Global epidemiology of cannabis use disorders and its trend from 1990 to 2019: Benchmarking analysis of the global burden of disease study.

Introduction: Cannabis is one of the most widely used psychoactive substances globally, with an increasing trend in its legalization for both medical and recreational purposes in various countries. While cannabis offers potential therapeutic benefits, its regular use can lead to the development of Cannabis Use Disorders (CUDs). Understanding the epidemiology of CUDs is crucial in assessing the public health burden associated with cannabis use. Methods: Epidemiological parameters of CUDs were assessed using the Global Burden of Disease (GBD) methodology across different age-groups, years, sexes, and locations worldwide from 1990-2019. Results: Globally, for both sexes combined, prevalent cases of CUDs increased steadily from 17.1 million(95%UI=12.7-22.8million) in 1990 to 23.8-million(95%UI=17.8-30.9 million) in 2019. All age-adjusted highest number of incidence observed in High-Income-North-America(HINA)(121/100,000), followed by Australasia(100/100,000), Oceania(83.97/100,000), Tropical Latin America(69.59/100,000). Globally, age-standardized disability-adjusted life years rate(ASDR) observed higher in HINA, followed by Australasia, and Western-Europe. In male, all-age incidence counts increased from 1.7 million(95%UI=1.3-2.4million) in 1990 to 2.4 million(95%UI=1.8-3.2 million) in 2019. The highest annual percentage of change in age-standardized incidence rate(ASIR) was found in East-Asia (22%) followed by Middle-East and North-Africa(MENA)(15%). The age group of 15-24 years exhibited the highest burden of CUDs. Conclusion: The widespread occurrence of CUDs on a global scale poses a substantial challenge to public health. Understanding the impact of CUDs and implementing evidence-based interventions is crucial in mitigating the associated individual, societal, and economic burdens. Continued research, collaboration, and knowledge dissemination are essential to inform policies, prevention efforts, and treatment strategies aimed at addressing CUDs on a global-scale.

Performance Improvement Program Review of Institutional Massive Transfusion Protocol Adherence: An Opportunity for Improvement.

BACKGROUND: Given the acuity of patients who receive MTPs and the resources they require, MTPs are a compelling target for performance improvement. This study evaluated adherence with our MTP's plasma:red blood cell ratio (FFPR) of 1:2 and platelet:red blood cell ratio (PLTR) of 1:12, to test the hypothesis that ratio adherence is associated with lower inpatient mortality. MATERIALS AND METHODS: The registry of an urban level I trauma center was queried for adult patients who received at least 6 units of packed red blood cells within 4 hours of presentation. Patients were excluded for interfacility transfer, cardiac arrest during the prehospital phase or within one hour of arrival, or for head AIS ≥5. Univariate analysis and multiple logistic regressions were performed to identify variables associated with early transfusion protocol noncompliance and the effect on inpatient mortality. RESULTS: Three hundred and eighty-three patients were included, with mean ISS of 25.9 ± 13.3 and inpatient mortality of 28.5%. Increasing age, ISS, INR, and total units of blood product transfused were associated with increased odds of mortality, while an increase in revised trauma score was associated with a decreased odds ratio of mortality. Achieving our goal ratios were protective against mortality, with OR of .451 (P = .013) and .402 (P=.003), respectively. DISCUSSION: Large proportions of critically injured patients were transfused fewer units of plasma and platelets than our MTP dictated; failure to achieve intended ratios at 4 hours was strongly associated with inpatient mortality. MTP processes and outcomes should be critically assessed on a regular basis as part of a mature performance improvement program to ensure protocol adherence and optimal patient outcome.

Preparation of composite coagulant for the removal of microplastics in water.

In this work, a composite flocculant (polyferric titanium sulfate-polydimethyldiallylammonium chloride [PFTS-PDMDAAC]) with a rich spatial network structure was prepared for the treatment of simulated wastewater containing polystyrene (PS) micro-nanoparticles. Characterization results showed that the surface of the PFTS-PDMDAAC was a three-dimensional network polymer of chain molecules that exhibited good thermal stability and formed an amorphous polymer containing multiply hydroxyl-bridged titanium and iron. When n(OH- ) : n(Fe) = 1:2, n(PO4 3- ) : n(Fe) = 0.35, n(Ti) : n(Fe) = 1:8, n(DMDAAC) : n(Fe) = 5:100, and the polymerization temperature is 60°C, the prepared composite flocculant has the best effect. The effects of dosage, pH, and agitation intensity on the flocculation properties of PFTS-PDMDAAC were also studied. The optimal removal rates of PS-µm and haze by PFTS-PDMDAAC were 85.60% and 90.10%, respectively, at a stirring intensity of 200 rpm, a pH of 9.0, and a PFTS-PDMDAAC dosage of 20 mg/L. The flocs produced by the PFTS-PDMDAAC flocculation were large and compact in structure, and the flocculation mechanism was mainly based on adsorption bridging. Kaolin played a promoting role in the process of PS-µm removal by PFTS-PDMDAAC floc and accelerated the formation of large and dense flocs. This study provided a reference for the coagulation method to remove micro-nanopollutants in the actual water treatment process. PRACTITIONER POINTS: A composite flocculant with rich spatial network structure (PFTS-PDMDAAC) was prepared. PFTS-PDMDAAC can effectively remove micro-nano polystyrene (PS) in wastewater. The floc produced by PFTS-PDMDAAC is large and compact in structure. The flocculation mechanism of PFTS-PDMDAAC is mainly adsorption bridging.

PLK1 as a cooperating partner for BCL2-mediated antiapoptotic program in leukemia.

The deregulation of BCL2 family proteins plays a crucial role in leukemia development. Therefore, pharmacological inhibition of this family of proteins is becoming a prevalent treatment method. However, due to the emergence of primary and acquired resistance, efficacy is compromised in clinical or preclinical settings. We developed a drug sensitivity prediction model utilizing a deep tabular learning algorithm for the assessment of venetoclax sensitivity in T-cell acute lymphoblastic leukemia (T-ALL) patient samples. Through analysis of predicted venetoclax-sensitive and resistant samples, PLK1 was identified as a cooperating partner for the BCL2-mediated antiapoptotic program. This finding was substantiated by additional data obtained through phosphoproteomics and high-throughput kinase screening. Concurrent treatment using venetoclax with PLK1-specific inhibitors and PLK1 knockdown demonstrated a greater therapeutic effect on T-ALL cell lines, patient-derived xenografts, and engrafted mice compared with using each treatment separately. Mechanistically, the attenuation of PLK1 enhanced BCL2 inhibitor sensitivity through upregulation of BCL2L13 and PMAIP1 expression. Collectively, these findings underscore the dependency of T-ALL on PLK1 and postulate a plausible regulatory mechanism.

Toxic effects of aging mask microplastics on E. coli and dynamic changes in extracellular polymeric matter.

Contamination of disposable medical masks has become a growing problem globally in the wake of Covid-19 due to their widespread use and improper disposal. Three different mask layers, namely the outer layer, the meltblown (MB) filler layer and the inner layers release three different types of microplastics, whose physical and chemical properties change after prolonged environmental weathering. In this study, physical and chemical changes of mask microplastics before and after aging were characterized by different characterization techniques. The toxic effect and mechanism of aged mask microplastics on Escherichia coli (E. coli) were studied by measuring the growth inhibition of mask microplastics, the change in ATPase activity, the change in malondialdehyde content and reactive oxygen species production, and the release of the chemical composition of exopolymeric substances (EPS). The microplastics of the aged MB filter layer had the most significant inhibitory effect on E. coli growth, reaching 19.2 % after 36 h. Also, under the influence of mask microplastics, ATPase activity of E. coli was inhibited and a large amount of EPS was released. The chemical composition of EPS has also changed. This study proposed the possible toxicity mechanism of mask microplastics and the self-protection mechanism of E. coli, and provided a reference for future research on the toxic effects of mask microplastics on environmental organisms.

One-step hydrothermal generation of oxygen-deficient N-doped blue TiO2-Ti3C2 for degradation of pollutants and antibacterial properties.

In this study, TiO2 was generated in situ on the surface of Ti3C2 by a hydrothermal process, and urea was added to form N-doped TiO2-Ti3C2. The surface morphology and functional group properties of the prepared materials were analyzed by SEM, TEM, XRD, XPS, etc. The results showed that anatase TiO2 formed on the surface of the Ti3C2 monolayer. Nitrogen-doped nanomaterials show good phenol degradation and good recyclability under visible light. At a urea content of 0.5 g, the photocatalytic degradation of phenol under visible light is best, reaching 88.9% in 3 h, with ·OH and ·O2- holes playing the leading role. However, at lower pH and higher ion concentration, the degradability of N-TiO2-Ti3C2 for phenol is reduced. Furthermore, the material prepared in this work is a two-dimensional layered material, and the adsorption of phenol best fits the Langmuir adsorption isotherm model and the pseudo-second-order kinetic equation. In terms of the antibacterial performance of the material, the N-doped TiO2-Ti3C2 nanomaterial made with 0.2 g of urea has an Escherichia coli scavenging efficiency of about 97.86%, which is an excellent antibacterial material. This study shows that the N-TiO2-Ti3C2 produced in this experiment can be used for environmental applications.

Fever in the returning traveler.

Evaluation of febrile illness in a returning traveler is challenging as it requires careful history taking and knowledge of local epidemiology of endemic and epidemic diseases. Incorporating information of host characteristics for susceptibility of infections is also important for endemic mycosis apart from history of tick bites and animal exposures. Laboratory tests directed by clinical and laboratory parameters will help to reach final diagnosis.

Targeting altered glycosylation in secreted tumor glycoproteins for broad cancer detection.

There is an urgent need to develop new tumor biomarkers for early cancer detection, but the variability of tumor-derived antigens has been a limitation. Here we demonstrate a novel anti-Tn antibody microarray platform to detect Tn+ glycoproteins, a near universal antigen in carcinoma-derived glycoproteins, for broad detection of cancer. The platform uses a specific recombinant IgG1 to the Tn antigen (CD175) as a capture reagent and a recombinant IgM to the Tn antigen as a detecting reagent. These reagents were validated by immunohistochemistry in recognizing the Tn antigen using hundreds of human tumor specimens. Using this approach, we could detect Tn+ glycoproteins at subnanogram levels using cell lines and culture media, serum, and stool samples from mice engineered to express the Tn antigen in intestinal epithelial cells. The development of a general cancer detection platform using recombinant antibodies for detection of altered tumor glycoproteins expressing a unique antigen could have a significant impact on cancer detection and monitoring.

Different weathering conditions affect the release of microplastics by masks.

A generation of microplastics caused by improper disposal of disposable masks has become a non-negligible environmental concern. In order to investigate the degradation mechanisms of masks and the release of microplastics under different environmental conditions, the masks are placed in 4 common environments. After 30 days of weathering, the total amount and release kinetics of microplastics released from different layers of the mask were studied. The chemical and mechanical properties of the mask were also discussed. The results showed that the mask released 25141±3543 particles/mask into the soil, which is much more than the sea and river water. The release kinetics of microplastics fit the Elovich model better. All samples correspond to the release rate of microplastics from fast to slow. Experiments show that the middle layer of the mask is released more than the other layers, and the amount of release was highest in the soil. And the tensile capacity of the mask is negatively correlated with its ability to release microplastics in the following order, which are soil > seawater > river > air > new masks. In addition, during the weathering process, the C-C/C-H bond of the mask was broken.

Venetoclax-Resistant T-ALL Cells Display Distinct Cancer Stem Cell Signatures and Enrichment of Cytokine Signaling.

Therapy resistance remains one of the major challenges for cancer treatment that largely limits treatment benefits and patient survival. The underlying mechanisms that lead to therapy resistance are highly complicated because of the specificity to the cancer subtype and therapy. The expression of the anti-apoptotic protein BCL2 has been shown to be deregulated in T-cell acute lymphoblastic leukemia (T-ALL), where different T-ALL cells display a differential response to the BCL2-specific inhibitor venetoclax. In this study, we observed that the expression of anti-apoptotic BCL2 family genes, such as BCL2, BCL2L1, and MCL1, is highly varied in T-ALL patients, and inhibitors targeting proteins coded by these genes display differential responses in T-ALL cell lines. Three T-ALL cell lines (ALL-SIL, MOLT-16, and LOUCY) were highly sensitive to BCL2 inhibition within a panel of cell lines tested. These cell lines displayed differential BCL2 and BCL2L1 expression. Prolonged exposure to venetoclax led to the development of resistance to it in all three sensitive cell lines. To understand how cells developed venetoclax resistance, we monitored the expression of BCL2, BCL2L1, and MCL1 over the treatment period and compared gene expression between resistant cells and parental sensitive cells. We observed a different trend of regulation in terms of BCL2 family gene expression and global gene expression profile including genes reported to be expressed in cancer stem cells. Gene set enrichment analysis (GSEA) showed enrichment of cytokine signaling in all three cell lines which was supported by the phospho-kinase array where STAT5 phosphorylation was found to be elevated in resistant cells. Collectively, our data suggest that venetoclax resistance can be mediated through the enrichment of distinct gene signatures and cytokine signaling pathways.

Application of Size Exclusion Chromatography with Multiangle Light Scattering in the Analytical Development of a Preclinical Stage Gene Therapy Program.

To provide safe recombinant adeno-associated viruses (rAAV) to patients, scalable manufacturing processes are required. However, these processes may introduce impurities that impact the performance and quality of the final drug product. Empty rAAV capsids are product-related impurities. Regulatory guidance requires that accurate analytical methods be implemented early in product development to measure the level of empty capsids. A process confirmation vector, produced from 200 L production, was used to develop and optimize a size exclusion chromatography with UV and multiangle light scattering (SEC-MALS) method. Vector produced from a 500 L production was used to assess the full-to-empty ratio using the following analytical methods: sedimentation velocity analytical ultracentrifugation (SV-AUC), droplet digital PCR (ddPCR) with capsid enzyme-linked immunosorbent assay (ELISA), bulk absorbance at 260/280 nm, cryogenic electron microscopy, and SEC-MALS. This test article was used for a 30-day, non-Good Laboratory Practices animal study that assessed biodistribution of the product (STRX-330). SEC-MALS outperformed the other methods and correlated well with SV-AUC values of full-to-empty particles. In addition, SEC-MALS agreed with ddPCR and ELISA measurements for vector genomes/mL and capsid particles/mL, respectively. SEC-MALS was linear, accurate, and precise while achieving chromatography quality control (QC) recommendations. Compared to other stability-indicating assays, SEC-MALS performed similarly to ddPCR, capsid ELISA, and infectivity assays in accelerated stress studies. In response to alkaline, but not acidic stress, SEC-MALS indicated distinct changes in the DNA content of the monomer Adeno-associated viruses (AAV) peak for STRX-330, which was supported by ddPCR data. Conversely, acidic treatment resulted in more aggregated vector, but did not impact the DNA content. This work indicates that SEC-MALS is a valuable analytical tool in the analytical development and QC testing of AAV. In addition, this work suggests that SEC-MALS can provide fundamental understanding of AAV in response to environmental stress. This may impact steps of the manufacturing process to minimize conditions that reduce performance.

Review of Impact of COVID-19 on Maternal, Neonatal Outcomes, and Placental Changes.

Coronavirus disease (COVID-19), caused by SARS-CoV-2, is a disease that has caused a global impact. COVID-19 is transmitted through airborne droplets, respiratory secretions, and direct contact. The pandemic has affected individuals of different ages, and studying the impact of COVID-19 on maternal and newborn outcomes is critical. In this review, we highlight the impact of COVID-19 infection in pregnancy and its repercussion in the maternal-fetal binomial. Physiological changes that occur during pregnancy have significant effects on the immune system, cardiopulmonary system, and coagulation, and these changes can result in an altered response to COVID-19 infection. The symptoms, risk factors, and maternal health consequences of COVID-19 were discussed. In addition, the impact of newborns born to mothers with COVID-19 was reviewed. Finally, placental changes and vertical transmission of COVID-19 during pregnancy were also discussed in this review.

Dental Caries and Oral Health Status of Psychoactive Substance Abusers.

Substance-abuse disorders are universally associated with comorbid illness. Tobacco is a widely abused substance across the globe and presents a critical public health problem. The precise correlation between tobacco use and dental caries remains unclear. Thus, the present study aimed to evaluate the correlation between tobacco use and dental caries. METHODOLOGY: Based on selection criteria, a total of 270 (age 20-50 years) participants were included in the study, and were categorized as group A (n = 135), consisting of tobacco users, and group B (n = 135), comprising healthy controls (non-users). The Decayed, Missing, and Filled index (DMFT) was used to measure caries status. The Simplified Oral Hygiene index was used to evaluate oral health. RESULTS: The tobacco group reported the use of cigarettes; smokeless tobacco in indigenous forms, such as gutka (areca nut, tobacco, and slaked lime), betel nut chewing; and a combination. Individuals with tobacco habits had a higher prevalence of dental caries (Mean DMFT 4.73 ± 4.32) compared to the non-habit group (Mean DMFT 3.17 ± 3.11 (p = 0.001). The Oral Hygiene index was significantly higher (indicating bad/poor oral hygiene) in tobacco abusers than those of non-users (p = 0.0001). Duration and frequency of tobacco use were correlated with the levels of moderate and severe caries (p = 0.001). CONCLUSION: Psychoactive substance abuse, such as smoking/smokeless tobacco consumption, is associated with higher prevalence of dental caries.

Phosphorylation-Dependent Regulation of WNT/Beta-Catenin Signaling.

WNT/ß-catenin signaling is a highly complex pathway that plays diverse roles in various cellular processes. While WNT ligands usually signal through their dedicated Frizzled receptors, the decision to signal in a ß-catenin-dependent or -independent manner rests upon the type of co-receptors used. Canonical WNT signaling is ß-catenin-dependent, whereas non-canonical WNT signaling is ß-catenin-independent according to the classical definition. This still holds true, albeit with some added complexity, as both the pathways seem to cross-talk with intertwined networks that involve the use of different ligands, receptors, and co-receptors. ß-catenin can be directly phosphorylated by various kinases governing its participation in either canonical or non-canonical pathways. Moreover, the co-activators that associate with ß-catenin determine the output of the pathway in terms of induction of genes promoting proliferation or differentiation. In this review, we provide an overview of how protein phosphorylation controls WNT/ß-catenin signaling, particularly in human cancer.

Cryoprecipitate use during massive transfusion: A propensity score analysis.

INTRODUCTION: Cryoprecipitate is frequently administered as an adjunct to balanced transfusion in the setting of traumatic hemorrhage. However, civilian studies have not demonstrated a clear survival advantage, and prior observational studies noted selection bias when analyzing cryoprecipitate use. Additionally, due to the logistics involved in cryoprecipitate administration, it is inconsistently implemented alongside standardized massive transfusion protocols. This study aims to evaluate the effects of early cryoprecipitate administration on inpatient mortality in the setting of massive transfusion for exsanguinating trauma and to use propensity score analysis to minimize selection bias. METHODS: The registry of an urban level 1 trauma center was queried for adult patients who received at least 6 units of packed red blood cells within 4 h of presentation. Univariate analysis, multiple logistic regression, and propensity score matching were performed. RESULTS: 562 patients were identified. Patients with lower median RTS (6.86 (IQR 4.09-7.84) vs 7.6 (IQR 5.97-7.84), P<0.01), decreased Glasgow coma scale (12 (IQR 4-15) vs 15 (IQR 10-15), P<0.01), and increased lactate (7.5 (IQR 4.3-10.2) vs 4.9 (IQR 3.1-7.2), P<0.01) were more commonly administered cryoprecipitate. Mortality was greater among those who received cryoprecipitate (40.2% vs 23.7%, p<0.01) on univariate analysis. Neither multiple logistic regression (OR 0.917; 95% confidence interval 0.462-1.822; p = 0.805) nor propensity score matching (average treatment effect on the treated 2.3%, p = 0.77) revealed that cryoprecipitate administration was associated with a difference in inpatient mortality. CONCLUSIONS: Patients receiving cryoprecipitate within 4 h of presentation were more severely injured at presentation and had increased inpatient mortality. Multivariable logistic regression and propensity score analysis failed to show that early administration of cryoprecipitate was associated with survival benefit for exsanguinating trauma patients. The prospect of definitively assessing the utility of cryoprecipitate in exsanguinating hemorrhage warrants prospective investigation.

Therapeutic drug monitoring of posaconazole delayed release tablet while managing COVID-19-associated mucormycosis in a real-life setting.

BACKGROUND: Along with COVID-19 pandemic, India has faced an outbreak of COVID-19-associated mucormycosis (CAM). Due to restricted availability of amphotericin B during this outbreak, clinicians were forced to use posaconazole or isavuconazole preparations as first-line or alternate therapy in many patients. We planned an early monitoring of posaconazole trough level while using delayed release (DR) tablet as first-line or alternate therapy. OBJECTIVES: Primary objective of the study was to determine percentage of patients achieving arbitrarily decided therapeutic posaconazole levels (≥1.2 µg/ml) after using standard dosages of posaconazole. Secondary objective was to identify potential factors associated with sub-therapeutic posaconazole levels. METHODS: We performed retrospective chart review of the hospitalised patients, who received posaconazole DR tablet as first-line or alternate therapy to treat CAM during outbreak period (March 1 to May 31, 2021). High-performance liquid chromatographic (HPLC) method was used to measure trough level of posaconazole. RESULTS: Posaconazole serum levels of 29 patients were analysed, who received posaconazole DR tablet. Majority (n = 23) were male with the median (range) age 53 (24-86) years. The mean (SD) posaconazole level was 1.66 (0.76) µg/ml. Sub-therapeutic posaconazole trough level was observed in 7 (24.1%) patients. Relatively younger patients were associated with lower posaconazole level (p = .046). Except two patients, all the patients tolerated posaconazole well. CONCLUSIONS: The study supports the posaconazole trough level measurement on day 4 while using posaconazole DR tablet as first-line or alternate therapy to treat mucormycosis during limited supply of amphotericin B.

Orofacial granulomatosis associated with gingival enlargement: a case report.

Orofacial granulomatosis (OFG) is an uncommon condition with varying clinical presentation. Gingival enlargement in children could be due to a varied etiology. The present case report is of an adolescent female with initial presentation of generalized gingival enlargement, lip swelling and perioral discoloration without any known etiopathological factors or systemic involvement. Conservative excision of the enlargement was performed and histopathological examination revealed a non caseating granulomatous lesion. Diagnosis of orofacial granulomatosis in context to sarcoidosis was arrived after excluding other granulomatous diseases. Follow up after 18 months showed no recurrence and regression of lip swelling and perioral discoloration. Gingival enlargement can be considered as one of the presenting features of sarcoidosis.

T cell receptor (TCR) signaling in health and disease.

Interaction of the T cell receptor (TCR) with an MHC-antigenic peptide complex results in changes at the molecular and cellular levels in T cells. The outside environmental cues are translated into various signal transduction pathways within the cell, which mediate the activation of various genes with the help of specific transcription factors. These signaling networks propagate with the help of various effector enzymes, such as kinases, phosphatases, and phospholipases. Integration of these disparate signal transduction pathways is done with the help of adaptor proteins that are non-enzymatic in function and that serve as a scaffold for various protein-protein interactions. This process aids in connecting the proximal to distal signaling pathways, thereby contributing to the full activation of T cells. This review provides a comprehensive snapshot of the various molecules involved in regulating T cell receptor signaling, covering both enzymes and adaptors, and will discuss their role in human disease.