Contemporary burden and trends of opioid-overdose mortality in New York State.

BACKGROUND: Limited research exists on contemporary opioid overdose mortality burden and trends in New York State, with most studies focusing on New York City. This study aimed to assess opioid overdose burden and death trends in New York State by age, sex, race/ethnicity, geographic area, opioid type, and overdose intent from 1999 to 2020. METHODS: Mortality data were obtained from the Centers for Disease Control and Prevention's WONDER database. Opioid overdose decedents were identified using relevant International Classification of Diseases, 10th Revision codes. Joinpoint regression analyzed trends, estimating annual and average annual percentage changes in age-adjusted mortality rates (AAMR). 95% confidence intervals were derived using the Parametric Method. RESULTS: From 1999 to 2020, New York State recorded 34,109 opioid overdose deaths (AAMR = 7.9 per 100,000 persons; 95% CI: 7.8-7.9). The overall trend increased by 12.6% per year (95% CI: 10.8, 14.4) from 2004 to 2020. Subgroups exhibited varying trends, with an 11.1% yearly increase among Non-Hispanic White persons from 2007 to 2020 (95% CI: 9.0, 13.2), a 24.6% annual rise among Non-Hispanic Black persons from 2012 to 2020 (95% CI: 17.7, 31.8), and an 18.3% increase yearly among Hispanic individuals from 2011 to 2020 (95% CI: 14.0, 22.9). Recent trends have worsened in both males and females, across all age groups, in both New York City (NYC) and areas outside NYC, and for heroin, natural and semisynthetic opioids, and synthetic opioids. CONCLUSIONS: Opioid overdose mortality in New York State has worsened significantly in the last two decades. Further research is essential to identify driving factors for targeted public health interventions.

Association of dexmedetomidine use with haemodynamics, postoperative recovery, and cost in paediatric anaesthesia: a hospital registry study.

BACKGROUND: Dexmedetomidine utilisation in paediatric patients is increasing. We hypothesised that intraoperative use of dexmedetomidine in children is associated with longer postanaesthesia care unit length of stay, higher healthcare costs, and side-effects. METHODS: We analysed data from paediatric patients (aged 0-12 yr) between 2016 and 2021 in the Bronx, NY, USA. We matched our cohort with the Healthcare Cost and Utilization Project-Kids' Inpatient Database (HCUP-KID). RESULTS: Among 18 104 paediatric patients, intraoperative dexmedetomidine utilisation increased from 51.7% to 85.7% between 2016 and 2021 (P<0.001). Dexmedetomidine was dose-dependently associated with a longer postanaesthesia care unit length of stay (adjusted absolute difference [ADadj] 19.7 min; 95% confidence interval [CI]: 18.0-21.4 min; P<0.001, median length of stay of 122 vs 98 min). The association was magnified in children aged ≤2 yr undergoing short (≤60 min) ambulatory procedures (ADadj 33.3 min; 95% CI: 26.3-40.7 min; P<0.001; P-for-interaction <0.001). Dexmedetomidine was associated with higher total hospital costs of USD 1311 (95% CI: USD 835-1800), higher odds of intraoperative mean arterial blood pressure below 55 mm Hg (adjusted odds ratio [ORadj] 1.27; 95% CI: 1.16-1.39; P<0.001), and higher odds of heart rate below 100 beats min-1 (ORadj 1.32; 95% CI: 1.21-1.45; P<0.001), with no preventive effects on emergence delirium requiring postanaesthesia i.v. sedatives (ORadj 1.67; 95% CI: 1.04-2.68; P=0.034). CONCLUSIONS: Intraoperative use of dexmedetomidine is associated with unwarranted haemodynamic effects, longer postanaesthesia care unit length of stay, and higher costs, without preventive effects on emergence delirium.

Hearing Loss Prevalence, Years Lived With Disability, and Hearing Aid Use in the United States From 1990 to 2019: Findings From the Global Burden of Disease Study.

OBJECTIVES: This article describes key data sources and methods used to estimate hearing loss in the United States, in the Global Burden of Disease study. Then, trends in hearing loss are described for 2019, including temporal trends from 1990 to 2019, changing prevalence over age, severity patterns, and utilization of hearing aids. DESIGN: We utilized population-representative surveys from the United States to estimate hearing loss prevalence for the Global Burden of Disease study. A key input data source in modeled estimates are the National Health and Nutrition Examination Surveys (NHANES), years 1988 to 2010. We ran hierarchical severity-specific models to estimate hearing loss prevalence. We then scaled severity-specific models to sum to total hearing impairment prevalence, adjusted estimates for hearing aid coverage, and split estimates by etiology and tinnitus status. We computed years lived with disability (YLDs), which quantifies the amount of health loss associated with a condition depending on severity and creates a common metric to compare the burden of disparate diseases. This was done by multiplying the prevalence of severity-specific hearing loss by corresponding disability weights, with additional weighting for tinnitus comorbidity. RESULTS: An estimated 72.88 million (95% uncertainty interval (UI) 68.53 to 77.30) people in the United States had hearing loss in 2019, accounting for 22.2% (20.9 to 23.6) of the total population. Hearing loss was responsible for 2.24 million (1.56 to 3.11) YLDs (3.6% (2.8 to 4.7) of total US YLDs). Age-standardized prevalence was higher in males (17.7% [16.7 to 18.8]) compared with females (11.9%, [11.2 to 12.5]). While most cases of hearing loss were mild (64.3%, 95% UI 61.0 to 67.6), disability was concentrated in cases that were moderate or more severe. The all-age prevalence of hearing loss in the United States was 28.1% (25.7 to 30.8) higher in 2019 than in 1990, despite stable age-standardized prevalence. An estimated 9.7% (8.6 to 11.0) of individuals with mild to profound hearing loss utilized a hearing aid, while 32.5% (31.9 to 33.2) of individuals with hearing loss experienced tinnitus. Occupational noise exposure was responsible for 11.2% (10.2 to 12.4) of hearing loss YLDs. CONCLUSIONS: Results indicate large burden of hearing loss in the United States, with an estimated 1 in 5 people experiencing this condition. While many cases of hearing loss in the United States were mild, growing prevalence, low usage of hearing aids, and aging populations indicate the rising impact of this condition in future years and the increasing importance of domestic access to hearing healthcare services. Large-scale audiometric surveys such as NHANES are needed to regularly assess hearing loss burden and access to healthcare, improving our understanding of who is impacted by hearing loss and what groups are most amenable to intervention.

Hispanic/Latino Ethnicity and Loss of Post-Surgery Independent Living: A Retrospective Cohort Study from a Bronx Hospital Network.

BACKGROUND: Black race is associated with postoperative adverse discharge to a nursing facility, but the effects of Hispanic/Latino ethnicity are unclear. We explored the Hispanic paradox, described as improved health outcomes among Hispanic/Latino patients on postoperative adverse discharge to nursing facility. METHODS: A total of 93,356 adults who underwent surgery and were admitted from home to Montefiore Medical Center in the Bronx, New York, between January 2016 and June 2021 were included. The association between self-identified Hispanic/Latino ethnicity and the primary outcome, postoperative adverse discharge to a nursing home or skilled nursing facility, was investigated. Interaction analysis was used to examine the impact of socioeconomic status, determined by estimated median household income and insurance status, on the primary association. Mixed-effects models were used to evaluate the proportion of variance attributed to the patient's residential area defined by zip code and self-identified ethnicity. RESULTS: Approximately 45.9% (42,832) of patients identified as Hispanic/Latino ethnicity and 9.7% (9074) patients experienced postoperative adverse discharge. Hispanic/Latino ethnicity was associated with lower risk of adverse discharge (relative risk [RRadj] 0.88; 95% confidence interval [CI], 00.82-0.94; P < .001), indicating a Hispanic Paradox. This effect was modified by the patient's socioeconomic status (P-for-interaction <.001). Among patients with a high socioeconomic status, the Hispanic paradox was abolished (RRadj 1.10; 95% CI, 11.00-1.20; P = .035). Furthermore, within patients of low socioeconomic status, Hispanic/Latino ethnicity was associated with a higher likelihood of postoperative discharge home with health services compared to non-Hispanic/Latino patients (RRadj 1.06; 95% CI, 11.01-1.12; P = .017). CONCLUSIONS: Hispanic/Latino ethnicity is a protective factor for postoperative adverse discharge, but this association is modified by socioeconomic status. Future studies should focus on postoperative discharge disposition and socioeconomic barriers in patients with Hispanic/Latino ethnicity.

Irrigation versus no irrigation in the treatment of chronic subdural hematoma: An updated systematic review and meta-analysis of 1581 patients.

Burr hole craniotomy is a common technique employed in the treatment of chronic subdural hematoma. However, its effectiveness and the occurrence of additional complications with various irrigation techniques utilized during the surgery remain unclear. The paper aims to compare the effectiveness and safety of burr hole craniotomy with and without irrigation in the treatment of chronic subdural hematoma. We conducted a systematic review by searching PubMed, Cochrane Library, Scopus, Ovid, and Web of Science for comparative studies that fit the eligibility criteria. All studies up to January 2023 were included, and the two groups were compared based on five primary outcomes using Review Manager Software. Data reported as odds ratio (OR) or risk ratio (RR) and 95% confidence interval (CI). A p-value of less than 0.05 was considered statistically significant. Our analysis included 12 studies with a total of 1581 patients. There was no significant difference between the two techniques in terms of recurrence rate (OR = 0.94; 95% CI [0.55, 1.06], p-value = 0.81) and mortality rate (RR = 1.05, 95% CI [0.46, 2.40], p-value = 0.91). Similarly, there was no significant difference in postoperative infection (RR = 1.15, 95% CI [0.16, 8.05], p-value = 0.89) or postoperative pneumocephalus (RR = 2.56, 95% CI [0.95, 6.89], p-value = 0.06). The burr hole drainage with irrigation technique was insignificantly associated with a higher risk of postoperative hemorrhagic complication (RR = 2.23, 95% CI [0.94, 5.29], p-value = 0.07); however, sensitivity analysis showed significant association based on the results of two studies (RR = 4.6, 95% CI [1.23, 17.25], p-value = 0.024). The two techniques showed comparable recurrence, mortality rate, postoperative infection, and postoperative pneumocephalus results. However, irrigation in burr hole craniotomy could possibly have a higher risk of postoperative hemorrhage compared with no irrigation, as observed during sensitivity analysis, which requires to be confirmed by other studies. Further research and randomized controlled trials are required to understand these observations better and their applicability in clinical practice.

Local anesthesia with sedation and general anesthesia for the treatment of chronic subdural hematoma: a systematic review and meta-analysis.

BACKGROUND: Surgery is the primary treatment for chronic subdural hematoma, and anesthesia significantly impacts the surgery's outcomes. A previous systematic review compared general anesthesia to local anesthesia in 319 patients. Our study builds upon this research, analyzing 4,367 cases to provide updated and rigorous evidence. METHODS: We systematically searched five electronic databases: PubMed, Cochrane Library, Scopus, Ovid Medline, and Web of Science, to identify eligible comparative studies. All studies published until September 2023 were included in our analysis. We compared six primary outcomes between the two groups using Review Manager Software. RESULTS: Eighteen studies involving a total of 4,367 participants were included in the meta-analysis. The analysis revealed no significant difference between the two techniques in terms of 'recurrence rate' (OR = 0.95, 95% CI [0.78 to 1.15], P = 0.59), 'mortality rate' (OR = 1.02, 95% CI [0.55 to 1.88], P = 0.96), and 'reoperation rate' (OR = 0.95, 95% CI [0.5 to 1.79], P = 0.87). Local anesthesia demonstrated superiority with a lower 'complications rate' than general anesthesia, as the latter had almost 2.4 times higher odds of experiencing complications (OR = 2.4, 95% CI [1.81 to 3.17], P < 0.00001). Additionally, local anesthesia was associated with a shorter 'length of hospital stay' (SMD = 1.19, 95% CI [1.06 to 1.32], P < 0.00001) and a reduced 'duration of surgery' (SMD = 0.94, 95% CI [0.67 to 1.2], P < 0.00001). CONCLUSION: Surgery for chronic subdural hematoma under local anesthesia results in fewer complications, a shorter length of hospital stay, and a shorter duration of the operation.

Medical research production in native languages: A descriptive analysis of PubMed database.

INTRODUCTION: Language barriers in medicine can hinder effective communication, comprehension, and patient care. While English has emerged as the dominant language in global medicine, the importance of native languages should not be overlooked. This article aims to examine the extent of publishing in native languages by analyzing the PubMed database literature to gain further insights into the usage of native languages in medicine and medical research. METHODS: In December 2023, a comprehensive examination of the PubMed literature was conducted for each of the 55 registered languages. We searched for records published in each language (e.g., German[lang]) by applying language filters. Ethnologue provided data on the number of worldwide native speakers for each language, facilitating a comparative analysis. RESULTS: By December 2023, PubMed contained over 36 million publications, with 86.5% of them published in English. German, French, and Russian came after English, with over 700 thousand publications each. Among the languages analyzed, fourteen had fewer than 50 publications, nineteen had fewer than 100, twenty-two had fewer than 500, and twenty-five had fewer than one thousand publications. European languages were well-represented with thousands of publications each, while widely spoken languages such as Hindi and Arabic had limited representation. CONCLUSION: The production of medical research in native languages reflects the attention given to native languages in medicine and medical education within each country. It is crucial to provide due attention to these language-related issues and explore strategies for including native languages in medicine to bridge the gaps in language and medicine.

Where there are fumes, there may be lung cancer: a systematic review on the association between exposure to cooking fumes and the risk of lung cancer in never-smokers.

PURPOSE: Lung cancer in never-smokers (LCINS) is the seventh leading cause of cancer, and exposure to cooking fumes has recently emerged as a potential risk factor. This systematic review is the first to summarize and evaluate the relationship between exposure to cooking fumes and the risk of LCINS. METHODS: This study conducted an online literature search of PubMed, CINAHL, and PsychInfo databases. Inclusion criteria were original research articles published in English, that assessed the relationship between exposure to cooking fumes and the risk of lung cancer between 1 January 2012 and 6 December 2022, and that included never-smokers. RESULTS: Thirteen case-control studies and three prospective cohort studies, focusing mostly on women with LCINS, met the inclusion criteria. Seven case-control studies reported an association between exposure to cooking oil fumes and an increased risk of LCINS. Two case-control studies found that using a fume extractor was associated with a decreased risk of LCINS. In other case-control studies, coal use was linked to an increased risk of LCINS, and participants who did not use a ventilator in their kitchens had a higher risk for LCINS. Poor ventilation [Adjusted Hazard Ratio (AHR) = 1.49; 95% CI: 1.15, 1.95] and poor ventilation in combination with coal use (AHR = 2.03; 95% CI: 1.35, 3.05) were associated with an increased risk for LCINS in one prospective cohort study. CONCLUSION: The evidence reviewed underscores the need to develop culturally-tailored interventions that improve access to affordable and clean fuel through engaging relevant stakeholders.

Conformational state of C-reactive protein is critical for reducing immune complex-triggered type I interferon response: Implications for pathogenic mechanisms in autoimmune diseases imprinted by type I interferon gene dysregulation.

Presence of autoantibodies targeting nuclear constituents, i.e., double-stranded DNA and small nuclear ribonucleoproteins (snRNPs), remain a cornerstone in systemic lupus erythematosus (SLE). Fcγ receptor IIa (FcγRIIa) dependent uptake of nucleic acid containing immune complexes (ICs) by plasmacytoid dendritic cells (PDCs) can activate toll-like receptors (TLRs) such as TLR7 and TLR9 resulting in type I interferon (IFN) production. Previously, the classical liver-derived acute-phase reactant C-reactive protein (CRP) has been suggested to reduce IC-induced type I IFN production, whereas monomeric (mCRP) vs. pentameric (pCRP) mediated effects have not yet been unraveled. Herein, peripheral blood mononuclear cells (PBMCs) or enriched blood DCs from healthy volunteers were stimulated with SLE sera, snRNP-IgG (ICs), or TLR ligands with or without pCRP, mCRP, or anti-FcγRIIa antibody. Type I IFNs and cytokine responses were investigated using quantitative PCR, ELISA, and flow cytometry. pCRP inhibited IFN gene expression in PBMCs and enriched DCs after incubation with ICs, compared to ICs alone, whereas mCRP had significantly less inhibitory effect. The effect was independent on the order in which IC or CRP was added to the cells. In addition, pCRP inhibited IFN induced by other TLR stimulators, implicating broader inhibitory effects induced by pCRP. We demonstrate pronounced immunoregulatory functions of CRP whereas the inhibitory properties were evidently dependent on CRP's intact conformational state. The inhibition of type I IFNs was not due to competition of FcγRs, or binding of CRP to the ICs. Our findings have implications for autoimmune IC-mediated conditions imprinted by type I IFN gene dysregulation.

Association Between the New York SAFE Act and Firearm Suicide and Homicide: An Analysis of Synthetic Controls, New York State, 1999‒2019.

Objectives. To assess the association between the New York Secure Ammunition and Firearms Enforcement Act (NY SAFE Act) and firearm suicide and homicide rates. Methods. We employed a synthetic controls approach to investigate the impact of the NY SAFE Act on firearm suicide and firearm homicide rates. We collected state-level data on firearm mortality from the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research (WONDER) database for the period 1999-2019. We derived statistical inference by using a permutation-based in-place placebo test. Results. The implementation of the NY SAFE Act was associated with a significant reduction in firearm homicide rates, demonstrating a decrease of 63%. This decrease corresponds to an estimated prevention of 1697 deaths between 2013 and 2019. However, there was no association between the NY SAFE Act and firearm suicide rates. Conclusions. As the responsibility for enacting firearm policies increasingly falls on states instead of the federal government, this study provides valuable information that can assist states in making evidence-based decisions regarding the development and implementation of firearm policies that prioritize public safety and aim to prevent firearm-related fatalities. (Am J Public Health. 2023;113(12):1309-1317. https://doi.org/10.2105/AJPH.2023.307400).

Examining the Trends in Motor Vehicle Traffic Deaths in New York City, 1999-2020.

Monitoring and understanding the trends in motor vehicle traffic (MVT) mortality is crucial for developing effective interventions and tracking progress in reducing deaths related to MVT. This study aimed to assess the trends in MVT mortality in New York City from 1999 through 2020. Publicly available de-identifiable mortality data were abstracted from the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research. MVT deaths were identified using the International Classification of Diseases Codes, 10th Revision: V02-V04 (.1, .9), V09.2, V12-V14 (.3-.9), V19 (.4-.6), V20-V28 (.3-.9), V29-V79 (.4-.9), V80 (.3-.5), V81.1, V82.1, V83-V86 (.0-.3), V87 (.0-.8), and V89.2. Age adjusted mortality rates (AAMR) were abstracted by county (Bronx; Kings; Queens; New York), age (in years) (< 25; 25-44; 45-64; ≥ 65), sex (male; female), race/ethnicity (Non-Hispanic Black; Non-Hispanic White; Asian/Pacific Islander; Hispanic), and road user type (motor vehicle occupant; motorcyclist; pedal cyclist; pedestrian). Joinpoint regression models were fitted to estimate the annual percentage change (APC) and average annual percentage change (AAPC) in AAMR during the study period. The Parametric Method was used to compute 95% confidence intervals (CI). Between 1999 and 2020, a total of 8,011 MVT deaths were recorded in New York City. Mortality rates were highest among males (age adjusted mortality rate (AAMR) = 6.4 per 100,000; 95% CI: 6.2, 6.5), Non-Hispanic Blacks (AAMR = 4.8; 95% CI: 4.6, 5.0), older adults (AAMR = 8.9; 95% CI: 8.6, 9.3), and persons from Richmond County (AAMR = 5.2; 95% CI: 4.8, 5.7). MVT death rates, overall, have declined by 3% per year (95% CI: -3.6, -2.3) from 1999 to 2020. The rates have fallen or stabilized by race/ethnicity, county of residence, road user type, and age group. In contrast, rates have increased by 18.1% per year among females and by 17.4% per year in Kings County from 2017 to 2020.The results of this study draw attention to the worsening trends in MVT mortality among females and in Kings County, New York City. Further investigation is needed to determine the underlying behavioral, social, and environmental factors contributing to this increase, such as polysubstance or alcohol abuse, psychosocial stressors, access to medical and emergency care, and compliance with traffic laws. These findings emphasize the importance of developing targeted interventions to prevent MVT deaths and ensure the health and safety of the community.

Meta-analysis of the effects of sulfate versus hydroxy trace mineral source on nutrient digestibility in dairy and beef cattle.

Trace mineral (TM) source can potentially alter nutrient digestibility through effects on microbial populations. A meta-analysis was conducted to determine whether sulfate versus hydroxy (IntelliBond) sources of supplemental Cu, Zn, and Mn had any effect on dry matter intake (DMI), dry matter digestibility, and neutral detergent fiber (NDF) digestibility. All available cattle studies (8 studies, 12 comparisons) were used to estimate the effect size (hydroxy mean - sulfate mean). Factors included in the analysis were method of digestibility analysis (total collection, marker-based, or 24 h in situ), study design (randomized design or Latin square), beef (n = 5) versus dairy (n = 7) cattle, and days on treatment; these factors were retained when P < 0.05. Dry matter digestibility was increased by hydroxy TM in beef (1.64 ± 0.35 units) but not in dairy models (0.16 ± 0.13 units) relative to sulfate TM. The NDF digestibility increased significantly with hydroxy versus sulfate TM, but digestibility assessment method influenced this response. Studies using total collection or undigested NDF as a flow marker showed a significant increase (2.68 ± 0.40 units and 1.08 ± 0.31 units, respectively) in NDF digestibility for hydroxy versus sulfate TM; but studies utilizing 24-h in situ incubation did not detect any change (-0.03 ± 0.23 units). These observations may reveal differences in precision of measurement or may indicate mineral effects beyond the rumen; total collection is considered the gold standard method. Hydroxy TM did not affect DMI per animal or per unit of body weight relative to sulfate TM. In conclusion, feeding hydroxy versus sulfate TM does not appear to affect DMI but, depending on type of cattle and method of measurement, can increase dry matter digestibility and NDF digestibility, which may be explained by differences in solubility of the TM sources in rumen, differentially affecting fermentation.

Differential trends in US suicide rates, 1999-2020: Emerging racial and ethnic disparities.

Suicide is an important cause of mortality in the United States. This study aimed to examine US suicide trends by race and ethnicity from 1999 to 2020. Publicly available de-identified data were extracted from the CDC's Wide-ranging Online Data for Epidemiologic Research. The International Classification of Diseases Codes, 10th Revision- X60-X84, U03, and Y87.0 were used to identify suicide decedents aged 10 years and above from 1999 to 2020. A Joinpoint regression model was fitted to estimate the annual percentage change (APC) and average annual percentage change in suicide rate over the study period. From 1999 to 2020, a total of 838,560 persons died by suicide in the US. Recent mortality trends have declined by 3.8% per year (95% CI: -7.1, -0.5) among Non-Hispanic Whites from 2018 to 2020, but have increased among Non-Hispanic Blacks (APC = 6.1; 95% CI: 5.0, 7.3), Asians/Pacific Islanders (APC = 1.5; 95% CI: 1.2, 1.9), American Indians/Alaska Natives (APC = 3.3; 95% CI: 3.0, 3.6), and Hispanics (APC = 3.8; 95% CI: 2.7, 5.0). Based on suicide mechanism, recent trends have increased by firearm (APC = 1.7; 95% CI: 1.5, 2.0) and suffocation (APC = 3.8; 95% CI: 3.5, 4.1), decreased by drug poisoning (APC = -2.9; 95% CI: -3.9, -1.9), and stabilized by non-drug poisoning (APC = 0.6; 95% CI: -2.4, 3.7). Racial and ethnic disparities exist in suicide trends in the United States. Further research to identify individual and contextual factors for the differences may guide effective public health intervention efforts.

Trends in lip, oral cavity, and pharyngeal cancer mortality in the United States, 1999-2019.

BACKGROUND: Changes in the epidemiology of lip, oral cavity, and pharyngeal (LOCP) cancers have been reported in the United States. This study aimed to examine recent trends in LOCP cancer mortality in the United States from 1999 to 2019. METHODS: National mortality data were extracted from CDC WONDER, 1999-2019. International Classification of Diseases Codes, 10th Revision-C00-C14, were used to identify decedents of malignant neoplasms of the lip, oral cavity, and pharynx. LOCP cancer mortality trends were assessed by fitting a Joinpoint regression model overall, and by race/ethnicity, sex, age, and US Census Region. Annual Percentage Changes (APC) were derived to estimate variations in mortality trends over time. RESULTS: The age-adjusted mortality rate (AAMR) for LOCP cancers was 2.5 per 100 000 (95% CI: 2.5-2.5), equivalent to 180 532 deaths during 1999-2019. Overall mortality trends have stabilized since 2009 (APC = 0.3; 95% CI: -0.1, 0.7), but an examination by subtype revealed rising mortality trends from cancers of the lip and oral cavity (APC = 1.2; 95% CI: 0.7, 1.6) and pharynx (APC = 3.2; 95% CI: 1.7, 4.8), and declining trends in malignancies of other and ill-defined areas of the lip, oral cavity, and pharynx (APC = -2.7; 95% CI: -3.4, -2.0). Trend variations were also noted by sex, age, US Census Region, and race/ethnicity. CONCLUSIONS: There are differential trends in mortality from LOCP cancers in the United States. Investigating the biological, individual, and contextual factors related to LOCP cancers would guide effective public health intervention efforts.

Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies.

A library of modified VEGFR-2 inhibitors was designed as VEGFR-2 inhibitors. Virtual screening was conducted for the hypothetical library using in silico docking, ADMET, and toxicity studies. Four compounds exhibited high in silico affinity against VEGFR-2 and an acceptable range of the drug-likeness. These compounds were synthesised and subjected to in vitro cytotoxicity assay against two cancer cell lines besides VEGFR-2 inhibitory determination. Compound D-1 showed cytotoxic activity against HCT-116 cells almost double that of sorafenib. Compounds A-1, C-6, and D-1 showed good IC50 values against VEGFR-2. Compound D-1 markedly increased the levels of caspase-8 and BAX expression and decreased the anti-apoptotic Bcl-2 level. Additionally, compound D-1 caused cell cycle arrest at pre-G1 and G2-M phases in HCT-116 cells and induced apoptosis at both early and late apoptotic stages. Compound D-1 decreased the level of TNF-α and IL6 and inhibited TNF-α and IL6. MD simulations studies were performed over 100 ns.

Anti-cancer and immunomodulatory evaluation of new nicotinamide derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: in vitro and in silico studies.

New nicotinamide derivatives 6, 7, 10, and 11 were designed and synthesised based on the essential features of the VEGFR-2 inhibitors. Compound 10 revealed the highest anti-proliferative activities with IC50 values of 15.4 and 9.8 µM against HCT-116 and HepG2, respectively compared to sorafenib (IC50 = 9.30 and 7.40 µM). Compound 7 owned promising cytotoxic activities with IC50 values of 15.7 and 15.5 µM against the same cell lines, respectively. Subsequently, the VEGFR-2 inhibitory activities were assessed for the titled compounds to exhibit VEGFR-2 inhibition with sub-micromolar IC50 values. Moreover, compound 7 induced the cell cycle cessation at the cycle at %G2-M and G0-G1phases, and induced apoptosis in the HCT-116. Compounds 7 and 10 reduced the levels of TNF-α by 81.6 and 84.5% as well as IL-6 by 88.4 and 60.9%, respectively, compared to dexamethasone (82.4 and 93.1%). In silico docking, molecular dynamics simulations, ADMET, and toxicity studies were carried out.

Design, Synthesis, Docking, DFT, MD Simulation Studies of a New Nicotinamide-Based Derivative: In Vitro Anticancer and VEGFR-2 Inhibitory Effects.

A nicotinamide-based derivative was designed as an antiproliferative VEGFR-2 inhibitor with the key pharmacophoric features needed to interact with the VEGFR-2 catalytic pocket. The ability of the designed congener ((E)-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazono)ethyl)phenyl)nicotinamide), compound 10, to bind with the VEGFR-2 enzyme was demonstrated by molecular docking studies. Furthermore, six various MD simulations studies established the excellent binding of compound 10 with VEGFR-2 over 100 ns, exhibiting optimum dynamics. MM-GBSA confirmed the proper binding with a total exact binding energy of -38.36 Kcal/Mol. MM-GBSA studies also revealed the crucial amino acids in the binding through the free binding energy decomposition and declared the interactions variation of compound 10 inside VEGFR-2 via the Protein-Ligand Interaction Profiler (PLIP). Being new, its molecular structure was optimized by DFT. The DFT studies also confirmed the binding mode of compound 10 with the VEGFR-2. ADMET (in silico) profiling indicated the examined compound's acceptable range of drug-likeness. The designed compound was synthesized through the condensation of N-(4-(hydrazinecarbonyl)phenyl)benzamide with N-(4-acetylphenyl)nicotinamide, where the carbonyl group has been replaced by an imine group. The in-vitro studies were consonant with the obtained in silico results as compound 10 prohibited VEGFR-2 with an IC50 value of 51 nM. Compound 10 also showed antiproliferative effects against MCF-7 and HCT 116 cancer cell lines with IC50 values of 8.25 and 6.48 µM, revealing magnificent selectivity indexes of 12.89 and 16.41, respectively.

Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2.

VEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to be VEGFR-2 inhibitors. The chemical structures were confirmed using IR, 1H-NMR, and 13C-NMR spectroscopy. The obtained compounds were examined for their anti-proliferative activities against the human cancer cell lines (HCT-116 and HepG2). VEGFR-2 inhibitory activities were determined for the titled compounds. Compound 8 exhibited the strongest anti-proliferative activities with IC50 values of 5.4 and 7.1 µM against HCT-116 and HepG2, respectively. Interestingly, compound 8 was the most potent VEGFR-2 inhibitor with an IC50 value of 77.02 nM (compare to sorafenib: IC50 = 53.65 nM). Treatment of HCT-116 cells with compound 8 produced arrest of the cell cycle at the G0-G1 phase and a total apoptosis increase from 3.05 to 19.82%-6.5-fold in comparison to the negative control. In addition, compound 8 caused significant increases in the expression levels of caspase-8 (9.4-fold) and Bax (9.2-fold), and a significant decrease in the Bcl-2 expression level (3-fold). The effects of compound 8 on the levels of the immunomodulatory proteins (TNF-α and IL-6) were examined. There was a marked decrease in the level of TNF-α (92.37%) compared to the control (82.47%) and a non-significant reduction in the level of IL-6. In silico docking, molecular dynamics simulations, and MM-PBSA studies revealed the high affinity, the correct binding, and the optimum dynamics of compound 8 inside the active site of VEGFR-2. Finally, in silico ADMET and toxicity studies indicated acceptable values of drug-likeness. In conclusion, compound 8 has emerged as a promising anti-proliferative agent targeting VEGFR-2 with significant apoptotic and immunomodulatory effects.

(E)-N-(3-(1-(2-(4-(2,2,2-Trifluoroacetamido)benzoyl)hydrazono)ethyl)phenyl)nicotinamide: A Novel Pyridine Derivative for Inhibiting Vascular Endothelial Growth Factor Receptor-2: Synthesis, Computational, and Anticancer Studies.

(E)-N-(3-(1-(2-(4-(2,2,2-Trifluoroacetamido)benzoyl)hydrazono)ethyl)phenyl)nicotinamide (compound 10) was designed as an antiangiogenic VEGFR-2 inhibitor with the essential pharmacophoric structural properties to interact with the catalytic pocket of VEGFR-2. The designed derivative was synthesized, and its structure was confirmed through Ms, elemental, 1H, and 13C spectral data. The potentiality of the designed pyridine derivative to bind with and inhibit the vascular endothelial growth factor receptor-2 (VEGFR-2) enzyme was indicated by molecular docking assessments. In addition, six molecular dynamic (MD) experiments proved its correct binding with VEGFR-2 over 100 ns. Additionally, the molecular mechanics energies, combined with the generalized born and surface area (MM-GBSA) analysis, identified the precise binding with optimum energy. To explore the stability and reactivity of the designed pyridine derivative, density functional theory (DFT) calculations, including electrostatic potential maps and total electron density, were carried out. Additionally, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis demonstrated its general likeness and its safety. The designed compound was synthesized to evaluate its effects against VEGFR-2 protein, cancer, and normal cells. The in vitro results were concordant with the in silico results, because the new pyridine derivative (compound 10) displayed VEGFR-2 inhibition with an IC50 value of 65 nM and displayed potent cytotoxic properties against hepatic (HepG2) and breast (MCF-7) cancer cell lines with IC50 values of 21.00 and 26.10 µM, respectively; additionally, it exhibited high selectivity indices against the normal cell lines (W-38) of 1.55 and 1.25, respectively. The obtained results present compound 10 as a new lead VEGFR-2 inhibitor for further biological investigation and chemical modifications.

Discovery of New VEGFR-2 Inhibitors: Design, Synthesis, Anti-Proliferative Evaluation, Docking, and MD Simulation Studies.

Four new nicotinamide-based derivatives were designed as antiangiogenic VEGFR-2 inhibitors. The congeners were synthesized possessing the pharmacophoric essential features to bind correctly with the VEGFR-2 active pocket. All members were evaluated for their cytotoxic and VEGFR-2 inhibitory potentialities. Compound 6 was the most potent showingIC50 values of 9.3 ± 0.02 and 7.8 ± 0.025 µM against HCT-116 and HepG-2 cells, respectively, and IC50 of 60.83 nM regarding VEGFR-2 enzyme inhibition. Compound 6 arrested the growth of HCT-116 cells at the pre-G1 and G2-M phases. Further, it induced both early and late apoptosis. Additionally, compound 6 caused a significant decrease in TNF-α and IL6 by 66.42% and 57.34%, respectively. The considered compounds had similar docking performances to that of sorafenib against the VEGFR-2 (PDB ID: 2OH4). The correct binding of compound 6 with VEGFR-2 was validated using MD simulations, and MM-GPSA calculations.