Undersea Hyperb Med. 2021 First-Quarter;48(1):97-102.
The term "intracranial abscess" (ICA) includes cerebral abscess, subdural empyema, and epidural empyema, which share many diagnostic and therapeutic similarities and, frequently, very similar etiologies. Infection may occur and spread from a contiguous infection such as sinusitis, otitis, mastoiditis, or dental infection; hematogenous seeding; or cranial trauma. In view of the high morbidity and mortality of ICA and the fact that hyperbaric oxygen therapy (HBO2) is relatively non-invasive and carries a low complication rate, the risk-benefit ratio favors adjunct use of HBO2 therapy in selected patients with intracranial abscess.
Autosomal STR and SNP characterization of populations from the Northeastern Peruvian Andes with the ForenSeq™ DNA Signature Prep Kit
Forensic Sci Int Genet. 2021 Feb 23;52:102487. doi: 10.1016/j.fsigen.2021.102487. Online ahead of print.
Autosomal DNA data from Peru for human identity testing purposes are scarce in the scientific literature, which hinders obtaining an appropriate portrait of the genetic variation of the resident populations. In this study we genetically characterize five populations from the Northeastern Peruvian Andes (Chachapoyas, Awajún, Wampís, Huancas and Cajamarca). Autosomal short tandem repeat (aSTR) and identity informative single nucleotide polymorphism (iiSNP) data from a total of 233 unrelated individuals are provided, and forensic genetic parameters are calculated for each population and for the combined set Northeastern Peruvian Andes. After correction for multiple testing in the whole dataset of the Northeastern Peruvian Andes, the only departure from Hardy-Weinberg equilibrium was observed in locus rs2111980. Twenty one out of 27 aSTR loci exhibited an increased number of alleles due to sequence variation in the repeat motif and flanking regions. For iiSNPs 33% of the loci displayed flanking region variation. The combined random match probability (RMP), assuming independence of all loci (aSTRs and iiSNPs), in the Chachapoyas, the population with the largest samples size (N = 172), was 8.14 × 10-62 for length-based data while for sequence-based was 4.15 × 10-67. In the merged dataset (Northeastern Peruvian Andes; N = 233), the combined RMP when including all markers were 2.96 × 10-61 (length-based) and 3.21 × 10-66 (sequence-based). These new data help to fill up some of the gaps in the genetic canvas of South America and provide essential length- and sequence-based background information for other forensic genetic studies in Peru.
Int J Surg Case Rep. 2021 Feb 15;80:105624. doi: 10.1016/j.ijscr.2021.02.010. Online ahead of print.
INTRODUCTION: Septic arthritis is an orthopedic emergency that requires rapid diagnosis and treatment. It is typically caused by occult bacteremia which allows bacteria to seed the joint or local invasion of a soft tissue infection. Most cases of septic arthritis are caused by gram-positive bacteria, with the most common culprit being Staphylococcus Aureus. The reason septic arthritis is an orthopedic emergency is because of rapid destruction to cartilage. The mechanism of injury to cartilage is two-fold: bacterial enzymes are directly toxic to joint cartilage, and buildup of exudate can tamponade blood flow and cause anoxic injury. Typically, the knee is the most commonly involved joint. This is followed by the hip, ankle, elbow, wrist, and shoulder in descending order of occurrence. Polyarticular disease makes up a small percentage of these cases and if present, it is usually asymmetric and will involve at least one knee joint.
PRESENTATION OF CASE: Bilateral joint septic arthritis is relatively rare. We present an uncommon case of atraumatic bilateral septic shoulders in an elderly man with a history of heart disease and insidious bilateral shoulder pain after golfing 18 holes. This presentation is unique not only in its rarity but also in its impact on our understanding of septic arthritis in the setting of medical comorbidities and a relatively unimpressive presentation. With a recent golfing day just prior to presentation, differential diagnoses other than septic arthritis included deltoid/rotator cuff muscle strain, acute on chronic rotator cuff tendinosis, acute on chronic rotator cuff tearing, acute flare up of osteoarthritis, rheumatoid arthritis, or crystalline arthropathy. With elevated inflammatory markers and an equivocal physical examination, our patient underwent advanced imaging via MRI and subsequent bilateral glenohumeral joint diagnostic aspirations that were consistent with septic arthritis due to his complaining of contralateral shoulder pain shortly after his admission. Immediately after said diagnosis was made, the patient was taken back for emergent bilateral open irrigation and debridement, as septic arthritis is an orthopedic emergency, and went on to recover appropriately on culture-directed intravenous antibiotic therapy.
DISCUSSION/CONCLUSION: This case report is impactful with regard to clinical practice for multiple reasons. First and foremost it is a cautionary tale for all clinicians with regard to the level of suspicion one must have for polyarticular septic arthritis in the setting of the multiply painful patient. Second, it demonstrates the utility of advanced imaging in the equivocal patient. Lastly, it underscores the importance of prompt diagnosis and treatment, validating the existing algorithm for septic arthritis.
Risk Factors for Esophageal Cancer, with an Emphasis on the Role of Specificity Protein Transcription Factors in Prognosis and Therapy
Crit Rev Oncog. 2020;25(4):355-363. doi: 10.1615/CritRevOncog.2020036449.
Specificity protein (Sp) transcription factors regulate the expression of genes associated with several cellular processes and play a critical role in early development. Typically, Sp protein expression decreases with age in healthy adults. Research has shown that Sp proteins can impact the development and transformation of cancer cells and other oncogenic processes, including survival, proliferation, spread, and metastasis. Among the Sp proteins, Sp1, Sp3, and Sp4 have been the main targets of study as they are shown to be highly expressed in cancer cells compared to healthy cells. Increased levels of Sp1 are correlated with poor prognosis in some malignancies, including gastrointestinal cancers. In this review, we discuss the role of Sp transcription factors and examine their activities as pro-oncogenic factors in esophageal cancer (EC). Other aspects presented in this review are potential therapeutic options for EC that target Sp1. We summarize the published information on preclinical results using mithramycin and tolfenamic acid.
Autophagy. 2021 Feb 8:1-382. doi: 10.1080/15548627.2020.1797280. Online ahead of print.
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
Nanoencapsulated hybrid compound SA-2 with long-lasting intraocular pressure-lowering activity in rodent eyes
Mol Vis. 2021 Jan 16;27:37-49. eCollection 2021.
PURPOSE: Glaucoma is a neurodegenerative disease of the eye with an estimated prevalence of more than 111.8 million patients worldwide by 2040, with at least 6 to 8 million projected to become bilaterally blind. Clinically, the current method of slowing glaucomatous vision loss is to reduce intraocular pressure (IOP). In this manuscript, we describe the in vitro cytoprotective and in vivo long lasting IOP-lowering activity of the poly D, L-lactic-co-glycolic acid (PLGA) nanoparticle-encapsulated hybrid compound SA-2, possessing nitric oxide (NO) donating and superoxide radical scavenging functionalities.
METHODS: Previously characterized primary human trabecular meshwork (hTM) cells were used for the study. hTM cells were treated with SA-2 (100 µM, 200 µM, and 1,000 µM), SA-2 PLGA-loaded nanosuspension (SA-2 NPs, 0.1%), or vehicle for 30 min. Cyclic guanosine monophosphate (cGMP) and super oxide dismutase (SOD) levels were analyzed using commercial kits. In another experiment, hTM cells were pretreated with tert-butyl hydrogen peroxide (TBHP, 300 µM) for 30 min followed by treatment with escalating doses of SA-2 for 24 h, and CellTiter 96 cell proliferation assay was performed. For the biodistribution study, the cornea, aqueous humor, vitreous humor, retina, choroid, and sclera were collected after 1 h of administration of a single eye drop (30 μl) of SA-2 NPs (1% w/v) formulated in PBS to rat (n = 6) eyes. Compound SA-2 was quantified using high performance liquid chromatography /mass spectrometry (HPLC/MS). For the IOP-lowering activity study, a single SA-2 NPs (1%) eye drop was instilled in normotensive rats eyes and in the IOP-elevated rat eyes (n = 3/group, in the Morrison model of glaucoma), or Ad5TGFβ2-induced ocular hypertensive (OHT) mouse eyes (n = 5/group). IOP was measured at various time points up to 72 h, and the experiment was repeated in triplicate. Mouse aqueous humor outflow facility was determined with multiple flow-rate infusion and episcleral venous pressure estimated with manometry.
RESULTS: SA-2 upregulated cGMP levels (six- to ten-fold) with an half maximal effective concentration (EC50) of 20.3 µM in the hTM cells and simultaneously upregulated (40-fold) the SOD enzyme when compared with the vehicle-treated hTM cells. SA-2 also protected hTM cells from TBHP-induced decrease in cell survival with an EC50 of 0.38 µM. A single dose of slow-release SA-2 NPs (1% w/v) delivered as an eye drop significantly lowered IOP (by 30%) in normotensive and OHT rodent eyes after 3 h post-dose, with the effect lasting up to 72 h. A statistically significant increase in aqueous outflow facility and a decrease in episcleral venous pressure was observed in rodents at this dose at 54 h.
CONCLUSIONS: Hybrid compound SA-2 upregulated cGMP in hTM cells, increased outflow facility and decreased IOP in rodent models of OHT. Compound SA-2 possessing an antioxidant moiety provided additive cytoprotective activity to oxidatively stressed hTM cells by scavenging reactive oxygen species (ROS) and increasing SOD enzyme activity. Additionally, the PLGA nanosuspension formulation (SA-2 NPs) provided longer duration of IOP-lowering activity (up to 3 days) in comparison with the free non-encapsulated SA-2 drug. The data have implications for developing novel, non-prostaglandin therapeutics for IOP-lowering and cytoprotective effects with the possibility of an eye drop dosing regimen of once every 3 days for patients with glaucoma.
Reporting and Tracking Objective Functional Outcome Measures: Implementation of a Summary Report for Gait and Balance Measures
Spine J. 2021 Feb 22:S1529-9430(21)00086-3. doi: 10.1016/j.spinee.2021.02.015. Online ahead of print.
The aim of this manuscript is to describe knowledge gaps in the literature, future directions, and emerging applications of gait and balance analysis in spine surgery with regard to functional outcomes measurement. Functional outcome measurement has been established as a useful clinical and research investigational tool in musculoskeletal disease. Evidence currently supports its use in the diagnosis, treatment, and outcome measurement of multiple musculoskeletal disease states, including spinal disease, and its usefulness continues to grow as literature develops. Gait and balance analysis has proven to be broadly applicable, but most clinicians remain unfamiliar and untrained in its usage. The logistical and communication barriers are also described with the potential solutions that are on the near horizon of research. This article describes our methodology for improving conveyance of functional outcome measures in spine surgery. Additionally, we provide a case example of an adult patient with spinal deformity who is examined pre and post operatively using our methodology.
Defining, conceptualizing, and measuring perceived maternal care quality in low- to high-income countries: a scoping review protocol
Syst Rev. 2021 Feb 24;10(1):61. doi: 10.1186/s13643-021-01608-6.
BACKGROUND: Health practitioners and researchers must be able to measure and assess maternal care quality in facilities to monitor, intervene, and reduce global maternal mortality rates. On the global scale, there is a general lack of consensus on how maternal care quality is defined, conceptualized, and measured. Much of the literature addressing this problem has focused primarily on defining, conceptualizing, and measuring clinical indicators of maternal care quality. Less attention has been given in this regard to perceived maternal care quality among women which is known to influence care utilization and adherence. Therefore, there is a need to map the literature focused on defining, conceptualizing, and measuring perceived maternal care quality across low-, middle-, and high-income country contexts.
METHODS: This scoping review protocol will follow the Arksey and O'Malley methodological framework. A comprehensive search strategy will be used to search for articles published from inception to 2020 in Ovid MEDLINE, Embase, AMED, and WHO Global Index Medicus. Gray literature will be included. Two independent reviewers will screen articles by title and abstract, then by full-text based on pre-determined inclusion/exclusion criteria. A third reviewer will arbitrate any discrepancies. This protocol outlines a four-step analytic approach that includes numerical, graphical, tabular, and narrative summaries to provide a comprehensive description of the body of literature.
DISCUSSION: The findings from this scoping review will provide a comprehensive overview of the existing evidence on perceived maternal care quality. The findings are expected to inform future work on building consensus around the definition and conceptualization of perceived maternal care quality, and lay the groundwork for future research aimed at developing measures of perceived maternal care quality that can be applied across country contexts. Consequently, this review may aid in facilitating coordinated efforts to measure and improve maternal care quality across diverse country contexts (i.e., low-, middle-, and high-income country contexts).
REVIEW REGISTRATION: This scoping review has been registered in the Open Science Framework (osf.io/k8nqh).
Smoking cessation and survival among people diagnosed with non-metastatic cancer.
BMC Cancer. 2020 Aug 05;20(1):726
Authors: Barnett TE, Lu Y, Gehr AW, Ghabach B, Ojha RP
BACKGROUND: We aimed to estimate the effects of smoking cessation on survival among people diagnosed with cancer.
METHODS: We used data from a Comprehensive Community Cancer Program that is part of a large urban safety-net hospital system. Eligible patients were diagnosed with primary invasive solid tumors between 2013 and 2015, and were current smokers at time of diagnosis. Our exposure of interest was initiation of smoking cessation within 6 months of cancer diagnosis. We estimated inverse probability weighted restricted mean survival time (RMST) differences and risk ratio (RR) for all cause 3-year mortality.
RESULTS: Our study population comprised 369 patients, of whom 42% were aged < 55 years, 59% were male, 44% were racial/ethnic minorities, and 59% were uninsured. The 3-year RMST was 1.8 (95% CL: - 1.5, 5.1) months longer for individuals who initiated smoking cessation within 6 months of cancer diagnosis. The point estimate for risk of 3-year mortality was lower for initiation of smoking cessation within 6 months of diagnosis compared with no initiation within 6 months (RR = 0.72, 95% CL: 0.37, 1.4).
CONCLUSIONS: Our point estimates suggest longer 3-year survival, but the results are compatible with 1.5 month shorter or 5.1 longer 3-year overall survival after smoking cessation within 6 months of cancer diagnosis. Future studies with larger sample sizes that test the comparative effectiveness of different smoking cessation strategies are needed for more detailed evidence to inform decision-making about the effect of smoking cessation on survival among cancer patients.
IMPLICATIONS FOR CANCER SURVIVORS: The benefits of smoking cessation after cancer diagnosis may include longer survival, but the magnitude of benefit is unclear.
PMID: 32758159 [PubMed - indexed for MEDLINE]
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-7.
Molecules. 2020 Jun 28;25(13):
Authors: Gütschow M, Eynde JJV, Jampilek J, Kang C, Mangoni AA, Fossa P, Karaman R, Trabocchi A, Scott PJH, Reynisson J, Rapposelli S, Galdiero S, Winum JY, Brullo C, Prokai-Tatrai K, Sharma AK, Schapira M, Azuma YT, Cerchia L, Spetea M, Torri G, Collina S, Geronikaki A, García-Sosa AT, Vasconcelos MH, Sousa ME, Kosalec I, Tuccinardi T, Duarte IF, Salvador JAR, Bertinaria M, Pellecchia M, Amato J, Rastelli G, Gomes PAC, Guedes RC, Sabatier JM, Estévez-Braun A, Pagano B, Mangani S, Ragno R, Kokotos G, Brindisi M, González FV, Borges F, Miloso M, Rautio J, Muñoz-Torrero D
Breakthroughs in Medicinal Chemistry [...].
PMID: 32605268 [PubMed - indexed for MEDLINE]
Osteoarthritis Cartilage. 2021 Feb 20:S1063-4584(21)00437-4. doi: 10.1016/j.joca.2021.02.382. Online ahead of print.
OBJECTIVE: Smoking represents a major issue for global public health. Owing to methodologic challenges, findings of an association between smoking and risk of knee osteoarthritis (OA) are inconsistent. We sought to assess the relation of onset of smoking cessation to the risk of OA sequelae, i.e., knee replacement, and to perform sub-cohort analysis according to weight change after smoking cessation.
DESIGN: Using The Health Improvement Network, we conducted a cohort study to examine the association between smoking cessation and risk of knee replacement among patients with knee OA. Participants who stopped smoking were further grouped into three sub-cohorts: weight gain (body mass index [BMI] increased>1.14 kg/m2), no substantial weight change (absolute value of BMI change<1.14 kg/m2), and weight loss (BMI loss>1.14 kg/m2) after smoking cessation.
RESULTS: We identified 108 cases of knee replacement among 1,054 recent quitters (26.7/1000 person-years) and 1,108 cases among 15,765 current smokers (17.4/1000 person-years). The rate difference of knee replacement in recent quitter cohort versus current smoker cohort was 10.4 (95% confidence interval [CI]:5.3-15.6)/1000 person-years and the adjusted hazard ratio (HR) was 1.30 (95%CI:1.05-1.59). Compared with current smokers, risk of knee replacement was higher among quitters with weight gain (HR=1.42,95%CI:1.01-1.98), but not among those with no substantial weight change (HR=1.29,95%CI:0.90-1.83) or those with weight loss (HR=1.11,95%CI:0.71-1.75).
CONCLUSIONS: Our large population-based cohort study provides the first evidence that smoking cessation was associated with a higher risk of knee replacement among individuals with knee OA, and such an association was due to weight gain after smoking cessation.
Endocrinol Diabetes Metab. 2020 Dec 25:e00218. doi: 10.1002/edm2.218. Online ahead of print.
INTRODUCTION: Coronavirus disease 2019 (COVID-19) has become a major global crisis. Preliminary reports have, in general, indicated worse outcomes in diabetes mellitus (DM) patients, but the magnitude of cardiovascular (CV) complications in this subgroup has not been elucidated.
METHODS: We included 142 patients admitted with laboratory-confirmed COVID-19 from April 1st to May 30th 2020; 71 (50%) had DM. We compared baseline demographics and study outcomes between those with or without DM using descriptive statistics. Multivariate logistic regression was used to estimate the adjusted odds ratio for the study outcomes in DM patients, compared to those without DM, stratified by age, sex and glycaemic control. CV outcomes of interest include acute myocarditis, acute heart failure, acute myocardial infarction, new-onset atrial fibrillation and composite cardiovascular end-point consisting of all individual outcomes above.
RESULT: Mean age was 58 years. The unadjusted rates were higher in DM patients compared to non-diabetics for the composite cardiovascular end-point (73.2% vs. 40.6% p < .0001), acute myocarditis (36.6% vs. 15.5% p = .004), acute heart failure (25.3% vs. 5.6% p = .001), acute myocardial infarction (9.9% vs. 1.4% p = .03) and new-onset atrial fibrillation (12.7% vs. 1.4% p = .009). After controlling for relevant confounding variables, diabetic patients had higher odds of composite cardiovascular end-point, acute heart failure and new-onset atrial fibrillation.
A cross-sectional study of latent tuberculosis infection, insurance coverage, and usual sources of health care among non-US-born persons in the United States.
A cross-sectional study of latent tuberculosis infection, insurance coverage, and usual sources of health care among non-US-born persons in the United States.
Medicine (Baltimore). 2021 Feb 19;100(7):e24838
Authors: Annan E, Stockbridge EL, Katz D, Mun EY, Miller TL
ABSTRACT: More than 70% of tuberculosis (TB) cases diagnosed in the United States (US) occur in non-US-born persons, and this population has experienced less than half the recent incidence rate declines of US-born persons (1.5% vs 4.2%, respectively). The great majority of TB cases in non-US-born persons are attributable to reactivation of latent tuberculosis infection (LTBI). Strategies to expand LTBI-focused TB prevention may depend on LTBI positive non-US-born persons' access to, and ability to pay for, health care.To examine patterns of health insurance coverage and usual sources of health care among non-US-born persons with LTBI, and to estimate LTBI prevalence by insurance status and usual sources of health care.Self-reported health insurance and usual sources of care for non-US-born persons were analyzed in combination with markers for LTBI using 2011-2012 National Health and Nutrition Examination Survey (NHANES) data for 1793 sampled persons. A positive result on an interferon gamma release assay (IGRA), a blood test which measures immunological reactivity to Mycobacterium tuberculosis infection, was used as a proxy for LTBI. We calculated demographic category percentages by IGRA status, IGRA percentages by demographic category, and 95% confidence intervals for each percentage.Overall, 15.9% [95% confidence interval (CI) = 13.5, 18.7] of non-US-born persons were IGRA-positive. Of IGRA-positive non-US-born persons, 63.0% (95% CI = 55.4, 69.9) had insurance and 74.1% (95% CI = 69.2, 78.5) had a usual source of care. IGRA positivity was highest in persons with Medicare (29.1%; 95% CI: 20.9, 38.9).Our results suggest that targeted LTBI testing and treatment within the US private healthcare sector could reach a large majority of non-US-born individuals with LTBI. With non-US-born Medicare beneficiaries' high prevalence of LTBI and the high proportion of LTBI-positive non-US-born persons with private insurance, future TB prevention initiatives focused on these payer types are warranted.
PMID: 33607853 [PubMed - as supplied by publisher]
Relationship of Neurofilament light (NfL) and Cognitive Performance in a Sample of Mexican Americans with Normal Cognition, Mild Cognitive Impairment and Dementia.
Relationship of Neurofilament light (NfL) and Cognitive Performance in a Sample of Mexican Americans with Normal Cognition, Mild Cognitive Impairment and Dementia.
Curr Alzheimer Res. 2021 Feb 18;:
Authors: Hall JR, Johnson LA, Peterson M, Julovich D, Como T, O'Bryant SE
INTRODUCTION: This study characterized the relationship between plasma NfL and cognition in a community-based sample of older Mexican Americans.
METHODS: 544 participants completed a battery of neuropsychological tests and were diagnosed using clinical criteria. NfL was assayed using Simoa. NfL levels across groups and tests were analyzed.
RESULTS: Difference in NfL was found between normal and impaired groups and was related to global cognition, processing speed, executive functions and a list of learning tasks with a significant negative effect for all diagnostic groups. NfL had a negative impact on processing speed, attention, executive functions and delayed and recognition memory for both normal and MCI groups.
DISCUSSION: The research supports plasma NfL as a marker of cognitive impairment related to neurodegenerative processes in Mexican Americans and may be a marker of early changes in cognition in those with normal cognition and at risk for developing MCI.
PMID: 33605860 [PubMed - as supplied by publisher]
Evaluation of a School-Based Child Physical and Sexual Abuse Prevention Program.
Health Educ Behav. 2021 Feb 19;:1090198120988252
Authors: Thompson EL, Zhou Z, Garg A, Rohr D, Ajoku B, Spence EE
BACKGROUND: Evidence-based child sexual and physical abuse prevention programs delivered in schools are needed and require rigorous evaluation of program effects prior to widespread dissemination. The Play it Safe! program is a one-time session delivered by trained facilitators to teach students about recognizing, resisting, and reporting abuse.
AIMS: To evaluate a school-based child sexual and physical abuse prevention intervention Play it Safe! among elementary school students using a cluster randomized design.
METHOD: Six elementary schools in Texas were matched on demographic characteristics, and then randomized to intervention or wait-list control groups. Participants included third to fifth graders (n = 539). Participants received the pretest assessing vignette-based knowledge of physical and sexual abuse prevention (14 items). The intervention group immediately had the program. One month later, both groups received a posttest using the same validated scale. Multilevel linear regression analyses were estimated, and interaction effects were used to evaluate the effect of Play it Safe! while controlling for other factors.
RESULTS: A statistically significant interaction between the treatment group and time (b = 1.30, p < .01) indicated a greater increase in the knowledge score over time in the intervention group. Moderating effect of grade was also observed as the intervention tended to have less effect for fifth grade compared with third grade (b = -1.04, p = .01).
CONCLUSION: This study provides evidence to support the efficacy of the Play it Safe! program for increasing children's physical and sexual abuse prevention knowledge and skills among a racially and ethnically diverse sample of elementary school students.
PMID: 33605168 [PubMed - as supplied by publisher]
Behav Pharmacol. 2021 Feb 15. doi: 10.1097/FBP.0000000000000618. Online ahead of print.
Newly emerging synthetic cannabinoid compounds continue to be found in the designer drug market. They are often targeted as a 'legal high' alternative to traditional cannabinoids via 'darknet' markets and their increased potency and efficacy are becoming a growing concern internationally. The purpose of this study was to determine whether 4-CN-CUMYL-BUTINACA, 4F-MDMB-BINACA, 5F-AEB, 5F-CUMYL-P7AICA and EMB-FUBINACA exhibited similar behavioral effects as Δ9-tetrahydrocannabinol (Δ9-THC). Locomotor activity was assessed in an open-field assay using Swiss-Webster mice. Male Sprague-Dawley rats were trained to discriminate between intraperitoneal injections of Δ9-THC (3 mg/kg) and vehicle. Following successful training, substitution tests for 4-CN-CUMYL-BUTINACA, 4F-MDMB-BINACA, 5F-AEB, 5F-CUMYL-P7AICA and EMB-FUBINACA were conducted. All of the test compounds decreased locomotor activity. 4-CN-CUMYL-BUTINACA (ED50 = 0.26 mg/kg), 4F-MDMB-BINACA (ED50 = 0.019 mg/kg), 5F-CUMYL-P7AICA (ED50 = 0.13 mg/kg) and EMB-FUBINACA (ED50 = 0.13 mg/kg) each fully substituted for the discriminative stimulus effects of the training dose of Δ9-THC, whereas 5F-AEB produced only a maximum of 67% drug-appropriate responding at 0.5 mg/kg. Higher doses produced piloerection, exophthalmos and convulsions. 4-CN-CUMYL-BUTINACA, 4F-MDMB-BINACA, 5F-CUMYL-P7AICA and EMB-FUBINACA are likely to produce similar subjective effects in humans as those produced by abused synthetic cannabinoids, and may therefore share similar abuse liability. In contrast, 5F-AEB may have a reduced abuse liability given its weaker THC-like discriminative stimulus effects but maybe more dangerous due to the adverse effects observed at doses needed to produce discriminative stimulus effects.
J Sex Res. 2021 Feb 17:1-7. doi: 10.1080/00224499.2021.1882929. Online ahead of print.
Sexual scripts and consent communication methods are seldom explored outside of heterosexual, cisgender relationships. To date, little research has been conducted to determine how sexual and gender minority (SGM) students conceptualize and communicate consent. This study explored SGM undergraduate students' (n = 81) sexual consent communication scripts using open-ended survey items. We conducted a thematic freelisting analysis to assess the domains of consent and non-consent scripts using Smith's Salience Score (S). Salient indicators of consent were verbal communication (S = .31; 38%); however, more specific forms of verbal communication were listed as a spectrum, including: asking (a request, S = .16; 23%), saying (a statement, S = .16; 20%), and telling (a command, S = .10; 13%). The most salient indicators of verbal non-consent were on a similar spectrum: saying no (S = .42; 9%), verbal communication broadly (S = .23; 27%), and telling no (S = .06; 7%). Salient physical indicators of both consent and non-consent also followed a spectrum in their descriptions. Future research among SGM college students should explore the meanings, patterns, and differences in consent communication and sexual scripts.
NCX 1741, a Novel Nitric Oxide-Donating Phosphodiesterase-5 Inhibitor, Exerts Rapid and Long-Lasting Intraocular Pressure-Lowering in Cynomolgus Monkeys
J Ocul Pharmacol Ther. 2021 Feb 15. doi: 10.1089/jop.2020.0126. Online ahead of print.
Purpose: We studied the IOP-lowering effects of NCX 1741, a novel nitric oxide (NO)-donating derivative of the phosphodiesterase type-5 inhibitor, avanafil, in Cynomolgus monkey with laser-induced ocular hypertension (OHT-monkeys). NCX 1193 (NO-donating moiety), NCX 1744 (NCX 1741 without ester nitrate moiety), and travoprost (PGF2α analogue) were used for comparison. Ocular exposure after NCX 1741 dosing also was addressed. Methods: Vehicle (phosphate buffer pH 6.0, Kolliphor® 5%, DMSO 0.3%, benzalkonium chloride 0.02%), NCX 1741, NCX 1193, NCX 1744, or travoprost were instilled (30 μL; single dose) masked and conscious IOPs were measured by pneumatonometry. LC-MS/MS-based methods were employed to monitor ocular exposure of NCX 1741 and main metabolites after ocular dosing in New Zealand White rabbits. Results: NCX 1741 (2.2%, 0.8 μmol/eye) lowered IOP with an Emax (ΔΔIOP, IOP change vs. pre-dose and vehicle) between 5 and 8 h post-dosing (ΔΔIOP5h, -5.3 ± 2.0 mmHg and ΔΔIOP8h, -6.0 ± 2.1 mmHg). Conversely, equimolar (0.47%, 0.8 μmol/eye) NCX 1193 IOP-lowering effects were maximal 3 h post-dosing (ΔΔIOP3h, -4.7 ± 1.6 mmHg) and declined thereafter (ΔΔIOP5h, -1.6 ± 1.1 mmHg). In a follow-up study, NCX 1741 (1.5%, 0.5 μmol/eye) was more effective than NCX 1744 despite a similar duration. Further, NCX 1741 was as effective as travoprost (0.1%, 0.06 μmol/eye) at 5 and 8 h post-dosing (travoprost, ΔΔIOP5h, -3.4 ± 2.2 mmHg and ΔΔIOP8h, -4.9 ± 1.3 mmHg) but had shorter duration (NCX 1741, ΔΔIOP24h, -1.5 ± 1.1 mmHg; travoprost, ΔΔIOP24h, -7.1 ± 2.8 mmHg). NCX 1741 resulted in significant aqueous humor exposure, as determined by the levels of the main metabolite, avanafil. Conclusions: NCX 1741 rapidly and effectively lowers IOP in OHT-monkeys for several hours post-dosing. How these effects translate in humans is still to be defined.
Minireview: The Role of Angiotensin II in in Chronic Intermittent Hypoxia-Induced Hypertension and Cognitive Decline
Am J Physiol Regul Integr Comp Physiol. 2021 Feb 17. doi: 10.1152/ajpregu.00222.2020. Online ahead of print.
Sleep apnea is characterized by momentary interruptions in normal respiration and leads to periods of decreased oxygen, or intermittent hypoxia. Chronic intermittent hypoxia is a model of the hypoxemia associated with sleep apnea and results in a sustained hypertension that is maintained during normoxia. Adaptations of the carotid body and activation of the renin-angiotensin system may contribute to the development of hypertension associated with chronic intermittent hypoxia. The subsequent activation of the brain renin-angiotensin system may produce changes in sympathetic regulatory neural networks that support the maintenance of the hypertension associated with intermittent hypoxia. Hypertension and sleep apnea not only increase risk for cardiovascular disease, but are also risk factors for cognitive decline and Alzheimer's disease. Activation of the angiotensin system could be a common mechanism that links these disorders.
J Med Chem. 2021 Feb 17. doi: 10.1021/acs.jmedchem.0c02000. Online ahead of print.
Human neuropeptide Y receptors (Y1R, Y2R, Y4R, and Y5R) belong to the superfamily of G protein-coupled receptors and play an important role in the regulation of food intake and energy metabolism. We identified and characterized the first selective Y4R allosteric antagonist (S)-VU0637120, an important step toward validating Y receptors as therapeutic targets for metabolic diseases. To obtain insight into the antagonistic mechanism of (S)-VU0637120, we conducted a variety of in vitro, ex vivo, and in silico studies. These studies revealed that (S)-VU0637120 selectively inhibits native Y4R function and binds in an allosteric site located below the binding pocket of the endogenous ligand pancreatic polypeptide in the core of the Y4R transmembrane domains. Taken together, our studies provide a first-of-its-kind tool for probing Y4R function and improve the general understanding of allosteric modulation, ultimately contributing to the rational development of allosteric modulators for peptide-activated G protein-coupled receptors (GPCRs).