GeTe/MoTe2 Van der Waals Heterostructures: Enabling Ultralow Voltage Memristors for Nonvolatile Memory and Neuromorphic Computing Applications.

Advanced electronic semiconducting Van der Waals heterostructures (HSs) are promising candidates for exploring next-generation nanoelectronics owing to their exceptional electronic properties, which present the possibility of extending their functionalities to diverse potential applications. In this study, GeTe/MoTe2 HS are explored for nonvolatile memory and neuromorphic-computing applications. Sputter-deposited Ag/GeTe/MoTe2/Pt HS cross-point devices are fabricated, and they demonstrate memristor behavior at ultralow switching voltages (VSET: 0.15 V and VRESET: -0.14 V) with very low energy consumption (≈30 nJ), high memory window, long retention time (104 s), and excellent endurance (105 cycles). Resistive switching is achieved by adjusting the interface between the Ag top electrode and the heterojunction switching layer. Cross-sectional transmission electron microscope images and conductive atomic force microscopy analysis confirm the presence of a conducting filament in the heterojunction switching layer. Further, emulating various synaptic functions of a biological synapse reveals that GeTe/MoTe2 HS can be utilized for energy-efficient neuromorphic-computing applications. A multilayer perceptron is implemented using the synaptic weights of the Ag/GeTe/MoTe2/Pt HS device, revealing high pattern accuracy (81.3%). These results indicate that HS devices can be considered a potential solution for high-density memory and artificial intelligence applications.

Anaplastic sarcoma of the kidney (DICER1-sarcoma of the kidney): A report from the International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear. METHODS: Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance. RESULTS: Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p = .07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively. CONCLUSION: ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors.

Evaluation of an emergency department opt-out provider-driven HIV and syphilis screening and linkage-to-care program.

OBJECTIVE: While the effectiveness of emergency departments (ED) in screening for HIV and syphilis is understood, less is known about dual screening programs. We aim to evaluate the impact of an opt-out provider-initiated HIV and syphilis program on screening, diagnosis, and linkage to care outcomes. METHODS: We performed a retrospective review of patients screened pre (2014-2017) and post (2017-2021) program implementation. Primary outcomes include HIV and syphilis screening, incidence of positive tests, and proportion of patients linked to care. Secondary outcomes included pre-exposure prophylaxis (PrEP) referral and successful linkage rates for HIV-negative syphilis-positive patients. RESULTS: Pre-implementation, 882 HIV tests were performed, of which 22 (2.49%) were new cases and 18 (81.82%) were linked to care; 754 syphilis tests were performed, of which 33 (4.38%) were active infections and 30 (90.91%) were treated. No eligible patients received PrEP referral. Post-implementation, 12,999 HIV tests were performed, of which 73 (0.56%) were new cases and 55 (75.34%) were linked to care; 10,885 syphilis tests were performed, of which 216 (1.98%) were active infections and 188 (87.04%) were treated. 25 (9.09%) eligible patients were referred for PrEP, and four (16.0%) attended their appointment. CONCLUSIONS: Post-implementation, there was a 1373.81% and 1343.63% increase in screening, and a 231.82% and 554.55% increase in positive cases of HIV and syphilis, respectively. Dual screening programs can be successfully implemented within the existing ED framework to increase screening and early detection for HIV and syphilis.

Postmodification of voxelotor (GBT 440) via [Rh]-catalyzed cross dehydrogenative coupling with olefins.

The directed Rh(III)-catalyzed cross dehydrogenative coupling of the pyrazole unit of the GBT-440 scaffold has been explored with simple as well as conjugated olefins to synthesize post-functionalized GBT-440 analogues. The screening of these synthesized compounds for improving the oxygen binding efficiency of the hemoglobin isolated from the sickled red blood cells revealed that some of these compounds are as good as GBT-440.

Acceptance of HIV pre-exposure prophylaxis (PrEP) referral among a sample of PrEP-eligible emergency department patients.

OBJECTIVE: Pre-exposure prophylaxis (PreP) reduces the rate of HIV transmission in high-risk groups. Emergency departments (EDs) frequently encounter patients at risk for HIV acquisition who are eligible for PrEP. ED HIV screening programs have prioritized testing and linkage to care for patients who test positive, but fail to refer HIV-negative patients to PrEP clinicians. Our objective was to estimate referral acceptance to a PrEP clinician among a sample of at-risk ED patients. METHODS: This single-center cross-sectional study electronically queried a prospectively acquired dataset of survey responses from a sample of patients presenting to an urban academic ED from March 2019 to February 2020. Patients completed a risk assessment as part of the HIV screening program. PrEP eligibility was based off survey responses in accordance with 2017 CDC PrEP eligibility criteria. Identified PrEP-eligible patients completed a PrEP questionnaire. The primary outcome was the proportion of PrEP-eligible patients who accepted referral to a PrEP clinician during their ED encounter. We secondarily report patient participant characteristics including the proportion of PrEP-eligible patients who were aware of and were knowledgeable about PrEP as a method to prevent transmission of HIV. RESULTS: In total, 360 patients completed a PrEP questionnaire, of which 287 (80%) were not currently taking PrEP and eligible for PrEP referral. 57% were males, with 41% Black/African American. Of the 287 eligible for PrEP, 61 (21.3%, 95% CI: 16.8-26.5) indicated awareness of PrEP, of which, 49 (80.3%, 95% CI: 67.8-89.0) demonstrated accurate knowledge of PrEP. PrEP referral was offered to 238 (82.9%, 95% CI: 78.0-87.0) patients, of which, 76 (31.9%, 95% CI: 26.1-38.3) accepted. CONCLUSIONS: Approximately one third of PrEP-eligible ED patients accepted PrEP referral during their ED encounter, demonstrating an opportunity for increased PrEP education and intentional referral for eligible patients. Variability in PrEP acceptability by demographic and risk subgroup may be an important consideration in efforts to expand PrEP utilization.

Emergency department screening for latent tuberculosis infection.

OBJECTIVE: Approximately 12.4 million people in the U.S. have latent tuberculosis infection (LTBI), 73% of whom are non-U.S. born. Identification and treatment of LTBI are essential for tuberculosis eradication. We evaluated an emergency department (ED) - based LTBI screening and linkage to care program. METHODS: We queried electronic records of a clinical prevention program located in a Midwestern, urban, academic ED that serves as the region's safety-net hospital. Program staff approached non-U.S. born ED patients from TB endemic areas. Patients received QuantiFERON-TB Gold Plus (QFT) blood testing and, if positive, were referred to treatment. The primary outcome was the proportion of tested patients newly diagnosed with LTBI. We secondarily report the number of patients linked to care who initiated LTBI treatment. RESULTS: The program approached 33 patients, of whom 24 (72.7%) were eligible, and 23 (95.8%) were tested. The majority were male (13, 56.5%), median age was 33 years (IQR 27-45), and 13 (56.5%) were from Latin America. Three patients (13.0%, 95% CI 0.03-0.35) were newly diagnosed with LTBI and linked to care; two (66.7%) started LTBI treatment. CONCLUSIONS: In this first report of an ED-based LTBI screening program implemented in a region with low TB prevalence, over 10% of high-risk ED patients tested positive for LTBI and were linked to treatment. Screening populations at risk for LTBI in EDs and linking them to public health treatment services should be prioritized in order to achieve TB elimination in the U.S.

Expression of HER2 and EGFR Proteins in Advanced Stage High-grade Serous Ovarian Tumors Show Mutual Exclusivity.

Human epidermal growth factors play an important role in ovarian carcinogenesis and are evaluated for prognostic and possible therapeutic roles in high-grade serous ovarian malignancies. The present study was undertaken to evaluate the expression of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) in advanced stage serous carcinoma and their influence on prognosis. The expression of HER2 and EGFR was studied in 59 cases of stage III and IV ovarian serous carcinomas by immunohistochemistry and fluorescent in situ hybridization. Of the 48 interpretable tumors for HER2, 6 tumors (12.5%) were scored as positive, 14 (29%) as equivocal and 28 tumors (58.5%) were negative by immunohistochemistry, while only 2/48 (4%) showed frank amplification by fluorescent in situ hybridization with ≥4 copies per cell. HER2 gene expression measured by quantitative polymerase chain reaction had good positive correlation with both protein expression and gene amplification. Although EGFR expression was seen in 32% of tumors, none of the tumors positive for HER2 protein or gene amplification had co-expression of EGFR indicating mutual exclusivity of their expression. Gene expression of both proteins also confirmed their inverse correlation (Pearsons CC=-0.15, P=0.3). Further there was no influence of protein or gene expression of these markers on the overall survival. In conclusion, HER2 and EGFR are expressed in a small percentage of tumors and the mutual exclusivity of these markers precludes the possibility of dual targeting with anti-HER2 and anti-EGFR therapy in advanced stage high-grade serous ovarian carcinoma.

Missed HIV diagnoses when screening only emergency department patients who have blood samples obtained for other clinical purposes.

OBJECTIVE: Emergency departments (EDs) are highly valued settings for HIV screening. Most large-volume ED HIV screening programs have attenuated operational barriers by screening only ED patients who already have a blood sample available for other clinical reasons. Our objective was to estimate the proportion of HIV positive patients who are missed when an ED excludes patients for whom HIV screening would be the only indication to obtain a blood sample. METHODS: This cross-sectional analysis used existing electronic records of patients seen between 2017 and 2019 by an urban, academic ED and its HIV screening program, which includes patients regardless of whether they receive other ED blood testing. The primary outcome was the proportion of patients tested by the screening program who were newly diagnosed with HIV (Sample 1) for whom HIV screening would be the only indication for venipuncture. We secondarily 1) estimate the proportion of ED patients who received venipuncture using a representative sample of consecutively approached participants which prospectively recorded whether patients had blood obtained or intravenous catheter placement during usual ED care (Sample 2) and 2) report patient characteristics including HIV risk factors for those with and without ED venipuncture for both groups. RESULTS: Of 41 persons newly diagnosed with HIV by the ED screening program (Sample 1), 13 (31.7%, 95%CI 18.6-48.2) did not undergo venipuncture for any reason other than their HIV test. The proportion of ED visits without a venipuncture (Sample 2) was 44.2% (95% CI 41.9-46.6). Patient characteristics were similar for both groups. CONCLUSIONS: Screening only those patients with a blood sample already available or easily obtainable due to usual ED care, misses many opportunities for earlier HIV diagnosis. Innovation in research, policy, and practice is needed to overcome still unaddressed barriers to ED HIV screening when HIV screening is the only indication for collection of a biological sample.

Estimated proportion of an urban academic emergency department patient population eligible for HIV preexposure prophylaxis.

OBJECTIVE: Pre-exposure prophylaxis (PrEP) is a highly effective but underutilized method of HIV prevention. Emergency departments (EDs) have access to at-risk populations meeting CDC eligibility criteria for PrEP. Characterizing this population could help motivate, develop, and implement ED interventions to promote PrEP uptake. METHODS: This cross-sectional study explored the proportion of patients from an urban, academic ED who met CDC 2017 PrEP eligibility criteria using three existing datasets that mimic patient selection strategies for HIV screening: 1) study of consecutively approached ED patients from 2008 to 2009 (analogous to non-targeted screening), 2) patients of the ED's HIV screening program in 2017 (analogous to risk-targeted screening), and 3) electronic health record (EHR) diagnostic codes in 2017 (analogous to EHR selected screening). The primary outcome was the proportion eligible for PrEP referral. Secondary outcomes included proportion by risk group: men who have sex with men (MSM), heterosexual men and women (HMW), and persons who inject drugs (PWID). RESULTS: The proportion eligible for PrEP was: 568/1970 (28.8%, 95% CI: 26.9-30.9) for consecutively approached patients, 552/3884 (14%, 95% CI: 13-15) for risk-targeted patients, and 605/66287 (0.9%, 95% CI: 0.8-1.0) for EHR diagnoses of all patients. For the two datasets with behavioral risk information, the proportion eligible was: MSM 1-2%, HMW 12-28%, and PWID 1-4%. CONCLUSIONS: A large subgroup of this ED population was eligible for PrEP referral. EDs are a compelling setting for development and implementation of HIV prevention interventions to assist in national efforts to expand PrEP.

Identifying ED patients with previous abnormal HIV or hepatitis C test results who may require additional services.

OBJECTIVES: Routine emergency department (ED) HIV or HCV screening may inadvertently capture patients already diagnosed but does not specifically prioritize identification of this group. Our objective was to preliminarily estimate the volume of this distinct group in our ED population through a pilot electronic health record (EHR) build that identified all patients with indications of HIV or HCV in their EHR at time of ED presentation. METHODS: Cross-sectional study of an urban, academic ED's HIV/HCV program for previously diagnosed patients August 2017-July 2018. Prevention program staff, alerted by the EHR, reviewed records and interviewed patients to determine if confirmatory testing or linkage to care was needed. Primary outcome was total proportion of ED patients for whom the EHR generated an alert. Secondary outcome was the proportion of patients assessed by program staff who required confirmatory testing or linkage to HIV/HCV medical care. RESULTS: There were 65,374 ED encounters with 5238 (8.0%, 95% CI: 7.8%-8.2%) EHR alerts. Of these, 3741 were assessed by program staff, with 798 (21%, 95% CI: 20%-23%) requiring HIV/HCV confirmatory testing or linkage to care services, 163 (20%) for HIV, 551 (69%) for HCV, and 84 (11%) for both HIV and HCV services. CONCLUSIONS: Patients with existing indication of HIV or HCV infection in need of confirmatory testing or linkage to care were common in this ED. EDs should prioritize identifying this population, outside of routine screening, and intervene similarly regardless of whether the patient is newly or previously diagnosed.

T-cell Receptor Excision Circles in Newborns with Heart Defects.

In the fetus, the cardiac neural crest gives rise to both the thymus and the conotruncus of the heart. In newborn screening for severe T-cell lymphopenia neonates with congenital heart defects may be detected. In this study, we investigated the occurrence of T-cell lymphopenia in neonates with or without 22q11.2 deletion syndrome (del) suffering from heart defects. This retrospective cohort study included 125 patients with heart defects. T-cell receptor excision circles (TRECs), a measure for T-cell lymphopenia, were quantified by RT-PCR using stored newborn screening blood spots. Three patient groups were compared: non-conotruncal defects (n = 57), conotruncal defects (n = 42), and 22q11.2 del with conotruncal defects (n = 26). Significantly lower TREC values were detected in patients with 22q11.2 del and conotruncal heart defects compared to those with non-syndromic conotruncal (p < 0.001) and non-conotruncal (p < 0.001) defects. In contrast, no significant difference was found between patients with non-syndromic conotruncal and non-conotruncal heart defects (p = 0.152). Low TREC levels were obtained in neonates treated with heart surgery/intervention within 2 weeks after birth and in those with a fatal outcome (p = 0.02) independent of patient group. A correlation was found between low TREC numbers and oxygen saturation, SpO2 below 95% (p = 0.017). The SpO2 was significantly lower in the non-syndromic conotruncal group compared to non-conotruncal (p < 0.001) and 22q11.2 del group (p = 0.015). No correlation was found between low neonatal TRECs and infections needing hospitalization later in life (p = 0.135). Patients with 22q11.2 del and conotruncal defects have significantly lower TREC levels compared to patients with heart defects without this syndrome.

The Trouble with Swallowing: Dysphagia as the Presenting Symptom in Lateral Medullary Syndrome.

BACKGROUND: Posterior circulation strokes account for approximately one-fourth of all ischemic strokes, but are frequently misdiagnosed by emergency providers. Current standard stroke screening tools such as the National Institutes of Health Stroke Scale and the Cincinnati Prehospital Stroke Scale are weighted toward anterior circulation stroke diagnosis. Lateral medullary syndrome, a type of posterior circulation stroke, can be particularly challenging to diagnose due to nonspecific presenting symptoms, such as dysphagia. CASE REPORT: This report describes a 65-year-old man who presented with dysphagia, dizziness, and hoarseness. An initial neurological examination did not reveal any gross deficits, and imaging to evaluate for posterior circulation stroke was not obtained. The patient presented the following day with worsening symptoms, prompting imaging that revealed a large cerebellar ischemic infarction. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although dysphagia frequently occurs in lateral medullary syndrome, it is rarely the presenting symptom in the emergency department. In patients with cerebrovascular risk factors who present with dysphagia, a complete neurological examination should be performed and noncontrast computed tomography (CT) of the head should be obtained if a neurological deficit is appreciated. Due to their poor sensitivity, CT scans can frequently miss posterior circulation strokes, therefore magnetic resonance imaging should be considered if provider suspicion remains high. Emergency providers are encouraged to have a high level of suspicion for this rare but debilitating stroke syndrome to avoid misdiagnosis and delayed care.

Avoidance of deep anesthesia and artificial airways in 1000 neonates and infants using regional anesthesia: A retrospective observational analysis.

BACKGROUND AND AIMS: Current concerns related to the anesthetic neurotoxicity have brought a renewed interest in regional anesthesia. Regional anesthesia reduces the need for opioids and inhalational anesthetics. The immaturity of the neonatal and infant nervous system may render them more prone to neurotoxicity. We describe our technique of anesthesia, which minimizes the exposure to general anesthetics and reduces airway instrumentation because the operability is rendered by the regional block. MATERIAL AND METHODS: This was a retrospective case series of neonates and infants undergoing common surface surgeries. We describe our technique of anesthesia where regional blocks are the mainstay. We also put up the data pertaining to block effectiveness, technique, end-tidal sevoflurane concentration and complications. RESULTS: One thousand patients, including neonates and infants, received central and peripheral nerve blockade. The failure rate in upper extremity blocks 0% without complications. 86.12% were given under ultrasonography (USG) guidance and 13.89% were given with peripheral nerve stimulation. The failure rate of sciatic block single shot and continuous was 0%. 92.53% were given with USG guidance while 7.46% received sciatic with nerve stimulation technique. Failure rate of caudal epidural block was 0. 78% requiring a rescue analgesic, 1.4% had blood in the needle. Out of the caudals, 33.33% were done with USG guidance and 66.67% blocks were given with traditional techniques. Out of the 322 penile + ring blocks given by traditional method, 1 block failed requiring rescue analgesics. The mean sevoflurane concentration was 1.2 +/- 0.32. CONCLUSION: It is feasible to conduct surface surgeries in the most vulnerable population such as neonates and infants under regional anesthesia without intubation and airway instrumentation.

Retrospective Review of Need for Delayed Naloxone or Oxygen in Emergency Department Patients Receiving Naloxone for Heroin Reversal.

BACKGROUND: Emergency departments (EDs) are experiencing an increasing number of heroin overdose visits. Currently, there is no generally agreed upon ED observation period for heroin overdose patients who receive naloxone. OBJECTIVES: We aimed to determine the safety of a 2-h observation period for heroin overdose patients who receive naloxone. METHODS: We performed a chart review of all patients who presented with any opioid-related complaint between 2009 and 2014 to our urban academic trauma center. Subset analysis of patients with isolated heroin overdose who received naloxone was performed, with the intent of excluding patients intoxicated with long-acting/enteral opioids. The primary outcome was the number of patients who required delayed intervention-specifically, additional naloxone or supplemental oxygen. RESULTS: Between 2009 and 2014, we recorded 806 visits to our ED for heroin use after receiving naloxone. Twenty-nine patients (3.6%) received a repeat dose of naloxone, and 17 patients (2%) received oxygen ≥2 h after initial naloxone administration. Our 2-h intervention rate was 4.6% (N = 37). This decreased to 1.9% (N = 15) after 3 h and 0.9% (N = 7) after 4 h. Patients with polysubstance use were more likely to receive repeat naloxone (p < 0.01), but not oxygen (p = 0.10). Preexisting cardiopulmonary conditions did not correlate with a need for supplemental oxygen (p = 0.24) or repeat naloxone (p = 0.30). CONCLUSIONS: A 2-h ED observation period for heroin overdose patients reversed with naloxone resulted in a delayed intervention rate of 5%. Clinicians may consider a 3-h observation period, with extra scrutiny in polysubstance abuse.

Low Lifetime Risk of Contralateral Breast Cancer in a Middle-Income Asian Country: Evidence to Guide Post-treatment Surveillance.

BACKGROUND: The rate of contralateral risk-reducing mastectomy (CRRM) is increasing in the West with controversial evidence of improved survival in early breast cancer patients. Although uptake of CRRM in Asia appears low, the trends may rise, and there is currently an urgent need to provide evidence for informed decision-making in clinical practice. This study aims to determine the risk of contralateral breast cancer (CBC) and its associated factors in an Asian setting. METHOD: A total of 2937 newly diagnosed patients with stage I and stage II breast cancer in University Malaya Medical Centre between Jan 1993 to Dec 2012 were included in the study. Multinomial logistic regression analysis allowing death to compete with CBC as a study outcome was used; patients with unilateral breast cancer who were alive were taken as reference. A stepwise backward regression analysis including age at diagnosis, ethnicity, family history of breast cancer, TNM stage, hormonal receptor status, HER2 status, chemotherapy, radiotherapy, and hormone therapy was conducted. RESULTS: Fifty women developed CBC, over a median follow-up of 6 years. The 5- and 10-year cumulative risk of contralateral breast cancer was 1.0% (95% CI 0.6-1.4%) and 2.8% (95% CI 2.0-3.6%), respectively. Young age at diagnosis of first cancer, positive family history, and stage I disease were independent predictors of CBC. DISCUSSION: The current study suggests that the risk of CBC is very low in a Southeast Asian setting. Any recommendations or practice of CRRM should be reviewed with caution and patients must be counseled appropriately.

Prevalence of Emergency Department Patients Presenting with Heroin or Prescription Opioid Abuse Residing in Urban, Suburban, and Rural Jefferson County.

BACKGROUND: Heroin and prescription opioid abuse in the United States is exhibiting a growing geographic ubiquity. OBJECTIVES: This study characterizes the changing geographic distribution of patients presenting with heroin and prescription opioid abuse to one urban emergency department (ED). METHODS: A retrospective review of patients with heroin and prescription opioid abuse from 2009-2014 was conducted in one adult urban ED. The primary outcome was the prevalence of heroin and prescription opioid patients residing in urban, suburban, and rural ZIP codes over time. RESULTS: From 2009 to 2014, 2695 patients presented for either heroin (N = 1436; 53%) or prescription opioid (N = 1259; 47%) abuse from 32 Jefferson County ZIP codes. Of the 32 ZIP codes, 15 were urban (47%), 13 suburban (41%), and 4 rural (12%). The prevalence of heroin patients (per 10,000 population) increased in each ZIP code from 2009-2014. After 2011, prescription opioid prevalence decreased in urban and suburban ZIP codes but increased in rural ones. Using segmented regression analysis, the increase in patients who used heroin residing in all ZIP codes and the decrease in patients abusing prescription opioids residing in urban areas was statistically significant after 2011. CONCLUSION: From 2009 to 2014, there was an increasing trend in ED patients using heroin who resided in urban, suburban, and rural ZIP codes. There was an increasing trend in prescription opioid prevalence in all regions from 2009 to 2011. After 2011, prescription opioid prevalence decreased in urban and suburban ZIP codes but not rural ZIP codes.

Shift in Drug vs Alcohol Prevalence in Milwaukee County Motor Vehicle Decedents, 2010-2016.

OBJECTIVE: The purpose of this study is to examine the prevalence of alcohol and nonalcohol drugs in motor vehicle crash (MVC) decedents in Milwaukee County, Wisconsin. METHODS: A retrospective review of MVC decedents in Milwaukee County from 2010 to 2016 was performed. Substances were divided into 5 categories based on chemical composition and clinical effects: alcohol, cocaine and its metabolite benzoylecgonine, opioids, cannabinoids, amphetamines and methamphetamines. Decedents were determined to be positive if any of these substances were detected on blood toxicology analysis. RESULTS: Sixty-five percent (n = 113) of MVC decedents tested positive for 1 substance, while polysubstance use (≥ 2 substances) was seen in 27% (n = 47). Alcohol was the most prevalent substance (n = 77, 44%), while cannabinoids were the second most prevalent (n = 50, 29%), and opioids were third most prevalent (n = 24, 14%). There was a statistically significant increase in the number of MVC decedents who tested positive for opioids from 2010 to 2016 (slope = 3.9, P < 0.01). The number of decedents who tested positive for alcohol only from 2010 to 2016 decreased significantly (slope = -3.9, P < 0.05), and 2016 was the first year in which the number of drug-positive decedents exceeded the number of alcohol-positive decedents. CONCLUSION: The prevalence of drugs exceeded that of alcohol in decedents for the first time in 2016 in Milwaukee County. While continued efforts to reduce alcohol-positive driving are encouraged, increased attention to drugged driving is needed to prevent further drug-positive fatalities.

Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves.

OBJECTIVE: Calcific aortic valve (AoV) disease is a significant clinical problem for which the regulatory mechanisms are poorly understood. Enhanced cell-cell adhesion is a common mechanism of cellular aggregation, but its role in calcific lesion formation is not known. Cadherin-11 (Cad-11) has been associated with lesion formation in vitro, but its function during adult valve homeostasis and pathogenesis is not known. This study aims to elucidate the specific functions of Cad-11 and its downstream targets, RhoA and Sox9, in extracellular matrix remodeling and AoV calcification. APPROACH AND RESULTS: We conditionally overexpressed Cad-11 in murine heart valves using a novel double-transgenic Nfatc1(Cre);R26-Cad11(TglTg) mouse model. These mice developed hemodynamically significant aortic stenosis with prominent calcific lesions in the AoV leaflets. Cad-11 overexpression upregulated downstream targets, RhoA and Sox9, in the valve interstitial cells, causing calcification and extensive pathogenic extracellular matrix remodeling. AoV interstitial cells overexpressing Cad-11 in an osteogenic environment in vitro rapidly form calcific nodules analogous to in vivo lesions. Molecular analyses revealed upregulation of osteoblastic and myofibroblastic markers. Treatment with a Rho-associated protein kinase inhibitor attenuated nodule formation, further supporting that Cad-11-driven calcification acts through the small GTPase RhoA/Rho-associated protein kinase signaling pathway. CONCLUSIONS: This study identifies one of the underlying molecular mechanisms of heart valve calcification and demonstrates that overexpression of Cad-11 upregulates RhoA and Sox9 to induce calcification and extracellular matrix remodeling in adult AoV pathogenesis. The findings provide a potential molecular target for clinical treatment.

Does ultrasound guidance add accuracy to continuous caudal-epidural catheter placements in neonates and infants?

BACKGROUND: Caudo-lumbar and caudo-thoracic epidural anesthesia is an established technique that carries a low risk of dural puncture or spinal cord trauma in infants. Traditionally catheter advancement is based on external measurements. However, malpositioning of catheters are known to occur. We hypothesized that caudal-epidural catheters inserted under real-time ultrasound guidance may be more accurate than the accuracy of the measurements traditionally used for their placement. METHODS: We studied 25 patients, aged 2 days to 5 months, posted for abdominal or thoracic surgery, receiving general anesthesia followed by caudo-epidural continuous block. External measurement defined as the distance from the caudal space and the surgically congruent vertebral level was measured in centimeters with the back gently flexed. Subsequently, a caudo-epidural block was performed in the same position. The epidural catheter insertion was followed under real-time ultrasound guidance till the predetermined vertebral level was reached. The actual length placed under real-time ultrasound scan was defined as the actual length. The high-frequency probe was placed longitudinal and paramedian to the spine. The vertebral level was determined by identifying the lumbosacral junction in longitudinal saggital view and counting the vertebrae up from L5. The catheter length at the skin was compared with the length recorded by external measurement. RESULTS: The actual length placed under real-time ultrasound scan were consistently longer than the external distance between the caudal space and selected vertebral level. The mean values of ultrasound were higher than the mean values of external measurement with a difference of 4.28 cm. Accuracy was not affected by age or affected by the selected vertebral level in the age group we studied. CONCLUSION: We conclude that catheters placed under ultrasound guidance are more accurate than the traditional method developed before the advent of ultrasound in young infants.

RIG-I-like receptor LGP2 protects tumor cells from ionizing radiation.

An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNß. Specifically (i) suppression of LGP2 leads to enhanced IFNß, (ii) cytotoxic effects following IR correlated with expression of IFNß inasmuch as inhibition of IFNß by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNß and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNß.