A simple and rapid spectrophotometric method for the determination of trans-chalcone in raw-materialand topical formulation / Método espectrofotométrico simples e rápido paradeterminação de trans-chalcona em matéria-primae em formulação tópica

Trans-chalcone (TC) is a flavonoid precursor characterized by a wide spectrum of action, with anti-inflammatory and antioxidant effects. However, no validated methods are available in official compendia for the analysis of this substance. Thus, the aim of this work was to develop and validate a simple, fast, and reproducible spectrophotometric method for the analysis of TC in raw material, and in topical pharmaceutical formulation containing TC. The established conditions were: methanol as extracting solvent, and detection wavelength of 309 nm by UV spectrophotometer. All tests followed the rules of Resolution RDC 166, 2017. The proposed method was selective. Linearity was demonstrated in the concentration range of 1 to 8 µg/mL (r = 0.999). Repeatability and intermediate precision were confirmed by low relative standard deviation values of 1.53% and 2.70% for TC, and of 1.73% and 2.91% for formulation containing TC. Accuracy, evaluated through recovery test, was adequate, with minimum of 98.24% and maximum of 100.23% of recovery. It was observed that the small deliberate modifications done did not interfere with the results, demonstrating the method is robust. The results showed that the method was considered suitable for the intended purpose, inexpensive, easy to apply, selective, linear, precise, accurate, and robust for the determination TC, and pharmaceutical formulation containing TC. Thus, the method developed satisfies the need for an analytical method for the determination of TC, and topical formulation containing TC, being effective, innovative and able to aid in the development of the pharmaceutical field.

Trans-chalcona (TC) é um precursor de flavonoides caracterizado por um amplo espectro de ação, como efeitos anti-inflamatórios e antioxidantes. No entanto, não há método validado disponível em compêndio oficial para análise deste composto. Então, o objetivo deste trabalho foi desenvolver e validar um método espectrofotométrico, simples, rápido e reprodutível para análise de TC em matéria-prima, e em formulação farmacêutica tópica contendo TC. As condições estabelecidas foram: metanol como o solvente de extração, e detecção no comprimento de onda de 309 nm por espectrofotometria no UV. Todos os testes seguiram as normas da RDC 166, 2017. O método proposto foi seletivo. A linearidade foi demonstrada na faixa de concentração de 1 a 8 µg/mL (r = 0.999). A repetibilidade e a precisão intermediária foram confirmadas pelos valores baixos de desvio padrão relativo de 1,53% e 2,70% para a TC, e de 1,73% e 2,91% para a formulação contendo TC. A exatidão, avaliada por meio de testes de recuperação, foi adequada, com mínimo de 98,24% e máximo de 100,04% de recuperação. Observou-se que pequenas modificações no método não interferiram nos resultados, demonstrando que o método é robusto. Os resultados demonstraram que o método foi adequado para a finalidade pretendida, barato, de fácil aplicação, seletivo, linear, preciso, exato e robusto para determinação de TC, e de formulação contendo TC. Então o método desenvolvido satisfaz as necessidades de um método analítico para determinação de TC, e de formulação tópica contendo TC, e é eficaz, inovador e pode contribuir para o desenvolvimento da área farmacêutica.

PD-L1 at the crossroad between RNA metabolism and immunosuppression.

Programmed death ligand-1 (PD-L1) is a key component of tumor immunosuppression. The uneven therapeutic results of PD-L1 therapy have stimulated intensive studies to better understand the mechanisms underlying altered PD-L1 expression in cancer cells, and to determine whether, beyond its immune function, PD-L1 might have intracellular functions promoting tumor progression and resistance to treatments. In this Opinion, we focus on paradigmatic examples highlighting the central role of PD-L1 in post-transcriptional regulation, with PD-L1 being both a target and an effector of molecular mechanisms featured prominently in RNA research, such as RNA methylation, phase separation and RNA G-quadruplex structures, in order to highlight vulnerabilities on which future anti-PD-L1 therapies could be built.

Optimal control strategies for toxoplasmosis disease transmission dynamics via harmonic mean-type incident rate.

Toxoplasma infection in humans is considered due to direct contact with infected cats. Toxoplasma infection (an endemic disease) has the potential to affect various organs and systems (brain, eyes, heart, lungs, liver, and lymph nodes). Bilinear incidence rate and constant population (birth rate is equal to death rate) are used in the literature to explain the dynamics of Toxoplasmosis disease transmission in humans and cats. The goal of this study is to consider the mathematical model of Toxoplasma disease with harmonic mean type incident rate and also consider that the population of humans and cats is not equal (birth rate and the death rate are not equal). In examining Toxoplasma transmission dynamics in humans and cats, harmonic mean incidence rates are better than bilinear incidence rates. The disease dynamics are first schematically illustrated, and then the law of mass action is applied to obtain nonlinear ordinary differential equations (ODEs). Analysis of the boundedness, positivity, and equilibrium points of the system has been analyzed. The reproduction number is calculated using the next-generation matrix technique. The stability of disease-free and endemic equilibrium are analyzed. Sensitivity analysis is also done for reproduction number. Numerical simulation shows that the infection is spread in the population when the contact rate ß h and ß c increases while the infection is reduced when the recovery rate δ h increases. This study investigates the impact of various optimal control strategies, such as vaccinations for the control of disease and the awareness of disease awareness, on the management of disease.

Compliance and adherence to hand hygiene practices for effective infection control.

Hand hygiene (HH) is the most effective way to curb the spread of healthcare-associated infections. Nonetheless, healthcare personnel encounter difficulties in adhering to WHO HH recommendations. This study aimed to investigate HH compliance and adherence after the implementation of an action plan in a municipal hospital in Moscow. An initial evaluation of HH compliance among clinical health workers was carried out in June 2022 according to the WHO HH guidelines followed by a 3-month re-audit of HH practices. The results were compared to the baseline to evaluate compliance and adherence to HH among healthcare personnel. From June to September 2022, there were 2,732 moments of contact with patients or their immediate surroundings. The HH total compliance rate significantly (p < 0.05) increased from 52.3% in June 2022 to 83.3% in September 2022 with a 75% overall total compliance rate. The profession-specific total compliance rate was highest among nurses (79.6%) and lowest among ancillary staff (69.7%). Staff were also more adherent to the before-moments compared to the after-moments of the HH guidelines. Monthly re-audits and providing feedback resulted in a significant improvement in compliance and adherence with HH guidelines after implementation of the action plan.

Effluent quality improvement in sequencing batch reactor-based wastewater treatment processes using advanced control strategies.

The treatment of wastewater is highly challenging due to large fluctuations in flowrates, pollutants, and variable influent water compositions. A sequencing batch reactor (SBR) and modified SBR cycle-step-feed process (SSBR) configuration are studied in this work to effectively treat municipal wastewater while simultaneously removing nitrogen and phosphorus. To control the amount of dissolved oxygen in an SBR, three axiomatic control strategies (proportional integral (PI), fractional proportional integral (FPI), and fuzzy logic controllers) are presented. Relevant control algorithms have been designed using plant data with the models of SBR and SSBR based on ASM2d framework. On comparison, FPI showed a significant reduction in nutrient levels and added an improvement in effluent quality. The overall effluent quality is improved by 0.86% in FPI in comparison with PI controller. The SSBR, which was improved by precisely optimizing nutrient supply and aeration, establishes a delicate equilibrium. This refined method reduces oxygen requirements while reliably sustaining important biological functions. Focusing solely on the FPI controller's performance in terms of total air volume consumption, the step-feed SBR mechanism achieves an excellent 11.04% reduction in consumption.

A randomized controlled trial of a novel home-based palliative care program: A report of a trial that could not be completed.

BACKGROUND: In response to a growing need for accessible, efficient, and effective palliative care services, we designed, implemented, and evaluated a novel palliative care at home (PC@H) model for people with serious illness that is centered around a community health worker, a registered nurse, and a social worker, with an advanced practice nurse and a physician for support. Our objectives were to measure the impact of receipt of PC@H on patient symptoms, quality of life, and healthcare utilization and costs. METHODS: We enrolled 136 patients with serious illness in this parallel, randomized controlled trial. Our primary outcome was change in symptom burden at 6 weeks. Secondary outcomes included change in symptom burden at 3 months, change in quality of life at 6 weeks and 3 months, estimated using a group t-test. In an exploratory aim, we examined the impact of PC@H on healthcare utilization and cost using a generalized linear model. RESULTS: PC@H resulted in a greater improvement in patient symptoms at 6 weeks (1.30 score improvement, n = 37) and 3 months (3.14 score improvement, n = 21) compared with controls. There were no differences in healthcare utilization and costs between the two groups. Unfortunately, due to the COVID-19 pandemic and a loss of funding, the trial was not able to be completed as originally intended. CONCLUSIONS: A palliative care at home model that leverages community health workers, registered nurses, and social workers as the primary deliverers of care may result in improved patient symptoms and quality of life compared with standard care. We did not demonstrate significant differences in healthcare utilization and cost associated with receipt of PC@H, likely due to inability to reach the intended sample size and insufficient statistical power, due to elements beyond the investigators' control such as the COVID-19 public health emergency and changes in grant funding.

Outcomes of Near-Total and Subtotal Resection of Sporadic Vestibular Schwannoma: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate tumor control and facial nerve outcomes after gross-total (GTR), near-total (NTR), and subtotal resection (STR) of sporadic vestibular schwannomas (VS). DATA SOURCES: PubMed, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus databases were searched in August 2021 through inception following PRISMA guidelines. REVIEW METHODS: English language articles reporting tumor control and facial nerve outcomes of adults (≥18 years) with NTR and STR of VS were evaluated. Study characteristics, demographics data, tumor characteristics, type of surgical intervention, and outcome measures on tumor control and facial nerve function were collected. Pooled relative risk (RR) estimates for tumor recurrence and facial nerve outcomes were calculated and stratified by extent of resection. RESULTS: From an initial search of 2504 articles, 48 studies were included in the analysis. When comparing 1108 patients who underwent NTR to 3349 patients with GTR, the pooled RR of recurrence in the NTR cohort was 2.94 (95% confidence interval [CI] 1.65-5.24, P = .0002). When comparing 1016 patients who underwent STR to 6171 patients with GTR, the pooled RR of recurrence in the STR cohort was 11.50 (95% CI 6.64-19.92, P < .0001). Estimates for risk of tumor regrowth for less-than-complete resection are presented. There was no elevated risk of adverse facial nerve outcome (defined as House-Brackmann grade III and above) in each category of extent of resection compared to GTR. CONCLUSION: Extent of resection predicts risk of tumor recurrence/regrowth following microsurgical resection. Favorable facial nerve outcome should be weighed against the increased risk of regrowth and the potential need for further treatment.

Sliding mode control for uncertain fractional-order reaction-diffusion memristor neural networks with time delays.

This paper investigates a sliding mode control method for a class of uncertain delayed fractional-order reaction-diffusion memristor neural networks. Different from most existing literature on sliding mode control for fractional-order reaction-diffusion systems, this study constructs a linear sliding mode switching function and designs the corresponding sliding mode control law. The sufficient theory for the globally asymptotic stability of the sliding mode dynamics are provided, and it is proven that the sliding mode surface is finite-time reachable under the proposed control law, with an estimate of the maximum reaching time. Finally, a numerical test is presented to validate the effectiveness of the theoretical analysis.

Synergistic quantification of mixed insulin preparations using time domain NMR techniques.

Diabetes patients often rely on tailored insulin therapies, necessitating precise blends of various insulin types to achieve optimal pharmacokinetic profiles, including the quantity and action duration of insulin absorption into the bloodstream. This study aimed to develop an accurate quantification method for mixed insulin preparations, consisting of Insulin-NPH and Insulin Regular in ratios varying between 0:100-100:0. Time Domain NMR (TD-NMR) techniques, T2 relaxation times, and T1T2 maps were used to analyze the mixtures. Individually, neither technique provided a reliable determination of insulin ratios. However, the integration of both methods through chemometrics has been proven to be a synergistic approach, yielding a robust quantification technique suitable for quality control in the assessment of mixed insulin drugs. This innovative combined TD-NMR method is non-invasive, cost-effective, and user-friendly, offering at the same time a significant potential for preventing health complications associated with improper insulin dosing. Furthermore, our work elucidates the broader applicability of converging multiple TD-NMR techniques for analyzing intricate mixtures.

Cyclodextrin-based metal-organic frameworks transforming drug delivery.

Cyclodextrin-based metal-organic frameworks (CD-MOFs) are gaining traction in the realm of drug delivery due to their inherent versatility and potential to amplify drug efficacy, specificity, and safety. This article explores the predominant preparation techniques for CD-MOFs, encompassing methods like vapor diffusion, microwave-assisted, and ultrasound hydrothermal approaches. Native CD-MOFs present compelling advantages in drug delivery applications. They can enhance drug loading capacity, stability, solubility, and bioavailability by engaging in diverse interactions with drugs, including host-guest, hydrogen bonding, and electrostatic interactions. Beyond their inherent properties, CD-MOFs can be customized as drug carriers through two primary strategies: co-crystallization with functional components and surface post-modifications. These tailored modifications pave the way for controlled release manners. They allow for slow and sustained drug release, as well as responsive releases triggered by various factors such as pH levels, glutathione concentrations, or specific cations. Furthermore, CD-MOFs facilitate targeted delivery strategies, like pulmonary or laryngeal delivery, enhancing drug delivery precision. Overall, the adaptability and modifiability of CD-MOFs underscore their potential as a versatile platform for drug delivery, presenting tailored solutions that cater to diverse biomedical and industrial needs.

Premenstrual syndrome is associated with differences in heart rate variability and attentional control throughout the menstrual cycle: A pilot study.

INTRODUCTION: Most persons with an active menstrual cycle suffer from a range of aversive symptoms (e.g. reduced ability to concentrate) in the days before their menstruation - the premenstrual syndrome (PMS). Biological and cognitive mechanisms of PMS are poorly understood. It has been shown that vagally mediated heart rate variability (vmHRV), a physiological marker of self-regulation, decreases during the PMS-affected cycle phase (luteal phase) only in individuals with high PMS symptomology. This study investigates the specific associations between vmHRV, PMS symptomology and cognitive self-regulation (attentional control). METHODS: In this between-subject study, participants completed an vmHRV baseline measurement through electrocardiography, a reaction time paradigm to measure attentional control (modified attention network test revised, ANT-R) and filled out a questionnaire regarding impact of PMS as well as current menstrual phase. RESULTS: Mixed Model analysis showed interactions effects in the hypothesized direction. VmHRV was decreased during the luteal phase only in individuals with higher PMS. Analogously, performance in the Executive Functioning of the ANT-R task was reduced in the luteal compared to the follicular phase only in individuals with increased PMS symptoms. No effects were found in the Orienting Network Score. DISCUSSION: The results point in the direction of associations between vmHRV, PMS and self-regulation. This could hint at common underlying mechanisms. Further research, however, must be conducted to examine causal pathways to confirm these associations.

HIV rapid tests Immunological internal control can be misleading.

OBJECTIVE: To assess whether internal controls (IC) of HIV rapid tests (HRT) and a rapid confirmatory assay (Geenius) were designed to solely prevent procedural missteps or wether they can also alert for insufficient sample quantity. MATERIAL AND METHODS: Thirteen tests were evaluated using distilled water, phosphate buffered saline, and HIV-1 positive serum samples : Autotest VIH® (Autotest) (AAZ-LMB), INSTITM HIV-1/HIV-2 Antibody Test (INSTI) (Biolytical), MULTISURE® HIV Rapid Test (MULTISURE) (MP Diagnostics Asia Pacific Pte. CE Ltd), Biosynex® HIVTOP (Biosynex), Exacto HIVTOP® (Biosynex), Exacto® TEST HIV PRO (Biosynex), GenieTM Fast HIV 1/2 (Bio-Rad laboratories), GeeniusTM HIV 1/2 Confirmatory Assay (Geenius) (Bio-Rad laboratories), VIKIA® HIV 1/2 (bioMérieux), FIRST RESPONSE® Test VIH 1-2.O CARTE (Premier Medical Corporation), Hexagon HIV (Human), DetermineTM HIV EARLY DETECT (Determine) (Abbott), and ONE STEP Anti-HIV 1&2 (InTec PRODUCTS, Xiamen, Fujian P. R. China). RESULTS: Among the 13 tests, 4 were invalid when tested without human serum sample: Autotest, Geenius, INSTI and MULTISURE. The Autotest and INSTI accurately labelled diluted samples, with a Test line positive at least one dilution below the IC. Geenius test line and IC were positive up to the same dilution with automated reading. However, MULTISURE IC was positive up to 1000-fold dilution higher than its test line, making it unsuitable to alert for low sample quantity.

Practice Patterns of Rate Control In Atrial Fibrillation and Clinical Outcomes From A Nationwide Cohort.

Atrial fibrillation (AF) is common, but limited data to guide selection of rate control medication (RCM). Reasons for selection are multivariable, and the impact on outcomes is unknown. We investigated prescribing patterns of RCM among patients with AF. Using a nationwide database, we identified 135,927 patients with AF. We stratified by baseline presence of heart failure with reduced ejection fraction (HFrEF) and examined prescription rates of RCM as a function of clinical variables. We also evaluated associations with clinical outcomes. Beta blockers (BB) were most commonly prescribed (44.6%), then calcium channel blockers (CCB) (14.0%) and digoxin (8.6%). Patients prescribed BB were more likely male (45.6% vs 43.4%, p < 0.0001), patients prescribed CCB were less likely male (12.0% vs 16.3%, p < 0.0001). There were higher rates of HF hospitalization (HFH) among females and those with Medicaid. Randomized trials are needed to define optimal choice of RCM.

A longitudinal analysis of COVID-19 prevention strategies implemented among US K-12 public schools during the 2021-2022 school year.

PURPOSE: Examine how school-based COVID-19 prevention strategy implementation varied over time, including by local characteristics. METHODS: School administrators (n=335) from a nationally representative sample of K-12 public schools completed four surveys assessing COVID-19 prevention strategies at two-month intervals between October 2021 and June 2022. We calculated weighted prevalence estimates by survey wave. Generalized estimating equations (GEE) were used to model longitudinal changes in strategy implementation, accounting for school and county covariates. RESULTS: Opening doors/windows, daily cleaning, and diagnostic testing were reported by ≥50% of schools at each survey wave. Several strategies were consistently implemented across the 2021-2022 school year (i.e., daily cleaning, opening doors and windows, diagnostic testing) while other strategies increased initially and then declined (i.e., contact tracing, screening testing, on-campus vaccination) or declined consistently throughout the school year (i.e., mask requirement, classroom distancing, quarantine). Although longitudinal changes in strategy implementation did not vary by school characteristics, strategy implementation varied by urban-rural classification and school level throughout the school year. CONCLUSIONS: Strategies that were consistently implemented throughout the school year were also reported by a majority of schools, speaking toward their feasibility for school-based infection control and prevention and potential utility in future public health emergencies.

Antimicrobial resistance and self-reported hand hygiene awareness before and after an infection prevention and control programme: a 7-year analysis in a small animal veterinary teaching hospital.

Infection prevention and control (IPC) in veterinary medicine is crucial to protect patients, owners, staff, and the public. An IPC programme is recommended for every animal hospital. The objective of this retrospective longitudinal study was to describe the changes in bacterial and multidrug-resistant (MDR) bacterial isolates and self-reported hand hygiene awareness and practices after an IPC programme to assess the long-term effect of this programme in small animal veterinary medicine. The IPC programme was implemented at our veterinary teaching hospital in April 2018, which included the establishment of an infection control task force, regular IPC lectures and poster campaigns, infrastructure improvement, and manual refinement. Laboratory-based surveillance was retrospectively conducted before and after the programme (January 2016-December 2022). Level and slope changes in bacterial isolates were evaluated using interrupted time-series analysis. Self-reported hand hygiene awareness and practices were assessed using an annual questionnaire. Additionally, hygiene product purchases during the study period were investigated. The monthly number of total and MDR bacterial isolates decreased significantly after the programme (MDR level change: -0.426; 95% confidence interval: -0.744, -0.109; P = 0.009; and MDR slope change: -0.035; 95% confidence interval: -0.058, -0.011; P = 0.003). Additionally, awareness of hand hygiene before touching animals improved after the programme. Overall self-reported hand hygiene practices improved, and hygiene product purchases significantly increased. These results suggested that the IPC programme may have long-term effects regarding reducing total and MDR bacterial isolates and improving hand hygiene awareness in veterinary medicine.

Risk assessment of the mechanical spread of bacterial pathogens due to Lasius neglectus ants infesting a tertiary hospital.

INTRODUCTION: Mechanical spread of microbial pathogens has been investigated in cockroaches, but less well in ants. Considerably less information is available for ants. An investigation into ant-borne mechanical pathogen transmission was triggered by an infestation of a tertiary care hospital with Lasius neglectus ants. METHODS: The L. neglectus infestation of the orthopedic surgery, the ear-nose-throat clinics and the eye clinics as well as of outdoor areas was monitored and correlated with seasonal and weather influences. Microbial colonization on the ants' exoskeleton as well as in homogenates of complete insects and decolonization dynamics of artificially Staphylococcus aureus colonization on the exoskeleton was assessed. RESULTS: In a low-level infestation setting, L. neglectus activity showed seasonal variations and was positively correlated with temperature (r=0.7515; P=0.0368) but not with precipitation (r=0.4699, P=0.2431). Colonization with environmental commensals dominated, while exoskeleton colonization with bacteria with potential etiological relevance for nosocomial infections was higher for ants from the inpatient setting (6%) than from outdoor areas (0%). Artificial colonization of the exoskeleton with S. aureus vanished to values statistically indistinguishable from baseline within 72 hours. CONCLUSIONS: Low colonization rates with etiologically relevant bacteria and rapid spontaneous decolonization in case of contamination make ant-borne transmissions to patients unlikely.

Quality control, safety assessment and preparation approaches of low molecular weight heparin.

Low Molecular Weight Heparins (LMWHs) are well-established for use in the prevention and treatment of thrombotic diseases, and as a substitute for unfractionated heparin (UFH) due to their predictable pharmacokinetics and subcutaneous bioavailability. LMWHs are produced by various depolymerization methods from UFH, resulting in heterogeneous compounds with similar biochemical and pharmacological properties. However, the delicate supply chain of UFH and potential contamination from animal sources require new manufacturing approaches for LMWHs. Various LMWH preparation methods are emerging, such as chemical synthesis, enzymatic or chemical depolymerization and chemoenzymatic synthesis. To establish the sameness of active ingredients in both innovator and generic LMWH products, the Food and Drug Administration has implemented a stringent scientific method of equivalence based on physicochemical properties, heparin source material and depolymerization techniques, disaccharide composition and oligosaccharide mapping, biological and biochemical properties, and in vivo pharmacodynamic profiles. In this review, we discuss currently available LMWHs, potential manufacturing methods, and recent progress for manufacturing quality control of these LMWHs.

Hallucination Proneness Alters Sensory Feedback Processing in Self-voice Production.

BACKGROUND: Sensory suppression occurs when hearing one's self-generated voice, as opposed to passively listening to one's own voice. Quality changes in sensory feedback to the self-generated voice can increase attentional control. These changes affect the self-other voice distinction and might lead to hearing voices in the absence of an external source (ie, auditory verbal hallucinations). However, it is unclear how changes in sensory feedback processing and attention allocation interact and how this interaction might relate to hallucination proneness (HP). STUDY DESIGN: Participants varying in HP self-generated (via a button-press) and passively listened to their voice that varied in emotional quality and certainty of recognition-100% neutral, 60%-40% neutral-angry, 50%-50% neutral-angry, 40%-60% neutral-angry, 100% angry, during electroencephalography (EEG) recordings. STUDY RESULTS: The N1 auditory evoked potential was more suppressed for self-generated than externally generated voices. Increased HP was associated with (1) an increased N1 response to the self- compared with externally generated voices, (2) a reduced N1 response for angry compared with neutral voices, and (3) a reduced N2 response to unexpected voice quality in sensory feedback (60%-40% neutral-angry) compared with neutral voices. CONCLUSIONS: The current study highlights an association between increased HP and systematic changes in the emotional quality and certainty in sensory feedback processing (N1) and attentional control (N2) in self-voice production in a nonclinical population. Considering that voice hearers also display these changes, these findings support the continuum hypothesis.

Risk factor analysis and nomogram for predicting poor symptom control in smoking asthmatics.

BACKGROUND: Smoking induces and modifies the airway immune response, accelerating the decline of asthmatics' lung function and severely affecting asthma symptoms' control level. To assess the prognosis of asthmatics who smoke and to provide reasonable recommendations for treatment, we constructed a nomogram prediction model. METHODS: General and clinical data were collected from April to September 2021 from smoking asthmatics aged ≥14 years attending the People's Hospital of Zhengzhou University. Patients were followed up regularly by telephone or outpatient visits, and their medication and follow-up visits were recorded during the 6-months follow-up visit, as well as their asthma control levels after 6 months (asthma control questionnaire-5, ACQ-5). The study employed R4.2.2 software to conduct univariate and multivariate logistic regression analyses to identify independent risk factors for 'poorly controlled asthma' (ACQ>0.75) as the outcome variable. Subsequently, a nomogram prediction model was constructed. Internal validation was used to test the reproducibility of the model. The model efficacy was evaluated using the consistency index (C-index), receiver operating characteristic (ROC) curve, calibration curve, and decision curve. RESULTS: Invitations were sent to 231 asthmatics who smoked. A total of 202 participants responded, resulting in a final total of 190 participants included in the model development. The nomogram established five independent risk factors (P<0.05): FEV1%pred, smoking index (100), comorbidities situations, medication regimen, and good or poor medication adherence. The area under curve (AUC) of the modeling set was 0.824(95%CI 0.765-0.884), suggesting that the nomogram has a high ability to distinguish poor asthma control in smoking asthmatics after 6 months. The calibration curve showed a C-index of 0.824 for the modeling set and a C-index of 0.792 for the self-validation set formed by 1000 bootstrap sampling, which means that the prediction probability of the model was consistent with reality. Decision curve analysis (DCA) of the nomogram revealed that the net benefit was higher when the risk threshold probability for poor asthma control was 4.5 - 93.9%. CONCLUSIONS: FEV1%pred, smoking index (100), comorbidities situations, medication regimen, and medication adherence were identified as independent risk factors for poor asthma control after 6 months in smoking asthmatics. The nomogram established based on these findings can effectively predict relevant risk and provide clinicians with a reference to identify the poorly controlled population with smoking asthma as early as possible, and to select a better therapeutic regimen. Meanwhile, it can effectively improve the medication adherence and the degree of attention to complications in smoking asthma patients.

Pyrethroid resistance and gene expression profile of a new resistant An. gambiae colony from Uganda reveals multiple resistance mechanisms and overexpression of Glutathione-S-Transferases linked to survival of PBO-pyrethroid combination.

Background: The effectiveness of long-lasting insecticidal nets (LLINs) are being threatened by growing resistance to pyrethroids. To restore their efficacy, a synergist, piperonyl butoxide (PBO) which inhibits cytochrome P450s has been incorporated into pyrethroid treated nets. A trial of PBO-LLINs was conducted in Uganda from 2017 and we attempted to characterize mechanisms of resistance that could impact intervention efficacy. Methods: We established an Anopheles gambiae s.s colony in 2018 using female mosquitoes collected from Busia district in eastern Uganda. We first assessed the phenotypic resistance profile of this colony using WHO tube and net assays using a deltamethrin dose-response approach. The Busia colony was screened for known resistance markers and RT-qPCR targeting 15 genes previously associated with insecticide resistance was performed. Results: The Busia colony had very high resistance to deltamethrin, permethrin and DDT. In addition, the colony had moderate resistance to alpha-cypermethrin and lambda-cyhalothrin but were fully susceptible to bendiocarb and fenitrothion. Exposure to PBO in combination with permethrin and deltamethrin resulted in higher mortality rates in both net and tube assays, with a higher mortality observed in net assays than tube assays. The kdr marker, Vgsc-995S was at very high frequency (91.7-98.9%) whilst the metabolic markers Coeae1d and Cyp4j5-L43F were at very low (1.3% - 11.5%) and moderate (39.5% - 44.7%) frequencies respectively. Our analysis showed that gene expression pattern in mosquitoes exposed to deltamethrin, permethrin or DDT only were similar in comparison to the susceptible strain and there was significant overexpression of cytochrome P450s, glutathione-s-transferases (GSTs) and carboxyl esterases (COEs). However, mosquitoes exposed to both PBO and pyrethroid strikingly and significantly only overexpressed closely related GSTs compared to unexposed mosquitoes while major cytochrome P450s were underexpressed. Conclusions: The high levels of pyrethroid resistance observed in Busia appears associated with a wide range of metabolic gene families.