Recent advances in synthetic strategies and SAR of thiazolidin-4-one containing molecules in cancer therapeutics.

Cancer is one of the life-threatening diseases accountable for millions of demises globally. The inadequate effectiveness of the existing chemotherapy and its harmful effects has resulted in the necessity of developing innovative anticancer agents. Thiazolidin-4-one scaffold is among the most important chemical skeletons that illustrate anticancer activity. Thiazolidin-4-one derivatives have been the subject of extensive research and current scientific literature reveals that these compounds have shown significant anticancer activities. This manuscript is an earnest attempt to review novel thiazolidin-4-one derivatives demonstrating considerable potential as anticancer agents along with a brief discussion of medicinal chemistry-related aspects of these compounds and structural activity relationship studies in order to develop possible multi-target enzyme inhibitors. Most recently, various synthetic strategies have been developed by researchers to get various thiazolidin-4-one derivatives. In this review, the authors highlight the various synthetic, green, and nanomaterial-based synthesis routes of thiazolidin-4-ones as well as their role in anticancer activity by inhibition of various enzymes and cell lines. The detailed description of the existing modern standards in the field presented in this article may be interesting and beneficial to the scientists for further exploration of these heterocyclic compounds as possible anticancer agents.

Polatuzumab vedotin, venetoclax, and an anti-CD20 monoclonal antibody in relapsed/refractory B-cell non-Hodgkin lymphoma.

The Phase 2 portion of this study evaluated safety and efficacy of polatuzumab vedotin 1.8 mg/kg and venetoclax 800 mg, plus fixed-dose obinutuzumab 1000 mg or rituximab 375 mg/m2 in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), respectively. Patients with complete response (CR) or partial response (PR)/stable disease (FL) or CR/PR (DLBCL) at end of induction (EOI; six 21-day cycles) received post-induction therapy with venetoclax and obinutuzumab or rituximab, respectively. Primary endpoint was CR rate at EOI. Safety-evaluable populations included 74 patients (FL cohort; median age 64 years; progression of disease within 24 months on first-line treatment, 25.7%; FL International Prognostic Index 3-5, 54.1%; ≥2 previous therapies, 74.3%) and 57 patients (DLBCL cohort; median age 65 years; International Prognostic Index 3-5, 54.4%; ≥2 previous therapies, 77.2%). The most common non-hematologic adverse events (mostly Grades 1-2) in the FL and DLBCL cohorts were diarrhea (55.4% and 47.4%, respectively) and nausea (47.3% and 36.8%); neutropenia was the most common Grades 3-4 toxicity (39.2% and 52.6%). Efficacy-evaluable populations included patients treated at the recommended Phase 2 dose (FL, n = 49; DLBCL, n = 48). CR rates at EOI were 59.2% (FL) and 31.3% (DLBCL); median progression-free survival was 22.8 months (95% confidence interval [CI], 14.5-not evaluable) and 4.6 months (95% CI, 3.6-8.1), respectively. Polatuzumab vedotin plus venetoclax and obinutuzumab/rituximab had acceptable safety in patients with R/R FL or DLBCL, with promising response rates in R/R FL, including high-risk patients.

Synthesis of C3-symmetric star shaped amphiphiles for drug delivery applications.

C 3-symmetric star-shaped aromatic compounds are known to possess unique characteristics which facilitate their industrial and biomedical applications. Herein, we report the design, synthesis, self-assembly and drug/dye delivery capabilities of C3-symmetric, hexa-substituted benzene-based amphiphiles. The synthesis of the hexa-substituted C3-symmetric core involves C-acetylation of phloroglucinol to yield the corresponding tri-acetyl derivative. This was further subjected to O-propargylation, followed by the carbonyl reduction of acetyl groups to yield the central core. Various hydrophilic (mPEG) and lipophilic units were then incorporated into this core via click and esterification reactions, respectively, to produce a new type of star shaped amphiphiles. So the obtained amphiphilic architectures have a tendency to aggregate in an aqueous medium forming nanosized assemblies with an inner hydrophobic core, allowing the substituents to control the tension-active properties. The critical aggregation concentration of the amphiphiles was evaluated by fluorescence measurement using the dye Nile red as a fluorescent probe. The hydrodynamic diameter of self-assembled aggregates in aqueous solution was studied by dynamic light scattering, while the actual size and morphology were determined by cryo-transmission electron microscopy (cryo-TEM) analysis. The physicochemical properties of the amphiphiles suggested their suitability for exploring their drug delivery applications. In this endeavor, the amphiphiles were utilized for the encapsulation of model hydrophobic entities and studying their subsequent release from their hydrophobic core in a controlled manner. The transport potential of the synthesised amphiphiles was explored for transdermal drug delivery. Furthermore, cytotoxicity studies were conducted using MCF7 and HeLa cells, which indicated that the nanocarriers had no toxic effect on the cells.

Pre-clinical and cellular safety assessment of oral administered DHA rich microalgae oil from Schizochytrium sp. (Strain ATCC-20889): acute, sub-chronic and genotoxicity.

The lack of toxicity data for DHA-rich oil from Schizochytrium sp. (Strain ATCC-20889) leads to its exclusion from the Qualified Presumption of Safety list. Therefore, present study addresses toxicity evaluation of DHA-rich microalgae oil using ex-vivo (cytotoxicity assay) and in-vivo methods (acute (OECD 423 guidelines), sub-chronic (OECD 452 guidelines), and genotoxicity assay). The ex-vivo results showed >90% cell viability of Caco-2 cells after 48 h of treatment (200 µg/mL of DHA). Additionally, the in-vivo acute toxicity study found that microalgae oil was nontoxic and classified under category 5 molecule according to OECD 423 guidelines with a highest degree of safety at 2000 mg/kg b.w. The in-vivo sub-chronic study revealed no significant mortality and changes in feed intake, body weight, haematological, biochemical, neurological, and urine parameters after repeated 180-days administration of DHA-rich microalgae oil at 250 mg/kg, 500 mg/kg, and 1000 mg/kg. Moreover, histopathology evaluation, comet assay, chromosomal aberration, and micronuclei assay also confirmed the nontoxic behavior of DHA-rich oil. Thus, the results from the ex-vivo and in-vivo studies indicate that DHA-rich oil from Schizochytrium sp. (Strain ATCC-20889) is safe for use as a novel food, and can be included in infants, adults, pregnant women, and children formula.

Methanolic fraction of Cassia fistula L. bark exhibits potential to combat oxidative stress and possess antiproliferative activity.

Cassia fistula L. is well known for its traditional medicinal properties as an anti-inflammatory, hepatoprotective, antifungal, antibacterial, antimutagenic, and wound healing agent. The aim of the present study was to determine antioxidant, genoprotective, and cytotoxic potential of different fractions of C. fistula bark including hexane (CaMH), chloroform (CaMC), ethyl acetate (CaME), and methanol (CaMM). Among all the fractions studied, CaMM exhibited maximal radical scavenging activity in antioxidant DPPH assay, Superoxide anion radical scavenging assay and nitric oxide radical scavenging assay displayed an IC50 value of 18.95, 29.41, and 13.38 µg/ml, respectively. CaMM fraction possessed the highest phenolic (130.37 mg gallic acid equivalent/g dry weight of extract) and flavonoid (36.96 mg rutin equivalent/g dry weight of fraction) content. Data demonstrated significant positive correlation between polyphenol levels and radical scavenging activity. Single cell gel electrophoresis (Comet assay) exhibited genoprotective potential of C. fistula bark fractions against DNA damage induced by hydrogen peroxide (H2O2) in human lymphocytes. CaMM fraction displayed highest protective ability against H2O2 induced-toxicity as evidenced by significant decrease in % tail DNA content from 30 to 7% at highest concentration (200 µg/ml). CaMM was found to be rich in catechin, gallic acid, chlorogenic acid, and kaempferol. The phenolic content and antioxidant ability of the fractions was markedly negatively correlated with H2O2- induced DNA damage in human lymphocytes. Cytotoxic potential was evaluated against dermal epidermoid carcinoma (A431), pancreatic (MIA PaCa-2) and brain glioblastoma (LN-18) cancer cell lines using MTT assay. Results showed that C. fistula bark fractions possessed highest toxicity against the skin carcinoma cells. CaMM fraction reduced over 50% cell growth at the concentration of 76.72 µg/ml in A431 cells. These findings suggest that fractions of C. fistula bark exhibit potential to be considered as therapeutic agents in various carcinomas.

Inpatient CPAP adherence may predict post-discharge adherence in hospitalized patients screened high risk for OSA.

RATIONALE: Despite increased recognition of sleep disordered breathing in hospitalized patients, studies are lacking on the impact of inpatient adherence with positive airway pressure (PAP) therapy on post-discharge adherence. OBJECTIVES: To assess the predictive value of inpatient adherence to PAP therapy on post-discharge compliance and adherence. METHODS: We reviewed data on individuals as part of a registry of a hospital-based sleep medicine program between August 2019 and December 2020. Consecutive patients identified as high risk for sleep disordered breathing based on our 2-tier screening process and initiated on Auto-PAP (APAP) therapy were included. Their adherence and post-discharge course were recorded. Primary objectives were polysomnography (PSG) compliance, sleep medicine clinic follow-up compliance, and 30-day adherence to PAP therapy if indicated by PSG. RESULTS: In total, 900 individuals were screened during the study period. Of these, 281 were offered inpatient PAP therapy. Patients on bilevel PAP therapy (88 patients) were excluded due to lack of objective compliance recording. Final analysis was performed on 193 patients. Of the 193 patients placed on inpatient APAP, 140 (73%) were adherent to the therapy with average usage of 367 min per day versus 140 min per day in the non-adherent (p < 0.001). There was no significant difference in oxygen desaturation index between the adherent and non-adherent groups (32.4 ± 21.9 events per hour and 34.5 ± 21.9 events per hour consistent; p = 0.5). No demographic and anthropometric characteristics or comorbid conditions were noted. Those who were adherent to PAP therapy in-hospital 47/140 (34%) underwent ambulatory PSG post-discharge compared to 7/53 (13%) of those non-adherent in-hospital (p = 0.002). The adherent group also had significantly higher likelihood for post-discharge clinic follow-up (p = 0.01) and adherence to outpatient PAP therapy (p = 0.01). CONCLUSIONS: Hospitalized patients identified as high risk for sleep disordered breathing have high adherence to PAP therapy during hospitalization and inpatient adherence predicts outpatient follow-up (both PSG testing and sleep clinic) and home PAP adherence.

How to interpret a negative high-resolution pulse oximetry in hospitalized patients screened for obstructive sleep apnea: an exploratory analysis.

INTRODUCTION: Obstructive sleep apnea (OSA) is a highly prevalent disorder that often is unrecognized. Recently, a novel protocol for screening hospitalized patients for OSA resulted in early initiation of positive airway pressure (PAP) therapy and early post-discharge follow-up. The protocol utilizes a combination of high-resolution pulse oximetry (HRPO) and home sleep apnea tests (HSATs); the former has been well-validated in previous studies against HSAT and polysomnography. While a definitive treatment plan can be generated for patients with a positive HRPO for OSA, it is less clear how best to manage patients with a negative HRPO. MATERIALS AND METHODS: A retrospective analysis of a registry of patients screened for OSA was conducted. Consecutive patients with HRPO-derived ODI (oxygen desaturation index) < 5/h who underwent same-night HRPO and HSAT were identified. The demographic and clinical characteristics of patients with ODI < 5/h and AHI (apnea hypopnea index) < 5/h were compared with patients with ODI < 5/h and AHI ≥ 5/h. RESULTS: The analysis revealed 190 patients with ODI < 5/h. Only 23 (12%) of these patients had AHI ≥ 5/h. When compared with patients who had ODI < 5/h and AHI < 5/h, there was no difference in most testing and patient characteristics. However, antiplatelet use and total time in minutes with saturation < 88% greater than 100 min were associated with a higher likelihood of discordant ODI and AHI. CONCLUSION: HRPO-derived ODI has a low rate of false negativity. Clinicians should be aware of the possibility of a false negative ODI for patients with antiplatelet use and time with saturation < 88% greater than 100 min and antiplatelet therapy.

iSleepFirst: burnout, fatigue, and wearable-tracked sleep deprivation among residents staffing the medical intensive care unit.

PURPOSE: This study aimed to evaluate the relationship between sleep, burnout, and psychomotor vigilance in residents working in the medical intensive care unit (ICU). METHODS: A prospective cohort study of residents was implemented during a consecutive 4-week. Residents were recruited to wear a sleep tracker for 2 weeks before and 2 weeks during their medical ICU rotation. Data collected included wearable-tracked sleep minutes, Oldenburg burnout inventory (OBI) score, Epworth sleepiness scale (ESS), psychomotor vigilance testing, and American Academy of Sleep Medicine sleep diary. The primary outcome was sleep duration tracked by the wearable. The secondary outcomes were burnout, psychomotor vigilance (PVT), and perceived sleepiness. RESULTS: A total of 40 residents completed the study. The age range was 26-34 years with 19 males. Total sleep minutes measured by the wearable decreased from 402 min (95% CI: 377-427) before ICU to 389 (95% CI: 360-418) during ICU (p < 0.05). Residents overestimated sleep, logging 464 min (95% CI: 452-476) before and 442 (95% CI: 430-454) during ICU. ESS scores increased from 5.93 (95% CI: 4.89, 7.07) to 8.33 (95% CI: 7.09,9.58) during ICU (p < 0.001). OBI scores increased from 34.5 (95% CI: 32.9-36.2) to 42.8 (95% CI: 40.7-45.0) (p < 0.001). PVT scores worsened with increased reaction time while on ICU rotation (348.5 ms pre-ICU, 370.9 ms post-ICU, p < 0.001). CONCLUSIONS: Resident ICU rotations are associated with decreased objective sleep and self-reported sleep. Residents overestimate sleep duration. Burnout and sleepiness increase and associated PVT scores worsen while working in the ICU. Institutions should ensure resident sleep and wellness checks during ICU rotation.

Circulating immune cell phenotype dynamics reflect the strength of tumor-immune cell interactions in patients during immunotherapy.

The extent to which immune cell phenotypes in the peripheral blood reflect within-tumor immune activity prior to and early in cancer therapy is unclear. To address this question, we studied the population dynamics of tumor and immune cells, and immune phenotypic changes, using clinical tumor and immune cell measurements and single-cell genomic analyses. These samples were serially obtained from a cohort of advanced gastrointestinal cancer patients enrolled in a trial with chemotherapy and immunotherapy. Using an ecological population model, fitted to clinical tumor burden and immune cell abundance data from each patient, we find evidence of a strong tumor-circulating immune cell interaction in responder patients but not in those patients that progress on treatment. Upon initiation of therapy, immune cell abundance increased rapidly in responsive patients, and once the peak level is reached tumor burden decreases, similar to models of predator-prey interactions; these dynamic patterns were absent in nonresponder patients. To interrogate phenotype dynamics of circulating immune cells, we performed single-cell RNA sequencing at serial time points during treatment. These data show that peripheral immune cell phenotypes were linked to the increased strength of patients' tumor-immune cell interaction, including increased cytotoxic differentiation and strong activation of interferon signaling in peripheral T cells in responder patients. Joint modeling of clinical and genomic data highlights the interactions between tumor and immune cell populations and reveals how variation in patient responsiveness can be explained by differences in peripheral immune cell signaling and differentiation soon after the initiation of immunotherapy.

Recent Efforts in Identification of Privileged Scaffolds as Antiviral Agents.

Viral infections are the most important health concern nowadays to mankind, which is unexpectedly increasing the health complications and fatality rate worldwide. The recent viral infection outbreak developed a pressing need for small molecules that can be quickly deployed for the control/treatment of re-emerging or new emerging viral infections. Numerous viruses, including the human immunodeficiency virus (HIV), hepatitis, influenza, SARS-CoV-1, SARS-CoV-2, and others, are still challenging due to emerging resistance to known drugs. Therefore, there is always a need to search for new antiviral small molecules that can combat viral infection with new modes of action. This review highlighted recent progress in developing new antiviral molecules based on natural product-inspired scaffolds. Herein, the structure-activity relationship of the FDA-approved drugs along with the molecular docking studies of selected compounds have been discussed against several target proteins. The findings of new small molecules as neuraminidase inhibitors, other than known drug scaffolds, Anti-HIV and SARS-CoV are incorporated in this review paper.

Genotoxic and mutagenic potential of 7-methylxanthine: an investigational drug molecule for the treatment of myopia.

7-Methylxanthine (7-MX, CAS No. 552-62-5, purity 99.46%) is the first orally administered drug candidate, which showed anti-myopic activity in different pre-clinical studies. In the present study, we investigated the in-vivo genotoxic and mutagenic toxicity of 7-MX in Wistar rats using comet/single-cell gel electrophoresis, chromosomal aberration and micronucleus assays after oral administration. For the single-dose study (72 h), two doses of 7-MX 300 and 2000 mg/kg body weight were selected. For a repeated dose 28 d study, three doses (250, 500, and 1000 mg/kg) of 7-MX were selected. The doses were administered via oral gavage in the suspension form. Blood and major vital organs such as bone marrow, lung and liver were used to perform comet/single cell gel electrophoresis, chromosomal aberration, and micronucleus assays. The in-vitro Ames test was performed on TA98 and TA100 strains. In the chromosomal aberration study, a non-significant increase in deformities such as stickiness, ring chromosome, and endoreduplication was observed in bone marrow cells of 7-MX treated groups. These chromosomal alterations were observed upon treatment with doses of 2000 mg/kg single dose for 72 h and 1000 mg/kg repeated dose for 28 d. At a dose of 500 mg/kg, DNA damage in terms of tail length, tail moment, % tail DNA and the olive tail moment was also found to be non-significant in 7-MX treated groups. The Ames test showed the non-mutagenic nature of 7-MX in both strains of TA98 and TA100 of Salmonella typhimurium with or without metabolic activation. Thus, the present work is interesting in view of the non- genotoxicity and non-mutagenicity of repeated doses of 7-MX.

The Role of Airway Management on Feeding Difficulties in Children With Pfeiffer Syndrome.

BACKGROUND: Pfeiffer syndrome is characterized by craniosynostosis, mid-face hypoplasia, broad thumbs, and often multilevel airway obstruction. Airway management is often required, including the use of positive airway ventilation, nasopharyngeal airway (NPA), or tracheostomy. OBJECTIVE: The objective of this study was to assess the impact an airway adjunct can have on feeding difficulties in children with Pfeiffer syndrome. METHODS: Retrospective review of patients diagnosed with Pfeiffer syndrome from January 1998 to January 2020 at one of England's 4 supraregional Craniofacial Units, Alder Hey Children's Hospital. Speech & Language Therapy case notes and medical notes were used to gather data, as well as the Oral Feeding Score component of the UK Craniofacial Outcome Score. RESULTS: Eleven patients were included. Six patients had no airway adjunct (55%): 3 had tracheostomy (27%) and 2 patients had NPA (18%). All patients with airway adjuncts were percutaneous endoscopic gastrostomy/percutaneous endoscopic jejunostomy fed. Those who did not require an airway adjunct had an Oral Feeding Score of 4.60 (SD: 0.49). The children who went on to have an airway adjunct had a mean preintervention Oral Feeding Score of 2.4 (SD: 0.8). The mean feeding score (postairway adjunct) in the NPA group was 2.0, compared with the tracheostomy group scoring 3.0. CONCLUSIONS: Children with Pfeiffer syndrome who require airway intervention have more significant feeding problems requiring feeding intervention. Although there were small numbers included in this study, there is a suggestion that airway adjuncts can contribute to feeding difficulties, particularly NPAs.

Acute incarcerated intrathoracic sleeve herniation after laparoscopic sleeve gastrectomy: an uncommon yet urgent complication-a comprehensive case report and literature review.

Laparoscopic sleeve gastrectomy (LSG) stands as one of the most frequently performed bariatric procedures in the USA. While hiatal hernia or intrathoracic migration of the staple line is frequently described as a chronic complication, this review article sheds light on the seldom-discussed acute presentation of this alarming complication. We present a compelling case of a young female who experienced sudden and intractable vomiting shortly after LSG. Utilizing a multidisciplinary approach, upper gastrointestinal imaging (UGI) and computed tomography (CT) scans unequivocally confirmed incarcerated intrathoracic migration of the gastric sleeve, necessitating immediate surgical intervention. Radiologists must be equipped with the knowledge to recognize subtle yet crucial imaging findings from UGI and CT scans to ensure timely intervention, thus mitigating the risks associated with this underreported acute complication of LSG and ultimately improving patient outcomes and safety.

Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial.

BACKGROUND: Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT). METHODS: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY)control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130. FINDINGS: Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44-61) in the younger age group and 76 years (73-78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41-59) in the younger age group and 78 years (75-82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5-2·3) in the half VLA group to 32·3 (24·8-42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7-1·6) for ChAd to 3·6 (2·4-5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0-1·5) in the half VLA group to 11·5 (9·4-14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7-1·6) for half VLA to 4·7 (3·1-7·1) for m1273. The results were similar between those aged 30-69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30-69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273. INTERPRETATION: All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination. FUNDING: UK Vaccine Taskforce and National Institute for Health Research.

Mechanistic basis and efficacy of targeting the ß-catenin-TCF7L2-JMJD6-c-Myc axis to overcome resistance to BET inhibitors.

The promising activity of BET protein inhibitors (BETi's) is compromised by adaptive or innate resistance in acute myeloid leukemia (AML). Here, modeling of BETi-persister/resistance (BETi-P/R) in human postmyeloproliferative neoplasm (post-MPN) secondary AML (sAML) cells demonstrated accessible and active chromatin in specific superenhancers/enhancers, which was associated with increased levels of nuclear ß-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells, confirming the mechanistic role of the ß-catenin-TCF7L2-JMJD6-c-Myc axis in BETi resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared with sensitive sAML blasts, displayed higher messenger RNA and protein expression of TCF7L2, JMJD6, and c-Myc and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of colocalization of nuclear ß-catenin with TBL1 and TCF7L2 by the small-molecule inhibitor BC2059 combined with depletion of BRD4 by BET proteolysis-targeting chimera reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or patient-derived AML blasts innately resistant to BETi. Therefore, multitargeted disruption of the ß-catenin-TCF7L2-JMJD6-c-Myc axis overcomes adaptive and innate BETi resistance, exhibiting preclinical efficacy against human post-MPN sAML cells.

Supramolecular Engineering of Alkylated, Fluorinated, and Mixed Amphiphiles.

The rational design of perfluorinated amphiphiles to control the supramolecular aggregation in an aqueous medium is still a key challenge for the engineering of supramolecular architectures. Here, the synthesis and physical properties of six novel non-ionic amphiphiles are presented. The effect of mixed alkylated and perfluorinated segments in a single amphiphile is also studied and compared with only alkylated and perfluorinated units. To explore their morphological behavior in an aqueous medium, dynamic light scattering (DLS) and cryogenic transmission electron microscopy/electron microscopy (cryo-TEM/EM) measurements are used. The assembly mechanisms with theoretical investigations are further confirmed, using the Martini model to perform large-scale coarse-grained molecular dynamics simulations. These novel synthesized amphiphiles offer a greater and more systematic understanding of how perfluorinated systems assemble in an aqueous medium and suggest new directions for rational designing of new amphiphilic systems and interpreting their assembly process.

A novel approach on water resource management with Multi-Criteria Optimization and Intelligent Water Demand Forecasting in Saudi Arabia.

Ever-increasing demands for freshwater resources have elevated the likelihood of severe water stress in several places of Saudi Arabia during the last several decades. With effective decision-making processes, development objectives on water resource management emerge. In the following series of research articles, recent innovations in various objective demand forecasting systems are examined and contrasted in terms of their utility in resolving tough challenges in water resource management. Hence, this study proposes a novel approach to water resource management integrating Multi-Criteria Optimization and Intelligent Water Demand Forecasting (MCO-IWDF). This framework addresses the challenges in allocating various water resources to multiple water sectors in a future changing environment. In order to plan for future water needs, water managers use a variety of tools. When forecasting future water demand, the most common method is to estimate current per-capita consumption (gpcd) and multiply this by the expected population growth. Conserving water in the Kingdom of Saudi Arabia to improve irrigation issues. This research analyzes the current situation of available water resources and the water demand in Saudi Arabia. The machine intelligence and big data analytic approach improve the proposed water resource management scheme. The simulation analysis identifies the highest performance in demand prediction accuracy of 98.96% and optimization ratio of 97.87% compared to the existing models. Over time, a mathematical model is used to conduct simulation experiments. Studying the problem, creating a model and collecting data are just some of the steps involved in simulation research. Response analysis and a simulation report are also part of this process. The case study analysis results in a significant satisfactory level of 99.23%.

Enhancing Recruitment and Retention of Minority Populations for Clinical Research in Pulmonary, Critical Care, and Sleep Medicine: An Official American Thoracic Society Research Statement.

Background: Well-designed clinical research needs to obtain information that is applicable to the general population. However, most current studies fail to include substantial cohorts of racial/ethnic minority populations. Such underrepresentation may lead to delayed diagnosis or misdiagnosis of disease, wide application of approved interventions without appropriate knowledge of their usefulness in certain populations, and development of recommendations that are not broadly applicable.Goals: To develop best practices for recruitment and retention of racial/ethnic minorities for clinical research in pulmonary, critical care, and sleep medicine.Methods: The American Thoracic Society convened a workshop in May of 2019. This included an international interprofessional group from academia, industry, the NIH, and the U.S. Food and Drug Administration, with expertise ranging from clinical and biomedical research to community-based participatory research methods and patient advocacy. Workshop participants addressed historical and current mistrust of scientific research, systemic bias, and social and structural barriers to minority participation in clinical research. A literature search of PubMed and Google Scholar was performed to support conclusions. The search was not a systematic review of the literature.Results: Barriers at the individual, interpersonal, institutional, and federal/policy levels were identified as limiting to minority participation in clinical research. Through the use of a multilevel framework, workshop participants proposed evidence-based solutions to the identified barriers.Conclusions: To date, minority participation in clinical research is not representative of the U.S. and global populations. This American Thoracic Society research statement identifies potential evidence-based solutions by applying a multilevel framework that is anchored in community engagement methods and patient advocacy.

Addressing rural health disparity with a novel hospital sleep apnea screening: Precision of a high-resolution pulse oximeter in screening for sleep-disordered breathing.

PURPOSE: High-resolution pulse oximetry (HRPO) may offer a low-cost and simple screening option for sleep-disordered breathing (SDB) that could be vitally important in rural areas with limited healthcare resources and specialty care. Our team hypothesized that application of this technology to a broad cohort of rural dwelling hospitalized individuals would demonstrate congruence similar to previous urban studies comparing HRPO to portable sleep monitors. METHODS: This retrospective study was conducted at West Virginia University Hospital and compared indices obtained from HRPO with those obtained from a type III portable sleep monitor (PM) on the same night. RESULTS: A total of 365 individuals underwent evaluation. The mean oxygen desaturation index (18.8 ± 19.3 events/h) from the HRPO was slightly higher than the mean respiratory event index (16.0 ± 18.1 events/h, p ≤ 0.001) from the PM. ROC curves were developed for thresholds of apnea severity predicted by the screening program. The AUC values for all three thresholds exceeded 0.92 and for a respiratory event index (REI) of ≥ 30 was 0.965. Indices from the PM and HRPO demonstrated agreement in those individuals with screening suggestive of moderate to severe disease. CONCLUSION: This study demonstrates that use of HRPO in screening for SDB in hospitalized patients from rural communities is as accurate as PM and may serve as a simple cost-effective tool to address sleep health disparities in these regions with significant health inequity. Our data extend previous findings by applying HRPO to a larger hospitalized cohort with highly prevalent cardiopulmonary disease.

Aetiological Profile and Short-Term Neurological Outcome of Haemorrhagic Stroke in Children.

BACKGROUND: Haemorrhagic stroke (HS) accounts for nearly half of the paediatric strokes. The aetiology of HS in childhood is not well defined in the Indian context. OBJECTIVES: To study the aetiological profile and short-term neurological outcome of children with HS from North India. METHODS: In a prospective observational study, consecutive patients >28 days to <12 years of age admitted with a diagnosis of HS were enrolled. Demography, clinical, radiological details and investigations were recorded. Short-term outcomes were assessed at three months follow-up with the Paediatric Cerebral Performance Category scale and Paediatric Stroke Outcome Measure (PSOM). RESULTS: A total of 48 children with HS were enrolled. The median age was 6 months (1-58 months), and 33 (69%) were <2 years old. Vitamin K deficiency-related bleeding disorder (VKDB, 44%), central nervous system infections (19%), arteriovenous malformations (13%) and inherited coagulation disorders (8%) were the most common risk factors for HS. VKDB and inherited coagulation disorders were more frequent in children <2 years of age, and arteriovenous malformations were more frequent in children >2 years of age (p = 0.001). During hospitalization, 21 (44%) children died. Older age, low Glasgow coma score (<8) at admission and paediatric intracerebral haemorrhage score ≥2 were associated with mortality at discharge (p = <0.05). Among survivors, 15 (56%) children had neurological deficits (PSOM >0.5) at three month follow-up. CONCLUSION: VKDB, inherited coagulation disorders, central nervous system infections and arteriovenous malformations were the most common risk factors for HS. VKDB is the single most important preventable risk factor for HS in infants.