bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Serotonin Signaling in the Remodeling of Thioridazine‐Induced Craniofacial Deformities in Xenopus laevis Pre‐metamorphic Tadpoles
Authors: Familia Jerson Steve , Pinet Kaylinnette , McLaughlin Kelly A 
Published: June 2021

Craniofacial abnormalities have recently been given special attention because of a rise in the number of microcephaly cases associated with the spread of the Zika virus. Microcephaly, however, is just one of various common craniofacial deformities that can occur in vertebrates during development. Since craniofacial development is well‐conserved across vertebrates, numerous model organisms can be utilized to study craniofacial development. To that end, our lab takes advantage of the tractable amphibian model system, Xenopus laevis. Our recent studies revealed pre‐metamorphic Xenopus tadpoles can self‐correct craniofacial defects induced by exposure to thioridazine HCl, a D2 dopamine receptor antagonist. The underlying molecular mechanism mediating this correction is unknown, and is thus the focus of our current work. Previously the Levin lab discovered that several developmental events, including the regulation of organ placement and cell movements during gastrulation, are mediated by neurotransmitters during development. Since the self‐correction of craniofacial defects includes both cell movement and tissue positioning, we are currently investigating whether the remodeling response is initiated and/or mediated by neurotransmitter‐dependent cellular pathways. Our current study utilized fluoxetine, a selective serotonin reuptake inhibitor, to block a candidate pathway throughout pre‐metamorphic stages in tadpoles. These experiments will help elucidate which signaling mechanism directs the correction of malformed craniofacial structures in tadpoles during pre‐metamorphic stages.Support or Funding InformationThe Paul G. Allen Frontiers Group, National Science Foundation, and American Society of Biochemistry and Molecular Biology
Cortactin controls morphological and electrophysiological properties during activity‐dependent synaptic plasticity at the Drosophila neuromuscular junction
Authors: Perez Marizabeth , Dominicci Carihann , Maldonado Carolina , Marie Bruno 
Published: June 2021

In the nervous system, changes in activity that lead to modifications in synaptic structure and function are referred to as synaptic plasticity and are thought to be the basis of learning and memory. Such modifications can be studied at the Drosophila neuromuscular junction (NMJ); a model used to decipher the molecular mechanisms underlying activity‐dependent synaptic plasticity. Recent work has shown that, after repeated stimulations, de novo synaptic structures form at the NMJ and an increase in the frequency of spontaneous release occurs. While the secreted molecule Wingless (Wg)/Wnt was shown to underlie the structural and electrophysiological changes during activity‐dependent plasticity at the NMJ, a challenge remains to understand how this signal mediates the cellular changes that lead to plasticity.In this work, we investigate the role of the actin regulator Cortactin (Cttn) in activity‐dependent synaptic plasticity. With confocal microscopy, we show that Cttn is present at the NMJ, pre and postsynaptically. Also, we show that the synaptic structures that are formed during synaptic plasticity are dependent on presynaptic Cttn expression. In addition, our electrophysiological recordings show that Cttn‐deficient NMJs have a significant reduction in the frequency of spontaneous release. Such reduction can only be rescued by the presynaptic expression of Cttn, which suggests that the neuronal expression of Cttn is necessary for maintaining the rate of spontaneous vesicle fusion at the NMJ. Moreover, presynaptic Cttn is required for the potentiation of spontaneous release that occurs after activity‐dependent synaptic plasticity. Indeed, there is no potentiation of spontaneous release in Cttn mutants and in NMJs depleted of presynaptic Cttn. However, this potentiation is achieved if Cttn is expressed presynaptically in Cttn mutants, or if Cttn is removed only postsynaptically. We argue that presynaptic Cttn is responsible for the structural and/or functional changes affecting active zones during activity‐dependent synaptic plasticity. Overall, our findings suggest that Cttn is an important regulator of structural and physiological synaptic properties in response to activity.Support or Funding InformationThis work was supported by the NIGMS 1P20GM103642 grant to BM and MP; NINDS SC2NS077924 and NSF HRD‐1137725 to BM. Work supported by NIMHD 8G12‐MD007600 RCMI grant. CD and CM received support from NIGMS RISE grant R25GM061838. MP received support from NIGMS RISE grant R25GM06115115.
Insulin signaling during immune challenges: Friend or foe?
Authors: Cambron Lizzette D , Greenlee Kendra J 
Published: June 2021

One commonality between humans, dogs, and even insects, is that when faced with an illness all three will cease eating. This response across varying taxa is called sickness‐induced anorexia (SIA). SIA is hypothesized to be an energy reallocation toward immune function. However, the mechanism mediating the response, and the signal telling the body to stop eating is still unknown. Along with this response, insulin signaling is conserved between vertebrate and invertebrates. Because insulin signaling plays a role in regulating many physiology processes such as metabolism, development, and reproduction, this experiment aimed to investigate the role of insulin signaling in immune responses, specifically that of SIA, using the tobacco hornworm, Manduca sexta. In the beginning of the last larval stage, caterpillars were injected with either vehicle (PBS) or Escherichia coli to initiate an immune challenge. Then, insulin signaling was either inhibited by wortmannin, a covalent inhibitor of phosphoinositide 3‐kinases, or increased with exogenous bovine insulin. Growth, feeding, development, and fecal pellet measurements were taken daily until prepupation, indicated by the appearance of the dorsal vessel. Caterpillars that were injected with E. coli exhibited SIA, as previously shown. We predicted that caterpillars lacking insulin signaling would still exhibit SIA in response to E. coli, however, in this and previous studies, wortmannin showed contradictory results, suggesting that wortmannin may be activating other pathways or incompletely inhibiting insulin signaling. Interestingly, SIA was completely blocked in caterpillars that received extra insulin, supporting the hypothesis that insulin signaling mediates feeding. Further studies are needed to discover the mechanism tying insulin signaling to immunity. Elucidating the mechanism behind SIA will lead to a better understanding of how insulin signaling and the immune system intertwine, improving how we treat diabetics which are more susceptible to contracting infections.Support or Funding InformationThis research was funded in part, by grants from the National Science Foundation (NSF IOS‐0953297 to KJG) and the NSF Graduate Research Fellowships Program.
Reversibly Constraining The Human U1 snRNP And The Spliceosome To A Pre‐mRNA Via An Engineered Site‐specific Disulfide Bond
Authors: McCarthy Patrick , Garside Erin , MacMillan Andrew , Krummel Daniel Pomeranz 
Published: June 2021

Pre‐messenger RNA splicing of protein‐coding RNA transcripts governs metazoan development. Pre‐mRNA splicing is catalyzed by the dynamic mega‐dalton spliceosome, formed by an ordered assembly of five U snRNPs (U1, U2, U4, U5 and U6 snRNPs) and non‐U snRNP proteins onto a pre‐mRNA substrate. The U snRNPs bind to and separate from the pre‐messenger RNA at key stages in the pre‐catalytic assembly of the spliceosome. The spliceosome assembly cycle is initiated with the recognition of the pre‐mRNA substrate 5′ splice site by the U1 snRNP which remains associated at this site during the recruitment of other U snRNPs. The U1 snRNP as well as the U4 snRNP and several other factors are subsequently displaced from their pre‐mRNA binding sites during the formation of a catalytic spliceosome. The mechanism, order, and importance of these displacement events is poorly understood, in part due to the challenges presented by the spliceosome's large size, dynamics, and crude source of material. In order to investigate the pre‐catalytic to catalytic transition undergone by the spliceosome, we have engineered a disulfide bond between a rationally designed U1‐C cysteine residue and a site‐specific thiol‐modified backbone of a pre‐mRNA substrate, allowing us to establish a reversible disulfide crosslink between a pre‐mRNA and the U1‐C protein alone as well as in the context of the U1 snRNP. This strategy will allow for a mechanistic elucidation of the critical pre‐catalytic to catalytic transition in spliceosome assembly, including examination of a possible sequential displacement of pre‐catalytic complexes in the activation of the spliceosome.Support or Funding InformationNational Science Foundation Award No. 1157892
Comparison of equipotent doses of intrathecal hyperbaric prilocaine 2% and hyperbaric bupivacaine 0.5% for elective caesarean section
Authors: Goffard Philippe , Leloup Renaud , Vercruysse Yoann , Fils Jean-François , Gautier Philippe Emmanuel , Kapessidou Yota 
Published: June 2021

BACKGROUND
Elective caesarean section is performed mainly under spinal anaesthesia using hyperbaric bupivacaine combined with opioids. Despite rapid onset, good quality anaesthesia, bupivacaine provides a long duration of motor block and is related to maternal hypotension. Current policies appeal for implementation of enhanced recovery procedures after caesarean section. Hyperbaric prilocaine is an intermediate-acting local anaesthetic known for its efficacy in ambulatory surgery. Evidence on the clinical relevance of intrathecal prilocaine use for caesarean section is currently lacking.

OBJECTIVES
We aimed to investigate whether hyperbaric prilocaine would offer a shorter motor block and recovery than bupivacaine, when comparing equipotent doses. We also assessed the characteristics of sensory block, maternal haemodynamics and side effects for both mother and newborn.

DESIGN
Prospective, randomised, double-blind, controlled, two-centre, clinical trial.

SETTING
One university teaching hospital and one general teaching hospital in Brussels, Belgium.

PATIENTS
American Society of Anesthesiologists’ physical status 2 parturients (n = 40) undergoing caesarean section under spinal anaesthesia.

INTERVENTIONS
Patients were randomly assigned to receive spinal anaesthesia using hyperbaric prilocaine 50 mg or hyperbaric bupivacaine 10 mg, both given with sufentanil 2.5 μg and morphine 100 μg. An epidural catheter was introduced as a backup in case of failure.

MAIN OUTCOMES
The primary outcome was the motor block regression (modified Bromage scale 1 to 6). Secondary outcomes included sensory block characteristics, first unassisted ambulation, maternal side effects, newborns’ parameters and overall satisfaction.

RESULTS
Median [IQR] motor block was significantly shorter in the hyperbaric prilocaine group (110 [104 to 150] min versus 175 [135 to 189] min, P = 0.001). First unassisted ambulation was achieved earlier after prilocaine (204.5 [177 to 246.5] min versus 314 [209.25 to 400] min, P = 0.007), and the incidence of maternal hypotension was significantly higher with bupivacaine (P = 0.033). No supplementary epidural analgesia was needed.

CONCLUSION
Prilocaine provides shorter motor block, faster recovery and better haemodynamic stability than bupivacaine while offering equivalent surgical anaesthesia.

TRIAL REGISTRATION
Clinicaltrials.gov: NCT02973048, EudraCT: 2016-003010-26.
Isolated diastolic vs. systolic hypertension phenotypes and outcomes: prospective cohort of newly diagnosed individuals with hypertension
Authors: Thomopoulos Costas , Andrikou Ioannis , Konstantinidis Dimitris , Iliakis Panagiotis , Kalos Theodoros , Polyzos Dimitrios , Drogkaris Sotirios , Siafi Eirini , Tousoulis Dimitrios , Stergiou George S. , Tsioufis Costas 
Published: June 2021

Aims:
To evaluate whether different hypertension phenotypes, namely, isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH) and systolic/diastolic hypertension (SDH) have a differential outcome effect by clinic and ambulatory blood pressure (BP) measurements.

Methods:
We prospectively evaluated in 569 never-treated patients with sustained hypertension (age 52.6 ± 11.6 years; men 55%; clinic BP 150 ± 15/95.5 ± 10 mmHg, systolic/diastolic; 24-h ambulatory BP 128.9 ± 12.6/80.6 ± 9.7) the incidence of major cardiovascular (CV) events within 5 years, after adjustment for confounders, including the rate of BP control and the weighted follow-up BP.

Results:
All participants received antihypertensive drug treatment (mean number of drugs 1.9 ± 1.1; follow-up visits 4.6/patient). Average clinic BP achieved during follow-up was 136 ± 12.6/83.9 ± 9.4 mmHg, with 39% of participants having clinic BP less than 140/90 mmHg in at least 75% of their visits, and 24% in 25–75% of visits. Prevalence of hypertension phenotypes defined using BP differed from that using ambulatory BP, whereas integration of both BP measurements reclassified the initial phenotype to another in 18% of participants. Although, no differential outcome effect was observed between clinic IDH and SDH assessed using clinic or ambulatory BP measurements, clinic BP-based ISH was associated with a higher outcome incidence than the IDH and SDH phenotypes (hazard ratio 4.8, 95% confidence interval 1.4–17.0, P = 0.015). ISH diagnosed by integration of clinic and ambulatory BP, also increased the outcome (hazard ratio 4.0, 95% confidence interval 1.0–15.6, P = 0.046).

Conclusion:
In hypertensive patients at low/moderate CV risk, IDH and SDH phenotypes defined by clinic BP measurements, equally determined CV events but to a lower extent compared with ISH.
Current state of antigen-specific immunotherapy for type 1 diabetes
Authors: Kreiner Frederik Flindt , von Scholten Bernt Johan , Coppieters Ken , von Herrath Matthias 
Published: June 2021

Purpose of review
Update on antigen-specific immunotherapy (ASIT) in type 1 diabetes (T1D) with focus on deoxyribonucleic acid (DNA)-induced immunization and the current obstacles to further research and clinical realization.

Recent findings
In T1D, immune system imbalances together with malfunctioning islet-specific processes cause autoreactive immune cells to destroy beta cells in the islets. ASIT may restore self-tolerance; however, the approach has yet to fully meet its promise and may require co-administration of antigen (preproinsulin) and suitable immune response modifiers.

Summary
A self-tolerant immune system may be regained using ASIT where T effector cells are repressed and/or T regulatory cells are induced. Administration of exogenous antigens has been safe in T1D. Conversely, adequate and lasting beta cell preservation has yet to be tested in sufficiently large clinical trials in suitable patients and may require targeting of multiple parts of the immunopathophysiology using combination therapies. DNA-based induction of native antigen expression to ensure important posttranscriptional modifications and presentation to the immune system together with tolerance-enhancing immune response modifiers (i.e., cytokines) may be more efficacious than exogenous antigens given alone. Progress is limited mainly by the scarcity of validated biomarkers to track the effects of ASIT in T1D.
Acromegaly: achieving timely diagnosis and improving outcomes by personalized care
Authors: Ioachimescu Adriana G. 
Published: June 2021

Purpose of review
Discuss recent literature regarding clinical manifestations and comorbidities in acromegaly, with focus on early diagnosis and customized care.

Recent findings
The mean interval between onset of clinical manifestations and diagnosis is currently 3–5 years. Women, especially younger than 50 years of age, experience longer delays, have lower insulin-like growth factor 1 (IGF-1) levels and larger tumors than men. Development of comorbidities usually precedes the diagnosis and is influenced by age, sex, and biochemical disease activity. Comorbidities other than irreversible osteoarticular structural changes usually improve after acromegaly treatment. In patients with diabetes, the course of hyperglycemia not only depends on biochemical control but also on specific acromegaly therapies. Quality of life is influenced by sex, as well as by acromegaly symptoms, biochemical activity, and treatment. Quality of life remains lower than general population despite biochemical remission.

Summary
Early diagnosis can be achieved by suspecting acromegaly based on suggestive clinical scenarios rather than obvious changes in appearance. Personalized care entails a proactive multidisciplinary approach to identify and treat comorbidities while carefully monitoring the effects of acromegaly treatment.
Digital dermatoses: skin disorders engendered by social media in tweens and teens
Authors: Young Trevor K. , Oza Vikash S. 
Published: June 2021

Purpose of review
Photograph-based social media use among children and adolescents has skyrocketed over the past decade, raising concerns about the implications for self-confidence and behavior in this population. Social media ‘challenges’ encourage participants to complete potentially dangerous tasks while sharing their completion of the tasks on social media. Many of these challenges affect the skin and lead to recognizable findings on physical examination. This review discusses the history of prominent social media challenges and their effects on the skin. Attention is also given to the effects of social media trends on self-confidence and body image in children and adolescents.

Recent findings
Over the past several years, there have been several notable social media trends that can harm the skin. These include the Kylie Jenner lip challenge, salt and ice challenge, deodorant challenge, eraser challenge, fire challenge, and hot water challenge. Participation in these challenges can cause morbidity in children and adolescent that should be recognized by clinicians.

Summary
Social media has become an important platform for communication and self-expression among children and adolescents. Pediatricians should remain aware of social trends in this age group and look out for cutaneous findings that may signal dangerous behavior on social media.
Incident Management in Health Care
Authors: Espin Sherry , D'Arpino Maryanne , Indar Alyssa , Gross Marketa 
Published: June 2021

Background:
Nearly 10% of patients experience a harmful patient safety incident in the hospital setting. Current evidence focuses on incident reporting, whereas little is known about how incidents are managed within organizations.

Purpose:
The aim of this study was to explore processes, tools, and resources for incident management in Canadian health care organizations.

Methods:
Qualitative focus groups were conducted with key stakeholders, representing clinicians, managers, executives, governors, patients, and families (n = 45).

Results:
Qualitative data were thematically analyzed and presented as 3 themes: (1) variations in incident reporting and management; (2) simplification of the incident management process; and (3) need for leadership to support just culture and redefine harm.

Conclusion:
The study findings support and inform efforts to create a patient safety culture in Canadian and international health care organizations. There is a need to develop a standardized, accessible incident reporting and management system for use across health care sectors to promote continuous learning and improvement about patient safety.
Survival following screening and preemptive antifungal therapy for subclinical cryptococcal disease in advanced HIV infection
Authors: Makadzange Tariro Azure , Hlupeni Admire , Machekano Rhoderick , Boyd Kathryn , Mtisi Takudzwa , Nyamayaro Primrose , Ross Christine , Vallabhaneni Snighdha , Balachandra Shirish , Chonzi Prosper , Ndhlovu Chiratidzo Ellen 
Published: June 2021

Objectives:
Our study's primary objective was to compare 1-year survival rates between serum cryptococcal antigen (sCrAg)-positive and sCrAg-negative HIV-positive individuals with CD4+ cell counts less than 100 cells/μl without symptoms of meningitis in Zimbabwe.

Design:
This was a prospective cohort study.

Methods:
Participants were enrolled as either sCrAg-positive or sCrAg-negative and followed up for 52 weeks or less, with death as the outcome. Lumbar punctures were recommended to all sCrAg-positives and inpatient management with intravenous amphotericin B and high-dose fluconazole was recommended to those with disseminated Cryptococcus. Antiretroviral therapy was initiated immediately in sCrAg-negatives and after at least 4 weeks following initiation of antifungals in sCrAg-positives. Multivariable logistic regression models were used to determine risk factors for mortality.

Results:
We enrolled 1320 participants and 130 (9.8%) were sCrAg positive, with a median sCrAg titre of 1 : 20. Sixty-six (50.8%) sCrAg-positives had lumbar punctures and 16.7% (11/66) had central nervous system (CNS) dissemination. Cryptococcal blood cultures were performed in 129 sCrAg-positives, with 10 (7.8%) being positive. One-year (48–52 weeks) survival rates were 83.9 and 76.1% in sCrAg-negatives and sCrAg-positives, respectively, P = 0.011. Factors associated with increased mortality were a positive sCrAg, CD4+ cell count less than 50 cells/μl and having presumptive tuberculosis (TB) symptoms.

Conclusion:
Our study reports a high prevalence of subclinical cryptococcal antigenemia and reiterates the importance of TB and a positive sCrAg as risk factors for mortality in advanced HIV disease (AHD). Therefore, TB and sCrAg screening remains a crucial component of AHD package, hence it should always be part of the comprehensive clinical evaluation in AHD patients.
High-risk human papilloma virus, precancerous lesions and cancer in anal condylomas
Authors: Albuquerque Andreia , Cappello Carmelina , Stirrup Oliver 
Published: June 2021

Introduction:
Anal condylomas are associated with human papillomavirus (HPV) infection and are a risk factor for anal squamous cell carcinoma (SCC).

Objective:
To conduct a meta-analysis evaluating the prevalence of anal high-risk HPV, high-grade squamous intraepithelial lesions (HSIL) and SCC in patients with condylomas. The standardized incidence ratio (SIR) and the incidence rate of anal SCC were also calculated.

Methods:
Three electronic databases were searched until April 2020. Meta-analyses were performed using random effects models.

Results:
Pooled prevalence estimate of high-risk HPV (HR-HPV) in anal condylomas was 40.2% (21.0–63.1) in immunocompromised and 16.4% (10.7–24.3) in nonimmunocompromised patients, with an odds ratio (OR) of 3.79 (1.51–9.52, P = 0.005) for immunocompromised patients. HR-HPV in condylomas with HSIL was 73.8% (39.1–92.5) and in non-HSIL cases was 17.7% (9.6–30.2), corresponding to an OR of 12.33 (2.97–51.21, P = 0.001) for those with HSIL. The prevalence of HSIL in condylomas was 24.0% (16.4–33.7) in immunocompromised and 11.8% (7.2–18.8) in nonimmunocompromised patients, with an OR of 2.51 (1.72–3.65, P < 0.001) for immunocompromised patients. The overall prevalence of anal SCC in anal condylomas was 0.3% (0.0–1.7). The SIR of anal SCC was 10.7 (8.5–13.5), 20.1 (14.4–28.2) in men and 7.7 (5.6–10.5) in women. The overall incidence rate of anal SCC was 6.5 per 100 000 person-years (3.6–11.7), 12.7 (9.1–17.8) in men and 4.7 (1.7–13) in women.

Conclusion:
Patients with a history of anal condylomas have a high risk of anal SCC, especially men. The prevalence of HR-HPV and HSIL in condylomas from immunocompromised patients is high. This information can change patient follow-up and treatment.