bluuebunny/crossref_metadata_2025 huggingface dataset:
Older Age at First Screening Colonoscopy is Associated With an Increased Risk of Colorectal Adenomas and Cancer
Authors: Obadina David , Haider Haider , Micic Dejan , Sakuraba Atsushi
Published: August 2022

Introduction:

The goal of colorectal cancer (CRC) screening is to detect precancerous polyps before cancer development or identification of cancer at an early stage. Guidelines have recommended screening colonoscopy to start at age 45. Our aim was to determine the impact of delays in performing the first screening colonoscopy on the risk of adenoma or CRC detection.

Methods:

We analyzed colonoscopy and histopathology data of average CRC risk patients who had their first screening colonoscopy between 2010 and 2017. Univariate and multivariable logistic regression was performed to determine the association between demographic variables and the risk of adenomas or CRC.

Results:

A total of 1155 average risk patients underwent their initial screening colonoscopy during the study period. Median age was 54 years (range of 45-87) and 58.2% were females. In multivariable analysis, older age at first screening colonoscopy was significantly associated with the detection of adenomatous polyps (odds ratio 1.05, 95% confidence interval 1.04-1.07, P<0.001) and CRC (odds ratio 1.11, 95% confidence interval 1.06-1.16, P<0.001). The association between age and risk of adenomatous polyps (F-test 35.43, P=0.0019) and CRC (F-test 36.94, P=0.0017) fit an exponential growth model. It was estimated that the detection rate doubled every 14.20 years and 4.75 years for adenomas and CRC, respectively.

Conclusion:

We found that older age at the initial performance of a screening colonoscopy was associated with increased detection of adenomatous polyps and CRC. This work highlights the need for guideline adherence for the prevention of CRC development.
Prophylactic Use of Antifibrinolytics During Pediatric Cardiac Surgery With Cardiopulmonary Bypass on Postoperative Bleeding and Transfusion: A Systematic Review and Meta-Analysis
Authors: Schertz Katherine , Karam Oliver , Demetres Michelle , Mayadunna Samantha , Faraoni David , Nellis Marianne E.
Published: August 2022

Objectives:

To determine the effect of intraoperative antifibrinolytics, including tranexamic acid (TXA), aminocaproic acid (EACA), or aprotinin, on bleeding in children undergoing cardiac surgery with cardiopulmonary bypass (CPB).

Data Sources:

Relevant articles were systematically searched from Ovid MEDLINE, Ovid EMBASE, CINAHL, Cochrane Library, and Web of Science to November 15, 2021.

Study Selection:

Abstracts were screened, and full texts were reviewed using predetermined inclusion and exclusion criteria using the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline.

Data Extraction:

A standardized data extraction tool was used.

Data Synthesis:

Sixty-eight studies including 28,735 patients were analyzed. TXA compared with placebo resulted in a mean decrease in chest tube output of 9.1 mL/kg (95% CI, 6.0–12.3 mL/kg), I
2 equals to 65.2%, p value of less than 0.001, platelet requirement of 2.9 mL/kg (95% CI, 0.1–5.8 mL/kg), I
2=72.5%, p value less than 0.001 and plasma requirement of 4.0 mL/kg (95% CI, 0.6–7.2 mL/kg), I
2 equals to 94.5%, p value less than0.001. Aprotinin compared with placebo resulted in a mean decrease in chest tube output of 4.3 mL/kg (2.4–6.2 mL/kg), I
2 equals to 66.3%, p value of less than 0.001, platelet transfusion of 4.6 mL/kg (95% CI, 0.6–8.6 mL/kg), I
2 equals to 93.6%, p value of less than 0.001, and plasma transfusion of 7.7 mL/kg (95% CI, 2.1–13.2 mL/kg), I
2 equals to 95.3%, p value of less than 0.001. EACA compared with placebo resulted in a mean decrease in chest tube output of 9.2 mL/kg (2.3–21.0 mL/kg), I
2 equals to 96.4%, p value of less than 0.001, RBC transfusion of 7.2 mL/kg (95% CI, 2.4–12.1 mL/kg), I
2 equals to 94.5%, p value equals to 0.002, and platelet transfusion of 10.7 mL/kg (95% CI, 2.9–18.5 mL/kg), I
2 equals to 0%, p value of less than 0.001. No statistical difference was observed in chest tube output when TXA was compared with aprotinin. Subgroup analysis of cyanotic patients showed a significant decrease in chest tube output, platelet requirement, and plasma requirement for patients receiving aprotinin. Overall, the quality of evidence was moderate.

Conclusions:

Antifibrinolytics are effective at decreasing blood loss and blood product requirement in children undergoing cardiac surgery with CPB although the quality of evidence is only moderate.
Prolonged Mechanical Ventilation in Pediatric Trauma Patients in a Combat Zone
Authors: Moulton Andrew W. , Schauer Steven G. , Borgman Matthew A.
Published: August 2022

OBJECTIVES:

It is well known that polytrauma can lead to acute lung injury. Respiratory failure has been previously observed in combat trauma, but not reported in children, who account for over 11% of bed days at deployed Military Treatment Facilities (MTFs) using significant resources. We seek to identify risk factors associated with prolonged mechanical ventilation (PMV) which is important in resource planning and allocation in austere environments.

DESIGN:

Retrospective review of prospectively collected data within the United States Department of Defense Trauma Registry.

SETTING:

Deployed U.S. MTFs in Iraq and Afghanistan from 2007 to 2016.

PATIENTS:

All pediatric subjects who required at least 1 day of mechanical ventilation, excluding patients who died on day 0.

INTERVENTIONS:

PMV was defined using the Youden index for mortality. A multivariable logistic regression model was then performed to identify factors associated with PMV.

MEASUREMENTS AND MAIN RESULTS:

The Youden index identified greater than or equal to 6 days as the cutoff for PMV. Of the 859 casualties included in the analysis, 154 (17.9%) had PMV. On univariable analysis, age, severe injury to the thorax and skin, 24-hour volume/kg administration of crystalloids, colloids, platelets, plasma, and packed RBCs was associated with PMV. In the multivariable model, odds ratios (95% CI) associated with PMV were crystalloids 1.04 (1.02–1.07), colloids 1.24 (1.04–1.49), platelets 1.03 (1.01–1.05), severe injury to the thorax 2.24 (1.41–3.48), and severe injury to the skin 4.48 (2.72–7.38). Model goodness-of-fit r
2 was 0.14.

CONCLUSIONS:

In this analysis of factors associated with PMV in pediatric trauma patients in a combat zone, in addition to severe injury to skin and thorax, we found that administration of crystalloids, colloids, and platelets was independently associated with greater odds of PMV. Our findings will help inform resource planning and suggest potential resuscitation strategies for future studies.
Using the Random Forest Algorithm to Detect the Activity of Graves Orbitopathy
Authors: Wang Minghui , Zhang Hanqiao , Dong Li , Li Yang , Hou Zhijia , Li Dongmei
Published: August 2022

Purpose:

The aim of this study is to establish a random forest model to detect active and quiescent phases of patients with Graves Orbitopathy (GO).

Methods:

A total of 243 patients (486 eyes) diagnosed with GO in Beijing TongRen hospital were included in the study. The Clinical Activity Score of GO was regarded as the golden standard, whereas sex, age, smoking status, radioactive I131 treatment history, thyroid nodules, thyromegaly, thyroid hormone, and Thyroid-stimulating hormone receptor antibodies were chosen as predictive characteristic variables in the model. The random forest model was established and compared with logistic regression analysis, Naive Bayes, and Support vector machine metrics.

Results:

Our model has a sensitivity of 0.81, a specificity of 0.90, a positive predictive value of 0.87, a negative predictive value of 0.86, an F1 score of 0.85, and an out-of-bag error of 0.15. The random forest algorithm showed a more precise performance compared with 3 other models based on the area under receiver operating characteristic curve (0.92 versus 0.77 versus 0.76 versus 0.75) and accuracy (0.86 versus 0.71 versus 0.69 versus 0.66).

Conclusions:

By integrating these high-risk factors, the random forest algorithm may be used as a complementary method to determine the activity of GO, with accurate and reliable performance.
Differences Between Impression Stone Pouring and Digital Pouring in Fully Guided Dental Implant Surgery: A Prospective Clinical Study
Authors: Anssari Hussein B. , AL-Anee Auday M.
Published: August 2022

Modern clinical protocols in implantology aim to reduce the duration and discomfort of the surgical phase while preserving excellent treatment results. The purpose of this study is to evaluate the clinical differences between impression stone pouring and impression digital pouring required for surgical guide fabrication in fully guided dental implant surgery. This study was conducted for partially edentulous patients with straightforward cases who did not require bone or soft tissue augmentation. Forty dental implants were installed in 14 patients (age range: 25–70 y) at the Dental Implant Unit, Oral and Maxillofacial Surgery Center, Gazi Alhariri Teaching Hospital, Medical City, Baghdad. The dental implants were guided into the most prosthetically suitable position using a surgical guide. Twenty of them were guided by conventional impression stone pouring to create the surgical guide, whereas the other 20 implants were installed using digital pouring for the dental impression to fabricate the surgical guide. The mean for impression stone pouring in regard to angular deviation of 4.33±3.435 degree, the depth difference was 1.29±0.90 mm and entry point deviation 0.99±0.84 mm. In contrast, the mean for digital pouring in regard to angular deviation of 3.34±2.10 degree, depth difference was 0.89±0.67 mm and entry point deviation was 0.83±0.61 mm. This study revealed that there was no significant difference between the 2 groups regarding all 3 variables at a P-value of 0.05. Neither biological nor mechanical complications occurred.
Adjuvant Therapy After Neoadjuvant Therapy for Esophageal Cancer
Authors: Raja Siva , Rice Thomas W. , Lu Min , Semple Marie E. , Blackstone Eugene H. , Murthy Sudish C. , Ahmad Usman , McNamara Michael , Toth Andrew J. , Ishwaran Hemant ,   for the Worldwide Esophageal Cancer Collaboration Investigators
Published: August 2022

Objective:

We hypothesized that, on average, patients do not benefit from additional adjuvant therapy after neoadjuvant therapy for locally advanced esophageal cancer, although subsets of patients might. Therefore, we sought to identify profiles of patients predicted to receive the most survival benefit or greatest detriment from adding adjuvant therapy.

Background:

Although neoadjuvant therapy has become the treatment of choice for locally advanced esophageal cancer, the value of adding adjuvant therapy is unknown.

Methods:

From 1970 to 2014, 22,123 patients were treated for esophageal cancer at 33 centers on 6 continents (Worldwide Esophageal Cancer Collaboration), of whom 7731 with adenocarcinoma or squamous cell carcinoma received neoadjuvant therapy; 1348 received additional adjuvant therapy. Random forests for survival and virtual-twin analyses were performed for all-cause mortality.

Results:

Patients received a small survival benefit from adjuvant therapy (3.2±10 months over the subsequent 10 years for adenocarcinoma, 1.8±11 for squamous cell carcinoma). Consistent benefit occurred in ypT3–4 patients without nodal involvement and those with ypN2–3 disease. The small subset of patients receiving most benefit had high nodal burden, ypT4, and positive margins. Patients with ypT1–2N0 cancers had either no benefit or a detriment in survival.

Conclusions:

Adjuvant therapy after neoadjuvant therapy has value primarily for patients with more advanced esophageal cancer. Because the benefit is often small, patients considering adjuvant therapy should be counseled on benefits versus morbidity. In addition, given that the overall benefit was meaningful in a small number of patients, emerging modalities such as immunotherapy may hold more promise in the adjuvant setting.
The physiology of failure: Identifying risk factors for mortality in emergency general surgery patients using a regional health system integrated electronic medical record
Authors: Baimas-George Maria , Ross Samuel W. , Hetherington Timothy , Kowalkowski Marc , Wang Huaping , Thompson Kyle , Cunningham Kyle , Matthews Brent D. , May Addison K. , Reinke Caroline E.
Published: August 2022

BACKGROUND

Emergency general surgery (EGS) patients have increased mortality risk compared with elective counterparts. Recent studies on risk factors have largely used national data sets limited to administrative data. Our aim was to examine risk factors in an integrated regional health system EGS database, including clinical and administrative data, hypothesizing that this novel process would identify clinical variables as important risk factors for mortality.

METHODS

Our nine-hospital health system's billing data were queried for EGS International Classification of Disease codes between 2013 and 2018. Codes were grouped by diagnosis, and urgent or emergent encounters were included and merged with electronic medical record clinical data. Outcomes assessed were inpatient and 1-year mortality. Standard and multivariable statistics evaluated factors associated with mortality.

RESULTS

There were 253,331 EGS admissions with 3.6% inpatient mortality rate. Patients who suffered inpatient and 1-year mortality were older, more likely to be underweight, and have neutropenia or elevated lactate. On multivariable analysis for inpatient mortality: age (odds ratio [OR], 1.7–6.7), underweight body mass index (OR, 1.6), transfer admission (OR, 1.8), leukopenia (OR, 2.0), elevated lactate (OR, 1.8), and ventilator requirement (OR, 7.1) remained associated with increased risk. Adjusted analysis for 1-year mortality demonstrated similar findings, with highest risk associated with older age (OR, 2.8–14.6), underweight body mass index (OR, 2.3), neutropenia (OR, 2.0), and tachycardia (OR, 1.7).

CONCLUSION

After controlling for patient and disease characteristics available in administrative databases, clinical variables remained significantly associated with mortality. This novel yet simple process allows for easy identification of clinical data points imperative to the study of EGS diagnoses that are critical in understanding factors that impact mortality.

LEVEL OF EVIDENCE

Prognostic and Epidemiologic; Level III.
Outcomes of Sorafenib for Recurrent Hepatocellular Carcinoma After Liver Transplantation in the Era of Combined and Sequential Treatments
Authors: Tovoli Francesco , Pallotta Dante Pio , Sansone Vito , Iavarone Massimo , De Giorgio Massimo , Ielasi Luca , Di Costanzo Giovan Giuseppe , Giuffrida Paolo , Sacco Rodolfo , Pressiani Tiziana , Di Donato Maria Francesca , Trevisani Franco , Fagiuoli Stefano , Piscaglia Fabio , Granito Alessandro
Published: August 2022

Background.

Sorafenib and other tyrosine kinase inhibitors are the current standard of care for hepatocellular carcinoma (HCC) recurring after liver transplantation (LT). Sorafenib is sometimes regarded as a scarcely effective treatment in this setting because of some studies showing a short overall survival (OS) indirectly compared with historical series of nontransplanted patients. Additional data from multicenter prospective studies are needed before drawing definite conclusions.

Methods.

Retrospective analyses of a large prospective multicenter dataset of sorafenib-treated HCC patients to report the characteristics and outcomes of LT recipients (n = 81).

Results.

At the baseline, LT patients had key prognostic features (high prevalence of metastatic disease, and low prevalence of macrovascular invasion, α-fetoprotein >400 ng/mL, ALBI grade >1, performance status >0) that differentiated them from the typical populations of non-LT patient reported in clinical trials and observational studies. Moreover, a relevant proportion of LT patients received concurrent locoregional (12.3%) and postprogression systemic treatments (34.2%), resulting in a median OS of 18.7 mo.

Conclusions.

Multimodal and sequential treatments are relatively frequent in post-LT HCC patients and contribute to a remarkable OS, together with favorable baseline characteristics. Despite the impossibility of matching with non-LT patients, our results indirectly suggest that the metastatic nature of post-LT recurrence and concurrent antirejection regimens should not discourage systemic treatments.
An Unusual Presentation of Pseudomonas citronellolis Bacteremia and Campylobacter Gastroenteritis Infection in a Human – A Case Report and Literature Review
Authors: Hwang Catherine S. , Rahmati Elham , Gerbino Anthony J. , Rose Tracie , Verma Punam , Schwartz Margot
Published: August 2022

Introduction

Pseudomonas citronellolis is an unusual pathogen in humans and has not been extensively described in the scientific literature. Herein, we present a case of bacteremia and septic shock due to Pseudomonas citronellolis following Camylobacter species gastroenteritis in a patient with immunosuppression.

Case Presentation

A man in his early 80s with myeloproliferative disorder on ruxolitinib presented with several days of worsening abdominal pain, which rapidly developed into septic shock with multi-organ failure and explosive diarrhea. Blood cultures grew gram-negative rods, later identified as Pseudomonas citronellolis and Bacteroides thetaiotaomicron . Repeated abdominal imaging revealed no evidence of intestinal perforation or megacolon. In addition, stool polymerase chain reaction was positive for Campylobacter species. His clinical course improved after a total of 14 days of meropenem with complete resolution of his symptoms and organ failure.

Conclusion

Pseudomonas citronellolis is a rare infection in humans. We postulate that Janus Associated Kinase (JAK) inhibition in myeloproliferative disorders heightened the risk of bacterial translocation and severe illness in the setting of Campylobacter gastroenteritis. Pseudomonas citronellolis may be identified more frequently as a pathogen in humans as more advanced diagnostic technologies become increasingly available in clinical microbiology.
Aquibacillus saliphilus sp. nov., a moderately halophilic bacterium isolated from a grey saltern
Authors: Cho Geon-Yeong , Whang Kyung-Sook
Published: August 2022

A novel moderately halophilic bacterium, designated strain KHM2T, was isolated from the sediment of a grey solar saltern located on Sinui Island, Shinan, Republic of Korea. Cells were rod-shaped, endospore-forming, Gram-stain-positive, motile and facultative anaerobic. Strain KHM2T performed anaerobic respiration using nitrates and did not produce glucose acids, indicating the absence of fermentation. Strain KHM2T grew at 10–45 °C (optimum, 37 °C), pH 6.0–10.0 (optimum, pH 8.0) and with 1.0–20.0 % (w/v) NaCl (optimum, 10.0%). Based on 16S rRNA gene sequence similarity and chemotaxonomic properties, strain KHM2T was assigned to the genus

Aquibacillus

, with high 16S rRNA gene sequence similarity to

Aquibacillus halophilus

B6BT (98.2%) and less than 96.8 % similarity to the other recognized members of the genus

Aquibacillus

. The polar lipid profile consisted of diphosphatidylglycerol (DPG), phosphatidylglycerol (PG) and one unidentified phospholipid (PL). Major fatty acids were anteiso-C15 : 0 and anteiso-C17 : 0. The average nucleotide identity and digital DNA–DNA hybridization values of strain KHM2T with

A. halophilus

B6BT were 77.6 and 22.0 %, respectively. Based on the results of polyphasic analysis, strain KHM2T is proposed to represent a bacterial species within the genus

Aquibacillus

with the name Aquibacillus saliphilus sp. nov. The type strain is KHM2T (=KACC 19068T=NBRC 112577T)
Pseudocitrobacter corydidari sp. nov., isolated from the Asian emerald cockroach Corydidarum magnifica
Authors: Guzman Juan , Poehlein Anja , Glaeser Stefanie P. , Schwengers Oliver , Blom Jochen , Hollensteiner Jacqueline , Kämpfer Peter , Vilcinskas Andreas
Published: August 2022

A Gram-negative bacterial strain, G163CMT, was isolated from the gut of the Asian emerald cockroach Corydidarum magnifica. The 16S rRNA gene sequence (1416 bp) of strain G163CMT showed 99.22% similarity to

Pseudocitrobacter faecalis

CCM 8479T and

Pseudocitrobacter vendiensis

CPO20170097T. The average nucleotide identity, digital DNA–DNA hybridization and average amino acid identity values of strain G163CMT were 92.4, 48.8 and 95.7% to

P. faecalis

CCM 8479T, and 93.3, 52.4 and 95.7% to

P. vendiensis

CPO20170097T. This strongly supports the designation of G163CMT as representing a new species in the genus

Pseudocitrobacter

. Phylogenetic trees based on the alignment of 16S rRNA, multilocus sequence analysis of six single-copy genes (fusA, pyrG, leuS, rpoB, recN and mnmE) and 107 core protein sequences consistently showed G163CMT to be a member of the genus

Pseudocitrobacter

, closely related to

P. vendiensis

CPO20170097T. In contrast to

P. faecalis

CCM 8479T and

P. vendiensis

CPO20170097T, the genome of G163CMT did not encode for proteins conferring resistance to antibiotics. However, all three genomes encoded a similar number of virulence factors and specialized metabolite biosynthetic proteins. The major fatty acids of strain G163CMT were C16:0 (31.5 %), C18:1 ω7c (22.6 %), C17:0 cyclo (15.3 %) and C14:0 (6.5 %). Based on the polyphasic results, we conclude that strain G163CMT represents a novel species of the genus

Pseudocitrobacter

and we propose the name Pseudocitrobacter corydidari sp. nov. with the type strain G163CMT (=DSM 112648T=CCM 9160T).
Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting
Authors: Diaz Perez Kimberly K. , Curtis Sarah W. , Sanchis-Juan Alba , Zhao Xuefang , Head Taylor , Ho Samantha , Carter Bridget , McHenry Toby , Bishop Madison R. , Valencia-Ramirez Luz Consuelo , Restrepo Claudia , Hecht Jacqueline T. , Uribe Lina Moreno , Wehby George , Weinberg Seth M. , Beaty Terri H. , Murray Jeffrey C. , Feingold Eleanor , Marazita Mary L. , Cutler David J. , Epstein Michael P. , Brand Harrison , Leslie Elizabeth J.
Published: August 2022

Purpose

Orofacial clefts (OFCs) are common birth defects including cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP). OFCs have heterogeneous etiologies, complicating clinical diagnostics as it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs, so we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls.

Methods

We evaluated 418 genes using genome sequencing and curated variants to assess their pathogenicity using American College of Medical Genetics criteria.

Results

9.04% of cases and 1.02% of controls had ‘likely pathogenic’ (LP) variants (p<0.0001), which was almost exclusively driven by heterozygous variants in autosomal genes. CP (17.6%) and CLP (9.09%) cases had the highest yield while CL cases had a 2.80% yield. Out of 39 genes with LP variants, nine genes, includingCTNND1andIRF6, accounted for more than half of the yield (4.64% of cases). Most variants (61.8%) were ‘variants of uncertain significance’ (VUSs), occurring more frequently in cases (p=0.004), but no individual gene showed a significant excess of VUSs.

Conclusion

These results underscore the etiological heterogeneity of OFCs and suggest sequencing could reduce the diagnostic gap in OFCs.
Nation-wide participation in FIT-based colorectal cancer screening in Denmark during the COVID-19 pandemic: An observational study
Authors: Olesen Tina Bech , Jensen Henry , Møller Henrik , Jensen Jens Winther , Andersen Berit , Rasmussen Morten
Published: August 2022

Background

Worldwide, most colorectal cancer screening programmes were paused at the start of the COVID-19 pandemic, whilst the Danish faecal immunochemical test (FIT)-based programme continued without pausing. We examined colorectal cancer screening participation and compliance with subsequent colonoscopy in Denmark throughout the pandemic.

Methods

We used data from the Danish Colorectal Cancer Screening Database among individuals aged 50-74 years old invited to participate in colorectal cancer screening from 2018-2021 combined with population-wide registries. Using a generalised linear model, we estimated prevalence ratios (PR) and 95% confidence intervals (CI) of colorectal cancer screening participation within 90 days since invitation and compliance with colonoscopy within 60 days since a positive FIT test during the pandemic in comparison with the previous years adjusting for age, month and year of invitation.

Results

Altogether, 3,133,947 invitations were sent out to 1,928,725 individuals and there were 94,373 positive FIT tests (in 92,848 individuals) during the study period. Before the pandemic, 60.7% participated in screening within 90 days. A minor reduction in participation was observed at the start of the pandemic (PR=0.95; 95% CI: 0.94-0.96 in pre-lockdown and PR=0.85; 95% CI: 0.85-0.86 in 1stlockdown) corresponding to a participation rate of 54.9% during pre-lockdown and 53.0% during 1st lockdown. This was followed by a 5-10% increased participation in screening corresponding to a participation rate of up to 64.9%. The largest increase in participation was observed among 55-59 year olds, individuals living alone or cohabiting and immigrants. The compliance with colonoscopy within 60 days was 89.9% before the pandemic. A slight reduction was observed during 1stlockdown (PR=0.96; 95% CI: 0.93-0.98), where after it resumed to normal levels.

Conclusions

Participation in the Danish FIT-based colorectal cancer screening programme and subsequent compliance to colonoscopy after a positive FIT result was only slightly affected by the COVID-19 pandemic.

Funding

The study was funded by the Danish Cancer Society Scientific Committee (grant number R321-A17417) and the Danish regions.
Csb1 moonlighting gives rise to functional redundancy with Csb2 in processing the pre-CRISPR transcript in type I-G CRISPR-Cas system
Authors: Chhetry Sunanda , Anand B
Published: August 2022

Archaea and bacteria use CRISPR-based adaptive immunity to limit the genome invasion by phages. Among the type-I CRISPR variant, the newly discovered type I-G exhibits unusual variation in the composition and architecture of Cas proteins. In order to understand how these structural differences, contribute to functional adaptations, we probed how the maturation of CRISPR RNA differs with respect to other well studied type I CRISPR variants. Type I-G consists of three Cas proteins, viz, Csb1, Csb2 and Csb3 that are predicted to form the ribonucleoprotein surveillance effector complex. We show that Csb2 from Bifidobacterium animalis is a metal independent endonuclease that cleaves site-specifically within the 5’ region of the CRISPR repeat RNA. The catalytic activity resides within the C-terminal region that is homologous to Cas6. Interestingly, Csb2 processes the pre-CRISPR transcript both as a stand-alone enzyme and as a subunit of the Cascade/I-G complex that comprises of Csb1, Csb2 and Csb3 in association with crRNA. Surprisingly, we discovered that Csb1-which is homologous to Cas7 that is catalytically inert in other type I systems-also shows metal independent RNase activity that is functionally analogous to Csb2 in processing the pre-CRISPR RNA. The presence of dual nucleases in the Cascade/I-G complex enhances the efficiency of CRISPR-based immunity. We suggest that the Csb1 moonlighting engenders functional redundancy between Csb1 and Csb2 that in turn could compensate for the intrinsic instability of Csb2 and accelerate the maturation of crRNA.
Rapastinel Accelerates Loss of Withdrawal Signs after Repeated Morphine and Blunts Relapse to Conditioned Place Preference
Authors: Armstrong Christopher , Ferrante Julia , Lamichhane Nidesh , Gamard C , Reavis Zachery , Walker Q.D. , Zucker N , Patkar A , Kuhn Cynthia
Published: August 2022

The purpose of the present study was to evaluate the efficacy of rapastinel, an allosteric modulator of NMDA receptor function, to accelerate the loss of opioid withdrawal symptoms and blunt or prevent relapse to morphine conditioned place preference (CPP) in rats. Two studies were conducted. In study 1, adult and adolescent male and female rats were treated with increasing doses of morphine (5 mg/kg, bid to 25 mg/kg bid) for 5 days. On day 6 animals were treated with naloxone (1 mg/kg) and withdrawal was assessed. They were then treated with saline or rapastinel (5 mg/kg) on days 6 and 8, and withdrawal assessed on day 9. Rapastinel treated animals exhibited significantly lower levels of withdrawal signs on day 9. No sex or age differences were observed. In Study 2, CPP for morphine was established in adult rats (males and females) by 4 daily pairings with saline and morphine (am/pm alternation). They were tested for CPP on day 5, and then treated with rapastinel (5 mg/kg) or saline daily on days 6-10 of extinction. On day 11 they received a final dose of rapastinel or saline followed by extinction. On day 12, animals received 1 mg/kg of morphine and were tested for relapse. Rapastinel did not affect extinction of CPP, but rapastinel-treated animals spent significantly less time in the previously morphine-paired side than saline-treated animals during the relapse trial. These findings of accelerated loss of withdrawal signs and blunted relapse to CPP suggest that rapastinel could provide an adjunctive therapy for opioid dependence during initiation of pharmacotherapy for opioid dependence.
Addressing structural mentoring barriers in postdoctoral training: A qualitative study
Authors: Lambert W. Marcus , Nana Nanda , Afonja Suwaiba , Saeed Ahsan , Amado Avelino C. , Golightly Linnie M.
Published: August 2022

Background

Structural mentoring barriers are policies, practices, and cultural norms that collectively disadvantage marginalized groups and perpetuate disparities in mentoring. While these mentoring barriers can be found early in the training pathway, failure to address or overcome these barriers at the postdoctoral training stage has a direct impact on faculty diversity and national efforts to retain underrepresented groups in research careers.

Methods

To better understand the mentoring barriers faced by postdoctoral trainees, and possible ways to address them, a diverse sample of postdoctoral scholars (“postdocs”) from across the United States were asked to participate in focus groups to discuss their training experiences. We conducted five 90-minute focus groups with 32 biomedical postdocs, including 20 (63%) women and 15 (47%) individuals from underrepresented racial/ethnic groups (URG). Participants were well-represented across years of training, and 65% were at least somewhat likely to pursue a research-intensive faculty career, similar to previously reported national averages.

Results

A social ecological framework was used to examine both the upstream and downstream manifestations of structural mentoring barriers, as well as mentor barriers, overall. Themes were categorized on four broad levels: Individual (attitudes, beliefs, knowledge, or behaviors that inform mentoring barriers), Interpersonal (mentoring barriers arising from dyadic, peer, or network relationships), Institutional (departmental, institutional, organizational mentoring barriers), or Systemic (mentoring barriers originating from policies or broad social and cultural norms). Notable structural barriers included (1) academic politics and scientific hierarchy, (2) inequalities resulting from mentor prestige, (3) the (over) reliance on one mentor, (4) the lack of formal training for academic and non-academic careers, and (5) the lack of institutional diversity and institutional mentor training. These structural barriers foster mentoring practices and behaviors that lead to poor work-life balance, poor communication, and research career attrition. To overcome these barriers, postdocs strongly encouraged developing a network or team of mentors and recommended institutional interventions that create more comprehensive professional development, mentorship, and belonging.

Conclusions

For postdoctoral scientists, structural mentoring barriers can permeate down to institutional, interpersonal, and individual levels, impeding a successful transition to an independent research career. It has become clear that large-scale changes in mentoring must come from addressing the policies, practices, and cultural norms that perpetuate poor mentoring. This work provides strong evidence for promoting mentorship networks and cultivating a “mentoring milieu” that fosters a supportive community and a strong culture of mentorship at all levels.
Viral respiratory epidemic modelling of societal segregation based on vaccination status
Authors: Hickey Joseph , Rancourt Denis G.
Published: August 2022

Background

Societal segregation of unvaccinated people from public spaces has been a novel and controversial COVID-era public health practice in many countries. Models exploring potential consequences of vaccination-status-based segregation have not considered how segregation influences the contact frequencies in the segregated groups. We systematically investigate implementing effects of segregation on population-specific contact frequencies and show this critically determines the predicted epidemiological outcomes, focusing on the attack rates in the vaccinated and unvaccinated populations and the share of infections among vaccinated people that were due to contacts with infectious unvaccinated people.

Methods

We describe a susceptible-infectious-recovered (SIR) two-population model for vaccinated and unvaccinated groups of individuals that transmit an infectious disease by person-to-person contact. The degree of segregation of the two groups, ranging from zero to complete segregation, is implemented using the like-to-like mixing approach developed for sexually-transmitted diseases, adapted for presumed SARS-CoV-2 transmission. We allow the contact frequencies for individuals in the two groups to be different and depend, with variable strength, on the degree of segregation.

Results

Segregation can either increase or decrease the attack rate among the vaccinated, depending on the type of segregation (isolating or compounding), and the contagiousness of the disease. For diseases with low contagiousness, segregation can cause an attack rate in the vaccinated, which does not occur without segregation.

Interpretation

There is no predicted blanket epidemiological advantage to segregation, either for the vaccinated or the unvaccinated. Negative epidemiological consequences can occur for both groups.
Dopamine-Modified Hyaluronic Acid (DA-HA) As A Novel Dopamine-Mimetics With Minimal Autoxidation And Cytotoxicity
Authors: Kim Sunpil , Kim Ye-Ji , Park Kyoung Hwan , Huh Kang Moo , Kang Sun-Woong , Lee C. Justin , Woo Dong Ho
Published: August 2022

Dopamine-modified hyaluronic acid (DA-HA) has been initially developed as an efficient coating and adhesion material for industrial uses. However, the biological activity and safety of DA-HA in the brain have not been explored yet. Here, we report a series of evidence that DA-HA exhibits similar functionality as dopamine (DA), but with much lower toxicity arising from autoxidation. DA-HA shows very little autoxidation even after 48-hour incubation. This is profoundly different from DA and its derivatives including L-DOPA, which all induce severe neuronal death after pre-autoxidation, indicating that autoxidation is the cause of neuronal death. Furthermore,in vivoinjection of DA-HA induces significantly lower toxicity compared to 6-OHDA, a well-known oxidized and toxic form of DA, and alleviates the apomorphine-induced rotational behavior in the 6-OHDA animal model of Parkinson’s disease. Our study proposes that DA-HA with DA-like functionalities and minimal toxicity can be an effective therapeutic substitute for L-DOPA in Parkinson’s disease.
“Knowledge practice gap of nurses towards COVID-19 patients’ dead body care in a tertiary care hospital”
Authors: Saini Girraj , Singh Mahendra , Panda Prasan Kumar , Sharma Manish Kumar , Punjot Pankaj , Meshram Raviprakash , Gupta Puneet Kumar
Published: August 2022

Aim

To know the dead body care of COVID-19 patients.

Objective

To determine health care professionals, knowledge, attitude, and practice towards Covid-19 dead body care.

To find the association of knowledge, attitude, practice with selected demographic variables.

Background

COVID-19 was a global pandemic and it was a serious note for health care professionals from many aspects. The virus was infective and causes serious infectionsto patients which were easily transmitted, hence specific dead body care is required for such kinds of patients. To keep this background in mind the study was conducted to identify the knowledge, practice and attitude towards COVID-19 dead body care among nurses.

Methodology

A cross sectional survey based study was done on 282 samples.Quantitative research design with purposive sampling technique data was collected for knowledge,attitude, and practice.

Result

Knowledge, attitude and practice were assessed and association was done with demographic profile. Hence the good knowledge, attitude and practicewere observed in experienced and trained nurses (p value<0.005. Whereas no significant changes were observed with age, gender and education qualification.

Conclusion

Overall knowledge, attitude and practice regarding COVID-19 dead body care were moderate to good. But it was important to identify the gap as it was a global pandemic and higher chances of spreading of infection.
UNDERSTANDING ACTIONS TAKEN BY FEMALE FAMILY CAREGIVERS AND CHALLENGES THEY FACED IN CARING FOR OLDER PEOPLE DURING COVID-19 PANDEMIC IN BELU DISTRICT, INDONESIA: A QUALITATIVE STUDY
Authors: Asa Gregorius Abanit , Fauk Nelsensius Klau , Ratu Melkianus , Dent Elsa , Ward Paul Russell
Published: August 2022

COVID-19 has rapidly impacted societies on a global scale, with older people among the most affected. To care for older people living in their own homes, female family caregivers play a pivotal role. The current study aimed to explore the actions of female family caregivers and the challenges they faced in taking care of older people living at homes during the COVID-19 pandemic in Belu district, Indonesia. This qualitative study involved twenty female family caregivers, who were recruited using a combination of purposive and snowball sampling techniques. Findings were grouped into two main categories: (i) actions of female family caregivers in taking care of older adults during the COVID-19 pandemic. These included limiting both visitations of extended family members and older adults’ activities outside homes; explaining the virus to older adults and controlling their access to news, social media and smartphones; providing nutrition, supplement and maintaining daily diets; and (ii) challenges they faced in taking care of older adults included excessive fear of contracting COVID-19 and possibility of transmitting it to older people; feeling stressed; tired and overburdened. The study highlights the significant role family caregivers played to protect older people living at home. The findings can inform government to develop intervention programs that address and support the needs of both family caregivers and older people living at home.
Probing weak lipid-lipid binding domain interactions with a mechanically transduced immunosorbent assay (METRIS)
Authors: Steimel Joshua P. , Sarkis Joe , Capraro Benjamin R. , Kirchhausen Tom , Alexander-Katz Alfredo
Published: August 2022

Protein-lipid interactions constitute a very important class of biological interactions critical for multiple cell and tissue functions. It is believed that most lipid-protein interactions are very weak, with affinities in the 1mM-1μM range. Here we study the interactions of multiple protein lipid binding domains with lipid membranes containing signaling lipids known as phosphatidylinositol phosphates (PIPs) using a new mechanically transduced immunosorbent assay (METRIS). We demonstrate that this assay can measure extremely weak interactions at PIP bilayer concentrations below 1%, which is close to the biological lipid concentration regime. In particular, we have studied the interaction of DrrAWT, DrrAK568A, PH-δ, and 2XFYVE as well as previously unexplored lipid binding domains such as Auxilin 1 (PTEN) and Auxilin 2 (GAK) against a wide palette of PIPs. Our results confirm that each of these domains interacts specifically with a PIP partner. In the case of Auxilin 1 and Auxilin 2, both proteins in the Clathrin endocytotic pathway, we find that their PTEN-like domain interacts specifically yet with ultra low affinity with PI3P and PI4P respectively. We have also found a new unknown medium-high affinity interaction between GAK with PI34P2. Our work, thus, provides a direct and robust method to measure and catalog protein lipid interactions which are important in many processes such as signaling and membrane sculpting. Furthermore, this assay can be extended in a straightforward manner to study other interactions such as ligand-receptor or antibody-antigen.
Individual risk attitudes arise from noise in neurocognitive magnitude representations
Authors: Garcia Miguel Barretto , de Hollander Gilles , Grueschow Marcus , Polania Rafael , Woodford Michael , Ruff Christian C.
Published: August 2022

Humans are generally risk averse: they prefer options with smaller certain outcomes over those with larger uncertain ones. This risk aversion is classically explained with a concave utility function, meaning that successive increases in monetary payoffs should increase subjective valuations by progressively smaller amounts. Here, we provide neural and behavioural evidence that risk aversion may also arise from a purely perceptual bias: The noisy logarithmic coding of numerical magnitudes can lead individuals tounderestimatethe size of larger monetary payoffs, leading to apparent risk aversion even when subjective valuation increases linearly with the estimated amount. A formal model of this process predicts that risk aversion should systematically increase when individuals represent numerical magnitudes more noisily. We confirmed this prediction by measuring both the mental and neural acuity of magnitude representations during a purely perceptual task and relating these measures to individual risk attitudes during separate financial decisions. Computational model fitting suggested that subjects based both types of choices on similar mental magnitude representations, with correlated precision across the separate perceptual and risky choices. Increased stimulus noise due to the presentation format of risky outcomes led to increased risk aversion, just as predicted by the model. The precision of the underlying neural magnitude representations was estimated with a numerical population receptive field model fitted to the fMRI data of the perceptual task. Subjects with more precise magnitude representations in parietal cortex indeed showed less variable behaviour and less risk-aversion in the separate financial choices. Our results highlight that individual patterns of economic behaviour may, at least partially, be determined by capacity limitations in perceptual processing rather than by processes that assign subjective values to monetary rewards.
Synaptic degeneration in neuronal circuits hinders memory recall, memory rescue, and learning
Authors: Li Kwan Tung , Ji Daoyun , Zhou Changsong
Published: August 2022

Neurodegeneration is a characteristic of Alzheimer’s disease (AD), but its effect on neural activity dynamics underlying memory deficits is unclear. Here, we studied the effects of synaptic degeneration on neural activities associated with memory recall, memory rescue by slow-gamma stimulation, and learning a new memory, in an integrate-and-fire neuronal network. Our results showed that reducing connectivity decreases the neuronal synchronisation of memory neurons at slow-gamma frequencies and impairs memory recall performance. Although slow-gamma stimulation rescued memory recall and slow-gamma oscillations, the rescue with reduced connectivity caused a side effect of activating mixed memories. During the learning of a new memory, reducing connectivity caused an impairment in storing the new memory, but did not affect previously stored memories. Our results reveal potential computational mechanisms underlying the memory deficits caused by synaptic degeneration in AD.
APE1 assembles biomolecular condensates to promote the ATR-Chk1 DNA damage response in nucleolus
Authors: Li Jia , Zhao Haichao , McMahon Anne , Yan Shan
Published: August 2022

Multifunctional protein APE1/APEX1/HAP1/Ref-1 (designated as APE1) plays important roles in nuclease-mediated DNA repair and redox regulation in transcription. However, it is unclear how APE1 regulates the DNA damage response (DDR) pathways and influences genome integrity directly or indirectly. Here we show that siRNA-mediated APE1-knockdown or APE1 inhibitor treatment attenuates the ATR-Chk1 DDR under stress conditions in multiple immortalized cell lines. Congruently, APE1 overexpression (APE1-OE) activates the ATR DDR under unperturbed conditions, which is independent of APE1 nuclease and redox functions. Structural and functional analysis reveals a direct requirement of the extreme N-terminal 33 amino acids (NT33) within APE1 in the assembly of distinct biomolecular condensates in vitro and DNA/RNA-independent activation of the ATR DDR. Overexpressed APE1 co-localizes with nucleolar NPM1 and assembles biomolecular condensates in nucleoli in cancer but not non-malignant cells, which recruits ATR and its direct activator molecules TopBP1 and ETAA1. APE1 W119R mutant is deficient in nucleolar condensation and liquid-liquid phase separation and is incapable of activating nucleolar ATR DDR. Lastly, APE1-OE-induced nucleolar ATR DDR activation leads to compromised ribosomal RNA transcription and reduced cell viability. Taken together, we propose distinct mechanisms by which APE1 regulates ATR DDR pathways and functions in genome integrity maintenance.
Co-fluctuations of neural activity define intra-V1 networks related to perceptual organization
Authors: Valdes-Sosa Mitchell , Ontivero-Ortega Marlis , Iglesias-Fuster Jorge , Lage-Castellanos Agustin , Galan-Garcia Lidice , Valdes-Sosa Pedro
Published: August 2022

Using functional resonance imaging (fMRI), we studied the relationship between perceptual organization and network topology within the primary visual cortex (V1). Twenty-six humans (male and female) were recorded during active observation of two Global and two Local Navon letters. Correlations between fMRI fluctuations from different V1 sites were measured (after removing stimulus-evoked signals) in windows specific to each condition. Intra-V1, like brain-wide networks, presented an overall decrease of correlations during stimulation compared to baseline and increased statistical dimensionality. Massive edgewise testing and network based-statistics (both corrected by FDR) identified differences between conditions of connection strengths that were mapped to the visual field. Global letters elicited long links mainly connecting V1 sites mapping the lower left/right visual quadrants. Shorter links were associated with Local letters, primarily mapped within the lower-left visual quadrant. Frequently link lengths exceeded V1 population receptive field sizes. These connections were not observed in the time-locked (feedforward) responses shared across participants. Thus, these networks reflect activity idiosyncratic to each participant, possibly generated by interactions within or feedback to V1. Perception would sculpt V1 connectivity, with specific increases in link strengths (in a background of decreases). These findings could help shed light on V1 as a “cognitive blackboard”.