bluuebunny/crossref_metadata_2025 huggingface dataset:
Meningitis and high-grade, second-degree atrioventricular block in an adolescent: causal effect or coincidence?
Authors: Murphy Lee D , Florez Amy R , Czosek Richard J , Cooper David S , Mah Kenneth E
Published: May 2021

We describe an adolescent withStreptococcus pneumoniaemeningitis and symptomatic high-grade, second-degree atrioventricular block requiring permanent pacemaker placement. It is difficult to ascertain if these two diagnoses were independent or had a causal relationship though ongoing symptoms were not present prior to the infection. Because of this uncertainty, awareness that rhythm disturbances can be cardiac in origin but also secondary to other aetiologies, such as infection, is warranted.
Evidence Based Approach to Capacity Assessment for Hospitalized Patients
Authors: Zulkosky Julie , Harms Ann
Published: May 2021

Medical decision-making capacity (MDMC) is inherent to the legal and ethical principles of respect for autonomy and is an essential element of informed consent. Qualitative and quantitative evidence to support a final decision of capacity should be the gold standard. General hospital policies and state laws mandate that a licensed provider make the final determination of capacity, but they do not specifically mandate who is responsible for those assessments. When a patient s decisional capacity fluctuates, the role of the nurse in a hospital setting is valuable because they have the most direct contact with the patient. Objective: Determine receptiveness of nursing staff to assessing capacity, to gather feedback on the Aid to Capacity Evaluation (ACE) tool, and to ascertain awareness of capacity by sixty nurses working on progressive care, trauma orthopedic, and medical/surgical units. Method: This project was completed at a Midwestern academic level I trauma center. Nurses on a medical/surgical, orthopedic trauma, and progressive care unit participated. Education about MDMC and the ACE tool were given to nurses verbally and in writing. They were asked to utilize the Aide to Capacity Evaluation (ACE) tool to assess patients whom they believed lacked decision-making capacity. After four weeks the nurses completed an evaluation. Results: Thirty nurses (50%) responded. Over 70% of those respondents used the tool at least once. 63% agreed that the format helped to systematically evaluate a patient and they found it easy to incorporate into practice. Overall, 73% of respondents would welcome more education about capacity. Conclusion: Given a standardized tool in conjunction with proper and continuous education, bedside nurses are in an optimal position to identify mental changes early, alert the provider so steps can be taken to optimize mental capacity, and assist with assessment of capacity with minimal disruption of care. Implementation of a tool such as the ACE can ensure accurate, reliable, and consistent assessments. Furthermore, providers would benefit from the extra time to gather information and complete focused assessments to make a determination of capacity with confidence.
Safety and Tolerability of Aripiprazole Lauroxil 2-Month Formulation With 1-Day Initiation for Treatment of Schizophrenia in the ALPINE Study
Authors: Bidollari Ilda , Vasios Alexa , Claxton Amy
Published: May 2021

Objective

Evaluate safety and tolerability of an aripiprazole lauroxil (AL) 2-month regimen using 1-day initiation in patients hospitalized for acute exacerbation of schizophrenia and transitioned to outpatient care.

Methods

In the 25-week, double-blind ALPINE study, adults hospitalized for an acute exacerbation of schizophrenia were randomized to AL (AL NanoCrystal Dispersion + oral aripiprazole 30 mg day 1; AL 1064 mg day 8 and q8wk) or the active control paliperidone palmitate (PP 234 mg day 1; PP 156 mg day 8 and q4wk), discharged after 2 weeks if clinically stable, and followed through the end of the study. Adverse events, including adverse events of special interest (AESIs; extrapyramidal symptoms [identified by non-mutually exclusive standardized MedDRA queries], sedation, hypotension, injection site reactions [ISRs], suicidal ideation and behavior) were monitored throughout the study.

Results

In total, 200 patients were randomized (AL, n=99; PP, n=101); 99 patients (AL, n= 56; PP, n=43) completed the study. Rates of AESIs in AL-treated patients were akathisia, 10%; Parkinson-like events, 2%; dyskinesia, 3%; dystonia, 9%; sedation, 7%; hypotension, 6%; ISRs, 18 % (including placebo); and suicidal ideation and behavior, 2 %. In PP-treated patients, AESI rates were akathisia, 12%; Parkinson-like events, 4%; dyskinesia, 5%; dystonia, 11%; sedation, 7%; hypotension, 4%; ISRs, 27% (including placebo); and suicidal ideation and behavior, 3%.

Conclusion(s)

No unexpected safety and tolerability findings were identified in patients treated with AL or PP who were hospitalized for acute schizophrenia exacerbation and transitioned to outpatient care in ALPINE. AESI profiles were consistent with each treatment’s respective known safety profile.

Funding

Alkermes, Inc.

Disclosures

All authors are employees of Alkermes, Inc., and may own stock/options in the company.
Evaluation of the Safety of Deutetrabenazine at Higher Doses to Treat Chorea in Huntington’s Disease
Authors: Frank Samuel , Vaughan Christina , Stamler David , Oakes David , Davis Mat D. , Gross Nicholas , Gordon Mark Forrest , Savola Juha-Matti , Wieman Maria , Eberly Shirley , Kayson Elise , Whaley Jacquelyn , Goldstein Jody , Testa Claudia M. ,   on behalf of the Huntington Study Group ARC-HD Investigators
Published: May 2021

Background

In the First-HD pivotal trial, the maximum deutetrabenazine dose evaluated to treat chorea associated with Huntington’s disease (HD chorea) was 48 mg/d, which is the approved maximum dose for this population. In ARC-HD, an open-label extension study evaluating the long-term efficacy and safety of deutetrabenazine to treat HD chorea, dosage ranged from 6 mg/d to 72 mg/d, with doses ≥12 mg/d administered twice daily. Doses in ARC-HD were increased by 6 mg/d per week in a response-driven manner based on efficacy and tolerability until 48 mg/d (Week 8). At the investigator’s discretion, further increases were permitted by 12 mg/d per week to a maximum of 72 mg/d. This post-hoc analysis evaluates the safety and tolerability of deutetrabenazine >48 mg/d compared to ≤48 mg/d to treat HD chorea in ARC-HD.

Methods

Patient counts and safety assessments were attributed to patients when they received a dose of either ≤48 mg/d or >48 mg/d. For 9 selected adverse events (AEs), we compared AE rates adjusted for duration of drug exposure (as number of AEs/year) at ≤48 mg/d or >48 mg/d. The AE rates were determined after titration when participants were on stable doses of deutetrabenazine.

Results

All 113 patients were exposed to doses ≤48 mg/d (177.1 patient-years) and 49 patients were ever exposed to doses >48 mg/d (74.1 patient-years). In patients taking deutetrabenazine >48 mg/d compared to ≤48 mg/d after the titration period, there were no apparent differences in exposure-adjusted AE rates.

Conclusions

Based on clinical experience, some patients with HD may benefit from doses higher than 48 mg/d to adequately control chorea. These doses were tolerated without apparent increase in the exposure-adjusted rates of selected AEs after titration. This analysis does not address the occurrence of other AEs or whether adequate efficacy was achieved at lower doses, factors that may have influenced dose increases.

Funding

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Quantifying Psychopathology in Rapid Readmissions
Authors: Suhail Sam K. , Sandhu Harpinder , Mellacheruvu Sandeep
Published: May 2021

Psychiatric readmissions contribute to a significant cost and healthcare burden to physicians, hospitals, and the healthcare system as an entity. Furthermore, as part of the Affordable Care Act, the Centers for Medicare and Medicaid Services (CMS) began to reduce financial coverage to hospitals with overwhelming rehospitalization rates. The purpose of this study was to do a systematic analysis on inpatient psychiatric readmission data and identify co-morbidities and risk factors that lead to high readmission rates. The data collection includes 163 patients with a total of 348 readmissions over the span of 90 days at one inner-city hospital in the Chicagoland area. Study findings suggest that higher rates of readmission are linked to cocaine abuse in both male and female populations. Diagnosis of bipolar in females and schizoaffective disorder in male populations were the among the highest for readmission. Key social factors such as homelessness and low socioeconomic status were identified to contribute to a large proportion of psychiatric readmission burden. However, an overwhelming amount of information was missing due to unobtained labs and lack of current patient social history. By using this data as well as data from electronic medical records (EMRs) to further investigate and identify other features of at-risk patients, hospitals can potentially address these markers to lower readmission rates. Ultimately, a higher understanding of the patients’ needs can be understood and can help develop standardized plans of care for prevalent psychiatric illnesses in these populations.
The Rapid Mood Screener: A Novel and Pragmatic Screener Tool for Bipolar I Disorder
Authors: Montano C. Brendan , Patel Mehul , Jain Rakesh , Masand Prakash S. , Harrington Amanda , Gillard Patrick , Sullivan Kate , McElroy Susan L. , Brown T. Michelle , Nelson Lauren , McIntyre Roger S.
Published: May 2021

Introduction

Approximately 70% of patients with bipolar disorder (BPD) are initially misdiagnosed, resulting in significantly delayed diagnosis of 7–10 years on average. Misdiagnosis and diagnostic delay adversely affect health outcomes and lead to the use of inappropriate treatments. As depressive episodes and symptoms are the predominant symptom presentation in BPD, misdiagnosis as major depressive disorder (MDD) is common. Self-rated screening instruments for BPD exist but their length and reliance on past manic symptoms are barriers to implementation, especially in primary care settings where many of these patients initially present. We developed a brief, pragmatic bipolar I disorder (BPD-I) screening tool that not only screens for manic symptoms but also includes risk factors for BPD-I (eg, age of depression onset) to help clinicians reduce the misdiagnosis of BPD-I as MDD.

Methods

Existing questionnaires and risk factors were identified through a targeted literature search; a multidisciplinary panel of experts participated in 2 modified Delphi panels to select concepts thought to differentiate BPD-I from MDD. Individuals with self-reported BPD-I or MDD participated in cognitive debriefing interviews (N=12) to test and refine item wording. A multisite, cross-sectional, observational study was conducted to evaluate the screening tool’s predictive validity. Participants with clinical interview-confirmed diagnoses of BPD-I or MDD completed a draft 10-item screening tool and additional questionnaires/questions. Different combinations of item sets with various item permutations (eg, number of depressive episodes, age of onset) were simultaneously tested. The final combination of items and thresholds was selected based on multiple considerations including clinical validity, optimization of sensitivity and specificity, and pragmatism.

Results

A total of 160 clinical interviews were conducted; 139 patients had clinical interview-confirmed BPD-I (n=67) or MDD (n=72). The screening tool was reduced from 10 to 6 items based on item-level analysis. When 4 items or more were endorsed (yes) in this analysis sample, the sensitivity of this tool for identifying patients with BPD-I was 0.88 and specificity was 0.80; positive and negative predictive values were 0.80 and 0.88, respectively. These properties represent an improvement over the Mood Disorder Questionnaire, while using >50% fewer items.

Conclusion

This new 6-item BPD-I screening tool serves to differentiate BPD-I from MDD in patients with depressive symptoms. Use of this tool can provide real-world guidance to primary care practitioners on whether more comprehensive assessment for BPD-I is warranted. Use of a brief and valid tool provides an opportunity to reduce misdiagnosis, improve treatment selection, and enhance health outcomes in busy clinical practices.

Funding

AbbVie Inc.
Psychiatry on a Shoestring: Developing New Standards of Care for a Severe, Prolonged, and Widespread Emergency
Authors: Black James E.
Published: May 2021

Study Objective

The COVID-19 crisis has severely stressed our healthcare system and pushed our economy to the brink. This long emergency will probably cause years of severe suffering in every region. Health expenses greatly increased, supply chains were disrupted, and governments coped with much less revenue. Good clinicians plan for ALL contingencies, and we need to consider that the current disaster may get much worse. How can we adapt psychiatry to a long emergency? This goes far beyond previous work on crisis standards of care because the emergency is severe, prolonged, and widespread. If we had to spend much less on psychotropics, which meds stay on the formulary? If we have to close hospitals, which patients get a bed? What adaptations could be used if demand exceeds the supply of providers? Very little is known about how to make severe, permanent cuts to healthcare. Our previous systematic review found no scholarship addressing the ethics of severe and prolonged healthcare rationing. Global catastrophes need a global health policy, but this one has no experts. The present study starts the project by surveying experts with related experience that could be useful in future plans.

Method

We used purposive sampling to find 18 professionals with experience in healthcare rationing from underserved, indigenous communities, homeless programs, and African nations. We also interviewed ethicists, pharmacists, administrators, NGO clinicians, and military. Interviews were transcribed and coded using basic inductive techniques. Because so little is known about this topic, we used grounded theory, an iterative approach to guide further sampling, refine interviews, and make some preliminary conclusions.

Results

Participants all agreed this crisis planning is extremely important and complex. They described diverse concerns regarding ethical decision making, with some having confidence with top-down government policy, and others recommending a grassroots approach. Minority participants had less confidence in government. There was no consensus on any best ethical framework. Most had confidence that clinicians will ultimately do the right thing. Native American leaders had confidence in a holistic, preventive approach. All agreed that social justice should be central in measuring economic impact of long emergencies and choosing ethical options. We collected suggestions for innovative approaches to rationing.

Conclusions

This research program illuminates the difficult ethical questions about adapting psychiatry to a prolonged, widespread, and severe emergency. Our interviews identify areas where severe but ethical cuts can be made in medications, hospitals, clinical staff, and administration. Next steps include evidence-based formularies, utilitarian staff cuts, and ethical standards for closing beds or revamping state hospitals. Underserved and diverse communities with rationing experience must have a voice in the discussion.
Long-Term Efficacy of Combination Therapy of Transcranial Magnetic Stimulation with Ketamine for Patients with Treatment-Resistant Depression
Authors: Best Steve , Pavel Dan G. , Haustrup Natalie
Published: May 2021

Background

Repetitive transcranial magnetic stimulation (rTMS) is a safe, effective and non-invasive treatment for many psychiatric illnesses, including treatment-resistant depression (TRD). Ketamine, an NMDA receptor antagonist, is also an effective antidepressant. This retrospective review examined the clinical benefits of combining these two established treatments for patients suffering from TRD in a novel approach coined combination TMS with ketamine (CTK).

Methods

A group of 28 adult patients with a primary diagnosis of unipolar (n=18) or bipolar (n=10) depression received three CTK treatments a week at a private neuropsychiatric practice. Patients were given a concurrent treatment of rTMS (1Hz; 40 minutes; 130% of motor threshold) with bio-marker-determined IV ketamine infusions (0.2–4.7 mg/kg; 30 minutes). The TMS coil was positioned on the mid-prefrontal area. Frequency of treatment was dependent on patient responsiveness (10–30 sessions), which was measured as symptom reduction on the Clinical Global Impression (CGI) scale. CGI data was evaluated pre-treatment, post-treatment and at two-year follow-up.

Results

Mean reduction in CGI severity for the patient group following CTK was 4.46 ± 0.54 at a 99% confidence interval and was deemed statistically significant using a paired t-test (a=0.01, t=22.81, p < 0.0001). This significant reduction in CGI severity was sustained for at least 2 years following treatment completion.

Conclusions

Despite years of unsuccessful treatments, all 28 patients in this trial obtained substantial and enduring reductions in their depressive symptoms following CTK therapy. Further research into method optimization and randomized controlled trials are warranted.
Treating Comorbid Childhood Bipolar Disorder and ADHD
Authors: Nemeth Darlyne G. , Chustz Kayla M. , Capps Cody M.
Published: May 2021

Objectives

Pediatric mania is difficult to distinguish from childhood hyperactivity. Both share 3 common symptoms: distractibility, motoric hyperactivity, and talkativeness. Oftentimes, children are referred from their pediatrician due to a lack of appropriate response to stimulant medication. Pediatricians have learned that merely raising the dose or changing the stimulant does not work. A thorough neuropsychological evaluation often reveals bipolar mania. They may have comorbid bipolar disorder and ADHD. This poster paper will examine measures that can assist in this important differential diagnosis as well as offer treatment options, including medication management.

Methods

This case study includes three pediatric patients diagnosed with childhood bipolar disorder and ADHD. A comprehensive psychoeducational assessment was conducted for each of the patients, which resulted in this comorbid diagnosis.

Results

One of the most helpful measures was the TOVA (i.e., Test of Variables of Attention). When a child’s attention and impulsivity scores are normal, and response time and variability scores are abnormal, both on and off medication, that is an indication of a mood disorder, These children also performed poorly on measures of processing speed, and verbal learning and interference tasks. Measures of affect and personality were important diagnostically. A combination of amantadine and either clonidine HCL ER or propranolol, as prescribed by a medical psychologist, were found to be effective in controlling the symptoms of this comorbid diagnosis.

Conclusions

An evaluation of children’s intellectual, attentional, behavioral, mood, and personality functioning is crucial for a differential diagnosis. In cases of comorbidity, ADHD and childhood bipolar disorder, the sooner the child is on appropriate medications, the better. When just the surface diagnosis of ADHD is medicated, the outcome is often problematic. There may be a poor response to treatment and a higher rate of suicide.
Proximal and distal influences on dietary change among a diverse group with prediabetes participating in a pragmatic, primary care nurse-led intervention: a qualitative study
Authors: Abel Sally L , Whitehead Lisa C , Tipene-Leach David C , Coppell Kirsten J
Published: May 2021

Objective:

To understand motivators, facilitators and challenges to dietary change amongst a diverse sample of New Zealanders with prediabetes participating in a primary care nurse-led individualised dietary intervention.

Design:

A qualitative study involving semi-structured, face-to-face interviews with a stratified sample of adults with prediabetes and BMI ≥ 25 kg/m2, purposefully selected from a larger 2-year primary care-based prediabetes dietary intervention study. Thematic analysis was undertaken. A socio-ecological model guided interpretation.

Setting:

Hawke’s Bay, Aotearoa/New Zealand, April 2018–March 2020.

Participants:

Fifty-eight people aged 28–69 years, with similar numbers of men and women, indigenous Māori and non-Māori, and those who had and had not regressed to normoglycaemia at 6 months.

Results:

Motivators for wanting to make dietary changes were determination not to progress to diabetes; wanting to be healthy and contribute to others and encouragement by others. Facilitators for adopting and maintaining changes were a strong desire to be healthy; personal determination and feeling supported. Challenges were compromised control over life and environmental factors; feeling unsupported by others; social occasions; financial constraints and living with other health conditions. Developing their own strategies to overcome challenges was empowering, enabling a sense of control. These factors were similar across demographic and glycaemic outcome groups.

Conclusions:

Influences on dietary change involved personal, interpersonal, organisational, environmental and policy factors. Although findings appeared similar across groups, dietary interventions need to address the specific ways motivators, facilitators and challenges manifest for individuals and social groups and be tailored accordingly within the context of the wider obesogenic and socio-economic environment.
Reassessing Eastern Mediterranean Tectonics and Earthquake Hazard From the 365 CE Earthquake
Authors: Ott Richard F. , Wegmann Karl W. , Gallen Sean F. , Pazzaglia Frank J. , Brandon Mark T. , Ueda Kosuke , Fassoulas Charalampos
Published: May 2021

The hallmark of great earthquakes in the Mediterranean is the 21 July 365 CE earthquake and tsunami that destroyed cities and killed thousands of people throughout the Eastern Mediterranean. This event is intriguing because most Mediterranean subduction forearcs exhibit pervasive crustal extension and minimal definitive evidence exists for great subduction megathrust earthquakes, consistent with weak seismic coupling. This conundrum has led many to favor rupture of a previously unrecognized upper plate splay fault south of Crete in an M
w 8.3–8.5 earthquake, uplifting a Cretan Holocene paleoshoreline by up to 9 m. Similar source mechanisms have been adapted for the region, which are commonly used for seismic and tsunami hazard estimation. We present an alternative model for Holocene paleoshoreline uplift and the 365 CE tsunami that centers on known active normal fault systems offshore of western and southwestern Crete. We use new and published radiocarbon dates and historical records to show that uplift of the Cretan paleoshoreline likely occurred during two or more earthquakes within 2–3 centuries. Visco‐elastic dislocation modeling demonstrates that the rupture of these normal faults fits observed data as well as reverse fault models but requires reduced slip and lower cumulative earthquake energy release (∼M
w 7.9). Tsunami modeling shows that normal‐fault ruptures produce strong tsunamis that better match historical reports than a hypothetical reverse fault. Our findings collectively favor the interpretation that damaging earthquakes and tsunamis in the Eastern Mediterranean can originate on normal faults, highlighting the potential hazard from tsunamigenic upper plate normal fault earthquakes.
An Unexpected Whistler Wave Generation Around Dipolarization Front
Authors: Chen G. , Fu H. S. , Zhang Y. , Su Z. P. , Liu N. G. , Chen L. , Ge Y. S. , Du A. M. , Liu C. M. , Wang Z. , Chen F.
Published: May 2021

Dipolarization front (DF)—a sharp boundary separating hot tenuous plasmas from cold dense plasmas—is followed by a strong Bz region, which is termed flux pileup region (FPR) or dipolarizing flux bundle (DFB). Using 9‐year (2001–2009) Cluster data, we show that the FPR hosts whistler waves because of the pancake distribution of electrons, whereas the DF boundary hosts lower hybrid drift waves due to the strong density and magnetic gradients statistically. Different from statistical results, we report an unexpected case: whistler waves are generated at the DF boundary rather than inside the FPR. Using Cluster data, we observed strong whistler waves at DF boundaries but no whistlers inside FPRs, although flux tubes inside the FPRs are significantly compressed and suprathermal electrons there are perpendicularly anisotropic. We calculate wave growth rates and successfully explain the generation/damping of these whistlers. We find that 1–4 keV electrons are responsible for generation/damping of these whistlers.
Simulating Melting in 2D Seismic Fault Gouge
Authors: Mollon Guilhem , Aubry Jérôme , Schubnel Alexandre
Published: May 2021

During an earthquake, fault slip weakening is often explained by frictional heating phenomena, generally promoting melt production on the fault surface. Here, we investigate the influence of melt production at the scale of the grains composing a fault gouge. We use a modern version of Discrete Element Modeling able to deal with realistic grain shapes in 2D, and couple it with a Multibody Meshfree Approach able to provide a satisfactory proxy for the mechanical behavior of molten grains. Frictional sliding of solid grains and viscous shearing of molten grains are monitored during simulations. Our results confirm the natural tendency of granular gouge to localize deformation in a thin layer, and thus to trigger local melt production. We also show that the appearance of melt is likely to enhance this localization, and might create a positive feedback to its own production. We propose guidelines for the future writing of a friction model including melting, inspired by these simulation results.
Laboratory Experiments on Tsunamigenic Discrete Subaqueous Volcanic Eruptions. Part 2: Properties of Generated Waves
Authors: Shen Yaxiong , Whittaker Colin N. , Lane Emily M. , White James D. L. , Power William , Nomikou Paraskevi
Published: May 2021

Submarine volcanic eruptions have the potential to generate tsunamis, which can cause destruction well beyond the range of the eruption itself. Here, we present a series of underwater eruption experiments in which a non‐condensing gas was injected into a water tank with a range of water depths and applied pressures. This study proposes an effective scaled water depth and categorizes underwater eruptions into three types: deep‐water eruptions, intermediate‐water eruptions, and shallow‐water eruptions. In deep‐water eruptions, most of the energy is dissipated within the water column before the plume reaches the surface, and negligible waves are generated. In intermediate‐water eruptions, reductions in water depth reduce the loss of energy to the water column, leaving more energy available for wave generation. This causes an increase in wave heights as water shallows, up to a point. In sufficiently shallow‐water cases, the water depth is so small that almost all of the energy from the eruptive jet or plume passes through the water and is dissipated into the air, so there is only small wave‐making potential, even with relatively intense source strength. Therefore, there exists a critical water depth at which an eruption with a given source intensity will generate the largest waves. That depth lies at the boundary between the intermediate‐ and shallow‐depth regimes, where the energy available for wave generation is at a maximum. This research reveals fundamental wave generation mechanisms related to underwater gas eruptions, thereby extending our understanding of submarine volcanic tsunami generation and providing a foundation for future hazard assessment.
Assessment of internal fit and micro leakage of conventionally fabricated ceramometallic restoration versus CAD wax and press veneering (in-vitro study)
Authors: Mansour Fatema Khaled , Ibrahim Rabab Mohammed , Mansour Hoda , Hamdy Ahmed Mohamed
Published: May 2021

Statement of problem

Accuracy of internal fit and microleakage for CAD-CAM systems used in metal coping fabrication and veneered with layering or pressing porcelain in ceramometallic restoration is unclear.

Material and methods

A master metal die was milled to resemble the right mandibular first molar preparation for coverage with ceramometallic restoration. Master die was duplicated to twenty-four resin specimen dies.They were divided into two groups according to metal coping construction technique using either conventional (C) or CAD (D) wax. Each group was subdivided into two subgroups (n = 6) according to the technique of porcelain veneering (layered or pressed) to fabricate ceramometallic restorations, where subgroup (CL, DL) were conventionally layered by porcelain and (CP, DP) were press veneered. A standardized thickness of metal and porcelain was performed in all specimens as per manufacturer’s instructions for techniques ceramometallic restoration construction.

Evaluation of internal fit was done with silicone replica technique using stereomicroscope at ×24 magnification where the thickness of silicon layer was measured at 20 reference points on each specimen. Then specimens were subjected to thermocycling. Sectioned specimens were assessed for microleakage using a stereomicroscope at ×12 magnification along die-cement interface with a five scale score.

Results

Mean internal gap values of veneering showed a statistically nonsignificant difference between specimens made with layering(L) and pressing(P). Different techniques of wax construction showed a non-significant difference in internal gap values between specimens made with conventional(C) and CAD(D) waxing. However, a significant difference was found in the internal gap at different sites. The highest internal gap was found at the occlusal surface, while the lowest gap was found at the finish line. The highest mean microleakage score was found with CAD wax and press veneering, while the lowest mean microleakage score was found with conventional wax and press veneering.

Conclusion

Both construction techniques of ceramometallic restoration were considered reliable in restoration production within a clinically acceptable range regarding internal fit and microleakage. There is a strong positive correlation between internal fit and microleakage of ceramometallic restoration constructed.
An infection-induced RhoB-Beclin 1-Hsp90 complex enhances clearance of uropathogenic Escherichia coli
Authors: Miao Chunhui , Yu Mingyu , Pei Geng , Ma Zhenyi , Zhang Lisong , Yang Jianming , Lv Junqiang , Zhang Zhi-Song , Keller Evan T. , Yao Zhi , Wang Quan
Published: May 2021

Host cells use several anti-bacterial pathways to defend against pathogens. Here, using a uropathogenic Escherichia coli (UPEC) infection model, we demonstrate that bacterial infection upregulates RhoB, which subsequently promotes intracellular bacteria clearance by inducing LC3 lipidation and autophagosome formation. RhoB binds with Beclin 1 through its residues at 118 to 140 and the Beclin 1 CCD domain, with RhoB Arg133 being the key binding residue. Binding of RhoB to Beclin 1 enhances the Hsp90-Beclin 1 interaction, preventing Beclin 1 degradation. RhoB also directly interacts with Hsp90, maintaining RhoB levels. UPEC infections increase RhoB, Beclin 1 and LC3 levels in bladder epithelium in vivo, whereas Beclin 1 and LC3 levels as well as UPEC clearance are substantially reduced in RhoB+/− and RhoB−/− mice upon infection. We conclude that when stimulated by UPEC infections, host cells promote UPEC clearance through the RhoB-Beclin 1-HSP90 complex, indicating RhoB may be a useful target when developing UPEC treatment strategies.
High-frequency head impact causes chronic synaptic adaptation and long-term cognitive impairment in mice
Authors: Sloley Stephanie S. , Main Bevan S. , Winston Charisse N. , Harvey Alex C. , Kaganovich Alice , Korthas Holly T. , Caccavano Adam P. , Zapple David N. , Wu Jian-young , Partridge John G. , Cookson Mark R. , Vicini Stefano , Burns Mark P.
Published: May 2021

Repeated head impact exposure can cause memory and behavioral impairments. Here, we report that exposure to non-damaging, but high frequency, head impacts can alter brain function in mice through synaptic adaptation. High frequency head impact mice develop chronic cognitive impairments in the absence of traditional brain trauma pathology, and transcriptomic profiling of mouse and human chronic traumatic encephalopathy brain reveal that synapses are strongly affected by head impact. Electrophysiological analysis shows that high frequency head impacts cause chronic modification of the AMPA/NMDA ratio in neurons that underlie the changes to cognition. To demonstrate that synaptic adaptation is caused by head impact-induced glutamate release, we pretreated mice with memantine prior to head impact. Memantine prevents the development of the key transcriptomic and electrophysiological signatures of high frequency head impact, and averts cognitive dysfunction. These data reveal synapses as a target of high frequency head impact in human and mouse brain, and that this physiological adaptation in response to head impact is sufficient to induce chronic cognitive impairment in mice.
RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex
Authors: Catlett Timothy S. , Onesto Massimo M. , McCann Alec J. , Rempel Sarah K. , Glass Jennifer , Franz David N. , Gómez Timothy M.
Published: May 2021

Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections formed during development which may contribute to symptoms of TSC, such as intellectual disabilities, autism, and epilepsy. Yet models examining the molecular basis for axonal guidance defects in developing human neurons have not been developed. Here, we generate human induced pluripotent stem cell (hiPSC) lines from a patient with TSC and genetically engineer counterparts and isogenic controls. By differentiating hiPSCs, we show that control neurons respond to canonical guidance cues as predicted. Conversely, neurons with heterozygous loss of TSC2 exhibit reduced responses to several repulsive cues and defective axon guidance. While TSC2 is a known key negative regulator of MTOR-dependent protein synthesis, we find that TSC2 signaled through MTOR-independent RHOA in growth cones. Our results suggest that neural network connectivity defects in patients with TSC may result from defects in RHOA-mediated regulation of cytoskeletal dynamics during neuronal development.
FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes are involved in angiogenesis and neoangiogenesis
Authors: Wang Cheng , Dai Xiaoyan , Wu Shengnan , Xu Wenjing , Song Ping , Huang Kai , Zou Ming-Hui
Published: May 2021

FUN14 domain-containing protein 1 (FUNDC1) is an integral mitochondrial outer-membrane protein, and mediates the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs). This study aims to determine the contributions of FUNDC1-mediated MAMs to angiogenesis in vitro and in vivo. In cultured endothelial cells, VEGF significantly increases the formation of MAMs and MAM-related proteins, including FUNDC1. Endothelial cell-specific deletion of FUNDC1, which disrupts MAM formation in endothelial cells, lowers VEGFR2 expression and reduces tube formation, spheroid-sprouting, and functional blood vessel formation in vitro and in vivo. Conversely, increased MAM formation using MAM linkers mimics the effects of VEGF and promotes endothelial angiogenesis. Mechanistically, increased MAMs formation led to increased levels of Ca2+ in cytosol, promoted the phosphorylation of serum response factor (SRF) and enhanced the binding of SRF to VEGFR2 promoter, resulting in increased VEGFR2 production, with consequent angiogenesis. Moreover, blocking FUNDC1-related MAM formation with a cell-penetrating inhibitory peptide significantly suppresses the expressions of downstream angiogenic genes and inhibits tumor angiogenesis. We conclude that decreased MAMs formation by silencing FUNDC1 can inhibit angiogenesis by decreasing VEGFR2 expression, and targeting FUNDC1-dependent MAMs might be a promising approach for treating human disorders characterized by defective angiogenesis.
Preserved structural connectivity mediates the clinical effect of thrombolysis in patients with anterior-circulation stroke
Authors: Schlemm Eckhard , Ingwersen Thies , Königsberg Alina , Boutitie Florent , Ebinger Martin , Endres Matthias , Fiebach Jochen B. , Fiehler Jens , Galinovic Ivana , Lemmens Robin , Muir Keith W. , Nighoghossian Norbert , Pedraza Salvador , Puig Josep , Simonsen Claus Z. , Thijs Vincent , Wouters Anke , Gerloff Christian , Thomalla Götz , Cheng Bastian
Published: May 2021

Thrombolysis with recombinant tissue plasminogen activator in acute ischemic stroke aims to restore compromised blood flow and prevent further neuronal damage. Despite the proven clinical efficacy of this treatment, little is known about the short-term effects of systemic thrombolysis on structural brain connectivity. In this secondary analysis of the WAKE-UP trial, we used MRI-derived measures of infarct size and estimated structural network disruption to establish that thrombolysis is associated not only with less infarct growth, but also with reduced loss of large-scale connectivity between grey-matter areas after stroke. In a causal mediation analysis, infarct growth mediated a non-significant 8.3% (CI95% [−8.0, 32.6]%) of the clinical effect of thrombolysis on functional outcome. The proportion mediated jointly through infarct growth and change of structural connectivity, especially in the border zone around the infarct core, however, was as high as 33.4% (CI95% [8.8, 77.4]%). Preservation of structural connectivity is thus an important determinant of treatment success and favourable functional outcome in addition to lesion volume. It might, in the future, serve as an imaging endpoint in clinical trials or as a target for therapeutic interventions.
Decoupling epithelial-mesenchymal transitions from stromal profiles by integrative expression analysis
Authors: Tyler Michael , Tirosh Itay
Published: May 2021

Epithelial-to-mesenchymal transition (EMT) is the most commonly cited mechanism for cancer metastasis, but it is difficult to distinguish from profiles of normal stromal cells in the tumour microenvironment. In this study we use published single cell RNA-seq data to directly compare mesenchymal signatures from cancer and stromal cells. Informed by these comparisons, we developed a computational framework to decouple these two sources of mesenchymal expression profiles using bulk RNA-seq datasets. This deconvolution offers the opportunity to characterise EMT across hundreds of tumours and examine its association with metastasis and other clinical features. With this approach, we find three distinct patterns of EMT, associated with squamous, gynaecological and gastrointestinal cancer types. Surprisingly, in most cancer types, EMT patterns are not associated with increased chance of metastasis, suggesting that other steps in the metastatic cascade may represent the main bottleneck. This work provides a comprehensive evaluation of EMT profiles and their functional significance across hundreds of tumours while circumventing the confounding effect of stromal cells.
Identification and characterization of a SARS-CoV-2 specific CD8+ T cell response with immunodominant features
Authors: Gangaev Anastasia , Ketelaars Steven L. C. , Isaeva Olga I. , Patiwael Sanne , Dopler Anna , Hoefakker Kelly , De Biasi Sara , Gibellini Lara , Mussini Cristina , Guaraldi Giovanni , Girardis Massimo , Ormeno Cami M. P. Talavera , Hekking Paul J. M. , Lardy Neubury M. , Toebes Mireille , Balderas Robert , Schumacher Ton N. , Ovaa Huib , Cossarizza Andrea , Kvistborg Pia
Published: May 2021

The COVID-19 pandemic caused by SARS-CoV-2 is a continuous challenge worldwide, and there is an urgent need to map the landscape of immunogenic and immunodominant epitopes recognized by CD8+ T cells. Here, we analyze samples from 31 patients with COVID-19 for CD8+ T cell recognition of 500 peptide-HLA class I complexes, restricted by 10 common HLA alleles. We identify 18 CD8+ T cell recognized SARS-CoV-2 epitopes, including an epitope with immunodominant features derived from ORF1ab and restricted by HLA-A*01:01. In-depth characterization of SARS-CoV-2-specific CD8+ T cell responses of patients with acute critical and severe disease reveals high expression of NKG2A, lack of cytokine production and a gene expression profile inhibiting T cell re-activation and migration while sustaining survival. SARS-CoV-2-specific CD8+ T cell responses are detectable up to 5 months after recovery from critical and severe disease, and these responses convert from dysfunctional effector to functional memory CD8+ T cells during convalescence.
LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells
Authors: Marqués-Torrejón María Ángeles , Williams Charles A. C. , Southgate Benjamin , Alfazema Neza , Clements Melanie P. , Garcia-Diaz Claudia , Blin Carla , Arranz-Emparan Nerea , Fraser Jane , Gammoh Noor , Parrinello Simona , Pollard Steven M.
Published: May 2021

Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.
Probing atomic-scale symmetry breaking by rotationally invariant machine learning of multidimensional electron scattering
Authors: Oxley Mark P. , Ziatdinov Maxim , Dyck Ondrej , Lupini Andrew R. , Vasudevan Rama , Kalinin Sergei V.
Published: May 2021

The 4D scanning transmission electron microscopy (STEM) method maps the structure and functionality of solids on the atomic scale, yielding information-rich data sets describing the interatomic electric and magnetic fields, structural and electronic order parameters, and other symmetry breaking distortions. A critical bottleneck is the dearth of analytical tools that can reduce complex 4D-STEM data to physically relevant descriptors. We propose an approach for the systematic exploration of 4D-STEM data using rotationally invariant variational autoencoders (rrVAE), which disentangle the general rotation of the object from other latent representations. The implementation of purely rotational rrVAE is discussed as are applications to simulated data for graphene and zincblende structures. The rrVAE analysis of experimental 4D-STEM data of defects in graphene is illustrated and compared to the classical center-of-mass analysis. This approach is universal for probing symmetry-breaking phenomena in complex systems and can be implemented for a broad range of diffraction methods.
Pesticides in a case study on no-tillage farming systems and surrounding forest patches in Brazil
Authors: da Silva Karlo Alves , Nicola Vitoria Beltrame , Dudas Rafaela Tavares , Demetrio Wilian Carlo , Maia Lilianne dos Santos , Cunha Luis , Bartz Marie Luise Carolina , Brown George Gardner , Pasini Amarildo , Kille Peter , Ferreira Nuno G. C. , de Oliveira Cíntia Mara Ribas
Published: May 2021

With the growing global concern on pesticide management, the relationship between its environmental recalcitrance, food security and human health has never been more relevant. Pesticides residues are known to cause significant environmental contamination. Here, we present a case study on long-term no-tillage farming systems in Brazil, where Glyphosate (GLY) has been applied for more than 35 years. GLY and its main breakdown product, aminomethylphosphonic acid (AMPA) were determined in topsoil (0–10 cm) samples from no-tillage fields and nearby subtropical secondary forests by high-performance liquid chromatography coupled with a fluorescence detector. In addition, the presence of carbamates, organochlorines, organophosphates and triazines were also screened for. GLY and AMPA were present in all soil samples, reaching values higher than those described for soils so far in the literature. A significant decrease for AMPA was observed only between the secondary forest and the farm's middle slope for site B. GLY and AMPA were observed respectively at peak concentrations of 66.38 and 26.03 mg/kg soil. GLY was strongly associated with forest soil properties, while AMPA associated more with no-tillage soil properties. Soil texture was a significant factor contributing to discrimination of the results as clay and sand contents affect GLY and AMPA retention in soils. This was the first study to report DDT and metabolites in consolidated no-tillage soils in Brazil (a pesticide fully banned since 2009). Based on human risk assessment conducted herein and the potential risk of GLY to local soil communities, this study offers a baseline for future studies on potential adverse effects on soil biota, and mechanistic studies.
COVID-Classifier: an automated machine learning model to assist in the diagnosis of COVID-19 infection in chest X-ray images
Authors: Zargari Khuzani Abolfazl , Heidari Morteza , Shariati S. Ali
Published: May 2021

Chest-X ray (CXR) radiography can be used as a first-line triage process for non-COVID-19 patients with pneumonia. However, the similarity between features of CXR images of COVID-19 and pneumonia caused by other infections makes the differential diagnosis by radiologists challenging. We hypothesized that machine learning-based classifiers can reliably distinguish the CXR images of COVID-19 patients from other forms of pneumonia. We used a dimensionality reduction method to generate a set of optimal features of CXR images to build an efficient machine learning classifier that can distinguish COVID-19 cases from non-COVID-19 cases with high accuracy and sensitivity. By using global features of the whole CXR images, we successfully implemented our classifier using a relatively small dataset of CXR images. We propose that our COVID-Classifier can be used in conjunction with other tests for optimal allocation of hospital resources by rapid triage of non-COVID-19 cases.