase and amplitude.

Long-term Risk of Right Coronary Artery Injury Following Catheter Ablation of Cavotricuspid Isthmus-dependent Flutter.

BACKGROUND: Radiofrequency ablation (RFA) of cavotricuspid isthmus (CTI)-dependent atrial flutter requires ablation of the tricuspid annulus overlying the right coronary artery (RCA). While considered safe, reports of acute and subacute RCA injury in human and animal studies raise the possibility of late RCA stenosis. OBJECTIVE: To compare the incidence and severity of angiographic RCA stenoses in patients who have undergone CTI RFA to a control group to assess the long-term risk of RCA damage. METHODS: A two-center retrospective case-cohort study was performed including all patients from 2002-2018 undergoing atrial fibrillation (AF) with CTI ablation (CTI+AF) or AF ablation alone with subsequent coronary angiography (CAG). The AF alone group served as controls due to anticipated similarity of baseline characteristics. Coronary arteries that are anatomically remote to the CTI were examined as prespecified falsification endpoints. CAG was scored by a blinded observer. RESULTS: 156 patients who underwent PVI with subsequent CAG (CTI+AF, n=81; AF alone, n=75) had no difference in baseline characteristics including age, sex, comorbidities, and medications. Mean time from ablation to CAG was similar (CTI+AF 5.0±3.7 years vs AF alone 5.4 ±3.9 years, p=0.5). The mid and distal RCA showed no difference in the average number of angiographic stenoses or lesion severity. In regression analysis, CTI ablation was not a predictor of RCA stenosis severity (p=0.6). There was no difference in coronary disease at sites remote to the CTI ablation (p=NS for all). CONCLUSION: There was no observed relationship between CTI RFA and the number or severity of angiographically apparent RCA stenoses in long-term follow up.

Evaluation of precision feeding standardized ileal digestible lysine and other amino acids to determine and meet the lactating sow's requirement estimates.

Two experiments evaluated the effects of precision feeding standardized ileal digestible (SID) Lys during lactation. Sows were blocked by parity and allotted to treatment on d 2 of lactation. In both experiments, sow body weight (BW), backfat (BF), loin depth (LD), and estimated N excretion were evaluated as well as litter growth performance. In Exp. 1, 95 sows and litters were used. Three dietary treatments were provided using 2 diets: a low (0.25% SID Lys) and high Lys diet (1.10% SID Lys). Treatments included a control diet (1.10% SID Lys) fed throughout lactation, and NRC or INRA treatment curves for Lys intake. Sows fed NRC or INRA treatment curves received blends of low and high Lys diets using a computerized lactation feeder (Gestal Quattro Opti Feeder, Jyga Technologies, St-Lambert-de-Lauzon, Quebec, CA) to target a specific Lys intake each day of lactation based on NRC and INRA models for parity and litter size. In Exp. 2, 56 sows and litters were used with three treatments, a control diet (1.10% SID Lys fed throughout lactation) and either a static or dynamic blend curve. For both curve treatments, low (0.40% SID Lys) and high Lys (1.10% SID Lys) diets were blended to reach target Lys intake. The difference between the static and dynamic curves was that the dynamic curves were adjusted based on actual Lys intake and static curves were not. Lysine intake curves were based on NRC model estimates, but targets were increased by 20% to target average Lys intake of 60 g/d across parities based on results of Exp. 1. In both experiments, no differences (P > 0.05) in sow average daily feed intake or sow BW, BF, or LD change were observed. Sows fed the control diets had greater Lys intake (g/day; P < 0.05) compared to sows fed either of the blended treatment curves. In Exp. 1, pigs from sows fed the control diet had greater (P < 0.05) BW at weaning and preweaning average daily gain (ADG) compared to sows fed the INRA treatment curve, with pigs from sows fed the NRC treatment curve intermediate. However, in Exp. 2, no differences (P > 0.05) were observed in pig weight at weaning or ADG. In both experiments, sows fed the blended treatment curves had lower (P < 0.05) calculated N excretion. In summary, for a litter size of 13.5 weaned pigs, 60 g/d of SID Lys is sufficient to maximize litter weight gain and can be achieved through blending low and high Lys diets. Precision feeding reduced N excretion compared to feeding a single diet throughout lactation.

Long COVID Illness: Disparities in Understanding and Receipt of Care in Emergency Department Populations.

STUDY OBJECTIVE: Most long coronavirus disease (long COVID) studies rely on traditional surveillance methods that miss underserved populations who use emergency departments (EDs) as their primary health care source. In medically underserved ED populations, we sought to determine (1) whether there are gaps in awareness and self-declared understanding about long COVID illness, and (2) the prevalence, impact on school/work attendance, and receipt of care for long COVID symptoms. METHODS: This study was a cross-sectional, convenience sample survey study of adult patients at 11 geographically representative US EDs from December 2022 to October 2023. Awareness and self-declared understanding about long COVID illness were measured. Prevalence, impact on school/work attendance, and receipt of care for long COVID symptoms were also assessed. RESULTS: Of 1,618 eligible patients, 1455 (89.9%) agreed to participate, including 33.4% African Americans and 30.9% Latino/a. Of the patients, 17.1% lacked primary care. In total, 33.2% had persistent COVID-19 symptoms lasting >1 month, and 20.3% had symptoms >3 months. Moreover, 49.8% with long COVID symptoms missed work/school because of symptoms; 30.3% of all participants and 33.5% of participants who had long COVID symptoms had prior awareness and self-declared understanding of long COVID. Characteristics associated with poor understanding of long COVID were African American race (adjusted odds ratio [aOR] 3.68, 95% confidence interval [CI] 2.66 to 5.09) and Latino/a ethnicity (aOR 3.16, 95% CI 2.15 to 4.64). Participants lacking primary care were less likely to have received long COVID care (24.6% versus 51.2%; difference 26.6%; 95% CI 13.7% to 36.9%). CONCLUSIONS: Despite high prevalence and impact on school/work attendance of long COVID symptoms, most of this ED population had limited awareness and self-declared understanding of long COVID, and many had not received care. EDs should consider the development of protocols for diagnosis, education, and treatment of long COVID illness.

Dynamics of amylopectin granule accumulation during the course of the chronic Toxoplasma infection is linked to intra-cyst bradyzoite replication.

The contribution of amylopectin granules (AG), comprised of a branched chain storage homopolymer of glucose, to the maintenance and progression of the chronic Toxoplasma gondii infection has remained undefined. Here we describe the role of AG in the physiology of encysted bradyzoites by using a custom developed imaging-based application AmyloQuant that permitted quantification of relative levels of AG within in vivo derived tissue cysts during the initiation and maturation of the chronic infection. Our findings establish that AG are dynamic entities, exhibiting considerable heterogeneity among tissue cysts at all post infection time points examined. Quantification of relative AG levels within tissue cysts exposes a previously unrecognized temporal cycle defined by distinct phases of AG accumulation and utilization over the first 6 weeks of the chronic phase. This AG cycle is temporally coordinated with overall bradyzoite mitochondrial activity implicating amylopectin in the maintenance and progression of the chronic infection. In addition, the staging of AG accumulation and it rapid utilization within encysted bradyzoites was associated with a burst of coordinated replication. As such our findings suggest that AG levels within individual bradyzoites, and across bradyzoites within tissue cysts may represent a key component in the licensing of bradyzoite replication, intimately linking stored metabolic potential to the course of the chronic infection. This extends the impact of AG beyond the previously assigned role that focused exclusively on parasite transmission. These findings force a fundamental reassessment of the chronic Toxoplasma infection, highlighting the critical need to address the temporal evolution of this crucial stage in the parasite life cycle.

Confirmatory information seeking is robust in psychologists' diagnostic reasoning.

OBJECTIVE: Across two experiments, we examined three cognitive biases (order effects, context effects, confirmatory bias) in licensed psychologists' diagnostic reasoning. HYPOTHESES: Our main prediction was that psychologist-participants would seek confirming versus disconfirming information after forming an initial diagnostic hypothesis, even given multiple opportunities to seek new information in the same case. We also expected that individual differences would affect diagnostic reasoning, such that psychologists with lower (vs. higher) cognitive reflection tendencies and larger (vs. smaller) bias blind spots would be more likely to demonstrate confirmatory bias. METHOD: In Study 1, we recruited 149 licensed psychologists (M = 18 years of experience; 44% women; 71% White) and exposed them to one of four randomly assigned vignettes that varied order effects (one set of symptoms in reversed orders) and context effects (court referral vs. employer referral). They rank ordered a list of four possible initial diagnostic hypotheses and received a piped follow-up choice of which of two pieces of information (confirmatory or disconfirmatory) they wanted to test their initial hypothesis. Study 2 (n = 131; M = 21 years of experience; 53% men; 68% White) replicated and extended Study 1, following the same procedure except offering three sequential choice opportunities. RESULTS: Both studies found robust confirmatory information seeking: 92% sought confirmatory information in Study 1, and confirmation persisted across three opportunities in Study 2 (90%, 84%, 77%), although it lowered with each opportunity (generalized logistic mixed regression model), F(2, 378) = 3.85, p = .02, ηp² = .02. CONCLUSION: These findings expand a growing body of research on bias in expert judgment. Specifically, psychologists may engage in robust confirmation bias in the process of forming diagnoses. Although further research is needed on bias and its impact on accuracy, psychologists may need to take steps to reduce confirmatory reasoning processes, such as documenting evidence for and against each decision element. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cortical sites critical to language function act as connectors between language subnetworks.

Historically, eloquent functions have been viewed as localized to focal areas of human cerebral cortex, while more recent studies suggest they are encoded by distributed networks. We examined the network properties of cortical sites defined by stimulation to be critical for speech and language, using electrocorticography from sixteen participants during word-reading. We discovered distinct network signatures for sites where stimulation caused speech arrest and language errors. Both demonstrated lower local and global connectivity, whereas sites causing language errors exhibited higher inter-community connectivity, identifying them as connectors between modules in the language network. We used machine learning to classify these site types with reasonably high accuracy, even across participants, suggesting that a site's pattern of connections within the task-activated language network helps determine its importance to function. These findings help to bridge the gap in our understanding of how focal cortical stimulation interacts with complex brain networks to elicit language deficits.

Predicting newborn birth outcomes with prenatal maternal health features and correlates in the United States: a machine learning approach using archival data.

BACKGROUND: Newborns are shaped by prenatal maternal experiences. These include a pregnant person's physical health, prior pregnancy experiences, emotion regulation, and socially determined health markers. We used a series of machine learning models to predict markers of fetal growth and development-specifically, newborn birthweight and head circumference (HC). METHODS: We used a pre-registered archival data analytic approach. These data consisted of maternal and newborn characteristics of 594 maternal-infant dyads in the western U.S. Participants also completed a measure of emotion dysregulation. In total, there were 22 predictors of newborn HC and birthweight. We used regularized regression for predictor selection and linear prediction, followed by nonlinear models if linear models were overfit. RESULTS: HC was predicted best with a linear model (ridge regression). Newborn sex (male), number of living children, and maternal BMI predicted a larger HC, whereas maternal preeclampsia, number of prior preterm births, and race/ethnicity (Latina) predicted a smaller HC. Birthweight was predicted best with a nonlinear model (support vector machine). Occupational prestige (a marker similar to socioeconomic status) predicted higher birthweight, maternal race/ethnicity (non-White and non-Latina) predicted lower birthweight, and the number of living children, prior preterm births, and difficulty with emotional clarity had nonlinear effects. CONCLUSIONS: HC and birthweight were predicted by a variety of variables associated with prenatal stressful experiences, spanning medical, psychological, and social markers of health and stress. These findings may highlight the importance of viewing prenatal maternal health across multiple dimensions. Findings also suggest that assessing difficulties with emotional clarity during standard obstetric care (in the U.S.) may help identify risk for adverse newborn outcomes.

Harnessing nucleotide metabolism and immunity in cancer: a tumour microenvironment perspective.

The tumour microenvironment (TME) is a dynamic nexus where cancer cell metabolism and the immune system intricately converge, with nucleotide metabolism (NM) playing a pivotal role. This review explores the critical function of NM in cancer cell proliferation and its profound influence on the TME and immune landscape. NM is essential for DNA and RNA synthesis and is markedly upregulated in cancer cells to meet the demands of rapid growth. This metabolic rewiring fuels cancer progression, but also shapes the TME, impacting the function and viability of immune cells. The altered nucleotide milieu in the TME can suppress immune response, aiding cancer cell evasion from immune surveillance. Drug discoveries in the field of NM have revealed different therapeutic strategies, including inhibitors of nucleotide synthesis and drugs targeting salvage pathways, which are discussed thoroughly in this review. Furthermore, the emerging strategy of combining NM-targeted therapies with immunotherapies is emphasised, particularly their effect on sensitising tumours to immune checkpoint inhibitors and enhancing overall treatment efficacy. The Human Genome Project paved the way for personalised medicine, countering the established 'one size fits all' approach to cancer treatment. Advances in understanding the TME and NM have spurred interest in personalised therapeutic strategies. This review highlights the potential of leveraging individual tumour metabolic profiles to guide treatment selection, aiming to optimise efficacy and minimise adverse effects. The strategic importance of targeting NM in cancer therapy and its synergistic potential with immunotherapies offers a path towards more effective and personalised cancer treatments.

A systematic review on the use of transforming powder dressing for wound care.

The transforming powder dressing (Altrazeal®, Uluru Inc, Addison, TX, USA) is simple to use, painless to apply and has a wear time of up to 30 days. This study aims to review the current literature to elucidate the impact of transforming powder dressing on healing, pain management and overall patient outcomes. We conducted a systematic review following Preferred Reporting Items of Systematic Reviews and Meta-Analyses guidelines. Data including study characteristics, patient demographics and wound outcomes were extracted. Our systematic review included 26 articles (n = 175). Of these articles, 13 (50%) were case reports, 10 (38.5%) were case series, 2 (7.7%) were randomised controlled trials and 1 (3.8%) was a cohort study. Wound types included venous ulcer (23.9%), pressure sore (19.7%), burn (15.5%), skin graft (13.4%), diabetic foot ulcer (4.2%), Mohs defect (3.5%) and other (19.6%). Complete re-epithelialization occurred in 90.1% of the wounds. A total of 19 studies (73%) discussed pain, each of which reported reduced pain with the use of transforming powder dressing. The evaluated studies collectively suggest that transforming powder dressing offers a promising re-epithelialization rate and analgesic effect across various wound types.

Evolution of pH-sensitive transcription termination in Escherichia coli during adaptation to repeated long-term starvation.

Fluctuating environments that consist of regular cycles of co-occurring stress are a common challenge faced by cellular populations. For a population to thrive in constantly changing conditions, an ability to coordinate a rapid cellular response is essential. Here, we identify a mutation conferring an arginine-to-histidine (Arg to His) substitution in the transcription terminator Rho. The rho R109H mutation frequently arose in Escherichia coli populations experimentally evolved under repeated long-term starvation conditions, during which the accumulation of metabolic waste followed by transfer into fresh media results in drastic environmental pH fluctuations associated with feast and famine. Metagenomic sequencing revealed that populations containing the rho mutation also possess putative loss-of-function mutations in ydcI, which encodes a recently characterized transcription factor associated with pH homeostasis. Genetic reconstructions of these mutations show that the rho allele confers plasticity via an alkaline-induced reduction of Rho function that, when found in tandem with a ΔydcI allele, leads to intracellular alkalization and genetic assimilation of Rho mutant function. We further identify Arg to His substitutions at analogous sites in rho alleles from species that regularly experience neutral to alkaline pH fluctuations in their environments. Our results suggest that Arg to His substitutions in Rho may serve to rapidly coordinate complex physiological responses through pH sensing and shed light on how cellular populations use environmental cues to coordinate rapid responses to complex, fluctuating environments.

Diisobutyl-ammonium tri-phenyl(2-thiolato-acetato-κ2 O,S)stannate(IV).

Crystals of the title salt, (C8H20N)[Sn(C6H5)3(C2H2O2S)], comprise diisobutyl-ammonium cations and mercapto-acetato-tri-phenyl-stannate(IV) anions. The bidentate binding mode of the mercapto-acetate ligand gives rise to a five-coordinated, ionic tri-phenyl-tin complex with a distorted cis-trigonal-bipyramidal geometry around the tin atom. In the crystal, charge-assisted ammonium-N-H⋯O(carboxyl-ate) hydrogen-bonding connects two cations and two anions into a four-ion aggregate. Two positions were resolved for one of the phenyl rings with the major component having a site occupancy factor of 0.60 (3).

Effectiveness of a serogroup B meningococcal vaccine against gonorrhea: A retrospective study.

BACKGROUND: Outer membrane vesicle (OMV) meningococcal serogroup B (MenB) vaccines might be protective against gonorrhea. We evaluated the effectiveness of MenB-4C, an OMV MenB vaccine, against gonorrhea. METHODS: We identified gonococcal mono-infections, chlamydial mono-infections, and gonococcal/chlamydial co-infections among persons aged 15-30 years in the electronic health records of Kaiser Permanente Northern California during 2016-2021. We determined MenB-4C vaccination status (vaccinated [≥1 MenB-4C vaccine dose] or unvaccinated [MenB-4C vaccine naïve]) at each infection. We used log-binomial regression with generalized estimating equations to calculate adjusted prevalence ratios (APR) and 95 % confidence intervals (CI) to determine if MenB-4C vaccination was protective against gonococcal mono-infections compared to chlamydial mono-infection. We also evaluated if MenB-4C vaccination was protective against gonococcal/chlamydial co-infections. Because of concerns with small sample size of vaccinated persons, we estimated effects using a limited model (adjusting for race/ethnicity only) and an expanded model (adjusting for additional potential confounders). RESULTS: Of 68,454 persons, we identified 558 (0.8 %) MenB-4C vaccinated persons and 85,393 infections (13,000 gonococcal mono-infections, 68,008 chlamydial mono-infections, and 4385 gonococcal/chlamydial co-infections). After adjusting for race/ethnicity, MenB-4C vaccination was 23 % protective against gonococcal mono-infection compared to chlamydial mono-infection (APR = 0.77, 95 % CI = 0.64-0.99) in the limited model but not in the expanded model. CONCLUSION: MenB-4C vaccination was protective against gonococcal mono-infection, independent of race/ethnicity. This protective effect was not observed when other potential confounders were included in the analysis. Protection against gonococcal/chlamydial co-infection was not observed. Efficacy data from clinical trials are needed.

Phenotypic and genotypic evaluation of bleeding diagnostic dilemmas: Two case studies.

Inherited platelet disorders (IPDs) are a heterogeneous group of conditions that present significant challenges in diagnosis and management. Here, we report two cases of patients presenting with clinically significant bleeding but with unclear etiologies by conventional clinical laboratory testing. Further evaluation, utilizing a combination of high-dimensional multiplexed mass cytometry and genetic sequencing, revealed the underlying causes of bleeding in both cases, leading to definitive diagnoses. These cases underscore the potential utility of combined multimodal approaches in evaluating patients with bleeding disorders. Moreover, these high-parameter methods can offer substantial mechanistic insights and can enhance our understanding of the molecular pathogenesis of IPDs. Future studies involving larger patient cohorts are needed to further validate this strategy, directly comparing its diagnostic yield and accuracy with current clinical laboratory testing approaches, which can ultimately improve patient care.

Sensitive Electrochemical and Thermal Detection of Human Noroviruses Using Molecularly Imprinted Polymer Nanoparticles Generated against a Viral Target.

Norovirus (NoV) is the predominant cause of foodborne illness globally; current detection methods are typically expensive, have inadequate sensitivities, and utilize biological receptors with poor stability. Therefore, accurate, cost-effective, and highly stable detection methods are needed to screen for NoV in foods. We developed molecularly imprinted polymer nanoparticles (nanoMIPs) to detect NoV using a small target epitope (12 amino acids) with a solid-phase synthesis approach. The performance of three batches of nanoMIPs with varying monomer compositions (nanoMIP-1, -2, and -3) were compared both experimentally and computationally. Surface plasmon resonance examined nanoMIP binding affinity to norovirus virus-like particles (NoV-LPs), whereby nanoMIP-1 had the lowest KD value of 0.512 µM. This is significant, as traditional targets for generation of norovirus ligands previously reported were generated against drastically larger norovirus capsid segments that have limitations in ease of production. Further, an electrochemical sensor was developed by covalently attaching the nanoMIPs to glassy carbon electrodes. In agreement with our predictions from density functional theory simulations, electrochemical impedance spectroscopy showed a sensitive response toward NoV-LPs for nanoMIP batches tested; however, nanoMIP-1 was optimal, with an excellent detection limit of 3.4 pg/mL (1.9 × 105 particles/mL). Due to its exceptional performance, nanoMIP-1 was immobilized to screen-printed electrodes and utilized within a thermal sensor, where it exhibited a low detection limit of 6.5 pg/mL (3.7 × 105 particles/mL). Crucially, we demonstrated that nanoMIP-1 could detect NoV in real food samples (romaine lettuce) by using electrochemical and thermal sensors. Consequently, the study highlights the exceptional potential of nanoMIPs to replace traditional biological materials (e.g., antibodies) as sensitive, versatile, and highly stable receptors within NoV sensors.

Pain, Substance Use Disorders, Mental Health, and Buprenorphine Treatment among Patients With and Without HIV.

Treatment of opioid use disorder (OUD) with buprenorphine improves outcomes and mortality among people with HIV (PWH). However, engagement is low and is influenced by comorbidities. We examined the impact of patterns of co-occurring pain, substance use disorders (SUDs), and mental health diagnoses on buprenorphine initiation and retention in PWH. The Veterans Aging Cohort Study contained 7,875 patients (2,702 PWH and 5,173 without HIV) with new OUD clinical encounters (2008-2017). Buprenorphine initiation and retention were derived from prescription data. We identified patterns of co-occurring diagnoses (via ICD codes) and assessed the effects of class membership on both outcomes using latent class analysis and regression analyses. The mean age of patients was 55, 98% were male, 58% Black, 8% Hispanic, and only 8% initiated buprenorphine within 12 months of OUD diagnosis. Four classes of co-occurring diagnoses were identified: "Few Co-occurring Diagnoses" (42.3%); "Multiple Pain Conditions" (21.3%); "Pain + SUD" (18.4%) and "Pain + SUD + Mental Health" (18.0%). Patients in the "Pain + SUD" class and "Pain + SUD + Mental Health" class were significantly less likely to initiate buprenorphine and had 59% and 45% lower odds, respectively, of initiating buprenorphine compared with patients in the "Few Co-occurring Diagnoses" class; this effect did not vary by HIV status. Buprenorphine retention was not significantly associated with HIV status or class membership. However, Black Veterans were less likely to initiate or be retained in buprenorphine treatment. Higher comorbidity burden was negatively associated with buprenorphine initiation but not with retention. More research is warranted to determine other factors that may influence treatment retention.