Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma.

BACKGROUND: Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) inhibitor approved for the treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3/2 alterations who have progression after platinum-containing chemotherapy. The effects of erdafitinib in patients with FGFR-altered metastatic urothelial carcinoma who have progression during or after treatment with checkpoint inhibitors (anti-programmed cell death protein 1 [PD-1] or anti-programmed death ligand 1 [PD-L1] agents) are unclear. METHODS: We conducted a global phase 3 trial of erdafitinib as compared with chemotherapy in patients with metastatic urothelial carcinoma with susceptible FGFR3/2 alterations who had progression after one or two previous treatments that included an anti-PD-1 or anti-PD-L1. Patients were randomly assigned in a 1:1 ratio to receive erdafitinib or the investigator's choice of chemotherapy (docetaxel or vinflunine). The primary end point was overall survival. RESULTS: A total of 266 patients underwent randomization: 136 to the erdafitinib group and 130 to the chemotherapy group. The median follow-up was 15.9 months. The median overall survival was significantly longer with erdafitinib than with chemotherapy (12.1 months vs. 7.8 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.47 to 0.88; P = 0.005). The median progression-free survival was also longer with erdafitinib than with chemotherapy (5.6 months vs. 2.7 months; hazard ratio for progression or death, 0.58; 95% CI, 0.44 to 0.78; P<0.001). The incidence of grade 3 or 4 treatment-related adverse events was similar in the two groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). Treatment-related adverse events that led to death were less common with erdafitinib than with chemotherapy (in 0.7% vs. 5.4% of patients). CONCLUSIONS: Erdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and FGFR alterations after previous anti-PD-1 or anti-PD-L1 treatment. (Funded by Janssen Research and Development; THOR ClinicalTrials.gov number, NCT03390504.).

Diphenhydramine-involved Fatal and Nonfatal Drug Overdoses in Tennessee, 2019-2022.

BACKGROUND: Diphenhydramine (DPH), known as the brand name Benadryl, is an over-the-counter medication associated with accidental ingestion leading to nonfatal overdoses. Additionally, DPH has been used in tandem with illicit substances leading to fatal drug overdoses. OBJECTIVE: In response to DPH being seized with illicit drugs as an adulterant, as well as its growing intentional misuse, we sought to explore its recent involvement in fatal and nonfatal drug overdoses in the state of Tennessee. METHODS: We conducted a statewide cross-sectional study to determine the characteristics of DPH-involved fatal and nonfatal overdoses in Tennessee during 2019-2022 using data from the State Unintentional Drug Overdose Reporting System, the Electronic Surveillance System for the Early Notification of Community-based Epidemics, and the National Forensic Laboratory Information System Public Data Query System. Frequencies were generated to compare demographic characteristics, circumstances, and toxicology between fatal and nonfatal DPH-involved overdoses. RESULTS: We identified 143 suspected nonfatal DPH and 409 fatal DPH-involved overdoses in Tennessee from 2019 to 2022. Nonfatal overdoses remained consistent while fatal overdoses peaked in 2021. Most nonfatal overdoses were under 18 (63.4%), while most fatal overdoses were between 18 and 64 years of age (95.7%). For fatal overdoses, fentanyl was the most prevalent substance on toxicology followed by prescription opioids. CONCLUSION: Nonfatal overdoses remained consistent while fatal overdoses peaked in 2021 in Tennessee. Use of DPH among other illicit substances lends to evidence suggesting its use as an adulterant. Monitoring of DPH-involved fatal and nonfatal overdoses is critical to inform harm reduction initiatives.

Prescription Opioid Characteristics and Nonfatal Overdose Among Patients Discharged from Tennessee Emergency Departments.

BACKGROUND: Despite increasing trends of nonfatal opioid overdoses in emergency departments (EDs), population-based studies comparing prescription opioid dosing patterns before and after nonfatal opioid overdoses are limited. OBJECTIVES: To evaluate characteristics of prescribing behaviors before and after nonfatal overdoses, with a focus on opioid dosage. METHODS: Included were 5,395 adult residents of Tennessee discharged from hospital EDs after a first nonfatal opioid overdose (2016-2017). Patients were linked to eligible prescription records in the Tennessee Controlled Substance Monitoring Database. We estimated odds ratios (OR) and 95% confidence intervals (CI) to evaluate characteristics associated with filling opioid prescriptions 90 days before overdose and with high daily dose (≥ 90 morphine milligram equivalents) 90 days after overdose. RESULTS: Among patients who filled a prescription both before and after an overdose, the percentage filling a low, medium, and high dose was 33.7%, 31.9%, and 34.4%, respectively, after an opioid overdose (n = 1,516). Most high-dose users before an overdose (>70%) remained high-dose users with the same prescriber after the overdose. Male gender, ages ≥ 35 years, and medium metro residence were associated with increased odds of high-dose filling after an opioid overdose. Patients filling overlapping opioid-benzodiazepine prescriptions and with > 7 days' supply had increased odds of filling high dose after an opioid overdose (OR 1.4, 95% CI 1.08-1.70 and OR 3.7, 95% CI 2.28-5.84, respectively). CONCLUSIONS: In Tennessee, many patients treated in the ED for an overdose are still prescribed high-dose opioid analgesics after an overdose, highlighting a missed opportunity for intervention and coordination of care between ED and non-ED providers.

Influence of basin-wide geomorphology on arsenic distribution in Nadia district.

The present study depicts the geospatial relation between basinal geomorphology and heterogeneous arsenic (As) distribution in the Bengal Delta Plain (BDP). The distribution pattern largely varies throughout the study area (higher: Karimpur-II AsT average 214.73 µgL-1; lower: Tehatta AsT average 27.84 µgL-1). Both safe (low As) and unsafe (high As) areas are identified within the single shallow aquifer (<50 m), where they are in close vicinity. Statistical analysis shows that Padma river basin is the most contaminated (AsT avg. 214.7 ± 160 µgL-1) and Churni-Ichhamati river basin (AsT avg. 108.54 ± 89.43 µgL-1) is the least contaminated with groundwater As. Moreover, the role of geomorphological features influencing the geospatial distribution of As has been studied and meandering features are found to correlate with high As wells (r2 = 0.52), whereas, natural levees are correlated with safer wells (r2 = 0.57). In the meandering features, the deposition of sedimentary organic matter (SOM) facilitates the reduction of As bearing Fe(III) oxy-hydroxides and subsequent higher As mobilization. In natural levees, surface derived labile organic matter (DOC and FOM, Fresh Organic Matter) from different land-use patterns (Habitation, degraded waterbodies, cattle dwelling, sanitation, etc.) is transported to shallow aquifers (notably protein rich leakage sewage). The fresh organic carbon transported to the shallow aquifers, thereby triggering As release by microbe-mediated reductive dissolution of hydrated Fe(III)-oxides (HFO). Iron reduction (mostly amorphous) is playing an important role in the release of As depending on basin-wise sedimentation pattern, local recharge, accumulation of silt/clay/micas at the top with corresponding reactive oxidation of organic carbon. These are important components and often helping the cyclic water-rock interaction of As causing such heterogeneous geospatial distribution. The delineation of aquifer with regard to safer and unsafe areas would immensely help to supply safe drinking water to the rural community.

Assessing the immediate impact of COVID-19 lockdown on the air quality of Kolkata and Howrah, West Bengal, India.

The worldwide spread of COVID-19 caused a nationwide lockdown in India from 24 March 2020 and was further extended up to 3 May 2020 to break off the transmission of novel Coronavirus. The study is designed to assess the changes in air quality from the pre-lockdown period to the during lockdown period in Kolkata and Howrah municipal corporation, West Bengal, India. GIS-based techniques include the spatial and temporal distribution of pollutants using interpolation method, and on the other hand, statistical methods like analysis of variance (ANOVA) was applied to determine the mean differences two phases and correlation matrix helps to understand the changing association of the pollutants in pre- and during lockdown phases. Significant correlations have been found among the pollutants, ANOVA (Two-Way) has shown the significant mean difference of NAQI between the two phases, F(1,611) = 465.723, p < 0.0001; pairwise comparison for Ballygunge has shown the highest mean difference 108.194 at p < 0.0001 significant level between lockdown and pre-lockdown phase. Significant positive correlation has been found between PM2.5, PM10 (0.99*); PM2.5, NO2 (0.81*); PM10, NO2 (0.81*); CO, NO2 (0.77*) and some negative correlations have also been found between O3, NO (- 0.15); O3 and NH3 (- 0.36) in the pre-lockdown phase. The reduction amount of mean concentration from the pre-lockdown phase to during lockdown of the main pollutants like PM2.5, PM10 and NO2 are ~ 58.71%, ~ 57.92% and ~ 55.23%. Near Rabindra Bharati University constant emission of PM2.5, 10 and NO2 have been recorded due to the nearby Cossipore thermal power station.

Record Linkage Approaches Using Prescription Drug Monitoring Program and Mortality Data for Public Health Analyses and Epidemiologic Studies.

BACKGROUND: The use of Prescription Drug Monitoring Program (PDMP) data has greatly increased in recent years as these data have accumulated as part of the response to the opioid epidemic in the United States. We evaluated the accuracy of record linkage approaches using the Controlled Substance Monitoring Database (Tennessee's [TN] PDMP, 2012-2016) and mortality data on all drug overdose decedents in Tennessee (2013-2016). METHODS: We compared total, missed, and false positive (FP) matches (with manual verification of all FPs) across approaches that included a variety of data cleaning and matching methods (probabilistic/fuzzy vs. deterministic) for patient and death linkages, and prescription history. We evaluated the influence of linkage approaches on key prescription measures used in public health analyses. We evaluated characteristics (e.g., age, education, sex) of missed matches and incorrect matches to consider potential bias. RESULTS: The most accurate probabilistic/fuzzy matching approach identified 4,714 overdose deaths (vs. the deterministic approach, n = 4,572), with a low FP linkage error (<1%) and high correct match proportion (95% vs. 92% and ~90% for probabilistic approaches not using comprehensive data cleaning). Estimation of all prescription measures improved (vs. deterministic approach). For example, frequency (%) of decedents filling an oxycodone prescription in the last 60 days (n = 1,371 [32%] vs. n = 1,443 [33%]). Missed overdose decedents were more likely to be younger, male, nonwhite, and of higher education. CONCLUSION: Implications of study findings include underreporting, prescribing and outcome misclassification, and reduced generalizability to population risk groups, information of importance to epidemiologists and researchers using PDMP data.

Prescribing patterns before and after a non-fatal drug overdose using Tennessee's controlled substance monitoring database linked to hospital discharge data.

We performed a statewide evaluation of prescribing patterns of controlled substances (CS) before and after an overdose, using Tennessee's Hospital Discharge Data System and the Controlled Substance Monitoring Database (CSMD). Adults' first non-fatal overdose discharges either from the emergency department (ED) or inpatient (IP) stay occurring between 2013 and 2016 were linked to prescriptions in the CSMD. The difference in the proportion of patients filling a prescription before versus after an overdose was calculated. Included were 49,398 patients with an overdose and a prescription record; most (60.5%) were treated in the ED. Among any drug type overdose the percentage of patients who filled a CS prescription within a year of experiencing an overdose was as follows: opioid analgesics: 59.1%, benzodiazepines: 37.3%, stimulants: 5.0%, muscle relaxants: 3.4%, concurrent opioid-benzodiazepines: 24.0% with the percent difference from before to after similar in both settings. Among patients treated for an opioid overdose, this represented a decrease in opioid analgesics filled by 9.7% (95%CI: -11.2, -8.3) among those treated in the ED, and by 7.1% (95% CI: -8.3, -5.9) among treated inpatients. Among patients treated for a heroin overdose, 12.2% (95%CI: -15.2, -9.3) fewer of those treated in the ED and 8.8% (95%CI: -15.0, -2.7%) fewer of treated inpatients filled a CS prescription in that year. The most common opioid analgesics included hydrocodone and oxycodone. The number of patients filling buprenorphine for treatment increased in the year after overdoses associated with any drug or opioids but decreased among those treated for a heroin overdose.

Sepiapterin alleviates impaired gastric nNOS function in spontaneous diabetic female rodents through NRF2 mRNA turnover and miRNA biogenesis pathway.

An impaired nitrergic system and altered redox signaling contribute to gastric dysmotility in diabetics. Our earlier studies show that NF-E2-related factor 2 (NRF2) and phase II antioxidant enzymes play a vital role in gastric neuronal nitric oxide synthase (nNOS) function. This study aims to investigate whether supplementation of sepiapterin (SEP), a precursor for tetrahydrobiopterin (BH4) (a cofactor of NOS) via the salvage pathway, restores altered nitrergic systems and redox balance in spontaneous diabetic (DB) female rats. Twelve-week spontaneous DB and age-matched, non-DB rats, with and without dietary SEP (daily 20 mg/kg body wt for 10 days) treatment, were used in this study. Gastric antrum muscular tissues were excised to investigate the effects of SEP in nitrergic relaxation and the nNOS-nitric oxide (NO)-NRF2 pathway(s). Dietary SEP supplementation significantly ( P < 0.05) reverted diabetes-induced changes in nNOS dimerization and function; nitric oxide (NO) downstream signaling molecules; HSP-90, a key regulator of nNOSα activity and dimerization; miRNA-28 that targets NRF2 messenger RNA (mRNA), and levels of microRNA (miRNA) biogenesis pathway components, such as DGCR8 (DiGeorge Syndrome Critical Region Gene 8) and TRBP (HIV1-1 transactivating response RNA-binding protein). These findings emphasize the importance of the BH4 pathway in regulating gastric motility functions in DB animals by modulating nNOSα dimerization in association with changes in enteric NRF2 and NO downstream signaling. Our results also identify a new pathway, wherein SEP regulates NRF2 mRNA turnover by suppressing elevated miRNA-28, which could be related to alterations in miRNA biogenesis pathway components. NEW & NOTEWORTHY This study is the first to show a causal link between NF-E2-related factor 2 (NRF2) and neuronal nitric oxide synthase (nNOS) in gastric motility function. Our data demonstrate that critical regulators of the miRNA biosynthetic pathway are upregulated in the diabetic (DB) setting; these regulators were rescued by sepiapterin (SEP) treatment. Finally, we show that low dihydrofolate reductase expression may lead to impaired nNOS dimerization/function-reduced nitric oxide downstream signaling and elevate oxidative stress by suppressing the NRF2/phase II pathway through miRNA; SEP treatment restored all of the above in DB gastric muscular tissue. We suggest that tetrahydrobiopterin supplementation may be a useful therapy for patients with diabetes, as well as women with idiopathic gastroparesis.

Surveillance of carbon monoxide-related incidents - Implications for prevention of related illnesses and injuries, 2005-2014.

BACKGROUND: Carbon monoxide (CO) is an insidious gas responsible for approximately 21,000 emergency department visits, 2300 hospitalizations, and 500 deaths in the United States annually. We analyzed 10 combined years of data from two Agency for Toxic Substances and Disease Registry acute hazardous substance release surveillance programs to evaluate CO incident-related injuries. METHODS: Seventeen states participated in these programs during 2005-2014. RESULTS: In those 10years, the states identified 1795 CO incidents. Our analysis focused on 897 CO incidents having injured persons. Of the 3414 CO injured people, 61.0% were classified as general public, 27.7% were employees, 7.6% were students, and 2.2% were first responders. More than 78% of CO injured people required hospital or pre-hospital treatment and 4.3% died. The location for most injured people (39.9%) were homes or apartments, followed by educational facilities (10.0%). Educational services had a high number of people injured per incident (16.3%). The three most common sources of CO were heating, ventilation, and air conditioning systems; generators; and motor vehicles. Equipment failure was the primary contributing factor for most CO incidents. CONCLUSIONS: States have used the data to evaluate trends in CO poisoning and develop targeted public health outreach. Surveillance data are useful for setting new policies or supporting existing policy such as making CO poisoning a reportable condition at the state level and requiring CO alarms in all schools and housing. Public health needs to remain vigilant to the sources and causes of CO to help reduce this injury and death.

PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma.

Panobinostat is an oral pan-deacetylase inhibitor that synergizes with bortezomib to inhibit both the aggresome and proteasome pathways in preclinical studies. PANORAMA 2 is a phase 2 trial of panobinostat in combination with bortezomib and dexamethasone to treat patients with relapsed and bortezomib-refractory multiple myeloma (with ≥2 prior lines of therapy, including an immunomodulatory drug, and patients who had progressed on or within 60 days of the last bortezomib-based therapy). Fifty-five heavily pretreated patients were enrolled (median, 4 prior regimens, including a median of 2 prior bortezomib-containing regimens). The overall response rate was 34.5% (1 near-complete response and 18 partial responses). An additional 10 patients achieved minimal response, for a clinical benefit rate of 52.7%. Median exposure and progression-free survival were 4.6 and 5.4 months, respectively. In patients who achieved a response, median time to response was 1.4 months, and median duration of response was 6.0 months. Common grade 3/4 adverse events, regardless of study drug relationship, included thrombocytopenia (63.6%), fatigue (20.0%), and diarrhea (20.0%). Only 1 patient had grade 3 peripheral neuropathy. Panobinostat, when combined with bortezomib and dexamethasone, can recapture responses in heavily pretreated, bortezomib-refractory multiple myeloma patients. This trial was registered at www.clinicaltrials.gov as #NCT01083602.

Effect of channel morphological changes on wetland transformation.

Keeping aside the traditional approaches to investigating floodplain wetland transformation, the current study investigated various aspects of it through changes in river channel morphology and drainage pattern. The study analyzed wetland transformation using satellite image-based machine learning and intensive fieldwork. Ordinary Least Square (OLS) regression was applied to identify dominant influencing factors among 24 contributing factors under six clusters to eight dependent phenomena of transformation. The result showed that 57 % of wetland area lost since 1991, and existing wetland has also experiencing hydrological scarcity. From 1991 to 2021, the area under low water depth (<1 m.) inflated from 18.55 % to 50.54 %, the hydro-period narrowed down, and the appearance of water become inconsistent. The OLS result showed that changes in channel morphology (bottle neck channel, embankment-driven carrying capacity enhancement, etc.), interruptions in river and wetland connecting channels (source closure, breaching the continuity, conversion in to agricultural land, etc.), and changes in flood ambience (regulated by dam construction, erection of embankments, etc.) majorly contributed to wetland transformation. Very high explainability was found in the cases of rate of wetland loss, decreasing water depth under greater depth, narrowing hydro-period (R2 > 0.9). The findings of this work would be a good policy document for floodplain wetland management.

Exploring trends in benzodiazepine-positive fatal drug overdoses in Tennessee, 2019-2021.

BACKGROUND: Benzodiazepine-positive overdoses increased between 2019 and 2021 in Tennessee. We sought to determine the changes in the number and characteristics of prescription and illicit benzodiazepine-positive fatal drug overdoses during this period. MATERIALS AND METHODS: A statewide study was conducted to determine changes in the number and characteristics of benzodiazepine-positive drug overdose decedents using 2019-2021 data from the Tennessee State Unintentional Drug Overdose Reporting System. The analyses were limited to Tennessee residents aged ≥ 18 years. A benzodiazepine-positive overdose was defined as any benzodiazepine on toxicology, regardless of the presence of other substances. Frequencies were generated to compare demographics, circumstances, prescription history, and toxicology between 2019 and 2021 for illicit and prescription benzodiazepine-positive fatal overdoses. RESULTS: Between 2019 and 2021, 1666 benzodiazepine-positive unintentional or undetermined fatal drug overdoses out of 5916 total overdoses that occurred among adult Tennessee residents with available toxicological information. Prescription benzodiazepines were identified in 80.7% of deaths, whereas illicit benzodiazepines were identified in 12.0% of deaths. Many decedents had an anxiety disorder (45.5%), while over half of all decedents had a history of substance use disorder (52.3%). Most benzodiazepine-positive overdoses involved fentanyl (71.3%). CONCLUSIONS: This analysis can inform local and regional public health workers to implement focused prevention and intervention efforts for people with co-occurring mental health conditions and substance use disorders to curb overdose epidemics among persons using benzodiazepines in Tennessee. Public health campaigns should focus on educating people on appropriate prescription medication use and the dangers of obtaining substances illicitly. Given the high proportion of opioids in this population, further education also is needed on the dangers of polysubstance drug use. The differences between prescription and illicit benzodiazepine-positive fatal overdoses indicate the need to develop substance-specific prevention and treatment strategies.

Phentermine involvement in fatal drug overdoses in Tennessee, 2019-2022.

INTRODUCTION: Phentermine, one of the most-commonly prescribed pharmaceuticals for weight-loss in the United States (US), has appeared on toxicology and listed as a cause of death in fatal drug overdoses in the state of Tennessee. This study aims to evaluate phentermine's involvement in fatal drug overdoses in the state of Tennessee. METHODS: We used Tennessee State Unintentional Drug Overdose Reporting System (SUDORS) data and controlled substances monitoring program data (CSMD) to evaluate demographics, prescription history and co-occurring substances on toxicology in phentermine-positive cases compared with all other SUDORS cases from January 1, 2019 to June 30, 2022. A subset of these cases which listed phentermine as a cause of death was also assessed. RESULTS: We identified 51 phentermine-positive cases, with a subset of 20 that listed phentermine as a cause of death. When compared to all SUDORS cases, a higher proportion of cases that listed phentermine as a cause of death were White race, females, and aged 35-44. Additionally, in all phentermine-positive cases, 41% (21) of decedents had not had a phentermine prescription dating back to 2012 and 20% (Lee et al., 1998) did not have one within the last 30 days. While there was a slight decline each year in the number of phentermine-positive cases, the number of cases that listed phentermine as a cause of death remained relatively consistent, with 95% (19) of cases having different prescriptions and/or illicit drugs listed as a cause of death along with phentermine. CONCLUSION: Phentermine was listed as a cause of death in 20 fatal drug overdoses in TN. Our findings suggest there may be differences in the characteristics of these decedents when compared to all SUDORS decedents, including distribution of age, gender, and race. We also found a large presence of other prescription and illicit drugs in toxicology and cause of death along with phentermine, as well as evidence of use of the drug without a prescription. Given the lack of currently available data about non-prescribed phentermine use and its involvement in fatal drug overdoses elsewhere, a need exists to both expand surveillance capabilities and broaden research to better inform policies governing this drug in the US and internationally.

Prevalence of hepatitis C virus among fatal drug overdoses in Tennessee: an analysis using 2019-2020 Tennessee State Unintentional Drug Overdose Reporting System Data.

PURPOSE: Given the nature of the co-occurring epidemics of hepatitis C virus (HCV) and fatal stimulant overdose, we sought to assess the prevalence of HCV among opioid and stimulant-positive overdoses. METHODS: We conducted a cross-sectional study to examine the prevalence of HCV among fatal drug overdoses in Tennessee using 2019-2020 data from the State Unintentional Drug Overdose Reporting System. We defined history of HCV using surveillance data and autopsy reports. Descriptive statistics were calculated for circumstances of overdose deaths for different categories of opioid and stimulant positivity on toxicology. RESULTS: Between 2019 and 2020, 3570 unintentional or undetermined drug overdose deaths occurred in Tennessee with an available autopsy. History of HCV was found in 24.6% of deaths. When assessing different involvement between stimulants and opioids, the highest prevalence of HCV was found for deaths where methamphetamine and opioids were present in toxicology (35.4%). Scene evidence of injection drug use occurred more frequently among decedents with a history of HCV (P < .0001). CONCLUSIONS: This analysis while descriptive highlights the importance of linking datasets to enhance infectious disease and drug overdose surveillance. Partnership between communicable disease and drug overdose surveillance teams should continue to identify relationships between disease and drug overdose and strengthen the evidence to tailor crucial treatment and prevention activities.

Using Natural Language Processing to Predict Fatal Drug Overdose From Autopsy Narrative Text: Algorithm Development and Validation Study.

BACKGROUND: Fatal drug overdose surveillance informs prevention but is often delayed because of autopsy report processing and death certificate coding. Autopsy reports contain narrative text describing scene evidence and medical history (similar to preliminary death scene investigation reports) and may serve as early data sources for identifying fatal drug overdoses. To facilitate timely fatal overdose reporting, natural language processing was applied to narrative texts from autopsies. OBJECTIVE: This study aimed to develop a natural language processing-based model that predicts the likelihood that an autopsy report narrative describes an accidental or undetermined fatal drug overdose. METHODS: Autopsy reports of all manners of death (2019-2021) were obtained from the Tennessee Office of the State Chief Medical Examiner. The text was extracted from autopsy reports (PDFs) using optical character recognition. Three common narrative text sections were identified, concatenated, and preprocessed (bag-of-words) using term frequency-inverse document frequency scoring. Logistic regression, support vector machine (SVM), random forest, and gradient boosted tree classifiers were developed and validated. Models were trained and calibrated using autopsies from 2019 to 2020 and tested using those from 2021. Model discrimination was evaluated using the area under the receiver operating characteristic, precision, recall, F1-score, and F2-score (prioritizes recall over precision). Calibration was performed using logistic regression (Platt scaling) and evaluated using the Spiegelhalter z test. Shapley additive explanations values were generated for models compatible with this method. In a post hoc subgroup analysis of the random forest classifier, model discrimination was evaluated by forensic center, race, age, sex, and education level. RESULTS: A total of 17,342 autopsies (n=5934, 34.22% cases) were used for model development and validation. The training set included 10,215 autopsies (n=3342, 32.72% cases), the calibration set included 538 autopsies (n=183, 34.01% cases), and the test set included 6589 autopsies (n=2409, 36.56% cases). The vocabulary set contained 4002 terms. All models showed excellent performance (area under the receiver operating characteristic ≥0.95, precision ≥0.94, recall ≥0.92, F1-score ≥0.94, and F2-score ≥0.92). The SVM and random forest classifiers achieved the highest F2-scores (0.948 and 0.947, respectively). The logistic regression and random forest were calibrated (P=.95 and P=.85, respectively), whereas the SVM and gradient boosted tree classifiers were miscalibrated (P=.03 and P<.001, respectively). "Fentanyl" and "accident" had the highest Shapley additive explanations values. Post hoc subgroup analyses revealed lower F2-scores for autopsies from forensic centers D and E. Lower F2-score were observed for the American Indian, Asian, ≤14 years, and ≥65 years subgroups, but larger sample sizes are needed to validate these findings. CONCLUSIONS: The random forest classifier may be suitable for identifying potential accidental and undetermined fatal overdose autopsies. Further validation studies should be conducted to ensure early detection of accidental and undetermined fatal drug overdoses across all subgroups.

Characteristics of fatal drug overdoses among college age decedents in Tennessee, 2019-2020.

Purpose: College age persons experienced unique disruptions to their regular lives during the COVID-19 pandemic, sometimes resulting in negative coping mechanisms. We examined changes in the number of and characteristics of college age fatal drug overdoses before and during the early COVID-19 pandemic. Methods: We conducted a statewide cross-sectional study to determine the changes in the number and characteristics of college age fatal drug overdose decedents before and during the COVID-19 pandemic using 2019-2020 data from the Tennessee State Unintentional Drug Overdose Reporting System. We defined college age as 18-24 years. Frequencies and rates were generated to compare demographics, circumstances, and toxicology between 2019 and 2020. Results: From 2019 to 2020, 336 college age persons experienced an unintentional or undetermined fatal drug overdose in Tennessee. Characteristics of college age decedents: mean age 21.7 years, 68.5% males, and 71.4% White. Rates of fatal overdoses among college age persons increased 50.0% overall, 150.1% for female decedents, and 141.7% for Black decedents. Fewer people were treated for substance use disorder or mental health conditions (p = 0.0243) in 2020. Conclusion: This analysis can inform local and regional public health workers to implement focused prevention and intervention efforts to curtail the overdose epidemic among college age persons in Tennessee.

Trends, patterns, and maternal characteristics of opioid prescribing during pregnancy in a large population-based cohort study.

BACKGROUND: Opioid use during pregnancy has been associated with adverse maternal and infant health outcomes. Prescription drug monitoring programs (PDMP) provide a population-based source of prescription data. We linked statewide PDMP and birth certificate data in Tennessee (TN) to determine patterns of prescription opioid and benzodiazepine use during pregnancy. METHODS: We constructed a cohort of 311,217 live singleton births from 2013 to 2016 with prescription history from 90 days before pregnancy to birth. Descriptive statistics were used to describe opioid prescription patterns during pregnancy overall, by maternal characteristics and by year. Multivariable logistic regression models estimated adjusted odds ratios and 95% confidence intervals for factors associated with prescription use. RESULTS: The prevalence of prescription use during pregnancy was 14.1% for opioid analgesics, 1.6% buprenorphine for medication-assisted treatment, and 2.6% for benzodiazepines. The prevalence of opioid analgesic use decreased from 16.6% (2013) to 11.8% (2016) (ptrend< 0.001). About 25% used for > 7 and 9.7% for > 30 days' supply. The most common types were hydrocodone (9.3%), codeine (3.4%), and oxycodone (2.9%). In adjusted models, lower education, lower income, pre-pregnancy obesity and smoking during pregnancy were associated with increased odds of any opioid and opioid analgesic use. CONCLUSION(S): Despite the encouraging trend of decreasing use of prescription opioid analgesics, the overall prevalence remained close to 12% with many women using for long durations. Use was associated with lower socioeconomic status, obesity, and prenatal smoking. Findings highlight the need for maternal education and resources, and provider support for implementation of evidence-based care.

Tetrahydrobiopterin (BH4), a cofactor for nNOS, restores gastric emptying and nNOS expression in female diabetic rats.

Gastroparesis is a debilitating disease predominantly affecting young women. Recently, dysregulation of neuronal nitric oxide synthase (nNOS) in myenteric plexus neurons has been implicated for delayed solid gastric emptying/gastroparesis in diabetic patients. In this study, we have explored the role of tetrahydrobiopterin (BH4), a major cofactor for nNOS activity and NO synthesis in diabetic gastroparesis. Diabetes was induced with single injection of streptozotocin (55 mg/kg body wt, ip) in female rats, with experiments performed on week 3 or 9 following induction, with or without 3-wk BH4 supplementation. Gastric pyloric BH4 levels were significantly decreased in diabetic female rats compared with control (18.6 +/- 1.45 vs. 31.0 +/- 2.31 pmol/mg protein). In vitro studies showed that 2,4-diamino-6-hydroxypyrimidine (DAHP), an inhibitor of BH4 synthesis, significantly decreased gastric NO release and nitrergic relaxation. Three-week dietary supplementation of BH4 either from day 1 or week 6 significantly attenuated diabetes-induced delayed gastric emptying for solids (3 wk: BH4, 67 +/- 6.7 vs. diabetic, 36.05 +/- 7.09; 9 wk: BH4, 57 +/- 8.45 vs. diabetic, 33 +/- 9.91) and diabetes-induced reduction in pyloric nNOS-alpha protein expression in female rats. Supplementation of BH4 significantly restored gastric nNOS-alpha dimerization in 9-wk-old diabetic female rats. In addition, BH4 treatment reversed (17.23 +/- 5.81 vs. 42.0 +/- 2.70 mmHg x s) the diabetes-induced changes in intragastric pressures (IGP) and gastric pyloric nitrergic relaxation (-0.62 +/- 0.01 vs. -0.22 +/- 0.07). BH4 deficiency plays a critical role in diabetes-induced alterations including delayed solid gastric emptying, increased IGP, reduced pyloric nitrergic relaxation, and nNOS-alpha expression in female rats. Supplementation of BH4 accelerates gastric emptying by restoring nitrergic system in diabetic female rats. Therefore, BH4 supplementation is a potential therapeutic option for female patients of diabetic gastroparesis.

Antiproliferative effect of peripheral benzodiazepine receptor antagonist PK11195 in rat mammary tumor cells.

This study aims to establish the antiproliferative effects of PK11195, a peripheral benzodiazepine receptor antagonist (PBR) in rat mammary tumor cells. Breast tumors were induced by administration of a carcinogen, dimethylbenz[a]anthracene to 50-day-old female rats maintained on a standard AIN-76A diet with casein as the protein source. The tumors were developed approximately after 120 days. The tumors were of grade I (20%), grade II (60%), and grade III (20%). The tumors were isolated and cultured in DMEM/F12 media with supplements. We characterized the properties of the isolated cells and study the effect of PK11195 on those cells. We were successful in growing breast tumor cells up to 30 passages for cellular characterization. These cells had high reactivity with Ki-67 and PCNA antibodies suggesting high proliferation rate. These cells were highly invasive as evident by matrigel invading ability. Furthermore, these cells acquired a positive response for CD-31 and VEGF antibodies suggesting angiogenic potential, and also possessed migrating ability/motility as evident by the wound healing properties. These cells expressed elevated levels of PBR, a cancer promoting gene. The proliferation, invasion and migration appear to decrease when treated with PK11195, a PBR antagonist. Furthermore, PK11195 treatment caused an increase in apoptosis as evident by increase in the levels of annexin V. However, the inhibition of cell proliferation by PK11195 was counteracted by Ro5-4864, a PBR agonist. Thus, PBR antagonist may be a potential therapeutic agent for the control of aggressiveness of breast cancer.