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Cover page of Kv1.3 inhibition attenuates neuroinflammation through disruption of microglial calcium signaling.

Kv1.3 inhibition attenuates neuroinflammation through disruption of microglial calcium signaling.

(2021)

In the last 5 years inhibitors of the potassium channel KV1.3 have been shown to reduce neuroinflammation in rodent models of ischemic stroke, Alzheimer's disease, Parkinson's disease and traumatic brain injury. At the systemic level these beneficial actions are mediated by a reduction in microglia activation and a suppression of pro-inflammatory cytokine and nitric oxide production. However, the molecular mechanisms for the suppressive action of KV1.3 blockers on pro-inflammatory microglia functions was not known until our group recently demonstrated that KV1.3 channels not only regulate membrane potential, as would be expected of a voltage-gated potassium channel, but also play a crucial role in enabling microglia to resist depolarizations produced by the danger signal ATP thus regulating calcium influx through P2X4 receptors. We here review the role of KV1.3 in microglial signaling and show that, similarly to their role in T cells, KV1.3 channels also regulated store-operated calcium influx in microglia.

Cover page of Pathogenicity and virulence of <i>Clostridium perfringens</i>.

Pathogenicity and virulence of Clostridium perfringens.

(2021)

Clostridium perfringens is an extremely versatile pathogen of humans and livestock, causing wound infections like gas gangrene (clostridial myonecrosis), enteritis/enterocolitis (including one of the most common human food-borne illnesses), and enterotoxemia (where toxins produced in the intestine are absorbed and damage distant organs such as the brain). The virulence of this Gram-positive, spore-forming, anaerobe is largely attributable to its copious toxin production; the diverse actions and roles in infection of these toxins are now becoming established. Most C. perfringens toxin genes are encoded on conjugative plasmids, including the pCW3-like and the recently discovered pCP13-like plasmid families. Production of C. perfringens toxins is highly regulated via processes involving two-component regulatory systems, quorum sensing and/or sporulation-related alternative sigma factors. Non-toxin factors, such as degradative enzymes like sialidases, are also now being implicated in the pathogenicity of this bacterium. These factors can promote toxin action in vitro and, perhaps in vivo, and also enhance C. perfringens intestinal colonization, e.g. NanI sialidase increases C. perfringens adherence to intestinal tissue and generates nutrients for its growth, at least in vitro. The possible virulence contributions of many other factors, such as adhesins, the capsule and biofilms, largely await future study.

Cover page of Integrated source-risk and uncertainty assessment for metals contamination in sediments of an urban river system in eastern China

Integrated source-risk and uncertainty assessment for metals contamination in sediments of an urban river system in eastern China

(2021)

Integrated source apportionment and risk assessment of metals is of great importance for contamination source control and remediation at the regional watershed scale. To identify metal sources and source-specific ecological risks, sediments were collected in the Wen-Rui Tang urban watershed for metal analysis. Risk assessment showed considerable and extremely high risk for Cu and Cd with large spatial variation. Positive matrix factorization model extracted three main sources with reasonable prediction efficacy for metal concentrations. Due to different toxicity coefficients for various metals, the low concentration contribution of source factor 2 (27.2%) contributed 83.7% of total risk, while a high concentration loading for factor 3 (40.8%) only contributed 4.6% to total risk. Predicted source-specific risk was similar to determined risk level for Cr, Ni and Pb; however, Cu and Cd were predicted with decreased risk, while Zn had increased risk. Triangular fuzzy number (TFN) coupled with stochastic simulation showed elevated trend in risk simulation for Cd and Cu when compared with determined risk. The uncertainties for risk evaluation appear to result from spatial variations in metal concentrations. Source apportionment and specific-risk assessment results suggest that different strategies may be required to address mitigation of elevated metal concentrations versus ecological risk.

Cover page of Data-Driven Real-Valued Timed-Failure-Propagation-Graph Refinement for Complex System Fault Diagnosis

Data-Driven Real-Valued Timed-Failure-Propagation-Graph Refinement for Complex System Fault Diagnosis

(2021)

Timed Failure Propagation Graphs (TFPGs) have been widely used for the failure modeling and diagnosis of safety-critical systems. Currently most TFPGs are manually constructed by system experts, a process that can be time-consuming, error-prone, and even impossible for systems with highly nonlinear and machine-learning-based components. This letter proposes a new type of TFPGs, called Real-Valued Timed Failure Propagation Graphs (rTFPGs), designed for continuous-state systems. More importantly, it presents a systematic way of constructing rTFPGs by combining the powers of human experts and data-driven methods: first, an expert constructs a partial rTFPG based on his/her expertise; then a data-driven algorithm refines the rTFPG by adding nodes and edges based on a given set of labeled signals. The proposed approach has been successfully implemented and evaluated on three case studies.

Cover page of Realness is a core feature of authenticity

Realness is a core feature of authenticity

(2021)

We established realness as the relatively stable tendency to act on the outside the way one feels on the inside, without regard for proximal personal or social consequences. In nine studies, we showed that realness is a) a core feature of individual differences in authenticity, b) generally adaptive but largely unrelated to agreeableness, c) highly stable, d) reliably observable in dyadic behavior, and e) predictive of responses to situations with potential for personal or social costs. Informants both perceive agreeable motives in real behavior and recognize that being real can be disagreeable. We concluded that realness represents an important individual difference construct that is foundational for authentic social behavior, and that being real comes with both costs and benefits.

Cover page of Relationship of parity and prior cesarean delivery to levonorgestrel 52 mg intrauterine system expulsion over 6 years.

Relationship of parity and prior cesarean delivery to levonorgestrel 52 mg intrauterine system expulsion over 6 years.

(2021)

Objective

Assess the relationship between parity and prior route of delivery to levonorgestrel 52 mg intrauterine system (IUS) expulsion during the first 72 months of use.

Study design

We evaluated women enrolled in the ACCESS IUS multicenter, Phase 3, open-label clinical trial of the Liletta levonorgestrel 52 mg IUS. Investigators evaluated IUS presence at 3 and 6 months after placement and then every 6 months and during unscheduled visits. We included women with successful placement and at least one follow-up assessment. We evaluated expulsion rates based on obstetric history; for prior delivery method subanalyses, we excluded 12 participants with missing delivery data. We determined predictors of expulsion using multivariable regression analyses.

Results

Of 1714 women with IUS placement, 1710 had at least one follow-up assessment. The total population included 986 (57.7%) nulliparous women. Sixty-five (3.8%) women experienced expulsion within 72 months, 50 (76.9%) within the first 12 months. Expulsion rates among nulliparous women (22/986 [2.2%]) or parous women with any pregnancy ending with a Cesarean delivery (6/195 [3.1%]) differed from parous women who only experienced vaginal deliveries (37/517 [7.2%]) (p < 0.001). In multivariable regression, obesity (adjusted odds ratio [aOR] 2.2, 95% confidence interval [CI] 1.3-3.7), parity (aOR 2.2, 95% CI 1.2-4.1), and non-white race (aOR 1.8, 95% CI 1.1-3.2) predicted expulsion. Among parous women, obesity (aOR 2.2, 95% CI 1.2-4.2) increased the odds and having ever had a cesarean delivery (aOR 0.4, 95% CI 0.1-0.9) decreased the odds of expulsion.

Conclusion

IUS expulsion occurs in less than 4% of users over the first 6 years of use and occurs mostly during the first year. Expulsion is more likely among obese and parous women.

Implications

Levonorgestrel 52 mg intrauterine system expulsion occured more commonly in parous than nulliparous women; the increase in parous women is primarily in women who had vaginal deliveries only. The association between obesity, delivery route, and IUS expulsion needs further elucidation.

Cover page of US referral center experience removing nonpalpable and difficult contraceptive implants with in-office ultrasonography: A case series.

US referral center experience removing nonpalpable and difficult contraceptive implants with in-office ultrasonography: A case series.

(2021)

Objectives

To assess referral center outcomes with removal of difficult or nonpalpable contraceptive implants using high-frequency point-of-care ultrasonography.

Study design

We present a case series examining patients referred to our specialty center from January 2019 through September 2020 for difficult or nonpalpable implant removal.

Results

Of the 54 referrals, 6 had palpable implants and 48 required ultrasonography. We localized 46 (96%) implants in-office, including 13 located subfascially; 2 Implanon implants could not be localized. We successfully completed 50 (96%) of 52 attempted in-office removals, including 12 (92%) subfascial implants.

Conclusion

High-frequency point-of-care ultrasonography can effectively localize nonpalpable contraceptive implants leading to successful in-office removal.

Implications

Specialists can use high-frequency point-of-care ultrasonography to localize nonpalpable implants without formal radiology scans and skilled technologists, optimizing patient time and convenience. However, the probe is expensive, and providers may need to consider this cost in the context of reimbursement for these highly specialized procedures.

Cover page of Lack of association of antihypertensive drugs with the risk and severity of COVID-19: A meta-analysis.

Lack of association of antihypertensive drugs with the risk and severity of COVID-19: A meta-analysis.

(2021)

Background

The association of antihypertensive drugs with the risk and severity of COVID-19 remains unknown.

Methods and results

We systematically searched PubMed, MEDLINE, The Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and medRxiv for publications before July 13, 2020. Cohort studies and case-control studies that contain information on the association of antihypertensive agents including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium-channel blockers (CCBs), β-blockers, and diuretics with the risk and severity of COVID-19 were selected. The random or fixed-effects models were used to pool the odds ratio (OR) with 95% confidence interval (CI) for the outcomes. The literature search yielded 53 studies that satisfied our inclusion criteria, which comprised 39 cohort studies and 14 case-control studies. These studies included a total of 2,100,587 participants. We observed no association between prior usage of antihypertensive medications including ACEIs/ARBs, CCBs, β-blockers, or diuretics and the risk and severity of COVID-19. Additionally, when only hypertensive patients were included, the severity and mortality were lower with prior usage of ACEIs/ARBs (overall OR of 0.81, 95% CI 0.66-0.99, p < 0.05 and overall OR of 0.77, 95% CI 0.66-0.91, p < 0.01).

Conclusions

Taken together, usage of antihypertensive drugs is not associated with the risk and severity of COVID-19. Based on the current available literature, it is not recommended to abstain from the usage of these drugs in COVID-19 patients.

Registration

The meta-analysis was registered on OSF (https://osf.io/ynd5g).

Cover page of A Retrospective Study of Corneal Endothelial Dystrophy in Dogs (1991-2014).

A Retrospective Study of Corneal Endothelial Dystrophy in Dogs (1991-2014).

(2021)

Purpose

To retrospectively evaluate the clinical data, diagnostic tests, treatments, and outcomes for dogs with corneal endothelial dystrophy (CED) and determine risk factors for CED when compared with a canine reference population.

Methods

Medical records of 99 dogs (1991-2014) diagnosed with CED at the University of California Davis Veterinary Medical Teaching Hospital were reviewed and compared with 458,680 dogs comprising the general hospital population during the study period. Retrieved data included signalment, examination findings, diagnoses, treatments, and outcomes associated with CED. The exact Pearson χ2 test or exact Kruskal-Wallis test was used to compare parameters between the groups. Progression of corneal edema was assessed using 3 independent Kaplan-Meier curves, identifying clinically significant changes in corneal opacity.

Results

Boston terriers, German wirehaired pointers, and Dachshunds were overrepresented in the CED-affected group, whereas Labradors were underrepresented. Dogs older than 11 years were overrepresented in the CED-affected group, whereas intact dogs were underrepresented. Surgical intervention was performed (n = 11) based on the severity of disease and secondary complications from CED. Median time to progression of corneal edema was 1) 368 days when an at-risk eye initially without edema developed edema at a subsequent visit, 2) 701 days when there was progression from mild to marked corneal edema, and 3) 340 days when there was progression from focal to diffuse corneal edema.

Conclusions

Many CED-affected dogs progress over months to years without surgical intervention, making dogs with CED a useful model for studying genetic predispositions and development of novel therapeutics for Fuchs endothelial corneal dystrophy.